bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracoronary Ghrelin Infusion Decreases Coronary Blood Flow in Anesthetized Pigs
Authors: Grossini Elena , Molinari Claudio , Mary David A. S. G. , Ghigo Ezio , Bona Gianni , Vacca Giovanni
Published: November 2006

The peptide ghrelin has been linked to the atherosclerotic process and coronary artery disease. We planned to study, for the first time, the primary effects of ghrelin on the intact coronary circulation and determine the mechanisms involved. In 24 sodium pentobarbitone-anesthetized pigs, changes in anterior descending coronary blood flow caused by intracoronary infusion of ghrelin at constant heart rate and arterial pressure were assessed using electromagnetic flowmeters. In 20 pigs, intracoronary infusion of ghrelin decreased coronary blood flow without affecting left ventricular maximum rate of change of left ventricular systolic pressure (dP/dtmax), filling pressures of the heart or plasma levels of GH. In four pigs, this decrease was graded by step increments of infused dose of the hormone. The mechanisms of the above response were studied in the 20 pigs by repeating the experiment after coronary flow had returned to the control values observed before infusion. The ghrelin-induced coronary vasoconstriction was not affected by iv atropine (five pigs) or phentolamine (five pigs). This response was abolished by iv butoxamine (five pigs) and intracoronary Nω-nitro-l-arginine methyl ester (five pigs), even after reversing the increase in arterial pressure and coronary vascular resistance caused by the two blocking agents with iv infusion of papaverine. The present study showed that intracoronary infusion of ghrelin primarily caused coronary vasoconstriction. The mechanisms of this response were shown to involve the inhibition of a vasodilatory β2-adrenergic receptor-mediated effect related to the release of nitric oxide.
P-type Na+/K+-ATPase and V-type H+-ATPase expression patterns in the osmoregulatory organs of larval and adult mosquitoAedes aegypti
Authors: Patrick Marjorie L. , Aimanova Karlygash , Sanders Heather R. , Gill Sarjeet S.
Published: November 2006

This study describes the expression patterns of P-type Na+/K+-ATPase and V-type H+-ATPase in the larval and adult forms of the mosquito Aedes aegypti and provides insight into their relative importance in ion transport function of key osmoregulatory organs. RT-PCR assays indicate that, at the level of the gene,both ATPases are expressed in all of the osmoregulatory tissues of larvae(midgut, Malpighian tubules, rectum and anal papillae) and adults (stomach,Malpighian tubules, anterior hindgut and rectum). Immunohistochemical studies determined that both ATPases are present in high levels in all the relevant organs, with the exception of the larval rectum (P-type Na+/K+-ATPase only). In larval gastric caeca, ATPase location corresponds to the secretory (basal P-type Na+/K+-ATPase, apical V-type H+-ATPase) and ion-transporting (V-type H+-ATPase on both membranes) regions as previously described. The two ATPases switch membrane location along the length of the larval midgut, indicating three possible regionalizations,whereas the adult stomach has uniform expression of basolateral P-type Na+/K+-ATPase and apical V-type H+-ATPase in each cell. In both larval and adult Malpighian tubules, the distal principal cells exhibit high expression levels of V-type H+-ATPase (apically and cytoplasmically) whereas P-type Na+/K+-ATPase is highly expressed in stellate cells found only in the distal two-thirds of each tubule. By contrast, the proximal principal cells express both P-type Na+/K+-ATPase (basal) and V-type H+-ATPase(apical). These results suggest a functional segregation along the length of the Malpighian tubules based on cell type and region. P-type Na+/K+-ATPase is the only pump apparent in the larval rectum whereas in the larval anal papillae and the adult hindgut (including the anterior hindgut and rectum with rectal pads), P-type Na+/K+-ATPase and V-type H+-ATPase localize to the basal and apical membranes, respectively. We discuss our findings in light of previous physiological and morphological studies and re-examine our current models of ion transport in these two developmental stages of mosquitoes that cope with disparate osmoregulatory challenges.
Correlation of C-start behaviors with neural activity recorded from the hindbrain in free-swimming goldfish (Carassius auratus)
Authors: Weiss Shennan A. , Zottoli Steven J. , Do Samantha C. , Faber Donald S. , Preuss Thomas
Published: November 2006

Startle behaviors in teleost fishes are well suited for investigations of mechanisms of sensorimotor integration because the behavior is quantifiable and much of the underlying circuitry has been identified. The teleost C-start is triggered by an action potential in one of the two Mauthner (M) cells. To correlate C-start behavior with electrophysiology, extracellular recordings were obtained from the surface of the medulla oblongata in the hindbrain,close to the M-axons, in freely swimming goldfish monitored using high-speed video. The recordings included action potentials generated by the two M-axons,as well as neighboring axons in the dorsal medial longitudinal fasciculus. Axonal backfills indicated that the latter originate from identifiable reticulospinal somata in rhombomeres 2-8 and local interneurons. Diverse auditory and visual stimuli evoked behaviors with kinematics characteristic of the C-start, and the amplitude of the first component of the hindbrain field potential correlated with the C-start direction. The onset of the field potential preceded that of the simultaneously recorded trunk EMG and movement initiation by 1.08±0.04 and 8.13±0.17 ms, respectively. A subsequent longer latency field potential was predictive of a counterturn. These results indicate that characteristic features of the C-start can be extracted from the neural activity of the M-cell and a population of other reticulospinal neurons in free-swimming goldfish.
New space-averaging procedure for inhomogeneous flow fields using balance equation formulations
Authors: Wattananusorn S
Published: November 2006

This paper features the possibility of averaging space-dependent flow fields using a coupling factor that links the equations of momentum and energy. The scheme is applied to the mean velocity, which is derived straightforwardly through the continuity equation. It creates a small imbalance, which can be eliminated later completely. Smaller discrepancies in the integration of systems of balance equations for inhomogeneous flow are the consequence. The procedure is verified on various flow patterns, and comparisons are made with other conventional methods and with some available experimental data. Despite investigating only numerical examples of incompressible flows here, the technique, in principle, is capable of dealing with compressible flows as well. Furthermore, the proposed method discards some variables required in other techniques while still providing useful and acceptable results for practical problems.
Dynamic response of large structural system including non-proportional damping with recursive component mode synthesis method
Authors: Kim C W
Published: November 2006

The modal frequency response problem including non-proportional damping is solved with the recursive component mode synthesis (RCMS) method. For large-scale structures, the RCMS method is used not only for computing the eigensolution, but also for forming the modal frequency response problem. The efficiency and accuracy of this approach are verified with examples of structural Finite-element model compared with the conventional industry approach that uses the block Lanczos method.
Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Features of Metabolic Syndrome
Authors: González-Sánchez José L , Martínez-Larrad María T , Sáez María E , Zabena Carina , Martínez-Calatrava María J , Serrano-Ríos Manuel
Published: November 2006

Background: The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene–null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans.

Methods: We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines.

Results: Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81, 95% confidence interval (CI) 1.15–2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01–2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P = 0.026).

Conclusions: Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations.
Molecular Beacon–Based Temperature Control and Automated Analyses for Improved Resolution of Melting Temperature Analysis Using SYBR I Green Chemistry
Authors: Nellåker Christoffer , Wållgren Ulf , Karlsson Håkan
Published: November 2006

Background: Melting temperature analysis of products amplified with SYBR I Green chemistry is a cheap and effective method for identification of sequence differences. When used in conventional quantitative real-time PCR instruments (qPCR), this method is limited by temperature variations over the heating block and low numbers of fluorescence measurements during the dissociation step, which hamper the ability of most instruments to report accurate and precise melting temperatures.

Methods: We designed a molecular beacon–based temperature indicator probe (Tm-probe) to control for variations in temperatures over the heating block of the instrument. In addition, we wrote an automated curve-fit analysis algorithm of dissociation data to use multiple data points with a gaussian curve fit to extrapolate precise melting temperatures.

Results: Use of the Tm-probe in conjunction with the analysis algorithm and multiple dissociations improved SDs of melting temperatures over a 96-well plate from 0.19 to 0.06 °C

Conclusions: Melting temperature analyses with SYBR I Green chemistry on conventional qPCR instruments can be improved by the use of a Tm-probe in conjunction with curve-fit analysis of data. Resolution improvement up to 3-fold is possible and allows additional melting temperatures to be identified.
Factitious Diarrhea Induced by Stimulant Laxatives: Accuracy of Diagnosis by a Clinical Reference Laboratory Using Thin Layer Chromatography
Authors: Shelton Joseph H , Santa Ana Carol A , Thompson Donald R , Emmett Michael , Fordtran John S
Published: November 2006

Background: Surreptitious ingestion of laxatives can lead to serious factitious diseases that are difficult to diagnose. Most cases involve ingestion of bisacodyl or senna. Thin layer chromatography (TLC) of urine or stool is the only commercially available test for these laxatives. Such testing is considered highly reliable, but its accuracy in clinical practice is unknown. Our aim was to evaluate the reliability of TLC laxative testing by a clinical reference laboratory in the United States.

Methods: Diarrhea was induced in healthy volunteers by ingestion of bisacodyl, senna, or a control laxative (n = 11 for each laxative group). Samples of urine and diarrheal stool were sent in blinded fashion to the clinical reference laboratory for bisacodyl and senna analysis.

Results: TLC testing for bisacodyl-induced diarrhea revealed a sensitivity of 73% and specificity of 91% when urine was tested and sensitivity and specificity of 91% and 96%, respectively, when stool was analyzed. When diarrhea was induced by senna, the TLC assay for senna failed to identify even a single urine or stool specimen as positive (zero% sensitivity).

Conclusions: Considering the expected prevalence of surreptitious laxative abuse in patients with chronic idiopathic diarrhea (2.4%–25%, depending on the clinical setting), TLC of urine or stool for bisacodyl by this reference laboratory would often produce misleading results, and testing for senna would have no clinical value. The major problems are false-positive tests for bisacodyl and false-negative tests for senna.
Rates of Recombination in the Ribosomal DNA of Apomictically Propagated Daphnia obtusa Lines
Authors: McTaggart Seanna J , Dudycha Jeffry L , Omilian Angela , Crease Teresa J
Published: November 2006

Ribosomal (r)DNA undergoes concerted evolution, the mechanisms of which are unequal crossing over and gene conversion. Despite the fundamental importance of these mechanisms to the evolution of rDNA, their rates have been estimated only in a few model species. We estimated recombination rate in rDNA by quantifying the relative frequency of intraindividual length variants in an expansion segment of the 18S rRNA gene of the cladoceran crustacean, Daphnia obtusa, in four apomictically propagated lines. We also used quantitative PCR to estimate rDNA copy number. The apomictic lines were sampled every 5 generations for 90 generations, and we considered each significant change in the frequency distribution of length variants between time intervals to be the result of a recombination event. Using this method, we calculated the recombination rate for this region to be 0.02–0.06 events/generation on the basis of three different estimates of rDNA copy number. In addition, we observed substantial changes in rDNA copy number within and between lines. Estimates of haploid copy number varied from 53 to 233, with a mean of 150. We also measured the relative frequency of length variants in 30 lines at generations 5, 50, and 90. Although length variant frequencies changed significantly within and between lines, the overall average frequency of each length variant did not change significantly between the three generations sampled, suggesting that there is little or no bias in the direction of change due to recombination.
Thermodynamics of Neutral Protein Evolution
Authors: Bloom Jesse D , Raval Alpan , Wilke Claus O
Published: November 2006

Naturally evolving proteins gradually accumulate mutations while continuing to fold to stable structures. This process of neutral evolution is an important mode of genetic change and forms the basis for the molecular clock. We present a mathematical theory that predicts the number of accumulated mutations, the index of dispersion, and the distribution of stabilities in an evolving protein population from knowledge of the stability effects (ΔΔG values) for single mutations. Our theory quantitatively describes how neutral evolution leads to marginally stable proteins and provides formulas for calculating how fluctuations in stability can overdisperse the molecular clock. It also shows that the structural influences on the rate of sequence evolution observed in earlier simulations can be calculated using just the single-mutation ΔΔG values. We consider both the case when the product of the population size and mutation rate is small and the case when this product is large, and show that in the latter case the proteins evolve excess mutational robustness that is manifested by extra stability and an increase in the rate of sequence evolution. All our theoretical predictions are confirmed by simulations with lattice proteins. Our work provides a mathematical foundation for understanding how protein biophysics shapes the process of evolution.
A Genetic Screen in Drosophila for Genes Interacting With senseless During Neuronal Development Identifies the Importin moleskin
Authors: Pepple Kathryn L , Anderson Aimée E , Frankfort Benjamin J , Mardon Graeme
Published: November 2006

Senseless (Sens) is a conserved transcription factor required for normal development of the Drosophila peripheral nervous system. In the Drosophila retina, sens is necessary and sufficient for differentiation of R8 photoreceptors and interommatidial bristles (IOBs). When Sens is expressed in undifferentiated cells posterior to the morphogenetic furrow, ectopic IOBs are formed. This phenotype was used to identify new members of the sens pathway in a dominant modifier screen. Seven suppressor and three enhancer complementation groups were isolated. Three groups from the screen are the known genes Delta, lilliputian, and moleskin/DIM-7 (msk), while the remaining seven groups represent novel genes with previously undefined functions in neural development. The nuclear import gene msk was identified as a potent suppressor of the ectopic interommatidial bristle phenotype. In addition, msk mutant adult eyes are extremely disrupted with defects in multiple cell types. Reminiscent of the sens mutant phenotype, msk eyes demonstrate reductions in the number of R8 photoreceptors due to an R8 to R2,5 fate switch, providing genetic evidence that Msk is a component of the sens pathway. Interestingly, in msk tissue, the loss of R8 fate occurs earlier than with sens and suggests a previously unidentified stage of R8 development between atonal and sens.
A Proteomic Strategy for Quantifying Polyubiquitin Chain Topologies
Authors: Xu Ping , Cheng Dongmei , Duong Duc M. , Rush John , Roelofs Jeroen , Finley Daniel , Peng Junmin
Published: November 2006

We present a method to probe the structure of polyubiquitin (polyUb) chains by mass spectrometry. As polyUb chains can be linked by any of seven lysine residues in the sequence of ubiquitin, the structural diversity of the chains could be enormous (e.g., as many as 70 configurations for tri‐Ub). To quantify the frequency of every lysine linkage, polyUb chains were digested by trypsin and analyzed by tandem mass spectrometry using synthetic isotope‐labeled peptides as internal standards. Employing a purified ubiquitin dimer to optimize conditions for trypsinization, we found that all tryptic sites except K33 could be reliably cleaved under insolution and in‐gel conditions. Because K33 miscleavage led to large underestimation of K29 linkage, its digestion efficiency was calculated to correct the measurement. The reverse‐phase chromatography was also adjusted to capture the small hydrophilic peptide of K29 linkage. In addition, the analysis of the K6‐linkage peptide was complicated by methionine oxidation and therefore the sample was treated with hydrogen peroxide to fully oxidize methionine to sulfoxide. While the method was sensitive enough to detect K48 and K63 linkages directly from total yeast extract, all linkages were quantified from pre‐enriched Ub‐conjugates, revealing that the concentration ratio of K6:K11:K27:K29:K33:K48:K63 was ˜40:120:20:15:5:100:40 in yeast during the log growth phase, and the sum of non‐K48 linkages was more than twice as abundant as the canonical K48 linkage. Moreover, increasing the concentration of ubiquitin in yeast raised the level of almost all linkages. Inhibiting proteasome activity augmented only K48‐ and K29‐linked chains, recapitulating their roles in proteolysis and suggesting non‐proteolytic functions of other linkages in vivo.
Intracellular Protein Degradation: From a Vague Idea, through the Lysosome and the Ubiquitin—Proteasome System, and onto Human Diseases and Drug Targeting Nobel Lecture
Authors: Ciechanover Aaron
Published: November 2006

Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lyso‐some by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely non‐lysosomal, but the mechanisms involved had remained obscure. The discovery of the ubiquitin‐proteasome system resolved this enigma. We now recognize that ubiquitin‐ and proteasome‐mediated degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of many human diseases, malignancies and neurodegenerative disorders among them, which led subsequently to an increasing effort to develop mechanism‐based drugs; one is already in use.
Synthetic Genetic Interaction Between the Ubiquitin‐Conjugating Enzyme Cdc34 and a tRNA Mutant
Authors: Holtzman Tzvi , Meimoun Ariella , Kornitzer Daniel
Published: November 2006

The ubiquitin‐conjugating enzyme Cdc34, in conjunction with the SCF ubiquitin ligase complexes, catalyzes the ubiquitination of protein substrates involved in various cellular pathways, including the cell cycle and amino acid synthesis. A synthetic lethality screen was carried out in S. cerevisiae with the hypomorphic allelele cdc34‐2 to uncover new genetic interactions with this component of the ubiquitin system. Three temperature‐sensitive mutants that are synthetically lethal with cdc34‐2 at its permissive temperature were characterized. They represent new alleles of the F‐box protein gene CDC4, of the ubiquitin‐activating enzyme Uba1, and an allele of SUP70/CDC65, encoding the unique tRNAGln(CUG). The uba1‐118 mutant displayed extremely enlarged cells and defects in cell cycle regulation. The N‐end rule substrate Arg‐lacZ and the UFD pathway substrate Pro‐LacZ were stabilized in the uba1‐118 strain. However, no defects were detected in either in vitro activity of Uba1‐118, or in degradation of several natural substrates of the ubiquitin system at the non‐permissive temperature, suggesting that the uba1‐118 allele differentially affects degradation of specific substrates. The sup70‐65 allele, which is synthetically lethal with cdc34‐2, consists of a basepair‐disrupting mutation at the top of the anticodon stem of tRNAGln(CUG). This allele was suggested to disrupt a regulatory role of tRNAGln(CUG) in nitrogen metabolism and morphogenesis at permissive temperature. At restrictive temperature, sup70‐65 cells arrest predominantly in G1, possibly reflecting the requirement for protein synthesis in cell‐cycle START control. The synthetic interaction of cdc34‐2 and sup70‐65 suggests that common targets are affected by both Cdc34 activity and tRNAGln(CUG).
Phosphorylation by COP9 Signalosome‐Associated CK2 Promotes Degradation of p27 during the G1 Cell Cycle Phase
Authors: Huang Xiaohua , Wagner Erika , Dumdey Renate , Peth Andreas , Berse Matthias , Dubiel Wolfgang , Berndt Christoph
Published: November 2006

The cell cycle regulator p27Kip1 (p27) is controlled by 26S proteasome‐mediated proteolysis by two different pathways. From the S till the G2 phase of the cell cycle, degradation of p27 takes place in the nucleus and is initiated by CDK2‐dependent phosphorylation of threonine 187 with subsequent ubiquitination by the SCFSkp2 ubiquitin ligase. During the G1 cell cycle phase (G1), p27 breakdown is cytosolic and is initiated by nuclear export with subsequent ubiquitination by a RING finger ligase called kip1 ubiquitination complex. Here we show that the COP9 signalosome (CSN) is a regulator of p27 proteolysis during G1. The CSN interacts with p27 and the CSN‐associated kinase CK2 phosphorylates p27 at two regions. One is central to the protein (amino acids 101–113), and the other was mapped near to the C‐terminus (amino acids 170–189). Elimination of the putative C‐terminal phosphorylation sites stabilizes ectopic p27 towards proteasomal degradation and abolishes CSN–p27 binding. Inhibition of CSN‐associated kinase activity by curcumin attenuates loss of p27 upon cell cycle re‐entry. Similar but not additive effects of the phosphoinositol‐3‐kinase blocker LY 290042 may point to a common pathway of CSN‐associated CK2 and protein kinase B/Akt (Akt) in regulating p27 abundance. Akt is found in Flag pulldowns of lysates obtained from cells permanently expressing Flag‐tagged CSN2, indicating that Akt is a novel kinase associated with the CSN. Thus, the CSN seems to regulate p27 proteolysis at G1 downstream of Ras‐mediated signal pathways.
Protein Quality Control by the Ubiquitin Proteolytic Pathway: Roles in Resistance to Oxidative Stress and Disease
Authors: Shang Fu , Dudek Edward , Liu Qing , Boulton Michael E. , Taylor Allen
Published: November 2006

There is now consensus that the accumulation of oxidatively modified proteins is cytotoxic and causally related to several age‐related diseases including the amyloid diseases and age‐related cataracts. There is also general agreement that the ubiquitin proteolytic pathway (UPP) provides a quality control mechanism to limit accumulation of modified proteins. We asked if and how oxidative stress is related to the function of the ubiquitin proteolytic pathway, and vice versa, with the objective of obtaining information that can lead to the development of strategies to delay age‐related “amyloid” or “protein precipitation” diseases such as cataracts and age‐related macular degeneration. Elevated levels of ubiquitin conjugates were observed when human, rabbit, bovine, and rat lens, retina, liver cells or tissues were exposed to mild oxidative stress, which was created by exposure to paraquat, diamide, peroxide, light together with lipofuscin, and radiomimetic drugs. The increase in ubiquitin conjugates derived from an increase in substrates as well as by hyperactivation of E1, rather than inactivation of the proteasome. Using a novel glutathiolated substrate, γC‐crystallin, we demonstrated that the UPP shows a previously unrecognized selectivity for such specifically oxidatively modified proteins. Selectivity of the pathway for other oxidatively modified proteins, specifically for protein carbonyls, was indicated in assays that employed the ubiquitin conjugation‐competent, but degradation‐resistant ubiquitin variant K6W‐ubiquitin. These experiments showed that failure to execute ubiquitin‐dependent proteolysis renders cells more susceptible to oxidative‐stress‐related cytotoxicity. Activity of the pathway is regulated in part by cellular redox status, specifically as affected by GSSG. Ubiquitination is enhanced when GSSG/GSH ratios are 0.02–0.15. Since there is potentiation of ubiquitination even when GSSG/GSH ratios are indistinguishable from basal levels, it appears that ubiquitination provides one of the most sensitive indicators of oxidative stress. Ubiquitination is attenuated when GSSG/GSH rises >0.2 and does not occur when GSSG/GSH ⩾ 2.9. The data indicate that inhibition of the pathway, which occurs upon aging, is associated with accumulation rather than the timely degradation of ubiquitin conjugates. They further suggest that if the system fails to keep up with production of substrates, high mass ubiquitin conjugates may accumulate and precipitate in cytotoxic aggregates such as are seen in many age‐related syndromes, including lens cataracts or in lipofuscin and drusen in the aging retina.
Proteasome Channel Opening as a Rate‐Limiting Step in the Ubiquitin‐Proteasome System
Authors: Rabinovich Efrat , Bajorek Monika , Glickman Michael , Bar‐Nun Shoshana
Published: November 2006

The 26S proteasome eliminates multiubiquitinated proteins in cytosol and nucleus, and from the secretory pathway by a mechanism known as ER‐associated degradation (ERAD). Access to the proteasomal 20S catalytic core particle is hindered by conserved N‐terminal tails of α‐subunits that form a gated pore into the central channel. Hence, the isolated 20S core particle possesses slower peptide hydrolysis rates and cannot degrade multiubiquitinated proteins. Purified catalytic particles from an α3α7ΔN open channel double mutant, in which the N‐terminal tails of α‐subunits from opposite sites of the α ring are deleted, showed significantly enhanced peptidase activity and proteolytic properties. Here we show that also in vivo the access of substrates to the proteasomal catalytic chamber partially limits the overall rate of protein elimination. This regulation applies to unstable cytosolic proteins of the N‐end rule and ubiquitin fusion degradation (UFD) pathways, as well as to ERAD substrates that must dislocate from the ER back to the cytosol in order to become ubiquitinated and degraded by the proteasome. Hence, even for a complicated multistep process such as ERAD, traffic through the proteasome itself is partially rate limiting for the entire proteolytic process. However, proteasome gating can be added to a growing list of phenomena that distinguish membrane ERAD substrates from lumenal ones because while gating hinders access of lumenal substrates, it is less effective in controlling the entry of membrane substrates. The open channel mutant is a new class of proteasome mutant, which is unrelated to the catalytic protease active sites or to the “classical” regulatory particle mutants. Its improved performance at high temperatures is in stark contrast to the behavior of the “classical” mutants, suggesting that the α3α7ΔN mutant adapts better to mild stress conditions.
Juvenile Coho Salmon Growth and Survival across Stream Network Seasonal Habitats
Authors: Ebersole Joseph L. , Wigington Parker J. , Baker Joan P. , Cairns Michael A. , Church M. Robbins , Hansen Bruce P. , Miller Bruce A. , LaVigne Henry R. , Compton Jana E. , Leibowitz Scott G.
Published: November 2006

Understanding watershed‐scale variation in juvenile salmonid survival and growth can provide insights into factors influencing demographics and can help target restoration and mitigation efforts for imperiled fish populations. We assessed growth, movement, and apparent overwinter survival of individually tagged juvenile coho salmon Oncorhynchus kisutch in a coastal Oregon watershed from June 2002 to June 2003 and related growth and survival parameters to stream characteristics. Fall body size of juvenile coho salmon was a good predictor of smolt size and survival, but smolt size was also influenced by overwintering location. This was due to strong spatial patterns in winter growth rates associated with residency and movement into a small intermittent tributary. Though nearly dry in midsummer, this stream supported high densities of spawning coho salmon in the fall, and juveniles rearing there exhibited relatively high growth rates and emigrated as larger smolts. Improved winter growth and survival of juvenile coho salmon utilizing tributary habitats underscore the importance of maintaining connectivity between seasonal habitats and providing a diversity of sheltering and foraging opportunities, particularly where main‐stem habitats have been simplified by human land uses.
Embryonic Stem Cell-Derived Neurons Form Functional Networks In Vitro
Authors: Ban Jelena , Bonifazi Paolo , Pinato Giulietta , Broccard Frederic D. , Studer Lorenz , Torre Vincent , Ruaro Maria Elisabetta
Published: November 2006

Embryonic stem (ES) cells provide a flexible and unlimited source for a variety of neuronal types. Because mature neurons establish neuronal networks very easily, we tested whether ES-derived neurons are capable of generating functional networks and whether these networks, generated in vitro, are capable of processing information. Single-cell electrophysiology with pharmacological antagonists demonstrated the presence of both excitatory and inhibitory synaptic connections. Extracellular recording with planar multielectrode arrays showed that spontaneous bursts of electrical activity are present in ES-derived networks with properties remarkably similar to those of hippocampal neurons. When stimulated with extracellular electrodes, ES-derived neurons fired action potentials, and the evoked electrical activity spread throughout the culture. A statistical analysis indicated that ES-derived networks discriminated between stimuli of different intensity at a single trial level, a key feature for an efficient information processing. Thus, ES-derived neurons provide a novel in vitro strategy to create functional networks with defined computational properties.
Rehabilitation of a sea wall in Mandal, Norway
Authors: Lothe A. E. , Birkeland T.
Published: November 2006

Gismerøy is a small island close to the city of Mandal on the south coast of Norway. The site has been selected for industrial development. An industrial estate was developed close to the sea with no particular attention to protection. The landfill and a factory building were nearly completely destroyed by two consecutive storms in May and October 2000. After the second storm, detailed studies and model tests were carried out to specify a reliable and safe design. The new design was based on a berm breakwater principle, but with some important local adaptations. It was also discovered that the wave runup due to a rock formation was so great that the rock would have to be removed. This work was especially challenging because there was a strong wish to preserve the infrastructure and investments that had already been laid down, and because the areas adjacent to the site are designated as natural recreational areas.
Evaporation from land surface in high latitude areas: a review of methods and study results
Authors: Shutov Vladimir , Gieck Robert E. , Hinzman Larry D. , Kane Douglas L.
Published: November 2006

Evaporation (ET) from land surfaces in high latitudes is examined on a circumpolar perspective based upon the study results obtained in various environments, from boreal forest (taiga) to the high Arctic desert. Direct and indirect methods of evaporation measurement are reviewed, as well as numerous computational techniques. We have focused upon methods conveniently adopted for calculating evaporation when detailed information on meteorological conditions within the surface boundary layer is not available. These methods range from complicated ones, such as eddy correlation, energy balance and Penman equations, to empirical relationships between ET and incoming solar radiation. Great attention was paid to the principles of each method, especially those developed in Russia as they differ from most of the methods utilized internationally. For example, the Budyko–Zubenok empirical scheme is based upon the principle of potential evaporation, which is affected by soil moisture (SM). This relationship between ET and SM, expressed in terms of the field capacity, has been found to be non-linear; a complication that is not typically accounted for in traditional approaches. This paper also contains a brief review of a number of evaporation case studies including Alaska (USA), north-western Russia and Siberian taiga, Yukon basin (Canada), mountainous forest on Hokkaido Island (Japan), Canadian Arctic and glacierized basins of Greenland.
Sediment transport to the Arctic Ocean and adjoining cold oceans*
Authors: Hasholt Bent , Bobrovitskaya Nelly , Bogen Jim , McNamara James , Mernild Sebastian H. , Milburn David , Walling Desmond E.
Published: November 2006

This paper reviews and synthesises available information on sediment transport to the Arctic Ocean and adjoining seas with open contact to the Atlantic and Pacific Oceans. Special emphasis is placed on calculation and estimation of the sediment flux from the mostly ungauged high Arctic areas on the American continent, in Greenland, and on islands in the Arctic Ocean, and from Russia. In the absence of reliable information on bedload fluxes for most rivers, attention is directed primarily to suspended sediment loads. By combining available monitoring data and estimates for ungauged areas, the total sediment transport to the Arctic Ocean is estimated to be 324–884 × 106 t yr−1. Of this total, a maximum of about 56% can be considered as monitored, while the rest is based on different types of estimate. It is clearly demonstrated that the monitoring network in the high Arctic is inadequate and that there is a lack of knowledge concerning the proportion of the load that actually reaches the sea, as well as bedload.
Evaluation of Occupational Therapy School-Based Consultation Service for Students with Fine Motor Difficulties
Authors: Wehrmann Susan , Chiu Teresa , Reid Denise , Sinclair Gerry
Published: November 2006

Purpose. This paper describes a 2-year study that addressed the perceived occupational performance changes among students with fine motor difficulties receiving occupational therapy school-based consultation (OTSBC) services. Method. The sample included 52 stakeholders of students with fine motor difficulties who received occupational therapy services. Six exploratory focus groups and one participatory and action-based focus group were conducted with parents, teachers, occupational therapists, and Community Care Access Centre case managers. Results. Results supported the benefits of OTSBC. Key concerns identified were the wait for service, confusion about service expectations, inadequate communication among stakeholders, school board issues, and constraints in the health care system. Recommendations identified were to train teachers, provide early intervention, address service delivery issues related to health and education systems, and promote awareness of occupational therapy service and its effectiveness. Practice Implications. Occupational therapists working with students with fine motor difficulties could consider providing formal education programs for teachers, promoting early intervention of fine motor problems, and communicating to stakeholders regarding the expectations and effectiveness of OTSBC.
Capecitabine for the Oral Treatment of Metastatic Breast Cancer
Authors: Cortés-Funes Hernán
Published: November 2006

Women with metastatic breast cancer require tailored chemotherapy that improves outcomes without compromising quality of life. Capecitabine, a pro-drug of 5-fluorouracil, is an oral fluoropyrimidine carbamate that is sequentially activated in a three-step process. This results in the preferential production of 5-fluorouracil in tumors rather than in normal surrounding tissue, improving the tolerability and efficacy of 5-fluorouracil. In combination with docetaxel, capecitabine is the first agent that has shown superior activity to single-agent docetaxel, and it is a particularly appropriate option for younger, fitter patients with rapidly progressing disease and/or visceral metastases. However, for older patients and those with comorbidities and/or after progression to taxanes, single-agent capecitabine may be the best option. Its role in earlier disease stages (adjuvant therapy) is being investigated.
What Information Should be Given to Women Invited for Mammographic Screening for Breast Cancer?
Authors: Duffy Stephen W , Tabar Laszlo , Chen Tony HH , Yen Amy MF , Dean Peter B , Smith Robert A
Published: November 2006

Mammography is the only proven frontline screening method for breast cancer. Following the demonstration of a reduction in breast cancer mortality with mammography, population mammographic screening services have been instituted, and there has been discussion in the medical literature of how to convey the pros and cons of screening to invited women. Much of the discussion has focused on the negative aspects of screening, such as false-positive and negative screens, overdiagnosis and anxiety. Also, some commentators have advocated rather cumbersome amounts of quantitative information. In this article we review the original evidence on the positive and negative aspects of screening, and show that the latter may have been exaggerated in the past. We suggest a few simple and clear points that should be made to the invited women, summarizing the positive and negative aspects without a mass of confusing statistics.
Pregnancy after the Age of 40
Authors: Kausar Sameena , Bewley Susan
Published: November 2006

Many regard childbearing as the most life-changing and perhaps the most desirable aspect of a women's life. Correspondingly, reduced fertility has a significant negative impact on a woman and her family. To this end, gynecologists work to preserve and restore fertility. Recently, however, in developed countries, more women are becoming pregnant later in life, whether by choice or circumstance. This could be a direct result of the increasing availability of both effective contraception and infertility treatment, but perhaps more pertinently the changing lifestyles and career choices that modern women make. This article offers a perspective on pregnancy after the age of 40, the impact on maternal and fetal outcomes, the social implications and the importance of prenatal counseling.
Chemoprevention of Breast Cancer
Authors: Cuzick Jack
Published: November 2006

Trials with tamoxifen have clearly shown that estrogen receptor-positive breast cancer risk can be reduced at a late stage in the natural history with prophylactic agents. Approximately half of the cases were prevented. The current challenge is to achieve this or better efficacy, and reduce side effects. A recent trial found that the selective estrogen receptor modulator raloxifene has similar efficacy to tamoxifen but fewer side effects. Long-term Phase III trials are currently underway studying two aromatase inhibitors. Results from other studies suggest that these agents have a better side-effect profile and may prevent 70–80% of receptor-positive breast cancers. New agents are needed for receptor-negative breast cancer and several possibilities are currently under investigation.
The Use of Antirheumatic Disease Drugs during Pregnancy
Authors: Hussain S M , Parke Ann L
Published: November 2006

Many connective tissue diseases occur more frequently in women, the female:male ratio for systemic lupus erythematosus is 9:1 and for rheumatoid arthritis is 3:1. These diseases frequently afflict young women, many of whom wish to become mothers. While some diseases (for example, rheumatoid arthritis) generally improve during pregnancy, other immune-mediated diseases may be exacerbated by pregnancy, putting both the mother and fetus at risk and making control of maternal disease a top priority. This review examines the current literature pertaining to the use of antirheumatic drugs during pregnancy, including aspirin and nonsteroidal anti-inflammatory drugs, corticosteroids, anticoagulants, the 4-aminoquinoline antimalarial drugs, immunomodulating drugs, antimetabolite drugs and other agents including sulfasazine and anticytokine therapy.
Gonadotropin-Releasing Hormone Antagonist in in Vitro Fertilization Superovulation
Authors: Seng Shay Way , Ong Kee Jiet , Ledger W L
Published: November 2006

The use of gonadotropin-releasing hormone (GnRH) antagonists in in vitro fertilization superovulation remains controversial. The GnRH agonist ‘long protocol’ has been seen as the gold standard for many years. Comparisons and meta-analyses of the efficacy of GnRH antagonists and agonists have been largely inconclusive, with the dataset being contaminated with outdated reports of poorer efficacy with GnRH antagonists, which have stemmed from studies of their use as a second-line drug in older women and women who were poor responders. This work cannot reflect the actual clinical effectiveness of GnRH antagonist and must be interpreted with care. The major advantages of GnRH antagonists use in superovulation include a gentler and more patient-friendly stimulation cycle with less hypoestrogenic side effects, with the potential to lower the risk of ovarian hyperstimulation and enhanced embryo growth. Our current clinical experience with GnRH antagonists in in vitro fertilization is limited, although there are a growing number of in vitro fertilization centers embracing this new technology. There is a clear need for a modern, suitably powered clinical trial to demonstrate the place of GnRH antagonist-based superovulation protocols and in subgroups of patients, such as polycystic ovary syndrome or poor responders.
Applying the Death Penalty to Crimes of Genocide
Authors: Ohlin Jens David
Published: November 2006

After the Rwandan genocide of 1994, the United Nations Security Council moved quickly to establish an international tribunal to indict the architects of the slaughter. Whether motivated by a sincere desire for international justice or a self-serving desire to assuage international guilt for the lack of significant military intervention, one thing is clear: the Security Council began a program that, when coupled with its establishment of the International Criminal Tribunal for the Former Yugoslavia, represented the most significant return to international criminal justice since the Allied prosecution of German war criminals at Nuremberg. But so much had changed since 1951. Whereas the Nuremberg Tribunal imposed death sentences for the most culpable instigators of the Holocaust, there would be no death sentences for the architects of the Hutu genocidal campaign against the Tutsi. Over the course of forty years, there was a sea shift in attitudes about the legality of the death penalty. When the Allies announced their decision to apply the death penalty at Nuremberg, few objected or suggested that executions would violate international human rights law. Indeed, Churchill was initially suspicious of the plan for a war crimes tribunal, having assumed that what remained of the Nazi leadership would simply be executed on the battlefield. As the proceedings unfolded, there were isolated calls for leniency and clemency, and even complaints of victors’ justice, but certainly no suggestion that executions violated international law as such.
Feminism and Its (DIS)contents: Criminalizing Wartime Rape in Bosnia and Herzegovina
Authors: Engle Karen
Published: November 2006

Today many feminists seem relatively content with the treatment of rape and other sexual violence against women under international criminal law. In the context of the conflict in Bosnia and Herzegovina in the early 1990s, feminist activists made a concerted effort to affect the statute establishing the International Criminal Tribunal for the Former Yugoslavia (ICTY), the rules of evidence under which rape and other crimes of sexual violence would be prosecuted, the form the indictments of crimes of sexual violence would take, and the strategies and legal argumentation made at both the trial and the appellate levels. For the most part, much to the surprise of many feminists themselves, they have been successful. As Joanne Barkan comments: “From the start, most observers considered the [ICTY] a sop to human rights and feminist activists who wanted intervention.... Almost no one expected it to succeed. And yet to some extent, at least for women, it did.”
Can Political Science Develop Alternative Careers for its Graduates?
Authors: Hargrove Erwin C.
Published: November 2006

The committee has been charged by the Council with exploring possibilities for employment of political scientists outside of universities in the present and future. This assignment is prompted by some historic facts. We can expect to see a 25 percent decline in the number of undergraduate students in the next decade. This means fewer faculty members. If graduate programs continue at their present size during that period, one-half of the Ph.D.s in political science will be employed outside of academic life by the late 1980s.

The discipline could encourage these trends by closing down many graduate programs, keeping the field small and academic, and focusing increasingly on undergraduate teaching. This may happen anyway as prospective graduate students disappear.

As an alternative the discipline could develop new kinds of graduate education which would prepare M.A. and Ph.D. students for professional careers outside academic life.