bluuebunny/crossref_metadata_2025 huggingface dataset:
Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans
Authors: Pihlajamäki Maija , Tanila Heikki , Könönen Mervi , Hänninen Tuomo , Hämäläinen Anne , Soininen Hilkka , Aronen Hannu J.
Published: April 2004

A number of studies in rodents and monkeys report a distinction between the contributions of the hippocampus and perirhinal cortex to memory, such that the hippocampus is crucial for spatial memory whereas the perirhinal cortex has a pivotal role in perception and memory for visual objects. To determine if there is such a distinction in humans, we conducted a functional magnetic resonance imaging study to compare the medial temporal lobe responses to changes in object identity and spatial configurations of objects. We found evidence for the predicted distinction between hippocampal and perirhinal cortical activations, although part of the hippocampus was also activated by identification of novel objects. Additionally, an anterior‐posterior activation gradient emerged inside the hippocampus and parahippocampal cortex. The anterior hippocampus, perirhinal cortex and anterior parahippocampal cortex are involved in perception of contextually novel objects, whereas the posterior hippocampus and posterior parahippocampal cortex are involved in processing of novel arrangements of familiar objects. These results demonstrate that there is a functional dissociation between processing of novel object identities and new spatial locations of objects among the subregions of medial temporal lobe structures in humans also.
Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats
Authors: Brake Wayne G. , Zhang Tie Yuan , Diorio Josie , Meaney Michael J. , Gratton Alain
Published: April 2004

While many experiment with drugs, relatively few individuals develop a true addiction. We hypothesized that, in rats, such individual differences in the actions of addictive drugs might be determined by postnatal rearing conditions. To test this idea, we investigated whether stimulant‐ and stress‐induced activation of nucleus accumbens dopamine transmission and dopamine‐dependent behaviours might differ among adults rats that had been either repeatedly subjected to prolonged maternal separation or a brief handling procedure or left undisturbed (non‐handled) during the first 14 days of life. We found that, in comparison with their handled counterparts, maternally separated and non‐handled animals are hyperactive when placed in a novel setting, display a dose‐dependent higher sensitivity to cocaine‐induced locomotor activity and respond to a mild stressor (tail‐pinch) with significantly greater increases in nucleus accumbens dopamine levels. In addition, maternally separated animals were found to sensitize to the locomotor stimulant action of amphetamine when repeatedly stressed under conditions that failed to sensitize handled and non‐handled animals. Finally, quantitative receptor autoradiography revealed a lower density of nucleus accumbens‐core and striatal dopamine transporter sites in maternally separated animals. Interestingly, we also found greatly reduced D3 dopamine receptor binding and mRNA levels in the nucleus accumbens‐shell of handled animals. Together, these findings provide compelling evidence that disruptions in early postnatal rearing conditions can lead to profound and lasting changes in the responsiveness of mesocorticolimbic dopamine neurons to stress and psychostimulants, and suggest a neurobiological basis for individual differences in vulnerability to compulsive drug taking.
Increased expression of TRPV1 receptor in dorsal root ganglia by acid insult of the rat gastric mucosa
Authors: Schicho Rudolf , Florian Waltraud , Liebmann Ingrid , Holzer Peter , Lippe Irmgard Th.
Published: April 2004

It is still unknown which receptors of peripheral sensory pathways encode and integrate an acid‐induced nociceptive event in the gastric mucosa. The transient receptor potential vanilloid receptor 1 (TRPV1) and the acid‐sensing ion channel 3 (ASIC3) are two nociception‐related receptors. Here we investigated (i) to what extent these receptors are distributed in stomach‐innervating neurons of dorsal root and nodose ganglia, using immunohistochemistry and retrograde tracing, and (ii) whether their expression is altered in response to a noxious acid challenge of the stomach. We also explored the presence of TRPV1 in the gastric enteric nervous system because of its possible expression by intrinsic sensory neurons. Most stomach‐innervating neurons in nodose ganglia were immunoreactive for TRPV1 (80%) and ASIC3 (75%), these results being similar in the dorsal root ganglia (71 and 82%). RT‐PCR and Western blotting were performed up to 6 h after oral application of 0.5 m HCl to conscious rats. TRPV1 protein was increased in dorsal root but not in nodose ganglia whereas TRPV1 and ASIC3 mRNAs remained unchanged. TRPV1 mRNA was detected in longitudinal muscle–myenteric plexus preparations of control stomachs and was not altered by the acid challenge. Combined vagotomy and ganglionectomy abolished expression of TRPV1, indicating that it may derive from an extrinsic source. In summary, noxious acid challenge of the stomach increased TRPV1 protein in spinal but not vagal or intrinsic sensory afferents. The TRPV1 receptor may be a key molecule in the transduction of acid‐induced nociception of the gastric mucosa and a mediator of visceral hypersensitivity.
Distinct mechanisms of bidirectional activity‐dependent synaptic plasticity in superficial and deep layers of rat entorhinal cortex
Authors: Solger Jörg , Wozny Christian , Manahan‐Vaughan Denise , Behr Joachim
Published: April 2004

The entorhinal cortex plays a key role in processing memory information in the brain; superficial layers relay information to, and deep layers receive information from, the hippocampus. The cellular mechanisms of memory are thought to include a number that produce long‐term potentiation (LTP) and depression (LTD) of synaptic strength. Our work presents evidence that LTP and LTD occur simultaneously at memory‐relevant synapses. We report here that low frequency stimulation generates NMDA receptor‐dependent LTD in Wistar rat superficial (layers II and III), and LTP in the deep entorhinal cortex layers (layers V and VI). LTP in deep layers is masked by simultaneously occurring voltage‐gated calcium channel‐dependent LTD. Our data support a novel mechanism for the sliding‐threshold (BCM) model of synaptic plasticity: The sliding thresholds for induction of LTP and LTD in entorhinal cortex deep layers will be driven by the relative activation state of NMDA receptors and voltage‐gated calcium channels. The co‐expression of LTD and LTP at presynaptic sites in the entorhinal cortex deep layers reveals an intriguing mechanism for differential processing of synaptic information, which may underlie the vast dynamic capacity for information storage by this cortical structure.
Effects of inescapable stress on LTP in the amygdala versus the dentate gyrus of freely behaving rats
Authors: Vouimba Rose‐Marie , Yaniv Dan , Diamond David , Richter‐Levin Gal
Published: April 2004

Stress impairs hippocampal long‐term potentiation (LTP), a model of synaptic plasticity that is assumed to underlie memory formation. In the amygdala, little is known about the effects of stress on LTP, or about its longevity. Here we assessed the ability of entorhinal cortex (EC) stimulation to induce LTP simultaneously in the basal amygdaloid nucleus (B) and in the dentate gyrus (DG) of freely behaving Wistar rats. We also tested whether LTP persists over days. Once established, we investigated the effects of acute vs. repeated inescapable stressful experiences on LTP in both structures. Results show that B, like DG, sustained LTP for 7 days. Furthermore, a single exposure to moderate stress facilitated LTP in B but did not affect DG LTP. Stress re‐exposure inhibited LTP in DG but only long‐lasting LTP (>3 days) in B. Behaviourally, animals exhibited a higher immobility when re‐exposed to the stressor than with a single/first exposure. These data support a role for B in memory storage. Furthermore, they support a differential involvement of the amygdala and hippocampus in memory formation and storage depending on the emotional characteristics of the experience.
How do target predictability and precueing affect the production of express saccades in monkeys?
Authors: Schiller Peter H. , Haushofer Johannes , Kendall Geoffery
Published: April 2004

The extent to which target predictability and precueing affect express saccade generation was determined in Rhesus monkeys. Target predictability, as manipulated by the probability with which targets appeared at various locations, had a strong influence on express saccade generation. Pre‐cueing the location of the appearance of an impending single target with an identical stimulus was effective in increasing express saccade generation when there was a gap of 50–150 ms between fixation spot termination and target onset. However, precueing was not effective when the gap time was set to 0 ms in the single target task, when several simultaneous targets appeared requiring a visual discrimination to be made using an oddity task, or when the precue was not identical to the target. These findings indicate that express saccades are facilitated by a restricted set of conditions that increase the predictability of target location and identity.
Semaphorin 3A‐mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons
Authors: Schwarting Gerald A. , Raitcheva Denitza , Crandall James E. , Burkhardt Constanze , Püschel Andreas W.
Published: April 2004

Semaphorins are known to play an important role in axon guidance of vertebrate olfactory sensory neurons to their targets in specific glomeruli of the olfactory bulb (OB). However, it is not clear how semaphorin‐mediated guidance contributes to a systematic hierarchy of cues that govern the organization of this system. Because of the putative role that odorant receptor molecules such as P2 could play in establishing appropriate glomerular destinations for growing olfactory axons, we have also determined the spatial organization of P2 glomeruli in semaphorin 3A (Sema3A) mutant mice. First, in the postnatal OB of control and Sema3A−/− mice, we analysed the trajectories of olfactory axons that express the Sema3A receptor, neuropilin‐1 (npn‐1) and the positions of npn‐1+ glomeruli. Sema3A at the ventral OB midline guides npn‐1+ axons to targets in the lateral and medial OB. Absence of Sema3A permits many npn‐1 axons to terminate aberrantly in the rostral and ventral OB. Second, in Sema3A−/− mice, many P2 axons are abnormally distributed throughout the ventral OB nerve layer and converge in atypical locations compared with littermate controls where P2 axons converge on stereotypically located lateral and medial glomeruli. In addition to their radically altered spatial distribution, P2 glomeruli in Sema3A−/− mice are significantly smaller and more numerous than in heterozygote littermates. These data show that Sema3A is an important repulsive olfactory guidance cue that establishes restricted npn‐1+ subcompartments in the olfactory bulb. Furthermore, Sema3A plays a key role in the convergence of axons expressing the odorant receptor P2 onto their appropriate targets.
The C‐terminal juxtamembrane region of the δ2 glutamate receptor controls its export from the endoplasmic reticulum
Authors: Matsuda Shinji , Hannen Rosalind , Matsuda Keiko , Yamada Nobuaki , Tubbs Thomas , Yuzaki Michisuke
Published: April 2004

Functions of ionotropic glutamate receptors (iGluRs) are tightly regulated by the intracellular trafficking of receptor proteins. Unlike other iGluRs that are considerably retained in the intracellular component, the δ2 glutamate receptor (GluRδ2) is efficiently expressed on the Purkinje cell surface. To understand the trafficking mechanism of iGluRs, we deleted various portions of the C‐terminal intracellular domain of GluRδ2 and analysed the localization of the mutant proteins in heterologous cells and neurons. Biotinylation assays indicated that GluRδ2 lacking the C‐terminal juxtamembrane region of 13 amino acids (region A) was not present on the cell surface. This mutant GluRδ2 was sensitive to endoglycosidase H, which digests unprocessed high‐mannose oligosaccharides on proteins retained in the endoplasmic reticulum (ER) or cis‐Golgi. Therefore, we concluded that region A is crucial for the transport of GluRδ2 beyond the trans‐Golgi to the cell surface. Because the immunostaining pattern of GluRδ2 lacking region A in cultured hippocampal neurons completely overlapped the pattern of fluorescence emitted by ER‐resident green fluorescent protein, region A is most likely necessary for GluRδ2's exit from the ER. Furthermore, this region is essential for the proper intracellular trafficking of GluRδ2 in Purkinje cells. Region A does not rely on a dihydrophobic motif or positively charged residues to participate in trafficking, but its function is dependent on the juxtamembrane position. Therefore, we propose that GluRδ2's efficient transport to the cell surface utilizes an unknown but general ER exit mechanism, which probably works in close relation to the membrane of heterologous cells and neurons.
Role of taurine uptake on the induction of long‐term synaptic potentiation
Authors: Del Olmo Nuria , Suárez Luz M. , Orensanz Luis M. , Suárez Francisco , Bustamante Julián , Duarte José M. , Del Río Rafael Martín , Solís José M.
Published: April 2004

Taurine application in the CA1 area of rat hippocampal slices induces a long‐lasting potentiation of excitatory synaptic transmission that has some mechanistic similitude with the late phase of long‐term potentiation (L‐LTP). Previous indirect evidence such as temperature and sodium dependence indicated that taurine uptake is one of the primary steps leading to the taurine‐induced synaptic potentiation. We show that taurine‐induced potentiation is not related to the intracellular accumulation of taurine and is not impaired by 2‐guanidinoethanesulphonic acid, a taurine transport inhibitor that is a substrate of taurine transporter. We have found that taurine uptake in hippocampal synaptosomes was inhibited by SKF 89976A, a GABA uptake blocker that is not transportable by GABA transporters. SKF 89976A prevents the induction of synaptic potentiation by taurine application. This effect is neither mimicked by nipecotic acid, a broad inhibitor of GABA transporters that does not affect taurine uptake, nor by NO‐711, a specific and potent inhibitor of GABA transporter GAT‐1. In addition, L‐LTP induced by trains of high‐frequency stimulation is also inhibited by SKF 89976A, and taurine, at a concentration that does not change basal synaptic transmission, overcomes such inhibition. We conclude that taurine induces synaptic potentiation through the activation of a system transporting taurine and that taurine uptake is required for the induction of synaptic plasticity phenomena such as L‐LTP.
Synaptic drive contributing to rhythmic activation of motoneurons in the deafferented stick insect walking system
Authors: Büschges Ansgar , Ludwar Björn Ch. , Bucher Dirk , Schmidt Joachim , DiCaprio Ralph A.
Published: April 2004

A general feature of motor patterns for locomotion is their cyclic and alternating organization. In walking, for example, rhythmic activity in leg motoneurons innervating antagonistic muscles of a joint is primarily antiphasic within each cycle. We investigate which role central pattern generating networks play in the generation of leg motoneuron activity in the absence of sensory feedback. We elicited activity in antagonistic flexor and extensor tibiae motoneurons in the deafferented mesothoracic ganglion of the stick insect by mechanically stimulating the head or abdomen, while recording intracellularly from their neuropilar processes. In most cases, tactile stimulation induced coactivation of tibial motoneurons. However, in ≈ 25% of the trials, tibial motoneurons generated alternating cycles consisting of bursts of action potentials that were terminated by strong inhibitory synaptic inputs. Injection of depolarizing current increased the amplitude of the inhibitory phase of the oscillation, while hyperpolarizing current decreased it and revealed a tonic depolarization of the motor neurons during the bout of rhythmic motor activity. The same results were gathered from recording tibial leg motoneurons during ‘twitching’ motor activity in decerebrated animals. Our results indicate that alternating rhythmic motoneuron activity in the deafferented stick insect walking system results from phasic inhibitory drive provided by central pattern generating networks. This inhibitory input patterns the firing of the motoneurons that results from a tonic depolarizing drive. This tonic depolarizing drive was also observed in tibial motoneurons of the deafferented mesothoracic ganglion during walking movements of the intact ipsilateral front leg.
The European Parliament's Legislative Powers Reconsidered – Assessing the Current State of the Procedural Models Literature
Authors: Selck Torsten
Published: April 2004

This article maps out the state of affairs of the academic literature which uses procedural spatial voting models to explain legislative decision-making in the European Union. Employing Tsebelis's (1994) article in which the author models the Union's co-operation procedure and using it as a reference point, I show that there is no clarity yet as to which of the several existing procedural model specifications yields the most convincing results. I conclude by suggesting how the current situation could be improved, and that procedural modelling might be integrated with other rational choice theory for a better understanding of the ongoing evolution of the policymaking instruments in the European Union.
The National Assembly for Wales, Civil Society and Consultation
Authors: Hodgson Lesley
Published: April 2004

The National Assembly for Wales has been serious in its statutory commitment to involve voluntary groups in the decision-making process of state and has developed a number of sophisticated mechanisms by which civil society groups can link into policymaking, one of which is the consultation process. Drawing on original research this article investigates consultation from the perspective of those involved in a range of voluntary activities. Evidence offered here suggests that whilst many groups have engaged in the process of consultation, the experience is not uniform but patchy, with many groups left feeling frustrated rather than truly consulted.
Economic Performance and Regime Legitimacy in Post-Communist Bulgaria
Authors: Vassilev Rossen
Published: April 2004

It is commonly assumed that socio-economic conditions strongly influence political attitudes. Since democratic rule is based on the consent of the ruled, a secure and stable democracy cannot be established and maintained without broad-based popular endorsement, which is especially important for nascent post-communist democracies. Painful economic difficulties may engender deep anti-system sentiments at the mass level, encouraging anti-regime activism at the elite level. From this perspective, democratic legitimacy is a function of regime performance. But the Bulgarian evidence fails to validate the hypothesis that system legitimacy depends on regime effectiveness or that socio-economic conditions determine mass-level political attitudes. In spite of the economic fiasco, Bulgaria's democratic regime remains capable of commanding popular support. While the economic performance deficit of catastrophic proportions has become a source of widespread popular dissatisfaction threatening regime stability, it has not led to democratic backsliding or collapse.
Adam Smith: Reforming Merchant Power. The Case for an Open Public Sphere
Authors: Glassford John
Published: April 2004

Two decades of Adam Smith revisionism have restored his reputation as a philosopher of some substance and refuted the idea that he was simply the ‘high priest’ of capitalism. Yet all too often Smith is still offered up as an ‘English empiricist’ in the tradition of Hobbes, Locke and Mill. In this article Smith's critique of mercantilism is re-read through a peculiar Scottish tradition of social thought which began with Hume and which delivers up a surprisingly fresh, open and contemporary thinker.
Resistance to Neoliberal Globalisation: A Case of ‘Militant Particularism’?
Authors: Ashman Sam
Published: April 2004

This article seeks to help redress the relative lack of discussion of the movement against neoliberal globalisation and the relative lack of empirical work about this movement. Firstly it argues that this movement is not opposed to globalisation per se but instead is developing a new internationalism in the course of challenging the neoliberal nature of contemporary globalisation. Secondly it argues that this challenge is producing a universalising dynamic which is moving the movement beyond being a series of isolated militant particularist struggles. The article uses interviews with leading participants within the movement to help clarify these arguments.
Preschool inclusion in the United States: a review of research from an ecological systems perspective
Authors: Odom Samuel L. , Vitztum Joann , Wolery Ruth , Lieber Joan , Sandall Susan , Hanson Marci J. , Beckman Paula , Schwartz Ilene , Horn Eva
Published: April 2004

Using an ecological systems conceptual framework proposed by Bronfenbrenner, research on the inclusion of preschool children with disabilities in programs with typically developing children was reviewed. Drawing mainly from studies conducted in the United States, research on child characteristics (biosystem), classroom practices (microsystem), family perspectives (mesosystem), social policy (exosystem), culture (macrosystem), and changes in variables across time (chronosystem) is described. Positive developmental and behavioral outcomes occur for children with and without disabilities in inclusive settings, although as a group, children with disabilities are not as socially integrated as their typically developing peers. Parent attitudes are generally positive although they voice some concerns about inclusion. Several social policy issues within the U.S. system (e.g., enforcement of standards, fiscal issues) serve as barriers to and facilitators of implementation of preschool inclusion, and cultural variables shape the nature of inclusive classrooms as well as family access to inclusive settings.
Rethinking Medical Ethics: A View From Below
Authors: Farmer Paul
Published: April 2004

In this paper, we argue that lack of access to the fruits of modern medicine and the science that informs it is an important and neglected topic within bioethics and medical ethics. This is especially clear to those working in what are now termed ‘resource‐poor settings’– to those working, in plain language, among populations living in dire poverty. We draw on our experience with infectious diseases in some of the poorest communities in the world to interrogate the central imperatives of bioethics and medical ethics. AIDS, tuberculosis, and malaria are the three leading infectious killers of adults in the world today. Because each disease is treatable with already available therapies, the lack of access to medical care is widely perceived in heavily disease‐burdened areas as constituting an ethical and moral dilemma. In settings in which research on these diseases are conducted but there is little in the way of therapy, there is much talk of first world diagnostics and third world therapeutics.

Here we call for the ‘resocialising’ of ethics. To resocialise medical ethics will involve using the socialising disciplines to contextualise fully ethical dilemmas in settings of poverty and, a related gambit, the systematic participation of the destitute sick. Clinical research across steep gradients also needs to be linked with the interventions that are demanded by the poor and otherwise marginalised. We conclude that medical ethics must grapple more persistently with the growing problem posed by the yawning ‘outcome gap’ between rich and poor.
The Distribution of Biomedical Research Resources and International Justice
Authors: Resnik David B.
Published: April 2004

According to some estimates, less than 10% of the world's biomedical research funds are dedicated to addressing problems that are responsible for 90% of the world's burden of disease. This paper explains why this disparity exists and what should be done about it. It argues that the disparity exists because: 1) multinational pharmaceutical and biotechnology companies do not regard research and development investments on the health problems of developing nations to be economically lucrative; and 2) governmental agencies that sponsor biomedical research face little political pressure to allocate funds for the problems of developing nations. This paper argues that developed nations have an obligation to address disparities related to biomedical research funding. To facilitate this effort, developed countries should establish a trust fund dedicated to research on the health problems of developing nations similar to the Global AIDS Fund.
Patents and Access to Drugs in Developing Countries: An Ethical Analysis
Authors: Sterckx Sigrid
Published: April 2004

More than a third of the world's population has no access to essential drugs. More than half of this group of people live in the poorest regions of Africa and Asia. Several factors determine the accessibility of drugs in developing countries. Hardly any medicines for tropical diseases are being developed, but even existing drugs are often not available to the patients who need them.

One of the important determinants of access to drugs is the working of the patent system. This paper first maps out some facts about the global patent regime that has emerged as a consequence of the conclusion of the WTO‐TRIPs Agreement in 1994. Attempts to construct a moral justification of the patent system have been based on three grounds: natural rights, distributive justice, and utilitarian arguments. This paper examines to what extent and on which grounds drug patents can be justified. The final section looks at the so‐called ‘Doha Declaration on the TRIPs Agreement and Public Health’, which was adopted by the WTO Ministerial Conference two years ago, recognising the primacy of public health over the interests of patent proprietors.
Promoting Equity in Health Through Research and Understanding
Authors: Starfield Barbara
Published: April 2004

Developing strategies to reduce inequities in health requires an understanding of how inequities occur, determining the salient factors in their production, and deciding which ones are most amenable to change. The recognition of several principles regarding the manifestations and genesis of inequities can help to decide on strategies. In making decisions, it is important to consider whether the aim is to reduce disparities in the occurrence of ill health or to reduce disparities in the severity (including co‐morbidity, disability, dysfunction and fatality) of ill health. Evidence shows that the major impact on equity of health services, particularly regarding their potential to reduce severity, is attributable to the strength of primary care resources and services in communities and countries. Virtually every influence on the genesis of inequities is determined by the political context in which policy is made. The issue of health services is not different in this regard from other types of strategies.

There is no longer any doubt about the pervasive influence of social factors on health. Almost two centuries of descriptive research provides convincing evidence of associations between social structures and relationships and health status in all countries and in all societies; if there is anything new from more recent research, it is that the association is not limited to differences between the lowest social strata and other social strata. Rather, the association is noted throughout the social spectrum. That is, there is a social gradient in health such that, for many if not most manifestations of ill health, the lower the social stratum, the worse the health.

The challenge for the future is to understand why this is the case, to create a consensus that these inequalities are unnecessary and unacceptable, and to devise strategies that are both effective and possible. This paper will focus on the first of these aims, in a context that facilitates attention to the second and third aims.
Ethics, Economics, and Aids in Africa
Authors: Selgelid Michael J.
Published: April 2004

AIDS in the Twenty‐First Century: Disease and Globalization, by Tony Barnett and Alan Whiteside. New York: Palgrave Macmillan. 2002. 416 pp. US$19.95 (paperback)

The Moral Economy of AIDS in South Africa, by Nicoli Nattrass. Cambridge, UK: Cambridge University Press. 2004. 222 pp. US$30.00 (paperback)
The Effects of the α2‐Adrenergic Receptor Agonists Clonidine and Rilmenidine, and Antagonists Yohimbine and Efaroxan, on the Spinal Cholinergic Receptor System in the Rat
Authors: Abelson Klas S. P. , Höglund A. Urban
Published: April 2004

Abstract: Cholinergic agonists produce spinal antinociception via mechanisms involving an increased release of intraspinal acetylcholine. The cholinergic receptor system interacts with several other receptor types, such as α2‐adrenergic receptors. To fully understand these interactions, the effects of various receptor ligands on the cholinergic system must be investigated in detail. This study was initiated to investigate the effects of the α2‐adrenergic receptor agonists clonidine and rilmenidine and the α2‐adrenergic receptor antagonists yohimbine and efaroxan on spinal cholinergic receptors in the rat. Spinal microdialysis was used to measure in vivo changes of acetylcholine after administration of the ligands, with or without nicotinic receptor blockade. In addition, in vitro binding properties of the ligands on muscarinic and nicotinic receptors were investigated. It was found that clonidine and rilmenidine increased, while yohimbine decreased spinal acetylcholine release. Efaroxan affected acetylcholine release differently depending on concentration. Nicotinic receptor blockade attenuated the effect of all ligands. All ligands showed poor binding affinity for muscarinic receptors. On the other hand, all ligands possessed affinity for nicotinic receptors. Clonidine and yohimbine binding was best fit to a one site binding curve and rilmenidine and efaroxan to a two site binding curve. The present study demonstrates that the tested α2‐adrenergic receptor ligands affect intraspinal acetylcholine release in the rat evoked by nicotinic receptor mechanisms in vivo, and that they possess binding affinity to nicotinic receptors in vitro. The binding of α2‐adrenergic receptor ligands to nicotinic receptors might affect the intraspinal release of acetylcholine.
The Effects of Inhibition of Haem Biosynthesis by Griseofulvin on Intestinal Iron Absorption
Authors: Laftah Abas H. , Raja Kishor B. , Beaumont Nick , Simpson Robert J. , Deacon Allan , Solanky Nita , Srai Surjit Kaila S. , Peters Timothy J.
Published: April 2004

Abstract: The relationship between haem biosynthesis and intestinal iron absorption in mice was investigated by ascertaining the effect of the haem synthesis inhibitor, griseofulvin, on duodenal iron absorption using both in vivo and in vitro measurements. Urinary 5‐aminolaevulinic acid levels were increased within 24 hr of feeding mice with griseofulvin diet (2.5% w/w), with more marked increases seen after 3–7 days. Urinary porphobilinogen levels also showed a similar trend. In vivo intestinal iron absorption was significantly reduced (P<0.05) in experimental mice, mainly due to reduction in the transfer of 59Fe from the enterocytes to the portal circulation. In vitro studies using isolated duodenal fragments also exhibited marked decreases in both iron uptake and Fe (III) reduction. Changes in mucosal Divalent Metal Transporter 1 (DMT‐1), Dcytb and Ireg1 (iron regulated protein 1) mRNA levels paralleled the changes in iron absorption. The reduction in iron absorption after griseofulvin treatment was normalised when mice were simultaneously injected with haem‐arginate. These data support the hypothesis that intermediates in haem biosynthesis, particularly 5‐aminolaevulinic acid, regulate intestinal iron absorption.
Effects of Combined Prenatal Stress and Toluene Exposure on Apoptotic Neurodegeneration in Cerebellum and Hippocampus of Rats
Authors: Ladefoged Ole , Hougaard Karin Sørig , Hass Ulla , Sørensen Ilona Krypsin , Lund Søren Peter , Svendsen Gitte Winkel , Lam Henrik Rye
Published: April 2004

Abstract: Pregnant Wistar rats were exposed to 1500 ppm toluene 6 hr/day from gestational day 7–20 or to chronical mild stress from gestational day 9–20 as single exposure or in combination. Behavioural, immunohistopathological, molecular biological, and neurochemical methods were applied to investigate the offspring for developmental neurotoxicity and level of apoptosis in the brain. The number of apoptotic cells in cerebellum postnatal day 22, 24, and 27 and in hippocampus (postnatal day 22, 24, and 27) were counted after visualization by the TUNEL staining or measured by DNA‐laddering technique. Caspase‐3 activity was determined in cerebellum (postnatal day 6, 22, 24, and 27) and in hippocampus (postnatal day 6 and 22). TUNEL staining and DNA‐laddering technique showed a marked decrease in number of apoptotic cells from postnatal day 22 to 27 in both cerebellum and hippocampus. Apparently, a peak in the number of TUNEL positive cells was identified in cerebellum at postnatal day 22. There was no statistically significant influence of exposure except that DNA‐laddering in cerebellum at postnatal day 27 was increased by toluene exposure. Caspase‐3 activity decreased in cerebellum and hippocampus with age. At postnatal day 6 stress and toluene, when singly exposed, increased activity in cerebellum whereas co‐exposure to stress and toluene did not. Stress increased caspase‐3 activity in hippocampus postnatal day 22. There was overall consistency between the results obtained by the three supplementary methods regarding the influence of exposure and age on apoptotic activity in cerebellum and hippocampus. New methods to quantitate the relative level of apoptosis measured as DNA‐laddering and the caspase‐3 activity in tissue are presented.
Bacterial Invasion: The Paradigms of Enteroinvasive Pathogens
Authors: Cossart Pascale , Sansonetti Philippe J.
Published: April 2004

Invasive bacteria actively induce their own uptake by phagocytosis in normally nonphagocytic cells and then either establish a protected niche within which they survive and replicate, or disseminate from cell to cell by means of an actin-based motility process. The mechanisms underlying bacterial entry, phagosome maturation, and dissemination reveal common strategies as well as unique tactics evolved by individual species to establish infection.
Hemocyte-Mediated Shell Mineralization in the Eastern Oyster
Authors: Mount Andrew S. , Wheeler A. P. , Paradkar Rajesh P. , Snider D.
Published: April 2004

The growth of molluscan shell crystals is usually thought to be initiated from solution by extracellular organic matrix. We report a class of granulocytic hemocytes that may be directly involved in shell crystal production for oysters. On the basis of scanning electron microscopy (SEM) and x-ray microanalysis, these granulocytes contain calcium carbonate crystals, and they increase in abundance relative to other hemocytes following experimentally induced shell regeneration. Hemocytes are observed at the mineralization front using vital fluorescent staining and SEM. Some cells are observed releasing crystals that are subsequently remodeled, thereby at least augmenting matrix-mediated crystal-forming processes in this system.
Protection from Cardiac Arrhythmia Through Ryanodine Receptor-Stabilizing Protein Calstabin2
Authors: Wehrens Xander H. T. , Lehnart Stephan E. , Reiken Steven R. , Deng Shi-Xian , Vest John A. , Cervantes Daniel , Coromilas James , Landry Donald W. , Marks Andrew R.
Published: April 2004

Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor–calcium release channel (RyR2) complex causes an intracellular Ca
2+
leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca
2+
leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.
Intracellular Parasite Invasion Strategies
Authors: Sibley L. D.
Published: April 2004

Intracellular parasites use various strategies to invade cells and to subvert cellular signaling pathways and, thus, to gain a foothold against host defenses. Efficient cell entry, ability to exploit intracellular niches, and persistence make these parasites treacherous pathogens. Most intracellular parasites gain entry via host-mediated processes, but apicomplexans use a system of adhesion-based motility called “gliding” to actively penetrate host cells. Actin polymerization–dependent motility facilitates parasite migration across cellular barriers, enables dissemination within tissues, and powers invasion of host cells. Efficient invasion has brought widespread success to this group, which includes
Toxoplasma, Plasmodium
, and
Cryptosporidium
.
Enigmatic Biodiversity Correlations: Ant Diversity Responds to Diverse Resources
Authors: Armbrecht Inge , Perfecto Ivette , Vandermeer John
Published: April 2004

A pattern noted in ecology is that diversity at one level begets diversity at other levels. In the case of consumers competing for similar resources, the diversity of those resources is thought to provide some degree of niche diversification in which a diverse set of consumer species can coexist. If, however, the diverse resources are not sufficiently distinct from one another, from the standpoint of the consumer species, such niche diversification will not exist. We experimentally show that a diverse array of twigs attracted 80% more species of twig-nesting ants than a monospecific collection of twigs. The specific tree species from which the twigs were derived did not explain the pattern. It appears that diversity per se at one level (twigs) creates conditions that promote diversity at another level (nesting ants).
Tip20p Prohibits Back-Fusion of COPII Vesicles with the Endoplasmic Reticulum
Authors: Kamena Faustin , Spang Anne
Published: April 2004

Directionality in intracellular trafficking is essential to ensure the correct localization of proteins along the secretory pathway. Here, we found evidence for an active mechanism that prohibited back-fusion of de novo–generated vesicles with their donor compartment. Tip20p is a peripheral membrane protein implicated in consumption of COPI vesicles at the endoplasmic reticulum. However, a specific mutant of
TIP20
did not interfere with COPII vesicle generation but allowed these vesicles to fuse back to the endoplasmic reticulum, a process that does not occur normally in the cell.
Plastic Deformation with Reversible Peak Broadening in Nanocrystalline Nickel
Authors: Budrovic Zeljka , Van Swygenhoven Helena , Derlet Peter M. , Van Petegem Steven , Schmitt Bernd
Published: April 2004

Plastic deformation in coarse-grained metals is governed by dislocation-mediated processes. These processes lead to the accumulation of a residual dislocation network, producing inhomogeneous strain and an irreversible broadening of the Bragg peaks in x-ray diffraction. We show that during plastic deformation of electrodeposited nanocrystalline nickel, the peak broadening is reversible upon unloading; hence, the deformation process does not build up a residual dislocation network. The results were obtained during in situ peak profile analysis using the Swiss Light Source. This in situ technique, based on well-known peak profile analysis methods, can be used to address the relationship between microstructure and mechanical properties in nanostructured materials.
Real-Time Quantum Feedback Control of Atomic Spin-Squeezing
Authors: Geremia JM , Stockton John K. , Mabuchi Hideo
Published: April 2004

Real-time feedback performed during a quantum nondemolition measurement of atomic spin-angular momentum allowed us to influence the quantum statistics of the measurement outcome. We showed that it is possible to harness measurement backaction as a form of actuation in quantum control, and thus we describe a valuable tool for quantum information science. Our feedback-mediated procedure generates spin-squeezing, for which the reduction in quantum uncertainty and resulting atomic entanglement are not conditioned on the measurement outcome.
SAM68: a downstream target of angiotensin II signaling in vascular smooth muscle cells in genetic hypertension
Authors: Mabrouk Mohammed El , Diep Quy N. , Benkirane Karim , Touyz Rhian M. , Schiffrin Ernesto L.
Published: April 2004

We investigated whether phosphatidylinositol 3-kinase (PI3K) and 68-kDa Src associated during mitosis (SAM68) are involved in angiotensin II (ANG II) growth signaling in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). PI3K activity was assessed by measuring the phosphorylation of the regulatory subunit p85α and kinase activity of the catalytic 110-kDa subunit of PI3K. The PI3K-SAM68 interaction was assessed by coimmunoprecipitation, and SAM68 activity was evaluated by poly(U) binding. SAM68 expression was manipulated by SAM68 antisense oligonucleotide transfection. VSMC growth was evaluated by measuring [3H]leucine and [3H]thymidine incorporation as indexes of protein and DNA synthesis, respectively. ANG II increased the phosphorylation of p85α and kinase activity of the 110-kDa PI3K subunit in VSMCs from SHR and transiently increased p85α-SAM68 association. In Wistar-Kyoto (WKY) rat cells, ANG II increased SAM68 phosphorylation without influencing poly(U) binding. In SHR, ANG II did not influence SAM68 phosphorylation but increased SAM68 binding to poly(U). ANG II stimulated phosphoinositol phosphate synthesis by PI3K in SAM68 immunoprecipitates in both groups, with significantly enhanced effects in SHR. Inhibition of PI3K, using the selective inhibitor LY-294002, and downregulation of SAM68, by antisense oligonucleotides, significantly decreased ANG II-stimulated incorporation of [3H]leucine and [3H]thymidine in VSMCs, showing the functional significance of PI3K and SAM68. Our data demonstrate that PI3K and SAM68 are involved in ANG II signaling and that SAM68 is differentially regulated in VSMCs from SHR. These processes may contribute to the enhanced ANG II signaling and altered VSMC growth in SHR.
Augmented systolic response to the calcium sensitizer EMD-57033 in a transgenic model with troponin I truncation
Authors: Soergel David G. , Georgakopoulos Dimitrios , Stull Linda B. , Kass David A. , Murphy Anne M.
Published: April 2004

Myocardial stunning is a form of acute reversible cardiac dysfunction that occurs after brief periods of ischemia and reperfusion. In several animal models, stunning is associated with proteolytic truncation of troponin I (TnI). Mice expressing the same proteolytic TnI fragment [TnI-(1–193)] demonstrate cardiac depression with a decreased maximal calcium-activated tension. We therefore hypothesized preferential improvement in mice expressing TnI-(1–193) treated with the calcium-sensitizing drug EMD-57033. TnI-(1–193) and nontransgenic myofibrils exhibited significant sensitization to calcium in Mg-ATPase assays after EMD-57033 exposure. However, only transgenic myofibrils exhibited an increase in maximal activity ( P = 0.023). EMD-57033 also increased maximal calcium-activated force in TnI-(1–193) muscle, such that it was comparable to nontransgenic cardiac muscle. EMD-57033 enhanced in vivo systolic function modestly in controls but had a marked effect in transgenic mice, with an almost threefold greater leftward shift of the end-systolic pressure-volume relation ( P = 0.0005). These data indicate a targeted efficacy of EMD-57033 in offsetting the contractile defect in TnI-(1–193) mice, and this may have therapeutic implications in models displaying this myofilament defect.
Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats
Authors: Jones John E. , Walker Jennifer L. , Song Yanli , Weiss Norbert , Cardoso Wellington V. , Tuder Rubin M. , Loscalzo Joseph , Zhang Ying-Yi
Published: April 2004

5-Lipoxygenase (5-LO) and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study, we examined the effects of 5-LO overexpression in rat lungs on pulmonary hypertension using a recombinant adenovirus expressing 5-LO (Ad5-LO). Transthoracic echocardiography and right heart catheterization data showed that 5-LO overexpression in the lung did not cause pulmonary hypertension in normal rats; however, it markedly accelerated the progression of pulmonary hypertension in rats treated with monocrotaline (MCT). An increase in pulmonary artery pressure occurred earlier in the rats treated with MCT + Ad5-LO (7–10 days) compared with those treated with control vector, MCT + adenovirus expressing green fluorescent protein (AdGFP), or MCT alone (15–18 days). The weight ratio of the right ventricle to left ventricle plus septum was higher in the MCT + Ad5-LO group than that of the MCT + AdGFP or MCT group (0.45 ± 0.08 vs. 0.35 ± 0.03 or 0.33 ± 0.06). Lung tissue histological sections from MCT + Ad5-LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT + AdGFP- or MCT-treated rats. Administration of 5-LO inhibitors, zileuton or MK-886, to either MCT- or MCT + Ad5-LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5-LO plays a critical role in the progression of pulmonary hypertension in rats and that the detrimental effect of 5-LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction.