bluuebunny/crossref_metadata_2025 huggingface dataset:
Orphan nuclear receptor SHP interacts with and represses hepatocyte nuclear factor-6 (HNF-6) transactivation
Authors: Lee Yong-Soo , Kim Don-Kyu , Kim Yong Deuk , Park Ki Cheol , Shong Minho , Seong Hyun-A , Ha Hyun Jung , Choi Hueng-Sik
Published: May 2008

SHP (small heterodimer partner; NR0B2) is an atypical orphan NR (nuclear receptor) that functions as a transcriptional co-repressor by interacting with a diverse set of NRs and transcriptional factors. HNF-6 (hepatocyte nuclear factor-6) is a key regulatory factor in pancreatic development, endocrine differentiation and the formation of the biliary tract, as well as glucose metabolism. In this study, we have investigated the function of SHP as a putative repressor of HNF-6. Using transient transfection assays, we have shown that SHP represses the transcriptional activity of HNF-6. Confocal microscopy revealed that both SHP and HNF-6 co-localize in the nuclei of cells. SHP physically interacted with HNF-6 in protein–protein association assays in vitro. EMSAs (electrophoretic mobility-shift assays) and ChIP (chromatin immunoprecipitation) assays demonstrated that SHP inhibits the DNA-binding activity of HNF-6 to an HNF-6-response element consensus sequence, and the HNF-6 target region of the endogenous G6Pase (glucose 6-phosphatase) promoter respectively. Northern blot analysis of HNF-6 target genes in cells infected with adenoviral vectors for SHP and SHP siRNAs (small inhibitory RNAs) indicated that SHP represses the expression of endogenous G6Pase and PEPCK (phosphoenolpyruvate carboxykinase). Our results suggest that HNF-6 is a novel target of SHP in the regulation of gluconeogenesis.
CXCR2 chemokine receptor antagonism enhances DOP opioid receptor function via allosteric regulation of the CXCR2–DOP receptor heterodimer
Authors: Parenty Geraldine , Appelbe Shirley , Milligan Graeme
Published: May 2008

Opioid agonists have a broad range of effects on cells of the immune system, including modulation of the inflammatory response, and opioid and chemokine receptors are co-expressed by many white cells. Hetero-oligomerization of the human DOP opioid and chemokine CXCR2 receptors could be detected following their co-expression by each of co-immunoprecipitation, three different resonance energy transfer techniques and the construction of pairs of individually inactive but potentially complementary receptor G-protein α subunit fusion proteins. Although DOP receptor agonists and a CXCR2 antagonist had no inherent affinity for the alternative receptor when either receptor was expressed individually, use of cells that expressed a DOP opioid receptor construct constitutively, and in which expression of a CXCR2 receptor construct could be regulated, demonstrated that the CXCR2 antagonist enhanced the function of DOP receptor agonists only in the presence of CXCR2. This effect was observed for both enkephalin- and alkaloid-based opioid agonists, and the effective concentrations of the CXCR2 antagonist reflected CXCR2 receptor occupancy. Entirely equivalent results were obtained in cells in which the native DOP opioid receptor was expressed constitutively and in which expression of the isolated CXCR2 receptor could be induced. These results indicate that a CXCR2 receptor antagonist can enhance the function of agonists at a receptor for which it has no inherent direct affinity by acting as an allosteric regulator of a receptor that is a heterodimer partner for the CXCR2 receptor. These results have novel and important implications for the development and use of small-molecule therapeutics.
Sugar binding to recombinant wild-type and mutant glucokinase monitored by kinetic measurement and tryptophan fluorescence
Authors: Zelent Bogumil , Odili Stella , Buettger Carol , Shiota Chiyo , Grimsby Joseph , Taub Rebecca , Magnuson Mark A. , Vanderkooi Jane M. , Matschinsky Franz M.
Published: May 2008

Tryptophan fluorescence was used to study GK (glucokinase), an enzyme that plays a prominent role in glucose homoeostasis which, when inactivated or activated by mutations, causes diabetes mellitus or hypoglycaemia in humans. GK has three tryptophan residues, and binding of D-glucose increases their fluorescence. To assess the contribution of individual tryptophan residues to this effect, we generated GST–GK [GK conjugated to GST (glutathione transferase)] and also pure GK with one, two or three of the tryptophan residues of GK replaced with other amino acids (i.e. W99C, W99R, W167A, W167F, W257F, W99R/W167F, W99R/W257F, W167F/W257F and W99R/W167F/W257F). Enzyme kinetics, binding constants for glucose and several other sugars and fluorescence quantum yields (ϕ) were determined and compared with those of wild-type GK retaining its three tryptophan residues. Replacement of all three tryptophan residues resulted in an enzyme that retained all characteristic features of GK, thereby demonstrating the unique usefulness of tryptophan fluorescence as an indicator of GK conformation. Curves of glucose binding to wild-type and mutant GK or GST–GK were hyperbolic, whereas catalysis of wild-type and most mutants exhibited co-operativity with D-glucose. Binding studies showed the following order of affinities for the enzyme variants: N-acetyl-D-glucosamine>D-glucose>D-mannose>D-mannoheptulose>2-deoxy-D-glucose≫L-glucose. GK activators increased sugar binding of most enzymes, but not of the mutants Y214A/V452A and C252Y. Contributions to the fluorescence increase from Trp99 and Trp167 were large compared with that from Trp257 and are probably based on distinct mechanisms. The average quantum efficiency of tryptophan fluorescence in the basal and glucose-bound state was modified by activating (Y214A/V452A) or inactivating (C213R and C252Y) mutations and was interpreted as a manifestation of distinct conformational states.
Splice-switching efficiency and specificity for oligonucleotides with locked nucleic acid monomers
Authors: Guterstam Peter , Lindgren Maria , Johansson Henrik , Tedebark Ulf , Wengel Jesper , El Andaloussi Samir , Langel Ülo
Published: May 2008

The use of antisense oligonucleotides to modulate splicing patterns has gained increasing attention as a therapeutic platform and, hence, the mechanisms of splice-switching oligonucleotides are of interest. Cells expressing luciferase pre-mRNA interrupted by an aberrantly spliced β-globin intron, HeLa pLuc705, were used to monitor the splice-switching activity of modified oligonucleotides by detection of the expression of functional luciferase. It was observed that phosphorothioate 2′-O-methyl RNA oligonucleotides containing locked nucleic acid monomers provide outstanding splice-switching activity. However, similar oligonucleotides with several mismatches do not impede splice-switching activity which indicates a risk for off-target effects. The splice-switching activity is abolished when mismatches are introduced at several positions with locked nucleic acid monomers suggesting that it is the locked nucleic acid monomers that give rise to low mismatch discrimination to target pre-mRNA. The results highlight the importance of rational sequence design to allow for high efficiency with simultaneous high mismatch discrimination for splice-switching oligonucleotides and suggest that splice-switching activity is tunable by utilizing locked nucleic acid monomers.
AcpA, a member of the GPR1/FUN34/YaaH membrane protein family, is essential for acetate permease activity in the hyphal fungus Aspergillus nidulans
Authors: Robellet Xavier , Flipphi Michel , Pégot Sylvine , MacCabe Andrew P. , Vélot Christian
Published: May 2008

In a previous study, alcS, a gene of the Aspergillus nidulans alc cluster, was shown to encode a protein that belongs to the GPR1/FUN34/YaaH membrane protein family. BLAST screening of the A. nidulans genome data identified additional genes encoding hypothetical proteins that could belong to this family. In this study we report the functional characterization of one of them, AN5226. Its expression is induced by ethanol and ethyl acetate (two inducers of the alc genes) and is mediated by the specific transcriptional activator of genes of the acetate-utilization pathway FacB. Growth of a null mutant (ΔAN5226) is notably affected when acetate is used as sole carbon source at low concentration and in a high pH medium, i.e. when protonated acetate, the form that can enter the cell by passive diffusion, is present in low amounts. Consistently, expression of AN5226 is also induced by acetate, but only when the latter is present at low concentrations. 14C-labelled acetate uptake experiments using germinating conidia demonstrate an essential role for AN5226 in mediated acetate transport. To our knowledge this report is the first to provide evidence for the identification of an acetate transporter in filamentous fungi. We have designated AN5226 as acpA (for acetate permease A).
Junction ribonuclease: a ribonuclease HII orthologue from Thermus thermophilus HB8 prefers the RNA–DNA junction to the RNA/DNA heteroduplex
Authors: Ohtani Naoto , Tomita Masaru , Itaya Mitsuhiro
Published: May 2008

The genome of an extremely thermophilic bacterium, Thermus thermophilus HB8, contains a single ORF (open reading frame) encoding an RNase-HII-like sequence. Despite the presence of significant amino acid sequence identities with RNase (ribonuclease) HII enzymes, the ORF TTHA0198 could not suppress the temperature-sensitive growth defect of an RNase-H-deficient Escherichia coli mutant and the purified recombinant protein could not cleave an RNA strand of an RNA/DNA heteroduplex, suggesting that the TTHA0198 exhibited no RNase H activity both in vivo and in vitro. When oligomeric RNA–DNA/DNAs were used as a mimic substrate for Okazaki fragments, however, the protein cleaved them only at the 5′ side of the last ribonucleotide at the RNA–DNA junction. In fact, the TTHA0198 protein prefers the RNA–DNA junction to the RNA/DNA hybrid. We have referred to this activity as JRNase (junction RNase) activity, which recognizes an RNA–DNA junction of the RNA–DNA/DNA heteroduplex and cleaves it leaving a mono-ribonucleotide at the 5′ terminus of the RNA–DNA junction. E. coli and Deinococcus radiodurans RNases HII also cleaved the RNA–DNA/DNA substrates at the same site with a different metal-ion preference from that for RNase H activity, implying that the enzymes have JRNase activity as well as RNase H activity. The specialization in the JRNase activity of the RNase HII orthologue from T. thermophilus HB8 (Tth-JRNase) suggests that the JRNase activity of RNase HII enzymes might be independent of the RNase H activity.
High membrane potential promotes alkenal-induced mitochondrial uncoupling and influences adenine nucleotide translocase conformation
Authors: Azzu Vian , Parker Nadeene , Brand Martin D.
Published: May 2008

Mitochondria generate reactive oxygen species, whose downstream lipid peroxidation products, such as 4-hydroxynonenal, induce uncoupling of oxidative phosphorylation by increasing proton leak through mitochondrial inner membrane proteins such as the uncoupling proteins and adenine nucleotide translocase. Using mitochondria from rat liver, which lack uncoupling proteins, in the present study we show that energization (specifically, high membrane potential) is required for 4-hydroxynonenal to activate proton conductance mediated by adenine nucleotide translocase. Prolonging the time at high membrane potential promotes greater uncoupling. 4-Hydroxynonenal-induced uncoupling via adenine nucleotide translocase is prevented but not readily reversed by addition of carboxyatractylate, suggesting a permanent change (such as adduct formation) that renders the translocase leaky to protons. In contrast with the irreversibility of proton conductance, carboxyatractylate added after 4-hydroxynonenal still inhibits nucleotide translocation, implying that the proton conductance and nucleotide translocation pathways are different. We propose a model to relate adenine nucleotide translocase conformation to proton conductance in the presence or absence of 4-hydroxynonenal and/or carboxyatractylate.
Angiopoietin-1 gene transfer improves impaired wound healing in genetically diabetic mice without increasing VEGF expression
Authors: Bitto Alessandra , Minutoli Letteria , Galeano Maria Rosaria , Altavilla Domenica , Polito Francesca , Fiumara Tiziana , Calò Margherita , Lo Cascio Patrizia , Zentilin Lorena , Giacca Mauro , Squadrito Francesco
Published: May 2008

Ang-1 (angiopoietin-1) improves the ineffective angiogenesis and impaired wound healing in diabetes; however, the mechanism underlying this positive effect is still far from being completely understood. In the present study, we investigated whether rAAV (recombinant adeno-associated virus)–Ang-1 gene transfer could improve wound repair in genetically diabetic mice (db+/db+) and the mechanism(s) by which it causes new vessel formation. An incisional skin-wound model in diabetic and normoglycaemic mice was used. After the incision, animals received rAAV–LacZ or rAAV–Ang-1 in the wound edge. After 7 and 14 days, wounds were used to (i) confirm Ang-1 gene transfer, (ii) assess histologically the healing process, (iii) evaluate wound-breaking strength, and (iv) study new vessel formation by PECAM-1 (platelet/endothelial cell adhesion molecule-1) immunostaining. Finally, we investigated VEGF (vascular endothelial growth factor) mRNA and protein levels, eNOS (endothelial NO synthase) expression and VEGFR-1 and VEGFR-2 (VEGF receptor-1 and -2 respectively) immunostaining. The efficiency of Ang-1 gene transfer was confirmed by increased mRNA and protein expression of the protein. rAAV–Ang-1 significantly improved the healing process, stimulating re-epithelization and collagen maturation, increasing breaking strength and significantly augmenting the number of new vessels, as indicated by PECAM-1 immunostaining. However, Ang-1 gene transfer did not modify the decrease in VEGF mRNA and protein expression in diabetic mice; in contrast, Ang-1 increased eNOS expression and augmented nitrate wound content and VEGFR-2 immunostaining and protein expression. Ang-1 gene transfer did not change vascular permeability. Similar results were obtained in normoglycaemic animals. In conclusion, our results provide strong evidence that Ang-1 gene transfer improves the delayed wound repair in diabetes by inducing angiogenesis in a VEGF-independent manner.
Effects of chronic L-NAME on nitrotyrosine expression and renal vascular reactivity in rats with chronic bile-duct ligation
Authors: Alcaraz Antonia , Hernández David , Iyú David , Mota Rubén , Atucha Noemí M. , Ortiz Antonio J. , García-Estañ Joaquín , Ortiz María C.
Published: May 2008

In liver cirrhosis, elevated levels of NO and ROS (reactive oxygen species) might greatly favour the generation of peroxynitrite. Peroxynitrite is a highly reactive oxidant and it can potentially alter the vascular reactivity and the function of different organs. In the present study, we evaluated whether peroxynitrite levels are related to the progression of renal vascular and excretory dysfunction during experimental cirrhosis induced by chronic BDL (bile-duct ligation) in rats. Experiments were performed at 7, 15 and 21 days after BDL in rats and in rats 21 days post-BDL chronically treated with L-NAME (NG-nitro-L-arginine methyl ester). Sodium balance, BP (blood pressure), basal RPP (renal perfusion pressure) and the renal vascular response to PHE (phenylephrine) and ACh (acetylcholine) in isolated perfused kidneys were measured. NO levels were calculated as 24-h urinary excretion of nitrites, ROS as TBARS (thiobarbituric acid-reacting substances), and peroxynitrite formation as the renal expression of nitrotyrosine. BDL rats had progressive sodium retention, and decreased BP, RPP and renal vascular responses to PHE and ACh in the time following BDL. They also had increasing levels of NO and ROS, and renal nitrotyrosine accumulation, especially in the medulla. All of these changes were either prevented or significantly decreased by chronic L-NAME administration. In conclusion, these results suggest that the increasing levels of peroxynitrite might contribute to the altered renal vascular response and sodium retention in the development of the experimental biliary cirrhosis. Moreover, the beneficial effects of decreasing NO synthesis are, at least in part, mediated by anti-peroxinitrite-related effects.
Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults
Authors: Schjerve Inga E. , Tyldum Gjertrud A. , Tjønna Arnt E. , Stølen Tomas , Loennechen Jan P. , Hansen Harald E. M. , Haram Per M. , Heinrich Garreth , Bye Anja , Najjar Sonia M. , Smith Godfrey L. , Slørdahl Stig A. , Kemi Ole J. , Wisløff Ulrik
Published: May 2008

Regular exercise training is recognized as a powerful tool to improve work capacity, endothelial function and the cardiovascular risk profile in obesity, but it is unknown which of high-intensity aerobic exercise, moderate-intensity aerobic exercise or strength training is the optimal mode of exercise. In the present study, a total of 40 subjects were randomized to high-intensity interval aerobic training, continuous moderate-intensity aerobic training or maximal strength training programmes for 12 weeks, three times/week. The high-intensity group performed aerobic interval walking/running at 85–95% of maximal heart rate, whereas the moderate-intensity group exercised continuously at 60–70% of maximal heart rate; protocols were isocaloric. The strength training group performed ‘high-intensity’ leg press, abdominal and back strength training. Maximal oxygen uptake and endothelial function improved in all groups; the greatest improvement was observed after high-intensity training, and an equal improvement was observed after moderate-intensity aerobic training and strength training. High-intensity aerobic training and strength training were associated with increased PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α) levels and improved Ca2+ transport in the skeletal muscle, whereas only strength training improved antioxidant status. Both strength training and moderate-intensity aerobic training decreased oxidized LDL (low-density lipoprotein) levels. Only aerobic training decreased body weight and diastolic blood pressure. In conclusion, high-intensity aerobic interval training was better than moderate-intensity aerobic training in improving aerobic work capacity and endothelial function. An important contribution towards improved aerobic work capacity, endothelial function and cardiovascular health originates from strength training, which may serve as a substitute when whole-body aerobic exercise is contra-indicated or difficult to perform.
Postprandial paradoxical IGFBP-1 response in obese patients with Type 2 diabetes
Authors: Lehtihet Mikael , Efendic Suad , Brismar Kerstin
Published: May 2008

IGFs (insulin-like growth factors), which in an unbound form induce glucose and amino acid uptake, circulate bound to IGFBPs (IGF-binding proteins), which modulate their bioavailability and activity. The aim of the present study was to examine the effect of a standard meal [2301 kJ (550 kcal)] on the serum levels of IGFBP-1 in obese patients with T2DM (Type 2 diabetes mellitus), non-obese patients with T1DM (Type 1 diabetes mellitus) and healthy controls, using the artificial pancreas (Biostator®) to obtain a normal glycaemic response to the meal. IGFBP-1 levels decreased by 50% over 2 h following the meal at a similar clearance in both the healthy controls and patients with T1DM, but no significant decline was seen in the patients with T2DM, despite a several-fold increase in insulin levels. The patients with T2DM were also studied during Sandostatin® (somatostatin) infusion to decrease the inappropriate secretion of glucagon during the meal. During the 210 min of somatostatin infusion, the glucagon response was suppressed and IGFBP-1 levels were increased concomitantly with the peak in insulin levels, without any significant decrease after the meal. In conclusion, the impaired IGFBP-1 response to meal-related hyperinsulinaemia in obese patients with T2DM suggests a decreased availability of active IGF-1, leading to a decrease in glucose uptake during and after a meal in these patients. The stimulated meal response to glucagon, which contributes to postprandial hyperglycaemia, could not explain the increase in serum IGFBP-1 in these obese patients with T2DM.
Association between PPARα gene polymorphisms and myocardial infarction
Authors: Reinhard Wibke , Stark Klaus , Sedlacek Kamil , Fischer Marcus , Baessler Andrea , Neureuther Katharina , Weber Stefan , Kaess Bernhard , Wiedmann Silke , Mitsching Stefan , Lieb Wolfgang , Erdmann Jeanette , Meisinger Christa , Doering Angela , Tolle Ralf , Jeron Andreas , Riegger Guenter , Hengstenberg Christian
Published: May 2008

PPARα (peroxisome-proliferator-activated receptor α) regulates the expression of genes that are involved in lipid metabolism, tissue homoeostasis and inflammation. Consistent rodent and human studies suggest a link between PPARα function and cardiovascular disease, qualifying PPARα [PPARA in HUGO (Human Genome Organisation) gene nomenclature] as a candidate gene for coronary artery disease. In the present study, we comprehensively evaluated common genetic variations within the PPARα gene and assessed their association with myocardial infarction. First, we characterized the linkage disequilibrium within the PPARα gene in an initial case-control sample of 806 individuals from the Regensburg Myocardial Infarction Family Study using a panel of densely spaced SNPs (single nucleotide polymorphisms) across the gene. Single SNP analysis showed significant association with the disease phenotype [OR (odds ratio)=0.74, P=0.012, 95% CI (confidence interval)=0.61–0.94 for rs135551]. Moreover, we identified a protective three-marker haplotype with an association trend for myocardial infarction (OR=0.76, P=0.067, 95% CI=0.56–1.02). Subsequently, we were able to confirm the single SNP and haplotype association results in an independent second case-control cohort with 667 cases from the Regensburg Myocardial Infarction Family Study and 862 control individuals from the WHO (World Health Organization) MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease) Augsburg project (OR=0.87, P=0.046, 95% CI=0.72–0.99 for rs135551 and OR=0.80, P=0.034, 95% CI=0.65–0.98 for the three-marker haplotype respectively). From these cross-sectional association results, we provide evidence that common variations in the PPARα gene may influence the risk of myocardial infarction in a European population.
Cancer-associated differences in acetylcholinesterase activity in bronchial aspirates from patients with lung cancer
Authors: Martínez-López de Castro Ana , Nieto-Cerón Susana , Aurelio Pons-Castillo , Galbis-Martínez Lilian , Latour-Pérez Juan , Torres-Lanzas Juan , Tovar-Zapata Isabel , Martínez-Hernández Pedro , Neptuno Rodríguez-López José , Cabezas-Herrera Juan
Published: May 2008

In non-neuronal contexts, ACh (acetylcholine) is thought to be involved in the regulation of vital cell functions, such as proliferation, differentiation, apoptosis and cell–cell interaction. In airways, most cells express the non-neuronal cholinergic system, each containing a specific set of components required for synthesis, signal transduction and ACh hydrolysis. The aim of the present study was determine the expression of cholinergic system components in bronchial aspirates from control subjects and patients with lung cancer. We conducted an analysis of cholinergic components in the stored soluble and cellular fraction of bronchial aspirates from non-cancerous patients and patients diagnosed with lung cancer. The results show that the fluid secreted by human lung cells contains enough AChE (acetylcholinesterase) activity to control ACh levels. Thus these findings demonstrate that: (i) AChE activity is significantly lower in aspirates from squamous cell carcinomas; (ii) the molecular distribution of AChE in both bronchial cells and fluids consisted of amphiphilic monomers and dimers; and (iii) choline acetyltransferase, nicotinic receptors and cholinesterases are expressed in cultured human lung cells, as demonstrated by RT–PCR (reverse transcriptase–PCR). It appears that the non-neuronal cholinergic system is involved in lung physiology and lung cancer. The physiological consequences of the presence of non-neuronal ACh will depend on the particular cholinergic signalling network in each cell type. Clarifying the pathophysiological actions of ACh remains an essential task and warrants further investigation.
Circulating levels of adiponectin and leptin at 23–25 weeks of pregnancy in women with impaired placentation and in those with established fetal growth restriction
Authors: Savvidou Makrina D. , Sotiriadis Alexandros , Kaihura Christine , Nicolaides Kypros H. , Sattar Naveed
Published: May 2008

Adiponectin and leptin, two adipose-tissue-derived proteins, have been reported to be elevated in women with established PE (pre-eclampsia). The aim of the present study was to investigate whether alterations in adiponectin and leptin levels predate the development of PE and FGR (fetal growth restriction) in women at increased risk of these complications, as assessed by Doppler examination of the uterine arteries during the second trimester of pregnancy. We also sought to investigate the circulating levels of adiponectin and leptin in women with established severe early-onset FGR. The study included three groups of pregnant women at 23–25 weeks: Group A (n=44) with normal uterine artery Doppler waveforms, Group B (n=49) with abnormal Doppler waveforms and normal fetal growth at the time of the examination, and Group C (n=15) with established severe FGR and abnormal Doppler waveforms. All women had plasma adiponectin and leptin measured by sensitive immunoassays. In Group B, 19 women had a normal outcome, 17 delivered infants with FGR and 13 developed PE. The women who developed PE delivered smaller babies earlier than women with a normal outcome (P<0.001). There were no significant differences in adiponectin levels between any of the groups (overall P=0.3). Leptin concentrations, expressed as MoM (multiples of the median) of Group A, were higher in women in Group C, i.e. established severe FGR at 2.5 (1.2–2.7) MoMs (overall P<0.001), compared with all of the other groups and subgroups. In conclusion, we found that, in pregnancies complicated by severe early-onset FGR, the maternal plasma concentration of leptin is twice as high as in normal pregnancies. However, the second trimester levels of maternal plasma adiponectin and leptin in pregnancies that subsequently develop PE and/or FGR are not significantly different from normal and, consequently, it is unlikely that these markers will be useful as predictors of these pregnancy complications.
Ischaemic and pharmacological preconditionings protect liver via adenosine and redox status following hepatic ischaemia/reperfusion in rats
Authors: Ajamieh Hussam H. , Candelario-Jalil Eduardo , Fernández Olga Sonia León , Gerbes Alexander L
Published: May 2008

Although IPC (ischaemic preconditioning) is considered as a protective strategy in HI/R (hepatic ischaemia/reperfusion), the mechanisms for this effect have not been fully elucidated. In the present study we investigate whether PPC (pharmacological preconditioning) by transient activation of A1R (adenosine A1 receptor) protects against long-term HI/R and whether the protective effects of IPC depend on A1R activation and whether both preconditionings affect remote organs. Wistar rats underwent IPC and long-term HI/R. Another set of animals were pharmacologically preconditioned with the A1R-agonist CCPA [2-chloro-N6-cyclopentyladenosine; 0.1 mg/kg of body weight, i.p. (intraperitoneally)] 24 h before HI/R. In other groups, rats received an A1R-antagonist, DPCPX (1,3-dipropyl-8-cyclopentylxanthine; 0.1 mg/kg of body weight, i.p.) 24 h before HI/R. Hepatic damage was evaluated by transaminase [AST (aspartate transaminase), ALT (alanine transaminase)] release; inflammation was assessed by hepatic MPO (myeloperoxidase) and serum TNFα (tumour necrosis factor α) and NO; oxidative stress was estimated by MDA (malondialdehyde) and 4-HDA (4-hydroxyalkenals), SOD (superoxide dismutase) activity, GSH and ADA (adenosine deaminase) as adenosine metabolism. Both preconditionings protected liver and lung against HI/R as indicated by the reduction in transaminases, MPO, MDA+4-HDA, NO, TNFα and ADA activity as compared with HI/R (P<0.05). However, pre-treatment with DPCPX abolished the protective effects of IPC and PPC. Preconditionings induced a significant increase in hepatic MnSOD (manganese SOD) activity and NO generation compared with the sham group, and this activity was abolished by DPCPX pre-treatment. A1R activation induced hepatic delayed preconditioning and blockade of A1R abolished hepatic IPC. IPC, as well as PPC, were able to prevent lung damage. These protective effects are associated with a reduction in oxidative stress, inflammation and endogenous antioxidant preservation.
Determinants of changes in blood glucose response to short-term exercise training in patients with Type 2 diabetes
Authors: Hordern Matthew D. , Cooney Louise M. , Beller Elaine M. , Prins Johannes B. , Marwick Thomas H. , Coombes Jeff S.
Published: May 2008

The aim of the present study was to determine the effects of a 4-week exercise training intervention on blood glucose, insulin sensitivity, BMI (body mass index) and cardiorespiratory fitness in patients with Type 2 diabetes, and to identify and establish criteria for patients who are more likely to improve their blood glucose from short-term exercise training. A randomized, controlled trial of exercise training, comprising two supervised and one non-supervised sessions of individualized cardiorespiratory and resistance exercise per week, was performed in 132 healthy patients with Type 2 diabetes (exercise training group, n=68), with the aim of accumulating a minimum of 150 min of moderate-intensity exercise for 4 weeks. BMI, waist circumference, blood pressure, blood lipid profile, blood glucose, insulin, insulin sensitivity [calculated by HOMAIR (homoeostasis model assessment of insulin resistance) and QUICKI (quantitative insulin check index)], β-cell function (calculated by HOMAβ-Cell), HbA1c (glycated haemoglobin) and V̇O2max (maximal oxygen consumption) were measured at baseline and at 4 weeks. The exercise training group had significant improvements in V̇O2max, BMI and triacylglycerols (triglycerides). There were no significant changes in blood glucose, HOMAIR, QUICKI or HOMAβ-Cell. Decreases in blood glucose were significantly predicted by baseline blood glucose and HbA1c, with these variables accounting for 15.9% of the change in blood glucose (P<0.001). ROC (receiver operator characteristic) curve analysis revealed that patients with a blood glucose >8.85 mmol/l (sensitivity=73%, specificity=78%) and HbA1c >7.15% (sensitivity=79%, specificity=60%) were more likely to achieve a clinically significant decrease in blood glucose. In conclusion, in apparently healthy patients with Type 2 diabetes, a 4-week exercise intervention improved cardiorespiratory fitness, BMI and triacylglycerols. Elevated blood glucose and HbA1c predicted improvements in blood glucose.
Relationship between peripheral and coronary function using laser Doppler imaging and transthoracic echocardiography
Authors: Khan Faisel , Patterson Dean , Belch Jill J.F. , Hirata Kumiko , Lang Chim C.
Published: May 2008

Vascular dysfunction in the coronary and peripheral circulations is an early prognostic marker of future cardiovascular events. Measurements of coronary and peripheral vascular function in resistance vessels can be made, but rely on invasive procedures, which make them unsuitable for routine application. An assessment of the direct correlation between vascular responses in skin and coronary vessels has not been made previously. In 27 normal healthy subjects (18–55 years of age), we examined the relationship between peripheral and coronary vascular function. Cutaneous perfusion was measured using the non-invasive technique of laser Doppler imaging during iontophoresis of acetylcholine and sodium nitroprusside, and cutaneous vascular conductance was calculated (laser Doppler perfusion/mean arterial pressure). Coronary flow reserve was measured using transthoracic echocardiography during intravenous adenosine infusion. Mean diastolic velocities were measured at baseline and peak hyperaemic conditions from the Doppler signal recordings. CVR (coronary velocity reserve) was defined as the ratio of hyperaemic to basal mean diastolic velocities. There were significant positive correlations between CVR and cutaneous vascular conductance for acetylcholine (r=0.399, P=0.039) and sodium nitroprusside (r=0.446, P=0.020). These results support the idea that peripheral measurements of skin blood flow are representative of generalized microvascular function including that of the coronary circulation in normal healthy subjects.
Dynamic cerebral autoregulatory capacity is affected early in Type 2 diabetes
Authors: Kim Yu-Sok , Immink Rogier V. , Stok Wim J. , Karemaker John M. , Secher Niels H. , van Lieshout Johannes J.
Published: May 2008

Type 2 diabetes is associated with an increased risk of endothelial dysfunction and microvascular complications with impaired autoregulation of tissue perfusion. Both microvascular disease and cardiovascular autonomic neuropathy may affect cerebral autoregulation. In the present study, we tested the hypothesis that, in the absence of cardiovascular autonomic neuropathy, cerebral autoregulation is impaired in subjects with DM+ (Type 2 diabetes with microvascular complications) but intact in subjects with DM− (Type 2 diabetes without microvascular complications). Dynamic cerebral autoregulation and the steady-state cerebrovascular response to postural change were studied in subjects with DM+ and DM−, in the absence of cardiovascular autonomic neuropathy, and in CTRL (healthy control) subjects. The relationship between spontaneous changes in MCA Vmean (middle cerebral artery mean blood velocity) and MAP (mean arterial pressure) was evaluated using frequency domain analysis. In the low-frequency region (0.07–0.15 Hz), the phase lead of the MAP-to-MCA Vmean transfer function was 52±10 ° in CTRL subjects, reduced in subjects with DM− (40±6 °; P<0.01 compared with CTRL subjects) and impaired in subjects with DM+ (30±5 °; P<0.01 compared with subjects with DM−), indicating less dampening of blood pressure oscillations by affected dynamic cerebral autoregulation. The steady-state response of MCA Vmean to postural change was comparable for all groups (−12±6% in CTRL subjects, −15±6% in subjects with DM− and −15±7% in subjects with DM+). HbA1c (glycated haemoglobin) and the duration of diabetes, but not blood pressure, were determinants of transfer function phase. In conclusion, dysfunction of dynamic cerebral autoregulation in subjects with Type 2 diabetes appears to be an early manifestation of microvascular disease prior to the clinical expression of diabetic nephropathy, retinopathy or cardiovascular autonomic neuropathy.
Protective effect of hydrogen sulfide in a murine model of acute lung injury induced by combined burn and smoke inhalation
Authors: Esechie Aimalohi , Kiss Levente , Olah Gabor , Horváth Eszter M. , Hawkins Hal , Szabo Csaba , Traber Daniel L.
Published: May 2008

Acute lung injury results in a severe inflammatory response, which leads to priming and activation of leucocytes, release of reactive oxygen and reactive nitrogen species, destruction of pulmonary endothelium, extravasation of protein-rich fluid into the interstitium and formation of oedema. Recently, H2S (hydrogen sulfide) has been shown to decrease the synthesis of pro-inflammatory cytokines, reduce leucocyte adherence to the endothelium and subsequent diapedesis of these cells from the microvasculature in in vivo studies, and to protect cells in culture from oxidative injury. In the present study, we hypothesized that a parenteral formulation of H2S would reduce the lung injury induced by burn and smoke inhalation in a novel murine model. H2S post-treatment significantly decreased mortality and increased median survival in mice. H2S also inhibited IL (interleukin)-1β levels and significantly increased the concentration of the anti-inflammatory cytokine IL-10 in lung tissue. Additionally, H2S administration attenuated protein oxidation following injury and improved the histological condition of the lung. In conclusion, these results suggest that H2S exerts protective effects in acute lung injury, at least in part through the activation of anti-inflammatory and antioxidant pathways.
A new class of silicon-carbon clusters: A full study of the hydrogenated SinC2H2, n=3,4,5, clusters in comparison with their isoelectronic carboranes C2BnHn+2
Authors: Zdetsis Aristides D.
Published: May 2008

The structural and electronic characteristics of the SinC2H2, n=3,4,5, clusters are studied by ab initio calculations based on coupled cluster and density functional theory using the hybrid B3LYP functional. It is demonstrated that all three clusters are structurally and electronically homologous to the corresponding isoelectronic organometallic carboranes C2BnHn+2. This homology, which is in full agreement with the analogy of Si62− and B6H62− demonstrated recently by the author [J. Chem. Phys. 127, 014314 (2007)], includes not only the ground states but also the lower-lying isomers as well. These lowest lying isomers can be obtained by ortho, para, and meta substitutions from the corresponding Sin2−, n=3,4,5, dianions. The energetic ordering of the low-lying isomers is in full agreement with the known valence and topological charge stability rules developed for carboranes. The hydrogenated clusters are much more stable than their nonhydrogenated counterparts. It is suggested that Si3C2H2, Si4C2H2, and Si5C2H2, which can be probably found in interstellar space, are special examples of a general class of silicon-carbon clusters of the form SinC2H2, with analogous properties and similarities to the corresponding carboranes C2BnHn+2. It is furthermore illustrated that the lowest energy structures of the SinC2 clusters can be obtained through a systematic and straightforward procedure from the SinC2H2 clusters. The present results could hopefully make possible the exploitation of the rich borane and carborane chemistry for the design and development of novel silicon and silicon-carbon composite nanomaterials.
Enhanced Seebeck coefficient in EuTe∕PbTe [100] short-period superlattices
Authors: Ishida Akihiro , Cao Daoshe , Morioka Sinsuke , Veis Martin , Inoue Yoku , Kita Takuji
Published: May 2008

Theoretical and experimental studies on Seebeck effect in EuTe∕PbTe superlattices were performed. Theoretical calculations, which take into account temperature dependent band gap, nonparabolicity, and anisotropy of effective masses in the PbTe conduction band, were performed in the framework of Boltzmann equation in which enhancement of Seebeck coefficient in EuTe∕PbTe short-period superlattices grown in [100] direction was predicted. The EuTe∕PbTe short-period superlattices with few monolayers EuTe were prepared on KCl (100) substrate and an enhanced Seebeck coefficient was observed in these superlattices as expected by theoretical calculations.
On global properties of certain homogeneous exact solutions of Einstein field equations
Authors: Ulanovskii M.
Published: May 2008

The aim of this paper is an application of some general results on homogeneous Lorentz manifolds to exact solutions of Einstein field equations. We study the relation “<” of a chronological sequence of events. We examine a number of known solutions and show that in all but one, the relation < is maximal, i.e., for every a and b from V4, one has both a<b and b<a.
Magnetism and clustering in Cu doped ZnO
Authors: Huang Dan , Zhao Yu-Jun , Chen Di-Hu , Shao Yuan-Zhi
Published: May 2008

The influence of defect charge state on the magnetism of Cu doped ZnO as well as the Cu defects clustering have been investigated by the first-principles calculations. We demonstrate that p-type ZnO:Cu could have ferromagnetic (FM) property, but n-type ZnO:Cu would not have local magnetic moment. Furthermore, the neutral substitutive Cu defects are found to be favorable in clustering, which maintains the FM ordering.
Census Fieldwork in the UK: The Bedrock for a Decade of Social Analysis
Authors: Simpson Ludi , Brown Mark
Published: May 2008

Interviews with fieldworkers from the UK 2001 Census give voice to a unique, grounded view of the operational quality of census-taking. While the overall response to the census has been estimated at 94%, enumerators and their managers explain why differential undercount between social and geographical groups remained a problem. Fieldworkers subjected the census to criticism, from form design and quality checks to address-listing and management. Postal return of census forms caused unexpected difficulties for field staff and expense for the census offices. The subcontracting of various census operations and inflexible operational procedures made it difficult to find and implement timely solutions to problems that arose. A relatively high proportion of missing and inconsistent responses was expected by experienced fieldworkers and put extra burden on the editing and imputation procedures.
Depth Representation of Moving 3-D Objects in Apparent-Motion Path
Authors: Hidaka Souta , Kawachi Yousuke , Gyoba Jiro
Published: May 2008

Apparent motion is perceived when two objects are presented alternately at different positions. The internal representations of apparently moving objects are formed in an apparent-motion path which lacks physical inputs. We investigated the depth information contained in the representation of 3-D moving objects in an apparent-motion path. We examined how probe objects—briefly placed in the motion path—affected the perceived smoothness of apparent motion. The probe objects comprised 3-D objects which were defined by being shaded or by disparity (convex/concave) or 2-D (flat) objects, while the moving objects were convex/concave objects. We found that flat probe objects induced a significantly smoother motion perception than concave probe objects only in the case of the convex moving objects. However, convex probe objects did not lead to smoother motion as the flat objects did, although the convex probe objects contained the same depth information for the moving objects. Moreover, the difference between probe objects was reduced when the moving objects were concave. These counterintuitive results were consistent in conditions when both depth cues were used. The results suggest that internal representations contain incomplete depth information that is intermediate between that of 2-D and 3-D objects.
Rebirth of synthetic hexaploids with global implications for wheat improvement
Authors: Mujeeb-Kazi Abdul , Gul Alvina , Farooq Muhammad , Rizwan Sumaira , Ahmad Iftikhar
Published: May 2008

Aegilops tauschii (syn.Triticum tauschii (Coss.) Schmalh., syn. Ae. squarrosa auct. Non L., 2n = 2x = 14, DD genome), with its numerous accessions and wide distribution, provides unparallelled genetic diversity for addressing global wheat production constraints through genetic improvement. From our working collection of ~750 Ae. tauschii accessions, hybridisation efforts produced 1014 synthetic hexaploid combinations (2n = 6x = 42, AABBDD), resulting from chromosome doubling of the F1 hybrids between elite Triticum turgidum L. s. lat. cultivars and Ae. tauschii accessions. The extensive production of synthetic hexaploids represents a step-wise progression over 2 decades in the generation of a valuable resource of user-friendly genetic diversity. The synthetic germplasm has been validated, maintained, screened, formed into targetted stress-related subsets for focused utilisation, and been allowed global distribution for use in pre-breeding/breeding with advent into molecular technologies. Abundant synthetic hexaploids with different Ae. tauschii accessions have been identified from their screening for yield per se, and various biotic/abiotic stresses. Encouraging diversity data have been obtained for key abiotic constraints such as drought, salinity, heat, and water-logging. A similar response was prevalent for the salient biotic stresses such as fusarium head scab, spot blotch, septoria leaf blotch, and karnal bunt. Global distribution of the selected synthetics has further added valuable information for several other stress constraints and led to utilisation of the synthetic diversity for molecular investigations. The superiority of the primary synthetics has been transferred with ease via pre-breeding/breeding to conventional bread wheat cultivars and varietal releases have started globally. The success and status of the D genome diversity are the focus of this paper and we are optimistic that researchers will devise additional strategies to harness other genomes as efficiently by adding on new technologies that ensure wheat production security in the decades ahead.
Phylogeography of the ancient Parabathynellidae (Crustacea:Bathynellacea) from the Yilgarn region of Western Australia
Authors: Guzik M. T. , Abrams K. M. , Cooper S. J. B. , Humphreys W. F. , Cho J.-L. , Austin A. D.
Published: May 2008

The crustacean order Bathynellacea is a primitive group of subterranean aquatic (stygobitic) invertebrates that typically inhabits freshwater interstitial spaces in alluvia. A striking diversity of species from the bathynellacean family Parabathynellidae have been found in the calcretes of the Yilgarn palaeodrainage system in Western Australia. Taxonomic studies show that most species are restricted in their distribution to a single calcrete, which is consistent with the findings of other phylogeographic studies of stygofauna. In this, the first molecular phylogenetic and phylogeographic study of interspecific relationships among parabathynellids, we aimed to explore the hypothesis that species are short-range endemics and restricted to single calcretes, and to investigate whether there were previously unidentified cryptic species. Analyses of sequence data based on a region of the mitochondrial (mt) DNA cytochrome c oxidase 1 gene showed the existence of divergent mtDNA lineages and species restricted in their distribution to a single calcrete, in support of the broader hypothesis that these calcretes are equivalent to closed island habitats comprising endemic taxa. Divergent mtDNA lineages were also observed to comprise four new and 12 recognised morphospecies. These results reflect the findings of previous studies of stygobitic arthropods (beetles, amphipods and isopods) from the Yilgarn region and reinforce the usefulness of using DNA-sequence data to investigate species boundaries and the presence of cryptic species.