bluuebunny/crossref_metadata_2025 huggingface dataset:
Sample Size Implications when Biases are Modelled Rather than Ignored
Authors: Gustafson Paul
Published: July 2006

Realistic statistical modelling of observational data often suggests a statistical model which is not fully identified, owing to potential biases that are not under the control of study investigators. Bayesian inference can be implemented with such a model, ideally with the most precise prior knowledge that can be ascertained. However, as a consequence of the non-identifiability, inference cannot be made arbitrarily accurate by choosing the sample size to be sufficiently large. In turn, this has consequences for sample size determination. The paper presents a sample size criterion that is based on a quantification of how much Bayesian learning can arise in a given non-identified model. A global perspective is adopted, whereby choosing larger sample sizes for some studies necessarily implies that some other potentially worthwhile studies cannot be undertaken. This suggests that smaller sample sizes should be selected with non-identified models, as larger sample sizes constitute a squandering of resources in making estimator variances very small compared with their biases. Particularly, consider two investigators planning the same study, one of whom admits to the potential biases at hand and consequently uses a non-identified model, whereas the other pretends that there are no biases, leading to an identified but less realistic model. It is seen that the former investigator always selects a smaller sample size than the latter, with the difference being quite marked in some illustrative cases.
Second-Order Residual Analysis of Spatiotemporal Point Processes and Applications in Model Evaluation
Authors: Zhuang Jiancang
Published: July 2006

The paper gives first-order residual analysis for spatiotemporal point processes that is similar to the residual analysis that has been developed by Baddeley and co-workers for spatial point processes and also proposes principles for second-order residual analysis based on the viewpoint of martingales. Examples are given for both first- and second-order residuals. In particular, residual analysis can be used as a powerful tool in model improvement. Taking a spatiotemporal epidemic-type aftershock sequence model for earthquake occurrences as the base-line model, second-order residual analysis can be useful for identifying many features of the data that are not implied in the base-line model, providing us with clues about how to formulate better models.
Minimum Volume Confidence Regions for a Multivariate Normal Mean Vector
Authors: Efron Bradley
Published: July 2006

Since Stein's original proposal in 1962, a series of papers have constructed confidence regions of smaller volume than the standard spheres for the mean vector of a multivariate normal distribution. A general approach to this problem is developed here and used to calculate a lower bound on the attainable volume. Bayes and fiducial methods are involved in the calculation. Scheffé-type problems are used to show that low volume by itself does not guarantee favourable inferential properties.
Assessing the Finite Dimensionality of Functional Data
Authors: Hall Peter , Vial Céline
Published: July 2006

If a problem in functional data analysis is low dimensional then the methodology for its solution can often be reduced to relatively conventional techniques in multivariate analysis. Hence, there is intrinsic interest in assessing the finite dimensionality of functional data. We show that this problem has several unique features. From some viewpoints the problem is trivial, in the sense that continuously distributed functional data which are exactly finite dimensional are immediately recognizable as such, if the sample size is sufficiently large. However, in practice, functional data are almost always observed with noise, for example, resulting from rounding or experimental error. Then the problem is almost insolubly difficult. In such cases a part of the average noise variance is confounded with the true signal and is not identifiable. However, it is possible to define the unconfounded part of the noise variance. This represents the best possible lower bound to all potential values of average noise variance and is estimable in low noise settings. Moreover, bootstrap methods can be used to describe the reliability of estimates of unconfounded noise variance, under the assumption that the signal is finite dimensional. Motivated by these ideas, we suggest techniques for assessing the finiteness of dimensionality. In particular, we show how to construct a critical point V^q such that, if the distribution of our functional data has fewer than q−1 degrees of freedom, then we should be willing to assume that the average variance of the added noise is at least V^q. If this level seems too high then we must conclude that the dimension is at least q−1. We show that simpler, more conventional techniques, based on hypothesis testing, are generally not effective.
Correlograms for Non-Stationary Autoregressions
Authors: Nielsen Bent
Published: July 2006

Analysis of time series often involves correlograms and partial correlograms as graphical descriptions of temporal dependence. Two methods are available for computing these statistics: one based on autocorrelations and the other on scaled autocovariances. For a stationary time series the resulting plots are nearly identical. When it comes to time series exhibiting non-stationary features these methods can lead to very different results. This has two consequences: incorrect inferences can be drawn when confusing these concepts; better discrimination between stationary and non-stationarity is achieved when using autocorrelations instead of, or along with, the autocovariances which are commonly used in statistical software.
Modelling Beyond Regression Functions: An Application of Multimodal Regression to Speed–Flow Data
Authors: Einbeck Jochen , Tutz Gerhard
Published: July 2006

For speed–flow data, which are intensively discussed in transportation science, common nonparametric regression models of the type y = m(x)+noise turn out to be inadequate since simple functional models cannot capture the essential relationship between the predictor and response. Instead a more general setting is required, allowing for multifunctions rather than functions. The tool proposed is conditional modes estimation which, in the form of local modes, yields several branches that correspond to the local modes. A simple algorithm for computing the branches is derived. This is based on a conditional mean shift algorithm and is shown to work well in the application that is considered.
Analysis of Functional Status Transitions by Using a Semi-Markov Process Model in the Presence of Left-Censored Spells
Authors: Cai Liming , Schenker Nathaniel , Lubitz James
Published: July 2006

To analyse functional status transitions in the older population better, we fit a semi-Markov process model to data from the 1992–2002 Medicare Current Beneficiary Survey. We used an analogue of the stochastic EM algorithm to address the problem of left censoring of spells in longitudinal data. The iterative algorithm converged robustly under various initial values for the unobserved elapsed durations of spells in progress at base-line. Results on life expectancy and recovery from functional limitations based on the semi-Markov process model differ from those based on the traditional multistate life-table method. The proposed treatment of left-censored spells has the potential to expand the modelling capability that is available to researchers in fields where left censoring is a concern.
Spatial attention freezes during the attention blink
Authors: Dell'Acqua R. , Sessa P. , Jolicœur P. , Robitaille N.
Published: July 2006

A variant of the rapid serial visual presentation paradigm was used to display sequentially two lateral sequences of stimuli, one to the left and one to the right of fixation, embedding two pairs of target stimuli, T1 and T2. T1 was composed of a pair of alphanumeric characters, and subjects had either to ignore T1 or to encode T1 for a delayed response. T2 was a lateral square of a prespecified color. The square had a small gap in one side, and the task for this stimulus was to report which side had the gap. When subjects were required to ignore T1, the T2‐locked ERP produced a clear N2pc, that is, a greater negativity at electrode sites contralateral to the position occupied by T2. This N2pc was followed by a sustained posterior contralateral negativity (SPCN). When subjects were required to monitor T1 in addition to T2, both the N2pc and the SPCN components amplitude depended on the difficulty of the task associated with T1. If T1 was composed of digits that had to be encoded for a delayed same/different judgment, both the N2pc and the SPCN components were entirely suppressed. Although attenuated, such components were present when T1 was composed of a pair of symbols that subjects could disregard. The results suggest that a set of mechanisms subserving the allocation of attention in the spatial domain, resulting in the N2pc, suffer significant interference from concurrent cognitive operations required to encode information into visual short‐term memory.
A reasoning bias revealed by electrodermal activity
Authors: Carbonnell Laurence , Vidal Franck , Sequeira Henrique , Caverni Jean‐Paul
Published: July 2006

The sufficiency of behavioral data supporting reasoning biases was challenged. Our objective was to test if physiological data could significantly support reasoning biases. Experiment 1: When performing a rule discovery task with feedback, participants sytematically gave the same response. This was not compatible with norms referring to a formal logic system, but was insufficient to conclude there was a reasoning bias. Only the knowledge of participants' expectations of feedback would merit this conclusion. Experiment 2: Participants' expectations were indexed by electrodermal activity. The results showed that when participants displayed the behavioral bias, they considered their responses to be correct and hence committed an error of logic. However, this error of logic did not prevent them from solving the task. This argues for a theory according to which human reasoning uses more economical strategies than the simple application of formal logical rules.
Agentic extraversion modulates the cardiovascular effects of the dopamine D2 agonist bromocriptine
Authors: Wacker Jan , Stemmler Gerhard
Published: July 2006

A recent psychobiological theory postulates a dopaminergic basis for the agency facet of extraversion, leading to the prediction that this personality trait modulates the psychophysiological effects of dopaminergic drugs. A single dose of the dopamine D2 receptor agonist bromocriptine reduces blood pressure in healthy volunteers. However, it is currently unknown whether this hypotensive effect of bromocriptine is modulated by agentic extraversion. Therefore, we measured resting cardiovascular activation in groups of healthy male volunteers either high or low in agentic extraversion, either under bromocriptine (1.25 mg) or placebo. Focusing the analyses on activation components derived from 18 cardiovascular variables, we found that bromocriptine reduces alpha‐adrenergic activation in the sample as a whole, whereas the effects on beta‐adrenergic and cholinergic activation are modulated by agentic extraversion.
Molecules Involved in the Modulation of Rapid Cell Death in
Xanthomonas
Authors: Raju K. K. , Gautam Satyendra , Sharma Arun
Published: July 2006

In earlier studies from this laboratory,
Xanthomonas campestris
pv. glycines was found to exhibit a nutrition stress-related postexponential rapid cell death (RCD). The RCD was exhibited in protein-rich media but not in starch or other minimal media. This RCD in
X. campestris
pv. glycines was found to display features similar to those of the programmed cell death (PCD) of eukaryotes. Results of the present study showed that the observed RCD in this organism is both positively and negatively regulated by small molecules. The amino acids glycine and
l
-alanine as well as the D isomers of valine, methionine, and threonine were found to induce the synthesis of an active caspase-3-like protein that was associated with the onset of RCD. Addition of pyruvate and citrate to the culture medium induced both the synthesis of active caspase-3-like protein and RCD. Higher levels of intracellular accumulation of pyruvate and citrate were also observed under conditions favoring RCD. On the other hand, dextrin and maltose, the hydrolytic products of starch, inhibited the synthesis of the caspase-3-like protein. Addition of glucose and cyclic AMP (cAMP) to the RCD-favoring medium prevented RCD. Glucose, cAMP, caffeine (a known inhibitor of a phosphodiesterase that breaks down cAMP), and forskolin (from the herb
Coleus forskholii
, known to activate the enzyme adenylate cyclase that forms cAMP) inhibited the caspase enzyme activity in vivo and consequently the RCD process. The addition of glucose and other inhibitors of RCD enhanced intracellular cAMP accumulation. This is the first report demonstrating the involvement of small molecules in the regulation of nutrition stress-related stationary-phase rapid cell death in
X. campestris
pv. glycines, which is programmed.
Identification and Characterization of anAzotobacter vinelandiiType I Secretion System Responsible for Export of the AlgE-Type Mannuronan C-5-Epimerases
Authors: Gimmestad Martin , Steigedal Magnus , Ertesvåg Helga , Moreno Soledad , Christensen Bjørn Erik , Espín Guadalupe , Valla Svein
Published: July 2006

Alginate is a linear copolymer of β-d-mannuronic acid and its C-5-epimer, α-l-guluronic acid. During biosynthesis, the polymer is first made as mannuronan, and various fractions of the monomers are then epimerized to guluronic acid by mannuronan C-5-epimerases. TheAzotobacter vinelandiigenome encodes a family of seven extracellular such epimerases (AlgE1 to AlgE7) which display motifs characteristic for proteins secreted via a type I pathway. Putative ATPase-binding cassette regions from the genome draft sequence of theA. vinelandiiOP strain and experimentally verified type I transporters from other species were compared. This analysis led to the identification of one putativeA. vinelandiitype I system (eexDEF). The corresponding genes were individually disrupted inA. vinelandiistrain E, and Western blot analysis using polyclonal antibodies against all AlgE epimerases showed that these proteins were present in wild-type culture supernatants but absent from theeexmutant supernatants. Consistent with this, the wild-type strain and theeexmutants produced alginate with about 20% guluronic acid and almost pure mannuronan (≤2% guluronic acid), respectively. TheA. vinelandiiwild type is able to enter a particular desiccation-tolerant resting stage designated cyst. At this stage, the cells are surrounded by a rigid coat in which alginate is a major constituent. Such a coat was formed by wild-type cells in a particular growth medium but was missing in theeexmutants. These mutants were also found to be unable to survive desiccation. The reason for this is probably that continuous stretches of guluronic acid residues are needed for alginate gel formation to take place.
The MgtC Virulence Factor of
Salmonella enterica
Serovar Typhimurium Activates Na
+
,K
+
-ATPase
Authors: Günzel Dorothee , Kucharski Lisa M. , Kehres David G. , Romero Michael F. , Maguire Michael E.
Published: July 2006

The
mgtC
gene of
Salmonella enterica
serovar Typhimurium encodes a membrane protein of unknown function that is important for full virulence in the mouse. Since
mgtC
is part of an operon with
mgtB
which encodes a Mg
2+
-transporting P-type ATPase, MgtC was hypothesized to function in ion transport, possibly in Mg
2+
transport. Consequently, MgtC was expressed in
Xenopus laevis
oocytes, and its effect on ion transport was evaluated using ion selective electrodes. Oocytes expressing MgtC did not exhibit altered currents or membrane potentials in response to changes in extracellular H
+
, Mg
2+
, or Ca
2+
, thus ruling out a previously postulated function as a Mg
2+
/H
+
antiporter. However, addition of extracellular K
+
markedly hyperpolarized membrane potential instead of the expected depolarization. Addition of ouabain to block the oocyte Na
+
,K
+
-ATPase completely prevented hyperpolarization and restored the normal K
+
-induced depolarization response. These results suggested that the Na
+
,K
+
-ATPase was constitutively activated in the presence of MgtC resulting in a membrane potential largely dependent on Na
+
,K
+
-ATPase. Consistent with the involvement of Na
+
,K
+
-ATPase, oocytes expressing MgtC exhibited an increased rate of
86
Rb
+
uptake and had increased intracellular free [K
+
] and decreased free [Na
+
] and ATP. The free concentrations of Mg
2+
and Ca
2+
and cytosolic pH were unchanged, although the total intracellular Ca
2+
content was slightly elevated. These results suggest that the serovar Typhimurium MgtC protein may be involved in regulating membrane potential but does not directly transport Mg
2+
or another ion.
TheBacillus subtilisPrimosomal Protein DnaD Untwists Supercoiled DNA
Authors: Zhang Wenke , Allen Stephanie , Roberts Clive J. , Soultanas Panos
Published: July 2006

The essentialBacillus subtilisDnaD and DnaB proteins have been implicated in the initiation of DNA replication. Recently, DNA remodeling activities associated with both proteins were discovered that could provide a link between global or local nucleoid remodeling and initiation of replication. DnaD forms scaffolds and opens up supercoiled plasmids without nicking to form open circular complexes, while DnaB acts as a lateral compaction protein. Here we show that DnaD-mediated opening of supercoiled plasmids is accompanied by significant untwisting of DNA. The net result is the conversion of writhe (Wr) into negative twist (Tw), thus maintaining the linking number (Lk) constant. These changes in supercoiling will reduce the considerable energy required to open up closed circular plectonemic DNA and may be significant in the priming of DNA replication. By comparison, DnaB does not affect significantly the supercoiling of plasmids. Binding of the DnaD C-terminal domain (Cd) to DNA is not sufficient to convert Wr into negative Tw, implying that the formation of scaffolds is essential for duplex untwisting. Overall, our data suggest that the topological effects of the two proteins on supercoiled DNA are different; DnaD opens up, untwists and converts plectonemic DNA to a more paranemic form, whereas DnaB does not affect supercoiling significantly and condenses DNA only via its lateral compaction activity. The significance of these findings in the initiation of DNA replication is discussed.
DNA Supercoiling and the Lrp Protein Determine the Directionality of
fim
Switch DNA Inversion in
Escherichia coli
K-12
Authors: Kelly Arlene , Conway Colin , Ó Cróinín Tadhg , Smith Stephen G. J. , Dorman Charles J.
Published: July 2006

Site-specific recombinases of the integrase family usually require cofactors to impart directionality in the recombination reactions that they catalyze. The FimB integrase inverts the
Escherichia coli fim
switch (
fimS
) in the on-to-off and off-to-on directions with approximately equal efficiency. Inhibiting DNA gyrase with novobiocin caused inversion to become biased in the off-to-on direction. This directionality was not due to differential DNA topological distortion of
fimS
in the on and off phases by the activity of its resident P

fimA

promoter. Instead, the leucine-responsive regulatory (Lrp) protein was found to determine switching outcomes. Knocking out the
lrp
gene or abolishing Lrp binding sites 1 and 2 within
fimS
completely reversed the response of the switch to DNA relaxation. Inactivation of either Lrp site alone resulted in mild on-to-off bias, showing that they act together to influence the response of the switch to changes in DNA supercoiling. Thus, Lrp is not merely an architectural element organizing the
fim
invertasome, it collaborates with DNA supercoiling to determine the directionality of the DNA inversion event.
Diverse Flavonoids Stimulate NodD1 Binding tonodGene Promoters inSinorhizobium meliloti
Authors: Peck Melicent C. , Fisher Robert F. , Long Sharon R.
Published: July 2006

NodD1 is a member of the NodD family of LysR-type transcriptional regulators that mediates the expression of nodulation (nod) genes in the soil bacteriumSinorhizobium meliloti. Each species of rhizobia establishes a symbiosis with a limited set of leguminous plants. This host specificity results in part from a NodD-dependent upregulation ofnodgenes in response to a cocktail of flavonoids in the host plant's root exudates. To demonstrate that NodD is a key determinant of host specificity, we expressednodDgenes from different species of rhizobia in a strain ofS. melilotilacking endogenous NodD activity. We observed thatnodgene expression was initiated in response to distinct sets of flavonoid inducers depending on the source of NodD. To better understand the effects of flavonoids on NodD, we assayed the DNA binding activity ofS. melilotiNodD1 treated with the flavonoid inducer luteolin. In the presence of luteolin, NodD1 exhibited increased binding tonodgene promoters compared to binding in the absence of luteolin. Surprisingly, although they do not stimulatenodgene expression inS. meliloti, the flavonoids naringenin, eriodictyol, and daidzein also stimulated an increase in the DNA binding affinity of NodD1 tonodgene promoters. In vivo competition assays demonstrate that noninducing flavonoids act as competitive inhibitors of luteolin, suggesting that both inducing and noninducing flavonoids are able to directly bind to NodD1 and mediate conformational changes atnodgene promoters but that only luteolin is capable of promoting the downstream changes necessary fornodgene induction.
Crystal Structure of a Type III Pantothenate Kinase: Insight into the Mechanism of an Essential Coenzyme A Biosynthetic Enzyme Universally Distributed in Bacteria
Authors: Yang Kun , Eyobo Yvonne , Brand Leisl A. , Martynowski Dariusz , Tomchick Diana , Strauss Erick , Zhang Hong
Published: July 2006

Pantothenate kinase (PanK) catalyzes the first step in the five-step universal pathway of coenzyme A (CoA) biosynthesis, a key transformation that generally also regulates the intracellular concentration of CoA through feedback inhibition. A novel PanK protein encoded by the gene
coaX
was recently identified that is distinct from the previously characterized type I PanK (exemplified by the
Escherichia coli coaA
-encoded PanK protein) and type II eukaryotic PanKs and is not inhibited by CoA or its thioesters. This type III PanK, or PanK-III, is widely distributed in the bacterial kingdom and accounts for the only known PanK in many pathogenic species, such as
Helicobacter pylori
,
Bordetella pertussis
, and
Pseudomonas aeruginosa
. Here we report the first crystal structure of a type III PanK, the enzyme from
Thermotoga maritima
(PanK
Tm
), solved at 2.0-Å resolution. The structure of PanK
Tm
reveals that type III PanKs belong to the acetate and sugar kinase/heat shock protein 70/actin (ASKHA) protein superfamily and that they retain the highly conserved active site motifs common to all members of this superfamily. Comparative structural analysis of the PanK
Tm
active site configuration and mutagenesis of three highly conserved active site aspartates identify these residues as critical for PanK-III catalysis. Furthermore, the analysis also provides an explanation for the lack of CoA feedback inhibition by the enzyme. Since PanK-III adopts a different structural fold from that of the
E. coli
PanK—which is a member of the “P-loop kinase”superfamily—this finding represents yet another example of convergent evolution of the same biological function from a different protein ancestor.
Similarities and Differences in Interactions of the Activity-Enhancing Chemoreceptor Pentapeptide with the Two Enzymes of Adaptational Modification
Authors: Lai Wing-Cheung , Barnakova Ludmila A. , Barnakov Alexander N. , Hazelbauer Gerald L.
Published: July 2006

Sensory adaptation and chemotaxis by
Escherichia coli
require a specific pentapeptide at the chemoreceptor carboxyl terminus. This sequence binds the two enzymes of receptor adaptational modification, enhancing catalysis, but with different binding features and mechanisms. We investigated the relative importance of each pentapeptide side chain for the two enhancing interactions.
Outer Membrane Vesicle Production by
Escherichia coli
Is Independent of Membrane Instability
Authors: McBroom Amanda J. , Johnson Alexandra P. , Vemulapalli Sreekanth , Kuehn Meta J.
Published: July 2006

It has been long noted that gram-negative bacteria produce outer membrane vesicles, and recent data demonstrate that vesicles released by pathogenic strains can transmit virulence factors to host cells. However, the mechanism of vesicle release has remained undetermined. This genetic study addresses whether these structures are merely a result of membrane instability or are formed by a more directed process. To elucidate the regulatory mechanisms and physiological basis of vesiculation, we conducted a screen in
Escherichia coli
to identify gene disruptions that caused vesicle over- or underproduction. Only a few low-vesiculation mutants and no null mutants were recovered, suggesting that vesiculation may be a fundamental characteristic of gram-negative bacterial growth. Gene disruptions were identified that caused differences in vesicle production ranging from a 5-fold decrease to a 200-fold increase relative to wild-type levels. These disruptions included loci governing outer membrane components and peptidoglycan synthesis as well as the σ
E
cell envelope stress response. Mutations causing vesicle overproduction did not result in upregulation of the
ompC
gene encoding a major outer membrane protein. Detergent sensitivity, leakiness, and growth characteristics of the novel vesiculation mutant strains did not correlate with vesiculation levels, demonstrating that vesicle production is not predictive of envelope instability.
Addiction Toxin Fst Has Unique Effects on Chromosome Segregation and Cell Division inEnterococcus faecalisandBacillussubtilis
Authors: Patel S. , Weaver K. E.
Published: July 2006

The Fst toxin of theEnterococcus faecalispAD1-encodedparaddiction module functions intracellularly to kill plasmid-free segregants. Previous results had shown that Fst induction results in membrane permeabilization and cessation of macromolecular synthesis, but only after 45 min. Electron micrographs of toxin-induced cells showed no obvious membrane abnormalities but did reveal defects in nucleoid segregation and cell division, begging the question of which is the primary effect of Fst. To distinguish the possibilities, division septae and nucleoids were visualized simultaneously with fluorescent vancomycin and a variety of DNA stains. Results showed that division and segregation defects occurred in some cells within 15 min after induction. At these early time points, affected cells remained resistant to membrane-impermeant DNA stains, suggesting that loss of membrane integrity is a secondary effect caused by ongoing division and/or segregation defects. Fst-resistant mutants showed greater variability in cell length and formed multiple septal rings even in the absence of Fst. Fst induction was also toxic toBacillus subtilis. In this species, Fst induction caused only minor division abnormalities, but all cells showed a condensation of the nucleoid, suggesting that effects on the structure of the chromosomal DNA might be paramount.
A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell
Authors: Westermark Pål O. , Kotaleski Jeanette Hellgren , Björklund Anneli , Grill Valdemar , Lansner Anders
Published: July 2006

The pancreatic β-cells respond to an increased glycolytic flux by secreting insulin. The signal propagation goes via mitochondrial metabolism, which relays the signal to different routes. One route is an increased ATP production that, via ATP-sensitive K+(KATP) channels, modulates the cell membrane potential to allow calcium influx, which triggers insulin secretion. There is also at least one other “amplifying” route whose nature is debated; possible candidates are cytosolic NADPH production or malonyl-CoA production. We have used mathematical modeling to analyze this relay system. The model comprises the mitochondrial NADH shuttles and the mitochondrial metabolism. We found robust signaling toward ATP, malonyl-CoA, and NADPH production. The signal toward NADPH production was particularly strong. Furthermore, the model reproduced the experimental findings that blocking the NADH shuttles attenuates the signaling to ATP production while retaining the rate of glucose oxidation (Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Aizawa S, Kasai H, Yazaki Y, Kadowaki T. Science 283: 981–985, 1999) and provides an explanation for this apparent paradox. The model also predicts that the mitochondrial malate dehydrogenase reaction may proceed backward, toward malate production, if the activity of malic enzyme is sufficiently high. An increased fatty acid oxidation rate was found to attenuate the signaling strengths. This theoretical study has implications for our understanding of both the healthy and the diabetic β-cell.
Expression and interaction of two compound heterozygous distal renal tubular acidosis mutants of kidney anion exchanger 1 in epithelial cells
Authors: Cordat Emmanuelle , Reithmeier Reinhart A. F.
Published: July 2006

Kidney AE1 (kAE1) is a glycoprotein responsible for the electroneutral exchange of chloride for bicarbonate, promoting the reabsorption of bicarbonate into the blood by α-intercalated cells of the collecting tubule. Mutations occurring in the gene encoding kAE1 can induce defects in urinary acidification resulting in distal renal tubular acidosis (dRTA). We expressed two kAE1 dRTA mutants, A858D, a mild dominant mutation, and ΔV850, a recessive mutation, in epithelial Madin-Darby canine kidney (MDCK) cells. Individuals heterozygous with wild-type (WT) kAE1 either did not display any symptoms of dRTA (ΔV850/WT) or displayed a mild incomplete form of dRTA (A858D/WT), while compound heterozygotes (ΔV850/A858D) had dRTA. We found that the A858D mutant was slightly impaired in the endoplasmic reticulum (ER) exit but could target to the basolateral membrane of polarized MDCK cells. Despite an altered binding to an inhibitor affinity resin, anion transport assays showed that the A858D mutant was functional at the cell surface. The ΔV850 mutant showed altered binding to the affinity resin but was predominantly retained in the ER, resulting in undetectable AE1 expression at the basolateral membrane. When coexpressed in MDCK cells, the WT protein, and to a lesser extent the A858D mutant, enhanced the cell surface expression of the ΔV850 mutant. The ΔV850 mutant also affected the cell surface expression of the A858D mutant. Compound heterozygous (A858D/ΔV850) patients likely possess a decreased amount of functional anion exchangers at the basolateral membrane of their α-intercalated cells, resulting in impaired bicarbonate transport into the blood and defective acid transport into the urine.
Regulation of cation transport in the distal nephron by mechanical forces
Authors: Satlin Lisa M. , Carattino Marcelo D. , Liu Wen , Kleyman Thomas R.
Published: July 2006

Thiazide and loop diuretics induce renal K+secretion, often leading to renal K+wasting and hypokalemia. This phenomenon has been proposed to reflect an increase in delivery to and reabsorption of Na+by the distal nephron, with a resultant increase in the driving force for passive K+efflux across the apical membrane. Recent studies suggest that cellular mechanisms that lead to enhanced rates of Na+reabsorption as well as K+secretion in response to increases tubular flow rates are more complex. Increases in tubular flow rates directly enhance the activity of apical membrane Na+channels and indirectly activate a class of K+channels, referred to as maxi-K, that are functionally inactive under low flow states. This review addresses the role of biomechanical forces, generated by variations in urinary flow rate and tubular fluid volume, in the regulation of transepithelial Na+and K+transport in the distal nephron. The question of why the distal nephron has evolved to include a component of flow-dependent K+secretion is also addressed.
Early developmental expression of two insulins in zebrafish (Danio rerio)
Authors: Papasani Madhusudhan R. , Robison Barrie D. , Hardy Ronald W. , Hill Rodney A.
Published: July 2006

We have cloned a second insulin gene in zebrafish and studied temporal and spatial expression of two zebrafish insulin genes. Zebrafish insulin-a ( insa) and -b ( insb) mRNAs are derived from two different DNA contigs on chromosomes 5 and 14, respectively, representing two different insulin genes. Real-time PCR studies suggest that insa is a maternal and also a postzygotic transcript. insa was observed at 1 h postfertilization (hpf) and was rapidly degraded by 6 and 12 hpf but induced at 24 hpf (i.e., after pancreas formation). Expression levels at 24 hpf were ∼220-fold higher than at 6 hpf and were significantly different from earlier time points. At 72 hpf (at time of hatching), zebrafish insa mRNA levels tended to be higher than at 24 hpf and were ∼727-fold higher compared with 6 hpf. This further increase in insa expression may be one of the many rapid physiological changes associated with hatching. insb expression was observed from 1 hpf and was significantly decreased from 12 hpf onward. Its expression levels at 12 and 24 hpf were approximately twofold and sixfold lower, respectively, compared with expression at 6 hpf. insb expression levels at 48 hpf were significantly lower than at 24 hpf but not different from 72 hpf. Expression levels at 72 hpf were ∼61-fold lower than at 6 hpf. In situ hybridization studies showed insb expression in proliferating blastomeres at 3 and 4 hpf. At later time points, insb expression was restricted to the brain and pancreas (24 and 48 hpf). insa expression was observed in the pancreas at 24 and 48 hpf. Expression of insb in blastomeres and head suggests that insb could be acting as a pro-growth, survival, and neurotrophic factor during development. Pancreatic insa and insb may both be involved in regulation of glucose homeostasis as in mammals.
Murine weight loss exhibits significant genetic variation during dietary restriction
Authors: Rikke Brad A. , Battaglia Matthew E. , Allison David B. , Johnson Thomas E.
Published: July 2006

We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined 5 cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from ∼60 to ∼85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40–50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with the health benefits of DR, independently of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.
The mappings of degree 1
Authors: Krein Maria N.
Published: July 2006

The maps of the form ,
called 1‐degree maps, are introduced and investigated. For
noncommutative algebras and modules over them 1‐degree maps give
an analogy of linear maps and differentials. Under some conditions
on the algebra 𝒜, contractibility of the group of
1‐degree isomorphisms is proved for the module l2(𝒜).
It is shown that these conditions are fulfilled for the algebra of
linear maps of a finite‐dimensional linear space. The notion of
1‐degree map gives a possibility to define a nonlinear Fredholm
map of l2(𝒜) and a Fredholm manifold modelled by
l2(𝒜). 1‐degree maps are also applied to some
problems of Markov chains.
Reduced Expression of the Melanocortin-1 Receptor in Human Liver during Brain Death
Authors: Gatti Stefano , Colombo Gualtiero , Turcatti Flavia , Lonati Caterina , Sordi Andrea , Bonino Ferruccio , Lipton James M. , Catania Anna
Published: July 2006

Objective: There is evidence that brain death has detrimental effects on peripheral organs. Clinical and experimental studies on organ donors showed marked inflammation in tissue samples of livers and kidneys collected during brain death. The inflammatory reaction is characterized by release of cytokines and inflammatory cell infiltration. Because melanocortins and their receptors are significant modulators of inflammation, we hypothesized that downregulation of melanocortin receptors during brain death could contribute to enhance inflammation. Methods: Using real-time polymerase chain reaction (PCR) analysis, we determined expression of melanocortin receptors in liver biopsies obtained from brain-dead organ donors before cold ischemia and in normal liver tissue during resection of benign focal lesions of the liver. Tissue biopsies were also analyzed for expression of intercellular adhesion molecule-1 (ICAM-1), which has a central function in inflammatory cell migration. Results: Expression of melanocortin-1 receptor (MC1R) mRNA was markedly reduced in liver samples obtained from brain-dead organ donors compared to hepatic tissue collected during resection of benign focal lesions of the liver. Conversely, expression of the adhesion molecule ICAM-1 was significantly increased in livers of brain-dead organ donors. Conclusions: Disruption of the endogenous anti-inflammatory circuit based on MC1R could contribute to tissue damage during brain death.
Statin Use before By-Pass Surgery Decreases the Incidence and Shortens the Duration of Postoperative Atrial Fibrillation
Authors: Ozaydin Mehmet , Dogan Abdullah , Varol Ercan , Kapan Sahin , Tuzun Nurullah , Peker Oktay , Aslan Suleyman M. , Altinbas Ahmet , Ocal Ahmet , Ibrisim Erdogan
Published: July 2006

Backround: The aim of the present observational study is to search the incidence of postoperative atrial fibrillation (AF) in patients with or without preoperative statin treatment. Methods andResults: The population consisted of 362 consecutive patients (267 on and 95 not on statin). Diabetes mellitus was more frequent in statin group (p = 0.03). Other demographic and procedural variables were similar in the both groups (All p > 0.05). Postoperative AF was less frequent and its duration was shorter in statin group compared to non-statin group (p = 0.03 and 0.0001, respectively). The Kaplan-Meier analysis showed the protective effect of statins against the risk of developing AF (p = 0.01). Conclusion: Statin treatment before the by-pass surgery decreases the incidence and shortens the duration of postoperative AF.
Warfarin-related outcomes in patients with antiphospholipid antibody syndrome managed in an anticoagulation clinic
Authors: Downing Jennifer , Blackburn Juan , Nutescu Edith , Wittkowsky Ann
Published: July 2006

Patients with antiphospholipid antibody syndrome (APA) are at elevated risk of venous and arterial thromboembolic complications. Oral anticoagulation with warfarin is recommended for secondary prevention of thromboembolism, but warfarin-related outcomes have not been systematically investigated when warfarin therapy is managed by a dedicated anticoagulation clinic.The objectives of the study were to evaluate warfarin-related monitoring outcomes, clinical endpoints and the use of healthcare resources as a result of warfarin-related complications in patients with APA compared to a group of patients without APA, all of whom were managed in an anticoagulation clinic setting. A retrospective observational cohort design was used to investigate patients with and without APA, all of whom had a history of venous or arterial thromboembolism, and were matched for age, gender and indication for oral anticoagulation. Thirty-six APA patients taking warfarin were compared to a matched cohort of 36 patients without APA. Monitoring outcomes (time in therapeutic range, clinic visits per year, frequency of warfarin dosing adjustments, reasons for out-of-range INRs) were similar between groups, as was the frequency of major bleeding complications (3.2%/pt-yr vs. 3.1%/pt-yr). However, recurrent thromboembolic events (9.6%/pt-yr vs 0) occurred more frequently in APA patients. APA patients required more emergency room visits (6.4%/pt-yr vs. 1.6%/pt-yr) and hospital admissions (14.4%/pt-yr vs.3.0%/pt-yr) to manage complications of warfarin therapy. In conclusion, despite similar monitoring outcomes obtained in a dedicated anticoagulation clinic setting, adverse clinical outcomes are significantly more frequent in patients with APA syndrome than in those without APA, and require more frequent use of healthcare resources.
Ovarian vein thrombosis: Incidence of recurrent venous thromboembolism and survival
Authors: Wysokinska Ewa , Hodge David , McBane Robert
Published: July 2006

For patients with ovarian vein thrombosis (OVT), neither the rate of recurrence nor the expected survival are well established. Clarification of these natural history data would aid in defining the optimal management. We studied all female patients with OVT seen at the Mayo Clinic between 1990 and 2006. Survival, recurrent venous thrombosis rates, and prothrombotic factors were compared to a randomly selected group of 114 female patients with lower extremity venous thrombosis (DVT). Patients with OVT (n=35; mean age 44.8 ± 17.9 years) were significantly more likely to be under hormonal stimulation (48%), have an underlying malignancy (34%), experienced recent pelvic infection (23%) or undergone recent surgery (20%), compared to DVT patients. Duringa mean follow-up period of 34.6 ± 44.3 months, three patients suffered three recurrent venous thrombi (event rate: three per 100 patient years of follow-up).This recurrence rate was comparable to patients with lower extremity DVT (2.2 per 100 patient years). Recurrent thrombosis involved the contralateral ovarian vein, left renal vein, and inferior vena cava. The five-year mortality rate for OVT patients was 43% compared to 20% for DVT patients (p=0.08). All OVT deaths were cancer related. Survival was greater in OVT patients without cancer compared to those with active cancer (p<0.0001). In conclusion, venous thromboembolism recurrence rates are low and comparable to lower extremity DVT. Therefore general treatment guidelines for lower extremity DVT may be applicable. Poor survival rates in OVT are principally governed by the presence of malignancy.
Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism
Authors: Marchiori Antonio , Noto Alfonso , Rossi Vincenza , Daniele Filomena , Santoro Caterina , Ricchio Roberto , De Lorenzo Roberto , Umbaca Rossella , Prandoni Paolo , Bova Carlo
Published: July 2006

Recent data have showna higher incidence of arterial events in patients with venous thromboembolism (VTE) of unknown origin than in those with the secondary form of disease. Whether patients with idiopathic VTE have a higher risk of subsequent arterial events than the general population is unknown. The aim was to evaluate the rates of subsequent arterial events in patients with idiopathic VTE and control subjects. In a retrospective cohort study we compared the rates of subsequent arterial events (i.e. acute myocardial infarction, ischemic stroke and peripheral arterial disease) in 151 consecutive patients with objectively confirmed spontaneousVTE and 151 control subjects randomly selected from the database of two family physicians. We collected information about cardiovascular risk-factors (hypertension, hypercholesterolemia, diabetes, obesity and smoke) at the time of VTE episode, or corresponding date for the controls, and considered the follow-up from this time. Patients and controls who had suffered from arterial events before the index date were excluded. During a mean follow-up of 43.1 (± 21.7) months there were 16 arterial events in theVTE patients and six in the control group (HR, 2.84; 95% CI, 1.11 to 7.27; p= 0.03).The difference remained significant after adjusting for age and other cardiovascular risk factors (HR 2.86; 95% CI, 1.07 to 7.62).Overall mortality was also higher in theVTE patients (12 vs.4 deaths). In conclusion, arterial events are more common in patients with previous idiopathic VTE than in the general population. These findings may have practical implications.
Ex vivo evaluation of anti-GPVI antibody in Cynomolgus monkeys: Dissociation between anti-platelet aggregatory effect and bleeding time
Authors: Matsumoto Yutaka , Takizawa Hisao , Nakama Kazuhiro , Gong Xiaoqi , Yamada Yoshihisa , Tandon Narendra , Kambayashi Junichi
Published: July 2006

Recent progress in the understanding of thrombus formation has suggested an important role of glycoprotein (GP)VI. In contrast to its pivotal role in collagen-induced platelet activation, it has been suggested that its blockade does not induce massive bleeding tendency. To demonstrate the dissociation between inhibitory effect on platelet aggregation and bleeding by GPVI blockade, we examined the effects of Fab fragment of OM2, an anti-human GPVI monoclonal antibody on ex vivo collagen-induced platelet aggregation and skin bleeding time after intravenous injection in cynomolgus monkeys. In a dose-escalation study, OM2 potently (>80%) inhibited collagen-induced platelet aggregation at the cumulative dose of 0. 2 mg/kg with a slight prolongation of bleeding time (1. 3 times baseline value). Furthermore, at 18. 8 mg/kg, the highest dose tested, prolongation of bleeding time was still mild (1. 9 times). In contrast, abciximab, Fab fragment of anti-GPIIb/IIIa antibody prolonged bleeding time by 5. 0 times at 0. 35 mg/kg, the lowest effective dose on platelet aggregation. Ina pharmacodynamic study,a bolus injection of OM2 at 0. 4 mg/kg produced potent inhibition of collagen-induced aggregation up to six hours after injection, showing longer half-life than that of abciximab. The injection of OM2 Fab did not induce thrombocytopenia and GPVI depletion in monkeys. These results suggest that blockade of GPVI by antibody can exerta potent inhibitory effect on collagen-induced platelet aggregation with a milder prolongation of bleeding time than blockade of GPIIb/IIIa. This study indicates that OM2 has the potential to be developed as a new class of therapeutic tool.
African Proverbs as a Medium of Fostering Intergenerational Relationships and Communication in the Niger Delta, Nigeria
Authors: Oduaran Akpovire , Oduaran Choja
Published: July 2006

This brief paper examines, from the point of view of ethnography, how the African proverbs selected from the Niger Delta of Nigeria have been used in fostering intergenerational relationships discourse in a globalizing world. This discussion adopts the ethnographic approach in exploring the meaning and functions aims, structures and the delivery modes of African proverbs used in intergenerational relationships as our peoples struggle with the threat to the erosion of some of the major positive artefacts in our culture. It concludes by synthesizing contemporary challenges seemingly minimizing the overall use and impacts of African proverbs in intergenerational relationships, and suggesting the possible implications of the discussion for networking regionally and globally.