bluuebunny/crossref_metadata_2025 huggingface dataset:
Themed Review: Lifestyle Interventions Across the Continuum of Type 2 Diabetes: Reducing the Risks of Diabetes
Authors: Franz Marion J.
Published: August 2007

Type 2 diabetes is a progressive disease that results from defects in insulin action (insulin resistance), insulin secretion (insulin deficiency), or both. The progressive decline in β-c ell function requires that medical therapy progress from lifestyle interventions for prevention of diabetes to medical nutrition therapy (MNT) alone for diabetes management to MNT in combination with glucose-lowering medications that target the multiple pathophysiologic aspects of diabetes to MNT with insulin. MNT also progresses from prevention of obesity or weight gain to improving insulin resistance to contributing to improved metabolic control of glucose, lipids, and blood pressure; however, MNT is important throughout the continuum of diabetes and its medical management. Early diagnosis and aggressive therapy decrease the risk of diabetes-related complications.
Clinician's Corner: Type 2 Diabetes: A Disease of Epidemic Proportion That Is Largely Preventable—But How?
Authors: Greenstone Clinton L.
Published: August 2007

In the United States, over 20 million Americans have diabetes and over a third of them are undiagnosed. Less than 50% of the adults in the United States engage in physical activity at the level currently recommended for health promotion. Over 70% of these diabetics will die of cardiovascular disease, the number one killer of all Americans. Physicians should identify and target the ones who are undiagnosed and at high risk (estimated to be over 40 million) and offer them comprehensive education and lifestyle interventions to prevent the development of this deadly and quality of life depleting illness in the prediabetics and better manage the ones who already have the disease. Such an approach will likely impact positively on lowering the mortality rate from diabetes and heart disease. There's a continuum of care and with the natural history of the declining function of the beta cell, we may in fact need to use medications to slow progression and treat diabetes. We should however use them thoughtfully and wisely as the stakes and risks are potentially high. Because of the safety of efficacy of Metformin, it should be our medication of first choice for nearly all our patients with impaired glucose tolerance and those with type 2 diabetes.
Excessive exposure to anionic surfaces maintains autoantibody response to β2-glycoprotein I in patients with antiphospholipid syndrome
Authors: Yamaguchi Yukie , Seta Noriyuki , Kaburaki Junichi , Kobayashi Kazuko , Matsuura Eiji , Kuwana Masataka
Published: August 2007

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder associated with autoantibodies to phospholipid (PL)–binding proteins, such as β2-glycoprotein I (β2GPI). We have recently reported that binding of β2GPI to anionic PL facilitates processing and presentation of the cryptic β2GPI epitope that activates pathogenic autoreactive T cells. To clarify mechanisms that induce sustained presentation of the dominant antigenic β2GPI determinant in patients with APS, T-cell proliferation induced by β2GPI-treated phosphatidylserine liposome (β2GPI/PS) was evaluated in bulk peripheral blood mononuclear cell cultures. T cells from patients with APS responded to β2GPI/PS in the presence of immunoglobulin G (IgG) anti-β2GPI antibodies derived from APS plasma, and this response was completely inhibited either by the depletion of monocytes or by the addition of anti-FcγRI antibody. These findings indicate that efficient presentation of the cryptic determinants can be achieved by monocytes undergoing FcγRI-mediated uptake of β2GPI-bound anionic surfaces in the presence of IgG anti-β2GPI antibodies. Finally, β2GPI-bound oxidized LDL or activated platelets also induced the specific T-cell response. Continuous exposure to these anionic surfaces may play a critical role in maintaining the pathogenic anti-β2GPI antibody response in patients with APS.
The topology of metabolic isotope labeling networks
Authors: Weitzel Michael , Wiechert Wolfgang , Nöh Katharina
Published: August 2007

Background

Metabolic Flux Analysis (MFA) based on isotope labeling experiments (ILEs) is a widely established tool for determining fluxes in metabolic pathways. Isotope labeling networks (ILNs) contain all essential information required to describe the flow of labeled material in an ILE. Whereas recent experimental progress paves the way for high-throughput MFA, large network investigations and exact statistical methods, these developments are still limited by the poor performance of computational routines used for the evaluation and design of ILEs. In this context, the global analysis of ILN topology turns out to be a clue for realizing large speedup factors in all required computational procedures.

Results

With a strong focus on the speedup of algorithms the topology of ILNs is investigated using graph theoretic concepts and algorithms. A rigorous determination of all cyclic and isomorphic subnetworks, accompanied by the global analysis of ILN connectivity is performed. Particularly, it is proven that ILNs always brake up into a large number of small strongly connected components (SCCs) and, moreover, there are natural isomorphisms between many of these SCCs. All presented techniques are universal, i.e. they do not require special assumptions on the network structure, bidirectionality of fluxes, measurement configuration, or label input. The general results are exemplified with a practically relevant metabolic network which describes the central metabolism of E. coli comprising 10390 isotopomer pools.

Conclusion

Exploiting the topological features of ILNs leads to a significant speedup of all universal algorithms for ILE evaluation. It is proven in theory and exemplified with the E. coli example that a speedup factor of about 1000 compared to standard algorithms is achieved. This widely opens the door for new high performance algorithms suitable for high throughput applications and large ILNs. Moreover, for the first time the global topological analysis of ILNs allows to comprehensively describe and understand the general patterns of label flow in complex networks. This is an invaluable tool for the structural design of new experiments and the interpretation of measured data.
A statistical method to incorporate biological knowledge for generating testable novel gene regulatory interactions from microarray experiments
Authors: Larsen Peter , Almasri Eyad , Chen Guanrao , Dai Yang
Published: August 2007

Background

The incorporation of prior biological knowledge in the analysis of microarray data has become important in the reconstruction of transcription regulatory networks in a cell. Most of the current research has been focused on the integration of multiple sets of microarray data as well as curated databases for a genome scale reconstruction. However, individual researchers are more interested in the extraction of most useful information from the data of their hypothesis-driven microarray experiments. How to compile the prior biological knowledge from literature to facilitate new hypothesis generation from a microarray experiment is the focus of this work. We propose a novel method based on the statistical analysis of reported gene interactions in PubMed literature.

Results

Using Gene Ontology (GO) Molecular Function annotation for reported gene regulatory interactions in PubMed literature, a statistical analysis method was proposed for the derivation of a likelihood of interaction (LOI) score for a pair of genes. The LOI-score and the Pearson correlation coefficient of gene profiles were utilized to check if a pair of query genes would be in the above specified interaction. The method was validated in the analysis of two gene sets formed from the yeast Saccharomyces cerevisiae cell cycle microarray data. It was found that high percentage of identified interactions shares GO Biological Process annotations (39.5% for a 102 interaction enriched gene set and 23.0% for a larger 999 cyclically expressed gene set).

Conclusion

This method can uncover novel biologically relevant gene interactions. With stringent confidence levels, small interaction networks can be identified for further establishment of a hypothesis testable by biological experiment. This procedure is computationally inexpensive and can be used as a preprocessing procedure for screening potential biologically relevant gene pairs subject to the analysis with sophisticated statistical methods.
The mitochondrial DNA control region shows genetically correlated levels of heteroplasmy in leukocytes of centenarians and their offspring
Authors: Rose Giuseppina , Passarino Giuseppe , Scornaienchi Vittorio , Romeo Giuseppe , Dato Serena , Bellizzi Dina , Mari Vincenzo , Feraco Emidio , Maletta Raffaele , Bruni Amalia , Franceschi Claudio , De Benedictis Giovanna
Published: August 2007

Background

Studies on heteroplasmy occurring in the mitochondrial DNA (mtDNA) control region (CR) in leukocytes of centenarians and younger subjects have shown that the C150T somatic transition is over-represented in centenarians. However, whether the occurrence/accumulation of heteroplasmy is a phenotypic consequence of extreme ageing or a genetically controlled event that may favor longevity is a question that deserves further attention. To clarify this point, we set up a Denaturing High Performance Liquid Chromatography (DHPLC) protocol to quantify mtDNA CR heteroplasmy. We then analyzed heteroplasmy in leukocytes of centenarians (100 subjects), their offspring and nieces/nephews (200 subjects, age-range 65–80 years, median age 70 years), and in leukocytes of 114 control subjects sex- and age-matched with the relatives of centenarians.

Results

The centenarians and their descendants, despite the different ages, showed similar levels of heteroplasmy which were significantly higher than levels in controls. In addition we found that heteroplasmy levels were significantly correlated in parent-offspring pairs (r = 0.263; p = 0.009), but were independent of mtDNA inherited variability (haplogroup and sequence analyses).

Conclusion

Our findings suggest that the high degree of heteroplasmy observed in centenarians is genetically controlled, and that such genetic control is independent of mtDNA variability and likely due to the nuclear genome.
Design and evaluation of Actichip, a thematic microarray for the study of the actin cytoskeleton
Authors: Muller Jean , Mehlen André , Vetter Guillaume , Yatskou Mikalai , Muller Arnaud , Chalmel Frédéric , Poch Olivier , Friederich Evelyne , Vallar Laurent
Published: August 2007

Background

The actin cytoskeleton plays a crucial role in supporting and regulating numerous cellular processes. Mutations or alterations in the expression levels affecting the actin cytoskeleton system or related regulatory mechanisms are often associated with complex diseases such as cancer. Understanding how qualitative or quantitative changes in expression of the set of actin cytoskeleton genes are integrated to control actin dynamics and organisation is currently a challenge and should provide insights in identifying potential targets for drug discovery. Here we report the development of a dedicated microarray, the Actichip, containing 60-mer oligonucleotide probes for 327 genes selected for transcriptome analysis of the human actin cytoskeleton.

Results

Genomic data and sequence analysis features were retrieved from GenBank and stored in an integrative database called Actinome. From these data, probes were designed using a home-made program (CADO4MI) allowing sequence refinement and improved probe specificity by combining the complementary information recovered from the UniGene and RefSeq databases. Actichip performance was analysed by hybridisation with RNAs extracted from epithelial MCF-7 cells and human skeletal muscle. Using thoroughly standardised procedures, we obtained microarray images with excellent quality resulting in high data reproducibility. Actichip displayed a large dynamic range extending over three logs with a limit of sensitivity between one and ten copies of transcript per cell. The array allowed accurate detection of small changes in gene expression and reliable classification of samples based on the expression profiles of tissue-specific genes. When compared to two other oligonucleotide microarray platforms, Actichip showed similar sensitivity and concordant expression ratios. Moreover, Actichip was able to discriminate the highly similar actin isoforms whereas the two other platforms did not.

Conclusion

Our data demonstrate that Actichip is a powerful alternative to commercial high density microarrays for cytoskeleton gene profiling in normal or pathological samples. Actichip is available upon request.
Oligomerization of the human immunodeficiency virus type 1 (HIV-1) Vpu protein – a genetic, biochemical and biophysical analysis
Authors: Hussain Amjad , Das Suman R , Tanwar Charu , Jameel Shahid
Published: August 2007

Background

The human immunodeficiency virus type 1(HIV-1) is a complex retrovirus and the causative agent of acquired immunodeficiency syndrome (AIDS). The HIV-1 Vpu protein is an oligomeric integral membrane protein essential for particle release, viral load and CD4 degradation. In silico models show Vpu to form pentamers with an ion channel activity.

Results

Using Vpu proteins from a primary subtype C and the pNL4-3 subtype B isolates of HIV-1, we show oligomerization of the full-length protein as well as its transmembrane (TM) domain by genetic, biochemical and biophysical methods. We also provide direct evidence of the presence of Vpu pentamers in a stable equilibrium with its monomers in vitro. This was also true for the TM domain of Vpu. Confocal microscopy localized Vpu to the endoplasmic reticulum and Golgi regions of the cell, as well as to post-Golgi vesicles. In fluorescence resonance energy transfer (FRET) experiments in live cells we show that Vpu oligomerizes in what appears to be either the Golgi region or intracellular vesicles, but not in the ER.

Conclusion

We provide here direct evidence that the TM domain, is critical for Vpu oligomerization and the most favourable channel assembly is a pentamer. The Vpu oligomerization appears to be either the Golgi region or intracellular vesicles, but not in the ER.
Disruption and pseudoautosomal localization of the major histocompatibility complex in monotremes
Authors: Dohm Juliane C , Tsend-Ayush Enkhjargal , Reinhardt Richard , Grützner Frank , Himmelbauer Heinz
Published: August 2007

Background

The monotremes, represented by the duck-billed platypus and the echidnas, are the most divergent species within mammals, featuring a flamboyant mix of reptilian, mammalian and specialized characteristics. To understand the evolution of the mammalian major histocompatibility complex (MHC), the analysis of the monotreme genome is vital.

Results

We characterized several MHC containing bacterial artificial chromosome clones from platypus (Ornithorhynchus anatinus) and the short-beaked echidna (Tachyglossus aculeatus) and mapped them onto chromosomes. We discovered that the MHC of monotremes is not contiguous and locates within pseudoautosomal regions of two pairs of their sex chromosomes. The analysis revealed an MHC core region with class I and class II genes on platypus and echidna X3/Y3. Echidna X4/Y4 and platypus Y4/X5 showed synteny to the human distal class III region and beyond. We discovered an intron-containing class I pseudogene on platypus Y4/X5 at a genomic location equivalent to the human HLA-B,C region, suggesting ancestral synteny of the monotreme MHC. Analysis of male meioses from platypus and echidna showed that MHC chromosomes occupy different positions in the meiotic chains of either species.

Conclusion

Molecular and cytogenetic analyses reveal new insights into the evolution of the mammalian MHC and the multiple sex chromosome system of monotremes. In addition, our data establish the first homology link between chicken microchromosomes and the smallest chromosomes in the monotreme karyotype. Our results further suggest that segments of the monotreme MHC that now reside on separate chromosomes must once have been syntenic and that the complex sex chromosome system of monotremes is dynamic and still evolving.
Comparative genomic analysis of the Tribolium immune system
Authors: Zou Zhen , Evans Jay D , Lu Zhiqiang , Zhao Picheng , Williams Michael , Sumathipala Niranji , Hetru Charles , Hultmark Dan , Jiang Haobo
Published: August 2007

Background

Tribolium castaneum is a species of Coleoptera, the largest and most diverse order of all eukaryotes. Components of the innate immune system are hardly known in this insect, which is in a key phylogenetic position to inform us about genetic innovations accompanying the evolution of holometabolous insects. We have annotated immunity-related genes and compared them with homologous molecules from other species.

Results

Around 300 candidate defense proteins are identified based on sequence similarity to homologs known to participate in immune responses. In most cases, paralog counts are lower than those of Drosophila melanogaster or Anopheles gambiae but are substantially higher than those of Apis mellifera. The genome contains probable orthologs for nearly all members of the Toll, IMD, and JAK/STAT pathways. While total numbers of the clip-domain serine proteinases are approximately equal in the fly (29), mosquito (32) and beetle (30), lineage-specific expansion of the family is discovered in all three species. Sixteen of the thirty-one serpin genes form a large cluster in a 50 kb region that resulted from extensive gene duplications. Among the nine Toll-like proteins, four are orthologous to Drosophila Toll. The presence of scavenger receptors and other related proteins indicates a role of cellular responses in the entire system. The structures of some antimicrobial peptides drastically differ from those in other orders of insects.

Conclusion

A framework of information on Tribolium immunity is established, which may serve as a stepping stone for future genetic analyses of defense responses in a nondrosophiline genetic model insect.
Effect of Macronutrient Composition on Postprandial Peptide YY Levels
Authors: Essah Paulina A. , Levy James R. , Sistrun Sakita N. , Kelly Susan M. , Nestler John E.
Published: August 2007

Background: Peptide YY (PYY) is released from the distal small intestine and colon after meals and reduces appetite by increasing satiety. The amount of PYY released is proportional to calories ingested. Fat ingestion has also been reported to stimulate PYY release.

Objective: The objective of the study was to determine whether macronutrient composition influences postprandial serum PYY levels by comparing 1 wk of a weight-maintenance low-carbohydrate, high-fat (LCHF) diet with a low-fat, high-carbohydrate (LFHC) diet.

Methods: In this randomized crossover study, 18 obese subjects (14 females, 4 males, mean body mass index 35.6 ± 2.9 kg/m2) were randomly assigned initially to 1 wk of a weight-maintenance LCHF or LFHC diet, after which a test meal of identical composition was given and serum PYY levels were assessed for 2.5 h postprandially. After a 1-wk washout period, subjects were crossed over and retested.

Results: After 1 wk, mean postprandial area under the curve PYY after the LCHF test meal was 1.5-fold greater than after the LFHC test meal (P < 0.001). The LCHF diet led to 55% higher levels of postprandial serum PYY levels, compared with the LFHC diet (P = 0.005).

Conclusions: These data show that a LCHF diet stimulates PYY secretion more than a LFHC diet in obese individuals.
Effect of Iodide on Human Choriogonadotropin, Sodium-Iodide Symporter Expression, and Iodide Uptake in BeWo Choriocarcinoma Cells
Authors: Li Huika , Richard Kerry , McKinnon Brett , Mortimer Robin H.
Published: August 2007

Context: Active placental transport of maternal iodide by the thyroidal sodium iodide symporter (NIS) provides an essential substrate for fetal thyroid hormone synthesis. NIS is expressed in trophoblast and is regulated by human choriogonadotropin (hCG). In thyroid, iodide down-regulates expression of several genes including NIS. Placentas of iodine-deficient rats demonstrate up-regulation of NIS mRNA, suggesting a role for iodide in regulating placental NIS.

Objectives and Methods: The objectives were to examine effects of iodide on expression of NIS and hCG in BeWo choriocarcinoma cells. Gene expression was studied by quantitative real-time PCR. Effects on NIS protein expression were assessed by Western blotting. Functional activity of NIS was measured by 125I uptake. Expression of hCG protein was assessed by immunoassay of secreted hormone.

Results: Iodide inhibited NIS mRNA and membrane protein expression as well as 125I uptake, which were paralleled by decreased βhCG mRNA expression and protein secretion. Iodide had no effects on pendrin expression. Addition of hCG increased NIS mRNA expression. This effect was partially inhibited by addition of iodide. The inhibitory effects of iodide on NIS mRNA expression were abolished by propylthiouracil and dithiothreitol.

Conclusions: We conclude that expression of placental NIS is modulated by maternal iodide. This may occur through modulation of hCG effects on NIS and hCG gene expression.
Body Mass Index Predicts Aldosterone Production in Normotensive Adults on a High-Salt Diet
Authors: Bentley-Lewis Rhonda , Adler Gail K. , Perlstein Todd , Seely Ellen W. , Hopkins Paul N. , Williams Gordon H. , Garg Rajesh
Published: August 2007

Context: The mechanisms underlying obesity-mediated cardiovascular disease are not fully understood. Aldosterone and insulin resistance both are associated with obesity and cardiovascular disease.

Objectives: The objectives of this study were to test the hypotheses that aldosterone production is elevated and associated with insulin resistance in overweight adults on a high-sodium diet.

Participants/Interventions: Healthy normotensive adults were categorized as lean body mass index (BMI) less than 25 kg/m2 (n = 63) or overweight BMI 25 kg/m2 or greater (n = 57). After 7 d of a high-sodium diet, participants fasted overnight and remained supine throughout hemodynamic and laboratory assessments and angiotensin II (AngII) stimulation.

Results: The overweight group, compared with the lean group, had higher 24-h urinary aldosterone (9.0 ± 0.8 vs. 6.6 ± 0.5 μg per 24 h; P = 0.003) and higher AngII-stimulated serum aldosterone (11.4 ± 1.0 vs. 9.0 ± 0.6 ng/dl; P = 0.04). There were no differences in 24-h urinary cortisol or sodium or supine measurements of plasma renin activity, serum aldosterone, or serum potassium. The homeostasis model assessment of insulin resistance was predicted by urinary aldosterone excretion (r = 0.32, P = 0.03) and serum aldosterone response to AngII stimulation (r = 0.28, P = 0.02) independent of age and BMI.

Conclusion: Urinary aldosterone excretion and AngII-stimulated aldosterone are increased in overweight, compared with lean, normotensive adults. The correlation of these measures of aldosterone production with insulin resistance suggests a potential role for aldosterone in the pathophysiology of obesity-mediated insulin resistance.
The Iran Conundrum
Authors: Cannistraro Vincent
Published: August 2007

Vincent Cannistraro is the former head of counterterrorism operations and analysis for the Central Intelligence Agency. He served in the National Security Council as director for intelligence programs during the Reagan administration and currently heads Cannistraro Associates, a security consulting firm located in McLean, Virginia.
George Tenet's Machiavellian Moment
Authors: Giraldi Philip
Published: August 2007

Philip Giraldi is a former CIA counterterrorism officer who served in Europe and the Middle East. He is a contributing editor for the American Conservative magazine and is currently a partner in Cannistraro Associates, a security consulting firm based in McLean, Virginia.
A Greek Exclusive Economic Zone in the Aegean Sea
Authors: Kariotis Theodore C.
Published: August 2007

Theodore C. Kariotis is professor of economics at Towson University, Maryland.
Effects of service-level constraint and failure-in-repair on an economic manufacturing quantity model
Authors: Chiu S W
Published: August 2007

This paper studies the effects of service-level constraint and failure-in-repair on an economic manufacturing quantity (EMQ) model with random defective rate. It starts with the proof that the long-run average cost of an EMQ model with backlogging permitted is less than or equal to that of the same model without backlogging. The relationship between the ‘imputed backorder cost’ and maximal permitted shortage level is dependent for decision making on whether or not the required service level is achievable. An equation that calculates the intangible backorder cost is proposed for dealing with situations when the required service level is not attainable. Finally, by utilizing this intangible backorder cost in the proposed mathematical analysis, an optimal lot-size policy that minimizes expected overall costs as well as satisfies the service-level constraint can be derived. A numerical example with a discussion that demonstrates the effects of service-level constraint and failure-in-repair on the EMQ model is provided.
Optimization using finite element analysis, neural network, and experiment in tube hydroforming of aluminium T joints
Authors: Mohammadi F , Kashanizade H , Mashadi M Mosavi
Published: August 2007

In tube hydroforming (THF) of T joints, loading conditions (internal pressure and axial feeding) should be determined in such a way that the tube does not wrinkle or burst and is fully calibrated. In the current study THF of an aluminium T joint is simulated with the finite element method (FEM) using a commercial code. An explicit method is used to overcome convergence problems that are encountered in an implicit method. Internal pressure and axial feeding are two variables in the optimization problem and the loading path is optimized. The objective function is the clamping force, and the constraints of wrinkling, minimum thickness, and calibration should be achieved. The objective and constraint functions are obtained by training a neural network and the objective function is minimized using several optimization methods including hill-climbing search, simulated annealing, and complex method. The axial feeding and internal pressure obtained by optimization methods are used to conduct an experiment. Thickness distribution, calibration pressure, and axial feeding in experiment and FEM are compared and it is shown that there is a good agreement between them.
Matrix metalloprotease-2 and -9 concentration and activity in serum and culture medium samples: a methodological reappraisal
Authors: Colotti Chiara , Angeli Valeria , Del Ry Silvia , Maltinti Maristelli , Vittorini Simona , Giannessi Daniela
Published: August 2007

Clin Chem Lab Med 2007;45:1292–8.
The soluble transferrin receptor reflects tumor load in chronic lymphocytic leukemia
Authors: Metzgeroth Georgia , Schultheis Beate , Kuhn Christian , Dorn-Beineke Alexandra , LaRosée Paul , Hehlmann Rüdiger , Hastka Jan
Published: August 2007

Clin Chem Lab Med 2007;45:1313–8.
Repair Capacity for Platinum-DNA Adducts Determines the Severity of Cisplatin-Induced Peripheral Neuropathy
Authors: Dzagnidze Anna , Katsarava Zaza , Makhalova Julia , Liedert Bernd , Yoon Min-Suk , Kaube Holger , Limmroth Volker , Thomale Juergen
Published: August 2007

The pronounced neurotoxicity of the potent antitumor drug cisplatin frequently results in the onset of peripheral polyneuropathy (PNP), which is assumed to be initially triggered by platination products in the nuclear DNA of affected tissues. To further elucidate the molecular mechanisms, we analyzed in a mouse model the formation and processing of the main cisplatin-induced DNA adduct (guanine–guanine intrastrand cross-link) in distinct neuronal cell types by adduct-specific monoclonal antibodies. Comparison of the adduct kinetics in cisplatin-injected mice either proficient or deficient for nucleotide excision repair (NER) functions revealed the essential role of this DNA repair pathway in protecting differentiated cells of the nervous system from excessive formation of such lesions. Hence, chronic exposure to cisplatin resulted in an accelerated accumulation of unrepaired intrastrand cross-links in neuronal cells of mice with dysfunctional NER. The augmented adduct levels in dorsal root ganglion (DRG) cells of those animals coincided with an earlier onset of PNP-like functional disturbance of their sensory nervous system. Independently from the respective repair phenotype, the amount of persisting DNA cross-links in DRG neurons at a given cumulative dose was significantly correlated to the degree of sensory impairment as measured by electroneurography. Collectively, these findings suggest a new model for the processing of cisplatin adducts in primary neuronal cells and accentuate the crucial role of effectual DNA repair capacity in the target cells for the individual risk of therapy-induced PNP.
P2X7Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis
Authors: Matute Carlos , Torre Iratxe , Pérez-Cerdá Fernando , Pérez-Samartín Alberto , Alberdi Elena , Etxebarria Estibaliz , Arranz Amaia M. , Ravid Rivka , Rodríguez-Antigüedad Alfredo , Sánchez-Gómez MaríaVictoria , Domercq María
Published: August 2007

Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X7purinergic receptors expressed by these cells. Sustained activation of P2X7receptorsin vivocauses lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X7antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X7activation and that this cell death process contributes to EAE. Importantly, P2X7expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X7receptor antagonists may be beneficial for the treatment of MS.
Membrane Estrogen Receptor-α Interactions with Metabotropic Glutamate Receptor 1a Modulate Female Sexual Receptivity in Rats
Authors: Dewing Phoebe , Boulware Marissa I. , Sinchak Kevin , Christensen Amy , Mermelstein Paul G. , Micevych Paul
Published: August 2007

In rats, female sexual behavior is regulated by a well defined limbic–hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in μ-opioid receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both membrane and intracellular receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-mediated membrane responsesin vivohave remained elusive. Recentin vitroevidence found that stimulation of membrane-associated estrogen receptor-α (ERα) led to activation of metabotropic glutamate receptor 1a (mGluR1a). Furthermore, mGluR1a signaling was responsible for the observed downstream effects of estradiol. Here we present data that show that ERα and mGluR1a directly interact to mediate a rapid estradiol-induced activation of MOR in the medial preoptic nucleus, leading to female sexual receptivity. In addition, blockade of mGluR1a in the arcuate nucleus of the hypothalamus resulted in a significant attenuation of estradiol-induced MOR internalization, leading to diminished female sexual behavior. These results link membrane-initiated estradiol actions to neural events modulating behavior, demonstrating the physiological importance of ERα-to-mGluR1a signaling.
Experience-Dependent Modification of Primary Sensory Synapses in the Mammalian Olfactory Bulb
Authors: Tyler William J. , Petzold Gabor C. , Pal Sumon K. , Murthy Venkatesh N.
Published: August 2007

Experience-dependent changes in neural circuits have traditionally been investigated several synapses downstream of sensory input. Whether experience can alter the strength of primary sensory synapses remains mostly unknown. To address this issue, we investigated the consequences of odor deprivation on synapses made by olfactory sensory axons in the olfactory bulb of rats. Odor deprivation triggered an increase in the probability of glutamate release from olfactory sensory neuron synapses. Deprivation also increased the amplitude of quantal synaptic currents mediated by AMPA- and NMDA-type glutamate receptors, as well as the abundance of these receptors in the glomerular region. Our results demonstrate that sensory experience is capable of modulating synaptic strength at the earliest stages of information transfer between the environment and an organism. Such compensatory experience-dependent changes may represent a mechanism of sensory gain control.
Protein Kinase Cζ and Glycogen Synthase Kinase-3β Control Neuronal Polarity in Developing Rodent Enteric Neurons, whereas SMAD Specific E3 Ubiquitin Protein Ligase 1 Promotes Neurite Growth But Does Not Influence Polarity
Authors: Vohra Bhupinder P. S. , Fu Ming , Heuckeroth Robert O.
Published: August 2007

Enteric nervous system (ENS) precursors migrate extensively before differentiating to form uni-axonal or multi-axonal neurons. ENS precursor survival, neurite growth, and cell migration are all directed by Ret kinase, but downstream signaling pathways are incompletely understood. We now demonstrate that proteins regulating polarity in other cells including partitioning defective 3 (PAR3), PAR6, protein kinase Cζ (PKCζ), and glycogen synthase kinase 3β (GSK3β) are expressed in developing enteric neurons with a polarized distribution. Blocking PKCζ or GSK3β reduces ENS precursor migration and induces the formation of multi-axonal neurons. Axon elongation also depends on SMURF1 (SMAD specific E3 ubiquitin protein ligase 1), which promotes RhoA degradation and associates with polarity proteins. SMURF1 inhibition, however, does not increase the number of multi-axonal neurons in ENS precursors. These data link cell surface Ret activation with molecular machinery controlling cytoskeletal dynamics and suggest that polymorphisms influencing PKCζ or GSK3β might alter Hirschsprung disease penetrance or expressivity by affecting ENS precursor migration.
SK Channels Provide a Novel Mechanism for the Control of Frequency Tuning in Electrosensory Neurons
Authors: Ellis Lee D. , Mehaffey W. Hamish , Harvey-Girard Erik , Turner Ray W. , Maler Leonard , Dunn Robert J.
Published: August 2007

One important characteristic of sensory input is frequency, with sensory neurons often tuned to narrow stimulus frequency ranges. Although vital for many neural computations, the cellular basis of such frequency tuning remains mostly unknown. In the electrosensory system ofApteronotus leptorhynchus, the primary processing of important environmental and communication signals occurs in pyramidal neurons of the electrosensory lateral line lobe. Spike trains transmitted by these cells can encode low-frequency prey stimuli with bursts of spikes and high-frequency communication signals with single spikes. Here, we demonstrate that the selective expression of SK2 channels in a subset of pyramidal neurons reduces their response to low-frequency stimuli by opposing their burst responses. Apamin block of the SK2 current in this subset of cells induced bursting and increased their response to low-frequency inputs. SK channel expression thus provides an intrinsic mechanism that predisposes a neuron to respond to higher frequencies and thus specific, behaviorally relevant stimuli.
Evidence for the Flexible Sensorimotor Strategies Predicted by Optimal Feedback Control
Authors: Liu Dan , Todorov Emanuel
Published: August 2007

Everyday movements pursue diverse and often conflicting mixtures of task goals, requiring sensorimotor strategies customized for the task at hand. Such customization is mostly ignored by traditional theories emphasizing movement geometry and servo control. In contrast, the relationship between the task and the strategy most suitable for accomplishing it lies at the core of our optimal feedback control theory of coordination. Here, we show that the predicted sensitivity to task goals affords natural explanations to a number of novel psychophysical findings. Our point of departure is the little-known fact that corrections for target perturbations introduced late in a reaching movement are incomplete. We show that this is not simply attributable to lack of time, in contradiction with alternative models and, somewhat paradoxically, in agreement with our model. Analysis of optimal feedback gains reveals that the effect is partly attributable to a previously unknown trade-off between stability and accuracy. This yields a testable prediction: if stability requirements are decreased, then accuracy should increase. We confirm the prediction experimentally in three-dimensional obstacle avoidance and interception tasks in which subjects hit a robotic target with programmable impedance. In additional agreement with the theory, we find that subjects do not rely on rigid control strategies but instead exploit every opportunity for increased performance. The modeling methodology needed to capture this extra flexibility is more general than the linear-quadratic methods we used previously. The results suggest that the remarkable flexibility of motor behavior arises from sensorimotor control laws optimized for composite cost functions.
Effects of Selective Attention on the Electrophysiological Representation of Concurrent Sounds in the Human Auditory Cortex
Authors: Bidet-Caulet Aurélie , Fischer Catherine , Besle Julien , Aguera Pierre-Emmanuel , Giard Marie-Helene , Bertrand Olivier
Published: August 2007

In noisy environments, we use auditory selective attention to actively ignore distracting sounds and select relevant information, as during a cocktail party to follow one particular conversation. The present electrophysiological study aims at deciphering the spatiotemporal organization of the effect of selective attention on the representation of concurrent sounds in the human auditory cortex. Sound onset asynchrony was manipulated to induce the segregation of two concurrent auditory streams. Each stream consisted of amplitude modulated tones at different carrier and modulation frequencies. Electrophysiological recordings were performed in epileptic patients with pharmacologically resistant partial epilepsy, implanted with depth electrodes in the temporal cortex. Patients were presented with the stimuli while they either performed an auditory distracting task or actively selected one of the two concurrent streams. Selective attention was found to affect steady-state responses in the primary auditory cortex, and transient and sustained evoked responses in secondary auditory areas. The results provide new insights on the neural mechanisms of auditory selective attention: stream selection during sound rivalry would be facilitated not only by enhancing the neural representation of relevant sounds, but also by reducing the representation of irrelevant information in the auditory cortex. Finally, they suggest a specialization of the left hemisphere in the attentional selection of fine-grained acoustic information.
Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration
Authors: Shaftel Solomon S. , Carlson Thaddeus J. , Olschowka John A. , Kyrkanides Stephanos , Matousek Sarah B. , O'Banion M. Kerry
Published: August 2007

The proinflammatory cytokine interleukin-1β (IL-1β) plays a significant role in leukocyte recruitment to the CNS. Although acute effects of IL-1β signaling in the mouse brain have been well described, studies elucidating the downstream effects of sustained upregulation have been lacking. Using the recently described IL-1βXATtransgenic mouse model, we triggered sustained unilateral hippocampal overexpression of IL-1β. Transgene induction led to blood–brain barrier leakage, induction of MCP-1 (monocyte chemoattractant protein 1) (CCL2), ICAM-1 (intercellular adhesion molecule 1), and dramatic infiltration of CD45-positive leukocytes comprised of neutrophils, T-cells, macrophages, and dendritic cells. Despite prolonged cellular infiltration of the hippocampus, there was no evidence of neuronal degeneration. Surprisingly, neutrophils were observed in the hippocampal parenchyma as late as 1 year after transgene induction. Their presence was coincident with upregulation of the potent neutrophil chemotactic chemokines KC (keratinocyte-derived chemokine) (CXCL1) and MIP-2 (macrophage inflammatory protein 2) (CXCL2). Knock-out of their sole receptor CXCR2 abrogated neutrophil infiltration but failed to reduce leakage of the blood–brain barrier.
Seizure-Associated, Aberrant Neurogenesis in Adult Rats Characterized with Retrovirus-Mediated Cell Labeling
Authors: Jessberger Sebastian , Zhao Chunmei , Toni Nicolas , Clemenson Gregory D. , Li Yan , Gage Fred H.
Published: August 2007

Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.
Differential Recruitment of the Hippocampus, Medial Prefrontal Cortex, and the Human Motion Complex during Path Integration in Humans
Authors: Wolbers Thomas , Wiener Jan M. , Mallot Hanspeter A. , Büchel Christian
Published: August 2007

Path integration, the ability to sense self-motion for keeping track of changes in orientation and position, constitutes a fundamental mechanism of spatial navigation and a keystone for the development of cognitive maps. Whereas animal path integration is predominantly supported by the head-direction, grid, and place cell systems, the neural foundations are not well understood in humans. Here we used functional magnetic resonance imaging and a virtual rendition of a triangle completion paradigm to test whether human path integration recruits a cortical system similar to that of rodents and nonhuman primates. Participants traveled along two legs of a triangle before pointing toward the starting location. In accordance with animal models, stronger right hippocampal activation predicted more accurate updating of the starting location on a trial-by-trial basis. Moreover, between-subjects fluctuations in response consistency were negatively correlated with bilateral hippocampal and medial prefrontal activation, and bilateral recruitment of the human motion complex (hMT+) covaried with individual path integration capability. Given that these effects were absent in a perceptual control task, the present study provides the first evidence that visual path integration is related to the dynamic interplay of self-motion processing in hMT+, higher-level spatial processes in the hippocampus, and spatial working memory in medial prefrontal cortex.
Gamma Oscillations Coordinate Amygdalo-Rhinal Interactions during Learning
Authors: Bauer Elizabeth P. , Paz Rony , Paré Denis
Published: August 2007

The rhinal cortices contribute to memory formation by integrating and transferring neocortical information to the hippocampus. Rhinal contributions to memory are likely influenced by the amygdala because strong reciprocal connections exist between these structures. In light of previous data showing that oscillations regulate neuronal activity during memory formation and recall, we tested the possibility that coherent oscillations serve to coordinate amygdalo-rhinal activity during learning. To this end, we performed simultaneous extracellular recordings of basolateral amygdala (BLA), perirhinal, and entorhinal activity. We first tested whether there are correlated fluctuations in the power of BLA and rhinal field activity during the waking state. Correlated power fluctuations were most pronounced in the 35–45 Hz band. Within each structure, firing probability fluctuated rhythmically with the fast oscillations, indicating that they were not volume conducted. To test whether fast oscillations coordinate BLA and rhinal activity during learning, animals were trained on a trace-conditioning task in which a visual conditioned stimulus (CS) predicted a food reward after a delay. The predictive value of the CS was learned gradually over 9 d. As learning progressed, the 35–45 Hz power increased in the BLA and rhinal cortices, particularly during the late part of the CS and delay. Moreover, the firing of BLA and rhinal neurons became rhythmically entrained by BLA oscillations at that time. Thus, our data suggest that neuronal interactions are coordinated by fast oscillations in the BLA–rhinal network. By telescoping the periods of effective neuronal interactions in short recurring time windows, these fast oscillations may facilitate rhinal interactions and synaptic plasticity.
Dendritic Backpropagation and the State of the Awake Neocortex
Authors: Bereshpolova Yulia , Amitai Yael , Gusev Alexander G. , Stoelzel Carl R. , Swadlow Harvey A.
Published: August 2007

The spread of somatic spikes into dendritic trees has become central to models of dendritic integrative properties and synaptic plasticity. However, backpropagating action potentials (BPAPs) have been studied mainly in slices, in which they are highly sensitive to multiple factors such as firing frequency and membrane conductance, raising doubts about their effectiveness in the awake behaving brain. Here, we examine the spatiotemporal characteristics of BPAPs in layer 5 pyramidal neurons in the visual cortex of adult, awake rabbits, in which EEG-defined brain states ranged from alert vigilance to drowsy/inattention, and, in some cases, to light sleep. To achieve this, we recorded extracellular spikes from layer 5 pyramidal neurons and field potentials above and below these neurons using a 16-channel linear probe, and applied methods of spike-triggered current source-density analysis to these records (Buzsáki and Kandel, 1998; Swadlow et al., 2002). Precise retinotopic alignment of superficial and deep cortical sites was used to optimize alignment of the recording probe with the axis of the apical dendrite. During the above network states, we studied BPAPs generated spontaneously, antidromically (from corticotectal neurons), or via intense synaptic drive caused by natural visual stimulation. Surprisingly, the invasion of BPAPs as far as 800 μm from the soma was little affected by the network state and only mildly attenuated by high firing frequencies. These data reveal that the BPAP is a robust and highly reliable property of neocortical apical dendrites. These events, therefore, are well suited to provide crucial signals for the control of synaptic plasticity during information-processing brain states.