bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Parametric Bootstrap Methods for Small Area Prediction
Authors: Hall Peter , Maiti Tapabrata 
Published: March 2006

SummaryThe particularly wide range of applications of small area prediction, e.g. in policy making decisions, has meant that this topic has received substantial attention in recent years. The problems of estimating mean-squared predictive error, of correcting that estimator for bias and of constructing prediction intervals have been addressed by various workers, although existing methodology is still restricted to a narrow range of models. To overcome this difficulty we develop new, bootstrap-based methods, which are applicable in very general settings, for constructing bias-corrected estimators of mean-squared error and for computing prediction regions. Unlike existing techniques, which are based largely on Taylor expansions, our bias-corrected mean-squared error estimators do not require analytical calculation. They also have the property that they are non-negative. Our prediction intervals have a high degree of coverage accuracy, O(n−3), where n is the number of areas, if double-bootstrap methods are employed. The techniques do not depend on the form of the small area estimator and are applicable to general two-level, small area models, where the variables at either level can be discrete or continuous and, in particular, can be non-normal. Most importantly, the new methods are simple and easy to apply.
Genetic Variations and Haplotype Structures of theABCB1Gene in a Japanese Population: An Expanded Haplotype Block Covering the Distal Promoter Region, and Associated Ethnic Differences
Authors: Sai K. , Itoda M. , Saito Y. , Kurose K. , Katori N. , Kaniwa N. , Komamura K. , Kotake T. , Morishita H. , Tomoike H. , Kamakura S. , Kitakaze M. , Tamura T. , Yamamoto N. , Kunitoh H. , Yamada Y. , Ohe Y. , Shimada Y. , Shirao K. , Minami H. , Ohtsu A. , Yoshida T. , Saijo N. , Kamatani N. , Ozawa S. , Sawada J. 
Published: March 2006

SummaryAs functionalABCB1haplotypes were recently reported in the promoter region of the gene, we resequenced theABCB1distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks −1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms −1789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re‐assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally‐important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis ofABCB1haplotype blocks will assist pharmacogenetic and disease‐association studies carried out using Asian subjects.
Spatio‐temporal dynamics of the egg‐laying‐inducing peptides during an egg‐laying cycle: a semiquantitative matrix‐assisted laser desorption/ionization mass spectrometry approach
Authors: Jiménez C. R. , Ter Maat A. , Pieneman A. , Burlingame A. L. , Smit A. B. , Li K. W. 
Published: March 2006

AbstractThe activity‐dependent release of peptides from the neuro‐endocrine caudodorsal cell (CDC) system of the freshwater snail Lymnaea stagnalis regulates egg laying and related behaviors. In this study, we optimized a mass spectrometry‐based approach to study the spatio‐temporal dynamics of peptides that are largely derived from the CDC hormone precursor during an egg‐laying cycle and a CDC discharge in vitro. Semi‐quantitative peptide mass profiling using matrix‐assisted laser desorption/ionization mass spectrometry (MALDI‐MS) indicated a massive depletion of peptides from the neurohemal area in the cerebral commissure (COM) during egg laying and the existence of a reserve pool of peptides in the CDC somata that were transported to the COM to restore peptide levels. The depletion of CDC peptides from the COM was correlated to their release during an induced electrical discharge in vitro. Moreover, MALDI‐MS of the releasate revealed extensive truncation of the carboxyl terminal peptide. Finally, two novel peptides of 1788 and 5895 Da, not encoded by the CDC hormone precursor, also exhibited temporal quantitative changes similar to those of CDC peptides. Sequencing of the peptide of 1788 Da by tandem mass spectrometry yielded the novel sequence HF(FH)FYGPYDVFQRDVamide. Together, this implicates a more complex set of CDC peptides for the regulation of egg laying than previously anticipated.
Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons
Authors: Shibasaki Koji , Nakahira Kensuke , Trimmer James S. , Shibata Riichi , Akita Masumi , Watanabe Shu‐Ichi , Ikenaka Kazuhiro 
Published: March 2006

AbstractCompartmentalization of neuronal function is achieved by highly localized clustering of ion channels in discrete subcellular membrane domains. Voltage‐gated potassium (Kv) channels exhibit highly variable cellular and subcellular patterns of expression. Here, we describe novel activity‐dependent synaptic targeting of Kv4.2, a dendritic Kv channel, in cerebellar granule cells (GCs). In vivo, Kv4.2 channels are highly expressed in cerebellar glomeruli, specializations of GC dendrites that form synapses with mossy fibres. In contrast, in cultured GCs, Kv4.2 was found localized, not to dendrites but to cell bodies. To investigate the role of synaptic contacts, we developed a co‐culture system with cells from pontine grey nucleus, the origin of mossy fibres. In these co‐cultures, synaptic structures formed, and Kv4.2 was now targeted to these synaptic sites in a manner dependent on synaptic activity. Activation of NMDA‐ and/or AMPA‐type glutamate receptors was necessary for the targeting of Kv4.2 in co‐cultures, and activation of these receptor systems in GC monocultures induced dendritic targeting of Kv4.2 in the absence of synapse formation. These results indicate that the proper targeting of Kv4.2 channels is dynamically regulated by synaptic activity. This activity‐dependent regulation of Kv4.2 localization provides a crucial yet dynamic link between synaptic activity and dendritic excitability.
Possible involvement of pyruvate kinase in acquisition of tolerance to hypoxic stress in glial cells
Authors: Shimizu Takahiro , Uehara Takashi , Nomura Yasuyuki 
Published: March 2006

AbstractNeurons are highly vulnerable to ischemic/hypoxic stress, while glial cells show tolerance to such stress. However, the mechanisms for tolerance acquisition in glial cells have yet to be established. We attempted to isolate and identify a stress protein that is upregulated in response to hypoxia in human astrocytoma CCF‐STTG1 cells. In particular, pyruvate kinase (PK) was upregulated by hypoxia in CCF‐STTG1 cells. Hypoxia‐inducible factor 1 (HIF‐1), the primary transcription factor that is responsible for multiple gene activation under hypoxia, plays a critical role in PK expression during hypoxic challenge. To determine whether newly synthesized PK is involved in tolerance to hypoxic stress, we established the PK‐overexpressing neuronal cells. Overexpression of the wild‐type, but not the kinase‐negative mutant, resulted in attenuation of the loss of cell viability and the typical apoptotic features by hypoxia or oxidative stress in SK‐N‐MC cells. These findings suggest that upregulation of PK may result in acquisition of tolerance against hypoxic stress, and that the antioxidant effect may be involved in the protective effect of PK.
Cerebral ischemia and the unfolded protein response
Authors: DeGracia Donald J. , Montie Heather L. 
Published: March 2006

AbstractWe review studies of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) following cerebral ischemia and reperfusion (I/R). The UPR is a cell stress program activated when misfolded proteins accumulate in the ER lumen. UPR activation causes: (i) a PERK‐mediated phosphorylation of eIF2α, inhibiting protein synthesis to prevent further accumulation of unfolded proteins in the ER and (ii) upregulation of genes coding for ER‐resident enzymes and chaperones and others, via eIF2α(p), and ATF6 and IRE1 activation. UPR‐induced transcription increases capacity of the ER to process misfolded proteins. If ER stress and the UPR are prolonged, apoptosis ensues. Multiple forms of ER stress have been observed following brain I/R. The UPR following brain I/R is not isomorphic between in vivo I/R models and in vitro cell culture systems with pharmacological UPR induction. Although PERK and IRE1 are activated in the initial hours of reperfusion, total PERK decreases, ATF6 is not activated, and there is delayed appearance of UPR‐induced mRNAs. Thus, multiple damage mechanisms associated with brain I/R alter UPR expression and contribute to a pro‐apoptotic phenotype in neurons. Insights resulting from these studies will be important for the development of therapies to halt neuronal death following brain I/R.
Characterization of an allosteric citalopram‐binding site at the serotonin transporter
Authors: Chen Fenghua , Larsen Mads Breum , Neubauer Henrik Amtoft , Sánchez Connie , Plenge Per , Wiborg Ove 
Published: March 2006

AbstractThe serotonin transporter (SERT), which belongs to a family of sodium/chloride‐dependent transporters, is the major pharmacological target in the treatment of several clinical disorders, including depression and anxiety. In the present study we show that the dissociation rate, of [3H]S‐citalopram from human SERT, is retarded by the presence of serotonin, as well as by several antidepressants, when present in the dissociation buffer. Dissociation of [3H]S‐citalopram from SERT is most potently inhibited by S‐citalopram followed by R‐citalopram, sertraline, serotonin and paroxetine. EC50 values for S‐ and R‐citalopram are 3.6 ± 0.4 µm and 19.4 ± 2.3 µm, respectively. Fluoxetine, venlafaxine and duloxetine have no significant effect on the dissociation of [3H]S‐citalopram. Allosteric modulation of dissociation is independent of temperature, or the presence of Na+ in the dissociation buffer. Dissociation of [3H]S‐citalopram from a complex with the SERT double‐mutant, N208Q/N217Q, which has been suggested to be unable to self‐assemble into oligomeric complexes, is retarded to an extent similar to that found with the wild‐type, raising the possibility that the allosteric mechanism is mediated within a single subunit. A species‐scanning mutagenesis study comparing human and bovine SERT revealed that Met180, Tyr495 and Ser513 are important residues in mediating the allosteric effect, as well as contributing to high‐affinity binding at the primary site.
Androgen‐induced neurite outgrowth is mediated by neuritin in motor neurones
Authors: Marron T. U. , Guerini V. , Rusmini P. , Sau D. , Brevini T. A. L. , Martini L. , Poletti A. 
Published: March 2006

AbstractIn the brain, the spinal cord motor neurones express the highest levels of the androgen receptor (AR). Experimental data have suggested that neurite outgrowth in these neurones may be regulated by testosterone or its derivative 5α‐dihydrotestosterone (DHT), formed by the 5α‐reductase type 2 enzyme. In this study we have produced and characterized a model of immortalized motor neuronal cells expressing the mouse AR (mAR) [neuroblastoma‐spinal cord (NSC) 34/mAR] and analysed the role of androgens in motor neurones. Androgens either activated or repressed several genes; one has been identified as the mouse neuritin, a protein responsible for neurite elongation. Real‐time PCR analysis has shown that the neuritin gene is expressed in the basal condition in immortalized motor neurones and is selectively up‐regulated by androgens in NSC34/mAR cells; the DHT effect is counteracted by the anti‐androgen Casodex. Moreover, DHT induced neurite outgrowth in NSC34/mAR, while testosterone was less effective and its action was counteracted by the 5α‐reductase type 2 enzyme inhibitor finasteride. Finally, the androgenic effect on neurite outgrowth was abolished by silencing neuritin with siRNA. Therefore, the trophic effects of androgens in motor neurones may be explained by the androgenic regulation of neuritin, a protein linked to neurone development, elongation and regeneration.
Preferentially impaired neurotransmitter release sites not their discreteness compromise the validity of microdialysis zero‐net‐flux method
Authors: Chen Kevin C. 
Published: March 2006

AbstractIntracerebral microdialysis is a popular technique for studying neurochemistry and neural circuits in various brain regions. Recent studies called into question the validity of the microdialysis zero‐net‐flux (ZNF) method by suggesting that this method significantly underestimates the basal level of extracellular dopamine as a result of the discreteness of dopamine release sites as well as the preferential damage to dopamine release over uptake. To identify which factor is most important in undermining the microdialysis ZNF measurements and the extent of underestimation, two mathematical models were developed to explore the influences of the discrete nature and the probe‐induced impairment in the neurotransmitter release. The two models differ in their characterizations of the transmitter release as spatially discrete and homogeneous, respectively. Simulations using physiologically reasonable parameters for striatal dopamine systems indicate that the preferential release site damage surrounding the implanted probe is the most important determinant to the underestimation of the microdialysis ZNF concentration. Under normal physiological conditions, the discreteness of neurotransmitter release sites is of minor importance, except when neuronal degeneration occurs. It is concluded that homogeneous models can adequately describe microdialysis operating processes as long as the corresponding tissue damage parameters in such models are appropriately incorporated.
Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent‐resistant membrane domains
Authors: Molander‐Melin Marie , Blennow Kaj , Bogdanovic Nenad , Dellheden Birgitta , Månsson Jan‐Eric , Fredman Pam 
Published: March 2006

AbstractThe formation of neurotoxic beta‐amyloid fibrils in Alzheimer's disease (AD) is suggested to involve membrane rafts and to be promoted, in vitro, by enriched concentrations of gangliosides, particularly GM1, and the cholesterol therein. In our study, the presence of rafts and their content of the major membrane lipids and gangliosides in the temporal cortex, reflecting late stages of AD pathology, and the frontal cortex, presenting earlier stages, has been investigated. Whole tissue and isolated detergent‐resistant membrane fractions (DRMs) were analysed from 10 AD and 10 age‐matched control autopsy brains. DRMs from the frontal cortex of AD brains contained a significantly higher concentration (µmol/µmol glycerophospholipids), of ganglioside GM1 (22.3 ± 4.6 compared to 10.3 ± 6.4, p < 0.001) and GM2 (2.5 ± 1.0 compared to 0.55 ± 0.3, p < 0.001). Similar increases of these gangliosides were also seen in DRMs from the temporal cortex of AD brains, which, in addition, comprised significantly lower proportions of DRMs. Moreover, these remaining rafts were depleted in cholesterol (from 1.5 ± 0.2 to 0.6 ± 0.3 µmol/µmol glycerophospholipids, p < 0.001). In summary, we found an increased proportion of GM1 and GM2 in DRMs, and accelerating plaque formation at an early stage, which may gradually lead to membrane raft disruptions and thereby affect cellular functions associated with the presence of such membrane domains.
Hypoxia‐inducible factor and nuclear factor kappa‐B activation in blood–brain barrier endothelium under hypoxic/reoxygenation stress
Authors: Witt Ken A. , Mark Karen S. , Huber Jason , Davis Thomas P. 
Published: March 2006

AbstractThis investigation focuses on transcription factor involvement in blood–brain barrier (BBB) endothelial cell‐induced alterations under conditions of hypoxia and post‐hypoxia/reoxygenation (H/R), using establishedin vivo/ex vivoandin vitroBBB models. Protein/DNA array analyses revealed a correlation in key transcription factor activation during hypoxia and H/R, including NFκB and hypoxia‐inducible factor (HIF)1. Electrophoretic mobility shift assays confirmed NFκB and HIF1 binding activityex vivoandin vitro, under conditions of hypoxia and H/R. Hypoxia‐ and H/R‐treated BBB endothelium showed increased HIF1α protein expression in both cytoplasmic and nuclear fractions, inex vivoandin vitromodels. Co‐immunoprecipitation of HIF1α and HIF1β was shown in the nuclear fraction under conditions of hypoxia and H/R in both models. Hypoxia‐ and H/R‐treated BBB endothelium showed increased expression of NFκB‐p65 protein in both cytoplasmic and nuclear fractions. Co‐immunoprecipitation of NFκB‐p65 with NFκB‐p50 was shown in the nuclear fraction under conditions of hypoxia and H/R in theex vivomodel, and after H/R in thein vitromodel. These data offer novel avenues in which to alter and/or investigate BBB activity across model systems and to further our understanding of upstream regulators during hypoxia and H/R.
Regulation of the preprotachykinin‐I gene promoter through a protein kinase A‐dependent, cyclic AMP response element‐binding protein‐independent mechanism
Authors: Calin‐Jageman Irina E. , Wang Jun , Bannon Michael J. 
Published: March 2006

AbstractPreprotachykinin‐I (PPT) gene expression is regulated by a number of stimuli that signal through cyclic AMP (cAMP)‐mediated pathways. In the present study, forskolin, an adenylyl cyclase stimulator, significantly increased PPT mRNA levels in PPT‐expressing RINm5F cells, an effect paralleled by an increase in PPT promoter‐luciferase reporter construct activity. The forskolin‐induced stimulation of PPT transcription was protein kinase A dependent (PKA), as shown by blockade with the PKA inhibitor N‐[2‐(p‐bromocinnamylamino) ethyl]‐5‐isoquinolinesulfonamide. We found that the activation protein 1/cAMP response element (AP1/CRE) site centered at − 196 relative to the transcription start site was important for basal and forskolin‐induced PPT promoter activity. Because of the involvement of PKA and the similarity of the AP1/CRE element to consensus CRE sequences, we investigated the role of CRE‐binding protein (CREB) in the regulation of the PPT promoter. Surprisingly, overexpression of a dominant‐negative CREB (i.e. CREB‐A) did not affect basal or forskolin‐induced PPT promoter activity. Furthermore, binding of CREB to the PPT promoter AP1/CRE site was not demonstrable in electrophoretic mobility shift assays. Rather, our experiments suggested that c‐Jun is a member of the complex that binds to this site. We conclude that, at least in RINm5F cells, cAMP‐mediated up‐regulation of PPT gene expression does not involve CREB or CREB‐related transcription factor recruitment to the AP1/CRE site.
Temperature dependence of Fe(III) and sulfate reduction rates and its effect on growth and composition of bacterial enrichments from an acidic pit lake neutralization experiment
Authors: MEIER J. , COSTA R. , SMALLA K. , BOEHRER B. , WENDT‐POTTHOFF K. 
Published: March 2006

ABSTRACTMicrobial Fe(III) and sulfate reduction are important electron transport processes in acidic pit lakes and stimulation by the addition of organic substrates is a strategy to remove acidity, iron and sulfate. This principle was applied in a pilot‐scale enclosure in pit lake 111 (Brandenburg, Germany). Because seasonal and spatial variation of temperature may affect the performance of in situ experiments considerably, the influence of temperature on Fe(III) and sulfate reduction was investigated in surface sediments from the enclosure in the range of 4–28 °C. Potential Fe(III) reduction and sulfate reduction rates increased exponentially with temperature, and the effect was quantified in terms of the apparent activation energy Ea measuring 42–46 kJ mol−1 and 52 kJ mol−1, respectively. Relatively high respiration rates at 4 °C and relatively low Q10 values (∼2) indicated that microbial communities were well adapted to low temperatures. In order to evaluate the effect of temperature on growth and enrichment of iron and sulfate‐reducing bacterial populations, MPN (Most Probable Number) dilution series were performed in media selecting for the different bacterial groups. While the temperature response of specific growth rates of acidophilic iron reducers showed mesophilic characteristics, the relatively high specific growth rates of sulfate reducers at the lowest incubation temperature indicated the presence of moderate psychrophilic bacteria. In contrast, the low cell numbers and low specific growth rates of neutrophilic iron reducers obtained in dilution cultures suggest that these populations play a less significant role in Fe and S cycling in these sediments. SSCP (Single‐Strand Conformation Polymorphism) or DGGE (Denaturing Gradient Gel Electrophoresis) fingerprinting based on 16S rRNA genes of Bacteria indicated different bacterial populations in the MPN dilution series exhibiting different temperature ranges for growth.
UNRESOLVED ISSUES IN DIALYSIS: Management of Intradialytic Hypertension: The Ongoing Challenge
Authors: Chen Joline , Gul Ambreen , Sarnak Mark J. 
Published: March 2006

ABSTRACTThere is no widely accepted definition of intradialytic hypertension. Arbitrary clinical definitions have included an increase in blood pressure during or immediately after hemodialysis, a rise in blood pressure during the second or third hour of dialysis, and an increase in blood pressure that is resistant to ultrafiltration. To date, no studies have evaluated the prevalence and prognostic importance of intradialytic hypertension. The pathogenesis of intradialytic hypertension is complex and is due in part to extracellular fluid volume expansion, increased cardiac output, activation of the renin‐angiotensin system and the sympathetic nervous system, increased circulating vasoactive substances resulting in peripheral vasoconstriction, erythropoietin use, and fluctuations in electrolytes and removal of antihypertensive medications during the dialysis procedure. Management strategies of intradialytic hypertension are based on expert opinion using the pathophysiologic principles described above. We conclude that additional epidemiologic, basic science, and interventional studies are needed to further elucidate the prevalence, prognostic importance, pathophysiology, and potential treatment of intradialytic hypertension.