bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Novel Mycobacterial 3-Hydroxyacyl-Thioester Dehydratase, HtdZ (Rv0130), by Functional Complementation in Yeast
Authors: Gurvitz Aner , Hiltunen J. Kalervo , Kastaniotis Alexander J.
Published: March 2008

We report on the identification of
Mycobacterium tuberculosis
HtdZ (Rv0130), representing a novel 3-hydroxyacyl-thioester dehydratase. HtdZ was picked up by the functional complementation of
Saccharomyces cerevisiae htd2
Δ cells lacking the dehydratase of mitochondrial type II fatty acid synthase. Mutant cells expressing HtdZ contained dehydratase activity, recovered their respiratory ability, and partially restored de novo lipoic acid synthesis.
Dihydrolipoamide Dehydrogenase Mutation Alters the NADH Sensitivity of Pyruvate Dehydrogenase Complex of
Escherichia coli
K-12
Authors: Kim Youngnyun , Ingram L. O. , Shanmugam K. T.
Published: March 2008

Under anaerobic growth conditions, an active pyruvate dehydrogenase (PDH) is expected to create a redox imbalance in wild-type
Escherichia coli
due to increased production of NADH (>2 NADH molecules/glucose molecule) that could lead to growth inhibition. However, the additional NADH produced by PDH can be used for conversion of acetyl coenzyme A into reduced fermentation products, like alcohols, during metabolic engineering of the bacterium.
E. coli
mutants that produced ethanol as the main fermentation product were recently isolated as derivatives of an
ldhA pflB
double mutant. In all six mutants tested, the mutation was in the
lpd
gene encoding dihydrolipoamide dehydrogenase (LPD), a component of PDH. Three of the LPD mutants carried an H322Y mutation (
lpd102
), while the other mutants carried an E354K mutation (
lpd101
). Genetic and physiological analysis revealed that the mutation in either allele supported anaerobic growth and homoethanol fermentation in an
ldhA pflB
double mutant. Enzyme kinetic studies revealed that the LPD(E354K) enzyme was significantly less sensitive to NADH inhibition than the native LPD. This reduced NADH sensitivity of the mutated LPD was translated into lower sensitivity of the appropriate PDH complex to NADH inhibition. The mutated forms of the PDH had a 10-fold-higher

K
i

for NADH than the native PDH. The lower sensitivity of PDH to NADH inhibition apparently increased PDH activity in anaerobic
E. coli
cultures and created the new ethanologenic fermentation pathway in this bacterium. Analogous mutations in the LPD of other bacteria may also significantly influence the growth and physiology of the organisms in a similar fashion.
Defining the Growth Conditions and Promoter-Proximal DNA Sequences Required for Activation of Gene Expression by CreBC in
Escherichia coli
Authors: Cariss S. James L. , Tayler Amy E. , Avison Matthew B.
Published: March 2008

CreBC is a two-component system that controls the expression of a number of genes in
Escherichia coli
(called the cre regulon) that encode diverse functions, including intermediary metabolic enzymes. Using a reporter construct, we have shown that cre regulon gene expression is activated during growth in minimal media when glycolytic carbon sources are being fermented. It also is activated during aerobic growth when fermentation products are being used as carbon sources. CreB and CreC are essential for the activation of cre regulon gene expression, but CreA and CreD, encoded as part of the
creABCD
gene cluster, are not. CreB binds to a TTCACnnnnnnTTCAC direct repeat (the cre tag) in vitro, and this sequence, which is associated with cre regulon gene promoters, is required for the control of gene expression in vivo. These observations support the hypothesis that CreBC is a functional two-component system involved in the metabolic control of transcription in
E. coli
and confirm that CreB is a DNA binding transcriptional regulator.
A NovelStaphylococcus aureusBiofilm Phenotype Mediated by the Fibronectin-Binding Proteins, FnBPA and FnBPB
Authors: O'Neill Eoghan , Pozzi Clarissa , Houston Patrick , Humphreys Hilary , Robinson D. Ashley , Loughman Anthony , Foster Timothy J. , O'Gara James P.
Published: March 2008

Device-associated infections involving biofilm remain a persistent clinical problem. We recently reported that four methicillin-resistantStaphylococcus aureus(MRSA) strains formed biofilm independently of theicaADBC-encoded exopolysaccharide. Here, we report that MRSA biofilm development was promoted under mildly acidic growth conditions triggered by the addition of glucose to the growth medium. Loss of sortase, which anchors LPXTG-containing proteins to peptidoglycan, reduced the MRSA biofilm phenotype. Furthermore introduction of mutations infnbAandfnbB, which encode the LPXTG-anchored multifunctional fibrinogen and fibronectin-binding proteins, FnBPA and FnBPB, reduced biofilm formation by several MRSA strains. However, these mutations had no effect on biofilm formation by methicillin-sensitiveS. aureusstrains. FnBP-promoted biofilm occurred at the level of intercellular accumulation and not primary attachment. Mutation offnbAorfnbBalone did not substantially affect biofilm, and expression of either gene alone from a complementing plasmid infnbA fnbBmutants restored biofilm formation. FnBP-promoted biofilm was dependent on the integrity of SarA but not through effects onfnbAorfnbBtranscription. Using plasmid constructs lacking regions of FnBPA to complement anfnbABmutant revealed that the A domain alone and not the domain required for fibronectin binding could promote biofilm. Additionally, an A-domain N304A substitution that abolished fibrinogen binding did not affect biofilm. These data identify a novelS. aureusbiofilm phenotype promoted by FnBPA and FnBPB which is apparently independent of the known ligand-binding activities of these multifunctional surface proteins.
Transcriptional Analysis and Functional Characterization of a Gene Pair Encoding Iron-Regulated Xenocin and Immunity Proteins of
Xenorhabdus nematophila
Authors: Singh Jitendra , Banerjee Nirupama
Published: March 2008

We describe a two-gene cluster encoding a bacteriocin, xenocin, and the cognate immunity protein in the insect-pathogenic bacterium
Xenorhabdus nematophila
, which infects and kills larval stages of the common crop pest
Helicoverpa armigera
. The two genes,
xcinA
and
ximB
, are present in the genome as a single transcriptional unit, which is regulated under SOS conditions. The stress-inducible promoter was activated by mitomycin C, glucose, and Fe
3+
depletion and at an elevated temperature when it was tested in
Escherichia coli
cells. Expression of the xenocin protein alone in
E. coli
inhibited the growth of this organism. The growth inhibition was abolished when the immunity protein was also present. A recombinant xenocin-immunity protein complex inhibited the growth of
E. coli
indicator cells when it was added exogenously to a growing culture. Xenocin is an endoribonuclease with an enzymatically active C-terminal domain. Six resident bacterial species (i.e.,
Bacillus
,
Enterobacter
,
Enterococcus
,
Citrobacter
,
Serratia
, and
Stenotrophomonas
species) from the
H. armigera
gut exhibited sensitivity to recombinant xenocin when the organisms were grown under iron-depleted conditions and at a high temperature. Xenocin also inhibited the growth of two
Xenorhabdus
isolates. This study demonstrates that Fe
3+
depletion acts as a common cue for synthesis of xenocin by
X. nematophila
and sensitization of the target strains to the bacteriocin.
Cloning, Solubilization, and Characterization of Squalene Synthase from
Thermosynechococcus elongatus
BP-1
Authors: Lee Sungwon , Poulter C. Dale
Published: March 2008

Squalene synthase (SQS) is a bifunctional enzyme that catalyzes the condensation of two molecules of farnesyl diphosphate (FPP) to give presqualene diphosphate (PSPP) and the subsequent rearrangement of PSPP to squalene. These reactions constitute the first pathway-specific steps in hopane biosynthesis in
Bacteria
and sterol biosynthesis in
Eukarya
. The genes encoding SQS were isolated from the hopane-producing bacteria
Thermosynechococcus elongatus
BP-1,
Bradyrhizobium japonicum
, and
Zymomonas mobilis
and cloned into an
Escherichia coli
expression system. The expressed proteins with a His
6
tag were found exclusively in inclusion bodies when no additives were used in the buffer. After extensive optimization, soluble recombinant
T. elongatus
BP-1 SQS was obtained when cells were disrupted and purified in buffers containing glycerol. The recombinant
B. japonicum
and
Z. mobilis
SQSs could not be solubilized under any of the expression and purification conditions used. Purified
T. elongatus
His
6
-SQS gave a single band at 42 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and molecular ion at
m/z
41886 by electrospray mass spectrometry. Incubation with FPP and NADPH gave squalene as the sole product. Incubation of the enzyme with [
14
C]FPP in the absence of NADPH gave PSPP. The enzyme requires Mg
2+
for activity, has an optimum pH of 7.6, and is strongly stimulated by detergent. Under optimal conditions, the
K

m

of FPP is 0.97 ± 0.10 μM and the
k
cat
is 1.74 ± 0.04 s
−1
. Zaragozic acid A, a potent inhibitor of mammalian, fungal, and
Saccharomyces cerevisiae
SQSs, also inhibited recombinant
T. elongatus
BP-1 SQS, with a 50% inhibitory concentration of 95.5 ± 13.6 nM.
Complete Genome Sequence of Uropathogenic
Proteus mirabilis
, a Master of both Adherence and Motility
Authors: Pearson Melanie M. , Sebaihia Mohammed , Churcher Carol , Quail Michael A. , Seshasayee Aswin S. , Luscombe Nicholas M. , Abdellah Zahra , Arrosmith Claire , Atkin Becky , Chillingworth Tracey , Hauser Heidi , Jagels Kay , Moule Sharon , Mungall Karen , Norbertczak Halina , Rabbinowitsch Ester , Walker Danielle , Whithead Sally , Thomson Nicholas R. , Rather Philip N. , Parkhill Julian , Mobley Harry L. T.
Published: March 2008

The gram-negative enteric bacterium
Proteus mirabilis
is a frequent cause of urinary tract infections in individuals with long-term indwelling catheters or with complicated urinary tracts (e.g., due to spinal cord injury or anatomic abnormality).
P. mirabilis
bacteriuria may lead to acute pyelonephritis, fever, and bacteremia. Most notoriously, this pathogen uses urease to catalyze the formation of kidney and bladder stones or to encrust or obstruct indwelling urinary catheters. Here we report the complete genome sequence of
P. mirabilis
HI4320, a representative strain cultured in our laboratory from the urine of a nursing home patient with a long-term (≥30 days) indwelling urinary catheter. The genome is 4.063 Mb long and has a G+C content of 38.88%. There is a single plasmid consisting of 36,289 nucleotides. Annotation of the genome identified 3,685 coding sequences and seven rRNA loci. Analysis of the sequence confirmed the presence of previously identified virulence determinants, as well as a contiguous 54-kb flagellar regulon and 17 types of fimbriae. Genes encoding a potential type III secretion system were identified on a low-G+C-content genomic island containing 24 intact genes that appear to encode all components necessary to assemble a type III secretion system needle complex. In addition, the
P. mirabilis
HI4320 genome possesses four tandem copies of the
zapE
metalloprotease gene, genes encoding six putative autotransporters, an extension of the
atf
fimbrial operon to six genes, including an
mrpJ
homolog, and genes encoding at least five iron uptake mechanisms, two potential type IV secretion systems, and 16 two-component regulators.
A resource-based version of the argument that cloning is an affront to human dignity
Authors: McDougall R
Published: March 2008

The claim that human reproductive cloning constitutes an affront to human dignity became a familiar one in 1997 as policymakers and bioethicists responded to the announcement of the birth of Dolly the sheep. Various versions of the argument that reproductive cloning is an affront to human dignity have been made, most focusing on the dignity of the child produced by cloning. However, these arguments tend to be unpersuasive and strongly criticised in the bioethical literature. In this paper I put forward a different argument that reproductive cloning is an affront to human dignity, one that looks beyond the dignity of the child produced. I suggest that allocating funds to such a pursuit can affront human dignity by diverting resources away from those existing people who lack sufficient health to enable them to exercise basic rights and liberties. This version of the argument posits cloning as an affront to human dignity in particular circumstances, rather than claiming the technology as intrinsically inconsistent with human dignity.
The claim for patient choice and equity
Authors: Barr D A , Fenton L , Blane D
Published: March 2008

Recently, commentators close to and within the UK government have claimed that patient choice can increase equity in the context of the National Health Service. This article critically examines the basis for this claim through analysis of recent speeches and publications authored by secretaries of state for health and their policy advisers. It is concluded that this claim has not developed prospectively from an analysis of the causes of healthcare inequity, or even with a consistent normative definition of equity. The limited justification that is “framed in causal explanations” of inequity has suffered from an apparent disregard of the available evidence.
Predictive genetic testing of children for adult-onset diseases and psychological harm
Authors: Malpas P J
Published: March 2008

One of the central arguments given to resist testing currently healthy, asymptomatic children for adult-onset diseases is that they may be psychologically harmed by the knowledge gained from such tests. In this discussion I examine two of the most serious arguments: children who are tested may face limited futures, and that testing may result in damage to the child’s self esteem (where the test result returns a positive diagnosis). I claim that these arguments do not stand up to critical evaluation. In conclusion, whilst I do not suggest that all at-risk children should be tested for adult-onset diseases we ought to listen carefully to some parental requests for such testing because the putative psychological harms may not be as significant or likely as initially thought. This is because parents generally have the best interests of their children at heart and if they are properly supported and educated about predictive genetic testing and the possible consequences, then the risk of psychological harms occurring may be ameliorated.
Ethical opinions and personal attitudes of young adults conceived by in vitro fertilisation
Authors: Siegel S , Dittrich R , Vollmann J
Published: March 2008

Background:

Today in vitro fertilisation (IVF) is a widespread and important technique of reproductive medicine. When the technique was first used, it was considered ethically controversial. This is the first study conducted of adult IVF-offspring in order to learn about their ethical opinions and personal attitudes towards this medical technology.

Methods:

We recruited the participants from the first cases of in vitro fertilisation in Germany at the Gynaecological Clinic of the University Hospital Erlangen. Our qualitative interview study consisted of in-depth, face-to-face interviews with 16 adults who had been conceived by IVF. Our data was analysed with methods of Grounded Theory.

Results:

For these adults, the most important factor influencing their personal attitudes towards IVF was the knowledge that they were deeply wanted children. The artificiality of their conception seemed irrelevant for their ethical opinion. All participants mentioned that it was important for them to be informed about the circumstances of their conception by their parents.

Conclusions:

IVF seems to be a medical technique which, although it affects intimate aspects of human existence, can be integrated into the lives of the affected persons without any great difficulties. The findings suggest that parents should inform their children about their fertilisation at an early age and as part of a process over time, not only on a single occasion. Physicians should advise IVF-parents accordingly.
Ethically problematic treatment decisions in different medical specialties
Authors: Saarni S I , Halila R , Palmu P , Vänskä J
Published: March 2008

Background: Ethical dilemmas are an integral part of medicine. Whether physicians actually feel that they have made ethically problematic treatment decisions or choices in their work is largely unknown. Identifying physicians with ethical problems, and the types of problems and underlying factors, might benefit organisational and educational efforts to help physicians solve ethical dilemmas in a constructive way. We investigated how the frequency and types of ethically difficult treatment decisions vary by specialty.

Method: A mail survey of all non-retired Finnish physicians (n = 17 172, response rate 75.6%) was conducted in 2004. Of those who had made any ethically problematic treatment decisions, the types of decisions and reasons given for these decisions were asked for. Factor analysis was used to investigate clustering of ethically problematic treatment decisions, and logistic regression to investigate the effect of specialty, adjusted for age and gender.

Results: Psychiatrists experienced ethically problematic treatment decisions most frequently, followed by pulmonologists, internists and neurologists. Problems were reported least often by pathologists, laboratory physicians and ophthalmologists. Overtreatment was more common than undertreatment in most specialties, with the exception of psychiatrists who emphasised undertreatment and patient rights issues.

Conclusion: Physicians of different specialties differ significantly regarding frequency and types of ethically problematic treatment decisions they have made. Psychiatrists differ from all other specialists in reporting more undertreatment and patient rights issues. Experiencing ethically problematic decisions might affect the quality of care and physician well-being in many ways. The findings could be useful for both under- and postgraduate ethics education.
Role of solvent nucleophilicity in excess-acidity plots for equilibria in sulfuric acid – water mixtures
Authors: Bentley T William
Published: March 2008

For protonation of a base B to give BH+and for reaction of carbocations R+with water to give ROH in a range of sulfuric acid – water mixtures, slopes of excess-acidity plots of equilibrium data are discussed. Formal connections between the excess-acidity approach and the Grunwald–Winstein (GW) and extended GW equations, noted previously by Bagno et al., are evaluated. It is proposed that a major factor is variations in the solvent dependence of the rates of reactions of the cations (BH+or R+) with water in the sulfuric acid – water mixtures. Rates of reactions of more stable cations (e.g., Ph3C+) with water are more sensitive to changes in solvent nucleophilicity, and the lower nucleophilicity of the water in sulfuric acid – water mixtures leads to an increase in [BH+]/[B] or [R+]/[ROH] concentration ratios (and hence to greater slopes m* in excess-acidity plots).Key words: excess acidity, sulfuric acid, kinetics, solvent nucleophilicity, solvolysis.
Wallach rearrangement of azoxypyridines and azoxypyridine N-oxides — Charge distributions and dramatic reactivity differences
Authors: Buncel Erwin , Keum Sam-Rok , Rajagopal Srinivasan , Kiepek Eric , Cox Robin A
Published: March 2008

Extension of our studies of the generic Wallach rearrangement (of azoxybenzene to 4-hydroxyazobenzene) to the heteroaromatic series (azoxypyridines and axoxypyridine N-oxides) has revealed some dramatic reactivity differences, particularly for the α and β compounds. We have studied the 3-isomers and the 4-isomers in each series, each with α and β forms, eight compounds in all, in the 100 wt% sulfuric acid region of acidity. In those cases in which a product could be observed, the α and β isomers both give the same one, the corresponding 4′-hydroxyazo compounds. All the compounds react much more slowly than does azoxybenzene itself, presumably because of the extra positive charge present in the substrates, but the β isomers have half-lives of seconds and the α isomers half-lives of hundreds of hours in the 100 wt% H2SO4 acidity region. The α compounds have measurable pKBH+ values, but the β compounds do not, exhibiting only a medium effect in the acidity region in which the α compounds protonate. This means that for the β compounds, the protonated intermediates must be much less stable and the postulated reaction intermediates must be much more stable than for the α compounds. To clarify this, we have obtained Mulliken charge distributions for the various species concerned, calculating the charge carried by each half of the molecule, larger charge separations being taken to indicate lesser stability. As far as we can establish, this is the first time that this technique has been used to indicate the stabilities of carbocationic species.Key words: azoxypyridines, azoxypyridine N-oxides, Wallach rearrangement, excess acidity, basicities, theoretical calculations, charge distributions, reactivities.
Generation, observation, and reactivity of furyl- and thienylketenes and bisketenes
Authors: Fu Nanyan , Allen Annette D , Chan Winnie , Kobayashi Shinjiro , Tidwell Thomas T , Tahmassebi Daryoush , Aguilar Angelica , Cabrera Eduardo Peña , Godoy Jazmin
Published: March 2008

2- and 3-Furylketenes (18 and 20), 2- and 3-thienylketenes (19 and 21), and bis(2,5-ketenyl)thiophene (24) have been generated as observable reactive intermediates by photochemical Wolff rearrangements. Stabilization energies of the monoketenes 18–21 have been determined by DFT computations of isodesmic energy changes, and these ketenes are predicted to be modestly destabilized relative to phenylketene. Rate constants for reaction of 18–21 with H2O and with n-BuNH2 have been measured and are similar to those of the 2-, 3-, and 4-pyridylketenes (1). The product of reaction of 2-furylketene (18) with H2O is calculated to be stable as an acid enol, and reaction of 18 with the stable free radical TEMPO forms a stable ester enol, consistent with stabilization by intramolecular H-bonding to the furyl oxygen. Bis(thienyl)-1,2-bisketenes 26 and 28 have been generated by photochemical cyclobutenedione ring opening and are highly reactive in ring closure. This is attributed to destabilization of the ketenes and stabilization of the cyclobutenediones by the electron donating aryl groups.Key words: ketenes, furans, thiophenes, reactive intermediates, photolysis, mechanisms.
The bioorganic chemistry of transglutaminase — from mechanism to inhibition and engineering
Authors: Keillor Jeffrey W , Chica Roberto A , Chabot Nicolas , Vinci Valerio , Pardin Christophe , Fortin Emanuelle , Gillet Steve M.F.G , Nakano Yukiko , Kaartinen Mari T , Pelletier Joelle N , Lubell William D
Published: March 2008

Through a multidisciplinary approach comprising organic synthesis, molecular biology, and physical organic kinetic studies, we have studied the mechanism of transglutaminase-mediated transamidation. More recently, we have applied our understanding of the mechanism to the design of reversible inhibitors and affinity labels for biological application. We have also undertaken the engineering of transglutaminase for its application as a “peptide synthase”. Herein, we present a brief overview of previously published work as well as recent results presented at the 2007 Merck–Frosst Centre for Therapeutic Research Award Lecture.Key words: transglutaminase, enzyme mechanism, enzyme inhibition, protein engineering
Increased myogenic responsiveness of skeletal muscle arterioles with juvenile growth
Authors: Samora Julie Balch , Frisbee Jefferson C. , Boegehold Matthew A.
Published: March 2008

Previous studies from this laboratory suggest that during juvenile growth, structural changes in the arteriolar network are accompanied by changes in some of the mechanisms responsible for regulation of tissue blood flow. To test the hypothesis that arteriolar myogenic behavior is altered with growth, we studied gracilis muscle arterioles isolated from Sprague-Dawley rats at two ages: 21–28 and 42–49 days. When studied at their respective in vivo pressures, the myogenic index (instantaneous slope of the active pressure-diameter curve) of arterioles from 42–49-day-old rats was more negative than that of arterioles from 21–28-day-old rats, indicating greater myogenic responsiveness. Endothelial denudation, or prostaglandin H2(PGH2)/thromboxane A2(TxA2) receptor antagonism without denudation, significantly reduced the myogenic responsiveness of arterioles from the older rats over a wide range of pressures but had no consistent effects on the myogenic responsiveness of arterioles from the younger rats. The heme oxygenase inhibitor chromium (III) mesoporphyrin IX chloride had no effect on the myogenic activity of arterioles from either age group. These findings indicate that microvascular growth in young animals is accompanied by an increase in the myogenic behavior of arterioles, possibly because PGH2or TxA2assumes a role in reinforcing myogenic activity over this period. As a result, the relative contribution of myogenic activity to blood flow regulation in skeletal muscle may increase during rapid juvenile growth.
Mechanics of the left ventricular myocardial interstitium: effects of acute and chronic myocardial edema
Authors: Desai Ketaki V. , Laine Glen A. , Stewart Randolph H. , Cox Charles S. , Quick Christopher M. , Allen Steven J. , Fischer Uwe M.
Published: March 2008

Myocardial interstitial edema forms as a result of several disease states and clinical interventions. Acute myocardial interstitial edema is associated with compromised systolic and diastolic cardiac function and increased stiffness of the left ventricular chamber. Formation of chronic myocardial interstitial edema results in deposition of interstitial collagen, which causes interstitial fibrosis. To assess the effect of myocardial interstitial edema on the mechanical properties of the left ventricle and the myocardial interstitium, we induced acute and chronic interstitial edema in dogs. Acute myocardial edema was generated by coronary sinus pressure elevation, while chronic myocardial edema was generated by chronic pulmonary artery banding. The pressure-volume relationships of the left ventricular myocardial interstitium and left ventricular chamber for control animals were compared with acutely and chronically edematous animals. Collagen content of nonedematous and chronically edematous animals was also compared. Generating acute myocardial interstitial edema resulted in decreased left ventricular chamber compliance compared with nonedematous animals. With chronic edema, the primary form of collagen changed from type I to III. Left ventricular chamber compliance in animals made chronically edematous was significantly higher than nonedematous animals. The change in primary collagen type secondary to chronic left ventricular myocardial interstitial edema provides direct evidence for structural remodeling. The resulting functional adaptation allows the chronically edematous heart to maintain left ventricular chamber compliance when challenged with acute edema, thus preserving cardiac function over a wide range of interstitial fluid pressures.
Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms
Authors: Saeedi Ramesh , Parsons Hannah L. , Wambolt Richard B. , Paulson Kim , Sharma Vijay , Dyck Jason R. B. , Brownsey Roger W. , Allard Michael F.
Published: March 2008

The metabolic actions of the antidiabetic agent metformin reportedly occur via the activation of the AMP-activated protein kinase (AMPK) in the heart and other tissues in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin has AMPK-independent effects on metabolism in heart muscle. Fatty acid oxidation and glucose utilization (glycolysis and glucose uptake) were measured in isolated working hearts from halothane-anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin (2 mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system, and no impairment of energetic state was observed in the intact hearts. Furthermore, the inhibition of AMPK by 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (Compound C), a well-recognized pharmacological inhibitor of AMPK, or the overexpression of a dominant-negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. The exposure of H9c2 cells to inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) or protein kinase C (PKC) partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.
CytochromeP-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries
Authors: Awumey Emmanuel M. , Hill Sylvie K. , Diz Debra I. , Bukoski Richard D.
Published: March 2008

The perivascular sensory nerve (PvN) Ca2+-sensing receptor (CaR) is implicated in Ca2+-induced relaxation of isolated, phenylephrine (PE)-contracted mesenteric arteries, which involves the vascular endogenous cannabinoid system. We determined the effect of inhibition of diacylglycerol (DAG) lipase (DAGL), phospholipase A2(PLA2), and cytochrome P-450 (CYP) on Ca2+-induced relaxation of PE-contracted rat mesenteric arteries. Our findings indicate that Ca2+-induced vasorelaxation is not dependent on the endothelium. The DAGL inhibitor RHC 802675 (1 μM) and the CYP and PLA2inhibitors quinacrine (5 μM) (EC50: RHC 802675 2.8 ± 0.4 mM vs. control 1.4 ± 0.3 mM; quinacrine 4.8 ± 0.4 mM vs. control 2.0 ± 0.3 mM; n = 5) and arachidonyltrifluoromethyl ketone (AACOCF3, 1 μM) reduced Ca2+-induced relaxation of mesenteric arteries. Synthetic 2-arachidonoylglycerol (2-AG) and glycerated epoxyeicosatrienoic acids (GEETs) induced concentration-dependent relaxation of isolated arteries. 2-AG relaxations were blocked by iberiotoxin (IBTX) (EC50: control 0.96 ± 0.14 nM, IBTX 1.3 ± 0.5 μM) and miconazole (48 ± 3%), and 11,12-GEET responses were blocked by IBTX (EC50: control 55 ± 9 nM, IBTX 690 ± 96 nM) and SR-141716A. The data suggest that activation of the CaR in the PvN network by Ca2+leads to synthesis and/or release of metabolites of the CYP epoxygenase pathway and metabolism of DAG to 2-AG and subsequently to GEETs. The findings indicate a role for 2-AG and its metabolites in Ca2+-induced relaxation of resistance arteries; therefore this receptor may be a potential target for the development of new vasodilator compounds for antihypertensive therapy.
Po2measurements in the microcirculation using phosphorescence quenching microscopy at high magnification
Authors: Golub Aleksander S. , Pittman Roland N.
Published: March 2008

In phosphorescence quenching microscopy (PQM), the multiple excitation of a reference volume produces the integration of oxygen consumption artifacts caused by individual flashes. We analyzed the performance of two types of PQM instruments to explain reported data on Po2in the microcirculation. The combination of a large excitation area (LEA) and high flash rate produces a large oxygen photoconsumption artifact manifested differently in stationary and flowing fluids. A LEA instrument strongly depresses Po2in a motionless tissue, but less in flowing blood, creating an apparent transmural Po2drop in arterioles. The proposed model explains the mechanisms responsible for producing apparent transmural and longitudinal Po2gradients in arterioles, a Po2rise in venules, a hypothetical high respiration rate in the arteriolar wall and mesenteric tissue, a low Po2in lymphatic microvessels, and both low and uniform tissue Po2. This alternative explanation for reported paradoxical results of Po2distribution in the microcirculation obviates the need to revise the dominant role of capillaries in oxygen transport to tissue. Finding a way to eliminate the photoconsumption artifact is crucial for accurate microscopic oxygen measurements in microvascular networks and tissue. The PQM technique that employs a small excitation area (SEA) together with a low flash rate was specially designed to avoid accumulated oxygen photoconsumption in flowing blood and lymph. The related scanning SEA instrument provides artifact-free Po2measurements in stationary tissue and motionless fluids. Thus the SEA technique significantly improves the accuracy of microscopic Po2measurements in the microcirculation using the PQM.
Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes
Authors: Lubet Ronald A. , Szabo Eva , Christov Konstantin , Bode Ann M. , Ericson Marna E. , Steele Vernon E. , Juliana M. Margaret , Grubbs Clinton J.
Published: March 2008

The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studies, continual treatment with Iressa at 10, 3, or 1 mg/kg body weight per day beginning 5 days after MNU reduced tumor multiplicity by 93%, 43%, and 20%, respectively. Treatment of rats bearing small palpable cancers with Iressa (10 mg/kg body weight per day) resulted in the complete regression of 70% of the tumors. Short-term treatment of tumor-bearing rats with Iressa caused decreases in cell proliferation and phosphorylated epidermal growth factor receptor and increases in apoptosis. To examine treatment regimens that might decrease the skin toxicity associated with Iressa, both intermittent treatments and combinations of lower doses of Iressa with other effective agents were evaluated. Treatment with Iressa (10 mg/kg body weight per day) continually or intermittently (either “3 weeks on/3 weeks off” or “4 days on/3 days off”) reduced cancer multiplicity by 91%, 24%, and 68%, respectively. However, all regimens reduced tumor weights >85%. Finally, combining suboptimal doses of Iressa with suboptimal doses of vorozole (an aromatase inhibitor) or targretin (a retinoid X receptor agonist) yielded greater chemopreventive efficacy than any of these agents given alone. [Mol Cancer Ther 2008;7(4):972–9]
What Has Happened to the Laws? The Treatment of Legal Material in 4QReworked Pentateuch
Authors: Bernstein Moshe
Published: March 2008

The biblical or non-biblical nature of the manuscripts currently identified as 4QReworked Pentateuch (4Q158; 4Q364–67) has been the subject of much scholarly discussion. This paper addresses a facet of those texts which has unfortunately been ignored in most of those discussions, namely their treatment of the legal material in the Pentateuch. An examination of the surviving legal portions of 4QReworked Pentateuch, manuscript by manuscript, indicates that much greater freedom is shown in handling the laws than in any known pentateuchal textual tradition. We find that laws are omitted from their original locations in the Pentateuch, and, almost without exception, do not reappear in a new location. There also appears to be almost no exegetical reworking of the laws. We conclude that we should not presume that the 4QRP texts included the entire Pentateuch, and that their omission of legal material should probably lead us to characterize some, if not all, of them as non-biblical.
Decoration, Destruction and Debauchery: Reflections on 1 Enoch 8 in Light of 4QEnb
Authors: Coblentz Bautch Kelley
Published: March 2008

This article takes up the distinctive text of Synkellos for 1 En. 8:1 and asks whether it offers the preferred reading or at least may be defended as an early variant rather than as an interpolation of the Byzantine chronographer. To that end, the article examines the Greek translation featured in Synkellos's Chronography and compares the text to other manuscript traditions, especially to the Aramaic fragments of Enoch found in Cave 4 of Qumran. Close examination leaves the author reluctant to dismiss the reading of Synkellos. Further, the author argues that Genesis 4 and 6 might have provided a warrant for this sort of interpretative tradition inasmuch as culture bringers (i.e. the Cainites) precede the account of the angels' descent and mating with women as one finds in Synkellos's version of 1 En. 8:1.
The Community Hymns Classification: A Proposal for Further Differentiation
Authors: Kim Harkins Angela
Published: March 2008

The hodayot scroll from Cave 1 is often cited as one of the classic examples of sectarian literature found at Qumran, yet this conceptualization ignores the great variety of language and style found throughout these compositions. Perhaps a refined understanding of the different literary types within the hodayot scroll can help lead scholars to a better understanding of the relationship between it and other writings from Qumran. This paper proposes that the specific group of hodayot known as the Community Hymns may be further differentiated into two types: those that show strong alignment with the yahad and those that do not show strong alignment.
A Conceptual Model for Organizational Citizenship Behavior Directed Toward the Environment
Authors: Daily Bonnie F. , Bishop James W. , Govindarajulu Nalini
Published: March 2008

This article extends the literature of organizational citizenship behavior in the context of environmental efforts. The authors provide support for the development of the construct, organizational citizenship behavior directed toward the environment (OCBE). They define OCBE as environmental efforts that are discretionary acts, within the organizational setting, not rewarded or required from the organization. This study also identifies key determinants of OCBE, including environmental concern, organizational commitment, perceived supervisory support for environmental efforts, and perceived corporate social performance. Directions for further research and implications for managers are provided.
Over the Long-Run? Short-Run Impact and Long-Run Consequences of Stakeholder Management
Authors: Garcia-Castro Roberto , Ariño Miguel A. , Canela Miguel A.
Published: March 2008

The stakeholder view of the firm has been justified under instrumental and normative bases. Whereas the instrumental basis argues that “enlightened stakeholder management” is a necessary precondition to seek shareholders’ value maximization, the normative basis relies on the observance of ethical norms by managers and the notion that the stakeholders should be treated as “ends.” Some scholars argue that both views actually converge. However, this article provides empirical evidence of the negative effects of stakeholder management in shareholders’ value in the short run and the positive effects over the long run, using a longitudinal database of 658 U.S. firms. Given the difficulties of anticipating the instrumental long-term financial effects of short-run decisions affecting the different stakeholders, the authors’ findings support the view of the normative basis for stakeholder theory based on ethics, norms, and heuristic criteria as a way to solve conflicts among the claims of different stakeholders.
Management of Resources and the Environment
Authors: Caldwell Lynton K.
Published: March 2008

Organization and administration are ob viously important to any public effort, but they are especially critical in relation to prob lems of the environment. These problems are characteristically complex and dynamic, do not conform to the boundaries of political jurisdictions, and pervade all levels of human organization — national, local, regional, and international. Environmental problems iden tified at any one of these levels seldom can be successfully attacked without cooperation from other levels.
Study on the Dynamical Behavior of a Real-Time Distributed Simulation System
Authors: Lin Kuo-Chi , Tan Shih-Wei , Kejun Chen
Published: March 2008

The typical time-critical distributed simulation system in military applications involves a large number of entities that interact with each other in real time. The dynamical behavior of this kind of system is very complicated. When there is a disturbance caused by, for example, time delay, the reaction of the system may not remain in the local area. Instead, it can propagate to a wide region and affect many entities. This paper uses a model called Self-Organized Criticality to ex plain the dynamical behavior of a real-time dis tributed simulation system. A generic war game program is used to simulate the real-time inter actions among the entities on a battlefield. The dynamical behavior of the war game is recorded after a large number of runs with randomly gen erated initial conditions. The results show that the system demonstrates the characteristics of Self-Organized Criticality.
Intelligent Computer-Aided Simulation, Design and Improvement of Heat Pumps
Authors: Wu Chih
Published: March 2008

The Rankine vapor cycle plays a very important role in heat pumps. Vapor heat pump cycle de sign is long and tedious. It is very necessary to obtain the cycle performance, including com pressor work, heat added, turbine work, cooling load, and coefficient of performance, quickly and accurately. This paper describes the use of an intelligent computer-aided software in simula tion, design and possible refinements of vapor heat pumps. Historical evolution and several differently arranged Rankine heat pump cycles are demonstrated. Objectives for improvements, constraints, and, consequently, design, which cannot be easily accomplished using conven tional methods, are emphasized. Using the soft ware increases engineers' interest and design ability in the vapor heat pump cycle.
Silt Erosion in Hydraulic Turbines: The Need for Real-Time Numerical Simulations
Authors: Bergeron Stephen Y. , Vu Thi C. , Vincent Alain P.
Published: March 2008

Direct numerical simulations of quartz particles, given a turbulent stationary velocity field, are per formed in "real time" on a Silicon Graphics work station. Interaction of the surrounding flozu on spherical particles is taken into account by a modi fied version of the Basset-Boussinesq-Oseen equa tion, including nonlinear resistance. Boundary con ditions (walls) are modeled with the use of reflection laws. Interactions between particles are neglected. The velocity field has been pre-computed with the k—∈ model over different geometries. Second-order accuracy numerical implementation and error esti mation are discussed. Impacts on s urfaces are ac counted for by means of direction and kinetic energy of incident particles. The areas with the highest probability of damage are then mapped. Real-time high-quality interactive graphics are an important aspect of this useful numerical tool.
Modeling and Simulative Performance Analysis of SMP and Clustered Computer Architectures
Authors: Burns Mark W. , George Alan D. , Wallace Brad A.
Published: March 2008

The performance cliaracteris tics of several classes of parallel computing systems are analyzed and com pared using high-fidelity modeling and execution- driven simulation. Processor, bus and network mod els are used to construct and simulate the architec tures of symmetric multiprocessors (SMPs), clusters of uniprocessors, and clusters of SMPs. To demon strate a typical use, the performance of ten systems is evaluated using a parallel matrix-multiplication algorithm. Because the performance of a parallel algo rithm on an architecture depends on its communica tion-to-computation ratio, an analysis of communica tion latencies for bus transactions, cache coherence, and network transactions is used to quantify each system's communication overhead. While low-level performance attributes are difficult to measure on experimental testbed systems, and are difficult to accurately represent in purely analytical models, with high fidelity simulative models they can be readily and accurately obtained. This level of detail allows the designer to rapidly prototype and evaluate the performance of parallel and distributed systems.
MPEG Traffic Generation Matching Intra- and Inter-GoP Correlation
Authors: Lombardo A. , Morabito G. , Palazzo S. , Schembra G.
Published: March 2008

VBR-compressed video traffic is expected to consti tute the majority of the B-ISDN network load in the immediate future. At the moment, the MPEG coding scheme is widely used for many types of ap plications. On account of the high burstiness and periodicity of the traffic generated by an MPEG en coder, it is crucial to obtain a model for the genera tion of sequences with the same statistical charac teristics of real MPEG traces. In this paper, after demonstrating that intra-GOP correlation, that is, the correlation between frames belonging to the same GoP', has to be taken into account, an accu rate model allowing the generation of an MPEG like trace is proposed. Moreover, as the MPEG traf fic has been demonstrated to be self-similar, that is, it presents a long-range dependence (LRD), the proposed algorithm applies a method based on the Fast Fourier Transform in order to generate self- similar traces. This algorithm allows generation of a trace, imposing the short-range dependence and LRD behavior and the probability density function of any given video sequence.
Input Data Analysis Using Neural Networks
Authors: Yilmaz Anil , Sabuncuoglu Ihsan
Published: March 2008

Simulation deals with real-life phenomena by constructing representative models of a system being questioned. Input data provide a driving force for such models. The requirement for iden tifying the underlying distributions of data sets is encountered in many fields and simulation applications (e.g., manufacturing economics, etc.). Most of the time, after the collection of the raw data, the true statistical distribution is sought by the aid of nonparametric statistical methods. In this paper, we investigate the feasi bility of using neural networks in selecting ap propriate probability distributions. The perfor mance of the proposed approach is measured with a number of test problems.
Simulation in the Service of Society
Authors: McLeod John , McLeod Suzette
Published: March 2008

In my 1982 book, Computer Modeling and Simulation: Principles of Good Practice, I emphasized the importance of definitions of terms to be used in the book by placing them right after the introduction, in the hope that by so doing readers would have a clearer understanding of what the rest of the book was about. I was pleased to find that one of the terms defined in the book, "Simuland—The real or hypothesized system which is, or is to be, simulated," has been given legitimacy by appearing in The New Shorter Oxford English Dictionary as, "That which is simulated by a mathematical or computer model" shown as having been introduced in the mid-twentieth century.

Now, some 18 years later, a group of "Glossarians" led by Scott Harmon of the Zetetex Company is taking ad vantage of progress in the art and science of M&S to pro duce a greatly enhanced glossary of terms and definitions. The following is an article by Scott on the subject.—JM