bluuebunny/crossref_metadata_2025 huggingface dataset:
Only One of the Five Ralstonia solanacearum Long-Chain 3-Ketoacyl-Acyl Carrier Protein Synthase Homologues Functions in Fatty Acid Synthesis
Authors: Cheng Juanli , Ma Jincheng , Lin Jinshui , Fan Zhen-Chuan , Cronan John E. , Wang Haihong
Published: December 2011

Ralstonia solanacearum
, a major phytopathogenic bacterium, causes a bacterial wilt disease in diverse plants. Although fatty acid analyses of total membranes of
R. solanacearum
showed that they contain primarily palmitic (C
16:0
), palmitoleic (C
16:1
) and
cis
-vaccenic (C
18:1
) acids, little is known regarding
R. solanacearum
fatty acid synthesis. The
R. solanacearum
GMI1000 genome is unusual in that it contains four genes (
fabF1
,
fabF2
,
fabF3
, and
fabF4
) annotated as encoding 3-ketoacyl-acyl carrier protein synthase II homologues and one gene (
fabB
) annotated as encoding 3-ketoacyl-acyl carrier protein synthase I. We have analyzed this puzzling apparent redundancy and found that only one of these genes,
fabF1
, encoded a long-chain 3-ketoacyl-acyl carrier protein synthase, whereas the other homologues did not play roles in
R. solanacearum
fatty acid synthesis. Mutant strains lacking
fabF1
are nonviable, and thus, FabF1 is essential for
R. solanacearum
fatty acid biosynthesis. Moreover,
R. solanacearum
FabF1 has the activities of both 3-ketoacyl-acyl carrier protein synthase II and 3-ketoacyl-acyl carrier protein synthase I.
Colonization and Transmission of Methicillin-Resistant Staphylococcus aureus ST398 in Nursery Piglets
Authors: Crombé Florence , Vanderhaeghen Wannes , Dewulf Jeroen , Hermans Katleen , Haesebrouck Freddy , Butaye Patrick
Published: December 2011

A transmission experiment was performed to evaluate the spread of methicillin-resistant
Staphylococcus aureus
(MRSA) ST398 in nursery piglets. Reproduction ratios (R
0
) in three experimental groups were found to vary between 3.92 and 52.54, indicating that after introduction, MRSA ST398 will spread easily among weaned piglets, with a tendency to become established.
Enantioselective synthesis of a taxol C ring
Authors: Ma Cong , Schiltz Stéphanie , Prunet Joëlle
Published: December 2011

An enantioselective synthesis of a C ring of taxol has been accomplished. The key step is an oxidative cleavage of a derivative of the Wieland–Miescher ketone. A first attempt of a Shapiro reaction modelling the coupling of the C ring with the A fragment of taxol was also successful.
Isotope exchange reactions of the hydrogen H-5 of selected pyrimidine derivatives and the preparation of tritium-labeled pyrimidines
Authors: Dračínský Martin , Jansa Petr , Elbert Tomáš
Published: December 2011

The hydrogen-to-deuterium isotope exchange reaction of hydrogen in position 5 of pyrimidine derivatives was studied using NMR techniques. The dependence of the reaction rate on the pH and on the solvent composition was explored. In tracer experiments using tritiated water, the application of this exchange reaction was tested for the preparation of pyrimidine derivatives labeled by tritium.
THE CLIC STUDY OF A MULTI-TeV LINEAR COLLIDER
Authors:   (for the CLIC team and the CLIC Collaboration), DELAHAYE J. P.
Published: December 2011

The article reviews the status of the Compact Linear Collider (CLIC) study towards feasibility demonstration of a novel and challenging technology which has been specially developed to extend Linear Colliders energy reach into the multi-TeV range in order to be complementary to LHC (Large Hadron Collider). A Conceptual Design Report is being published summarizing the performance of a High Energy facility based on such a technology as well as the results of the R&D performed to address its feasibility.
B→J/ψρ DECAY WITHIN QCD FACTORIZATION APPROACH
Authors: SAYAHI MAHBOOBEH , MEHRABAN HOSSEIN
Published: December 2011

In this paper, the hadronic decays B+→J/ψρ+ and B0→J/ψρ0 have been analyzed in "QCD factorization" method. The effective coefficients [Formula: see text] have been calculated for three helicity states (h = 0, +, -) which given three contributions of amplitude. We have assumed two scenarios for J/ψ. First, we have considered that J/ψ behaves as a light meson in comparison with B-meson and in other scenario, we have considered mass of J/ψ in our calculations. The branching ratios are calculated in these conditions and also in different energy scales. The obtained results are in agreement with available experimental data at second scenario and μ = mb/2.
STATIONARY WAVE ASSOCIATED WITH AN INFLOW PROBLEM IN THE HALF LINE FOR VISCOUS HEAT-CONDUCTIVE GAS
Authors: NAKAMURA TOHRU , NISHIBATA SHINYA
Published: December 2011

We study the large-time behavior of solutions to an ideal polytropic model of compressible viscous gases in one-dimensional half space. We consider an inflow problem where the gas enter into the region through the boundary, and we show that a corresponding stationary solution is time-asymptotically stable in both the subsonic and transonic cases. The proof of asymptotic stability is based on a priori estimates of the perturbation from the stationary solution, which are derived by a standard energy method, provided the boundary strength and the initial perturbation in a certain Sobolev space are sufficiently small.
FORMATION OF SINGULARITY AND SMOOTH WAVE PROPAGATION FOR THE NON-ISENTROPIC COMPRESSIBLE EULER EQUATIONS
Authors: CHEN GENG
Published: December 2011

We define the notion of compressive and rarefactive waves and derive the differential equations describing smooth wave steepening for the compressible Euler equations with a varying entropy profile and general pressure laws. Using these differential equations, we directly generalize Lax's singularity (shock wave) formation results (established in 1964 for hyperbolic systems with two variables) to the 3 × 3 compressible Euler equations for a polytropic ideal gas. Our results are valid globally without restriction on the size of the variation of initial data.
MODIFIED WAVE OPERATORS FOR NONLINEAR SCHRÖDINGER EQUATIONS IN LOWER ORDER SOBOLEV SPACES
Authors: HAYASHI NAKAO , WANG HUIMEI , NAUMKIN PAVEL I.
Published: December 2011

We study the final value problem for the nonlinear Schrödinger equations in one or two space dimensions with the gauge-invariant nonlinearity of the critical long-range power and nonresonant polynomial nonlinearities of the same power, which are not gauge invariant. We construct a unique global solution (for positive time) which is asymptotic for large time to a given profile with sufficiently small norm in lower order Sobolev spaces with decay at the spatial infinity and at the zero frequency.
Hepatic cellular senescence pathway genes are induced through histone modifications in a diet-induced obese rat model
Authors: Zhang Xiyuan , Zhou Dan , Strakovsky Rita , Zhang Yukun , Pan Yuan-Xiang
Published: December 2011

Overnutrition, such as a high-fat (HF) diet, is a feature followed by some in developed nations that leads to obesity and fatty liver disease. In rats, when fed a fat-high diet, some develop obesity (obesity prone, OP) while others display an obesity-resistant (OR) phenotype. The present study investigated the differences between OP and OR rats on their activation of hepatic cellular senescence pathways on a HF diet. Male OP and OR rats were fed a HF diet containing 45% kcal from fat for 13 wk, and livers were collected for analysis by quantitative real-time PCR, Western blot, and chromatin immunoprecipitation. OP rats were 41% heavier than OR rats, despite consuming the same amount of food. Triacylglycerol levels were increased significantly in both plasma and liver of OP rats. Gene analysis demonstrated a significant increase of both the amount and the transcription rates of p16INK4aand p21Cip1mRNA in OP rats. The increased p16INK4aand p21Cip1also caused a significant decrease in the level of phosphorylation of retinoblastoma protein. In OP rats, the increase of p16INK4awas associated with the higher acetylation levels of histone H4 at the p16INK4apromoter and coding region and lower methylation level of histone H3 lysine-27 in the p16INK4acoding region. The increase of p21Cip1was associated with increased acetylation of both histone H3 and H4 and decreased trimethylation of histone H3 lysine-27 at the p21Cip1promoter. In the p21Cip1coding region, dimethylation of histone H3 lysine-4 was significantly higher ( P <0.05) in livers of OP rats compared with OR rats.
Comparison of effects of a selective 5-HT reuptake inhibitor versus a 5-HT4 receptor agonist on in vivo neurogenesis at the rectal anastomosis in rats
Authors: Kawahara Isao , Kuniyasu Hiroki , Matsuyoshi Hiroko , Goto Kei , Obata Koji , Misawa Hiromi , Fujii Hisao , Takaki Miyako
Published: December 2011

It was recently reported that activation of enteric neural 5-HT4 receptors (SR4) promotes reconstruction of enteric neural circuit injury in distal gut of guinea pigs and that this reconstruction involves neural stem cells. We aimed to explore a novel approach using a selective serotonin reuptake inhibitor (SSRI), which increases endogenous 5-HT, to repair enteric nerve fiber injury in the rat distal gut. Enteric nerve fiber injury was performed by rectal transection and subsequent end-to-end one-layer anastomosis. The SSRI fluvoxamine maleate (100 μmol/l) was applied locally at the anastomotic site to compare with the 5-HT4 agonist mosapride citrate (100 μmol/l) (applied for patent) applied locally and orally. Unlike mosapride, fluvoxamine failed to promote the regeneration of the nerve fiber tract across the anastomosis. Furthermore, fluvoxamine did not generate anti-distal-less homeobox 2 (DLX2)- and anti-SR4-positive cells (neural stem cells) and/or anti-neurofilament (NF)-positive cells (neural cells) in newly formed granulation tissue at the anastomosis, whereas these cell types were observed in mosapride-treated preparations. In contrast to its effects in guinea pigs, mosapride generated 5-bromo-2′-deoxyuridine (BrdU)-positive neural cells in ganglia sites 3 mm oral and anal from the anastomosis 2 wk after nerve fiber injury. All actions of mosapride were observed after local and or oral applications. These findings indicate that local SSRI treatment does not induce in vivo nerve fiber tract growth across the anastomosis in the rat distal gut. Mosapride induces nerve fiber tract growth across the anastomosis, mediated through enteric neural stem cells possibly from neural crest-derived stem cells or mesenchymal stem cells in the bone marrow.
Helicobacter pyloridefense against oxidative attack
Authors: Stent Andrew , Every Alison L. , Sutton Philip
Published: December 2011

Helicobacter pylori is a microaerophilic, gram-negative pathogen of the human stomach. Despite the chronic active gastritis that develops following colonization, H. pylori is able to persist unharmed in the stomach for decades. Much of the damage caused by gastric inflammation results from the accumulation of reactive oxygen/nitrogen species within the stomach environment, which can induce oxidative damage in a wide range of biological molecules. Without appropriate defenses, this oxidative damage would be able to rapidly kill nearby H. pylori, but the organism employs a range of measures, including antioxidant enzymes, biological repair systems, and inhibitors of oxidant generation, to counter the attack. Despite the variety of measures employed to defend against oxidative injury, these processes are intimately interdependent, and any deficiency within the antioxidant system is generally sufficient to cause substantial impairment of H. pylori viability and persistence. This review provides an overview of the development of oxidative stress during H. pylori gastritis and examines the methods the organism uses to survive the resultant damage.
Hydrocortisone normalizes oxygenation and cGMP regulation in lambs with persistent pulmonary hypertension of the newborn
Authors: Perez Marta , Lakshminrusimha Satyan , Wedgwood Stephen , Czech Lyubov , Gugino Sylvia F. , Russell James A. , Farrow Kathryn N. , Steinhorn Robin H.
Published: December 2011

In the pulmonary vasculature, cGMP levels are regulated by soluble guanylate cyclase (sGC) and phosphodiesterase 5 (PDE5). We previously reported that lambs with persistent pulmonary hypertension of the newborn (PPHN) demonstrate increased reactive oxygen species (ROS) and altered sGC and PDE5 activity, with resultant decreased cGMP. The objective of this study was to evaluate the effects of hydrocortisone on pulmonary vascular function, ROS, and cGMP in the ovine ductal ligation model of PPHN. PPHN lambs were ventilated with 100% O2 for 24 h. Six lambs received 5 mg/kg hydrocortisone every 8 h times three doses (PPHN-hiHC), five lambs received 3 mg/kg hydrocortisone followed by 1 mg·kg−1·dose−1 times two doses (PPHN-loHC), and six lambs were ventilated with O2 alone (PPHN). All groups were compared with healthy 1-day spontaneously breathing lambs (1DSB). O2 ventilation of PPHN lambs decreased sGC activity, increased PDE5 activity, and increased ROS vs. 1DSB lambs. Both hydrocortisone doses significantly improved arterial-to-alveolar ratios relative to PPHN lambs, decreased PDE5 activity, and increased cGMP relative to PPHN lambs. High-dose hydrocortisone also increased sGC activity, decreased PDE5 expression, decreased ROS, and increased total vascular SOD activity vs. PPHN lambs. These data suggest that hydrocortisone treatment in clinically relevant doses improves oxygenation and decreases hyperoxia-induced changes in sGC and PDE5 activity, increasing cGMP levels. Hydrocortisone reduces ROS levels in part by increasing SOD activity in PPHN lambs ventilated with 100% O2. We speculate that hydrocortisone increases cGMP by direct effects on sGC and PDE5 expression and by attenuating abnormalities induced by oxidant stress.
Eugenol attenuates pulmonary damage induced by diesel exhaust particles
Authors: Zin Walter A. , Silva Ana G. L. S. , Magalhães Clarissa B. , Carvalho Giovanna M. C. , Riva Douglas R. , Lima Crystianne C. , Leal-Cardoso Jose H. , Takiya Christina M. , Valença Samuel S. , Saldiva Paulo H. N. , Faffe Débora S.
Published: December 2011

Environmentally relevant doses of inhaled diesel particles elicit pulmonary inflammation and impair lung mechanics. Eugenol, a methoxyphenol component of clove oil, presents in vitro and in vivo anti-inflammatory and antioxidant properties. Our aim was to examine a possible protective role of eugenol against lung injuries induced by diesel particles. Male BALB/c mice were divided into four groups. Mice received saline (10 μl in; CTRL group) or 15 μg of diesel particles DEP (15 μg in; DIE and DEUG groups). After 1 h, mice received saline (10 μl; CTRL and DIE groups) or eugenol (164 mg/kg; EUG and DEUG group) by gavage. Twenty-four hours after gavage, pulmonary resistive (ΔP1), viscoelastic (ΔP2) and total (ΔPtot) pressures, static elastance (Est), and viscoelastic component of elastance (ΔE) were measured. We also determined the fraction areas of normal and collapsed alveoli, amounts of polymorpho- (PMN) and mononuclear cells in lung parenchyma, apoptosis, and oxidative stress. Est, ΔP2, ΔPtot, and ΔE were significantly higher in the DIE than in the other groups. DIE also showed significantly more PMN, airspace collapse, and apoptosis than the other groups. However, no beneficial effect on lipid peroxidation was observed in DEUG group. In conclusion, eugenol avoided changes in lung mechanics, pulmonary inflammation, and alveolar collapse elicited by diesel particles. It attenuated the activation signal of caspase-3 by DEP, but apoptosis evaluated by TUNEL was avoided. Finally, it could not avoid oxidative stress as indicated by malondialdehyde.
Metanephros Transplantation Inhibits the Progression of Vascular Calcification in Rats with Adenine-Induced Renal Failure
Authors: Yokote Shinya , Yokoo Takashi , Matsumoto Kei , Ohkido Ichiro , Utsunomiya Yasunori , Kawamura Tetsuya , Hosoya Tatsuo
Published: December 2011

Background/Aim: Recent research has shown that transplanted metanephroi form primitive vascularized kidneys with histologically recognizable renal features. The aim of the present study was to determine the metabolic function of transplanted metanephroi in rats with chronic renal failure (CRF), with particular reference to secondary hyperparathyroidism and vascular calcification. Methods: CRF was induced in 11-week-old male Wistar rats by maintaining them on a 0.75% adenine diet for 4 weeks, followed by normal diet for an additional 2 weeks. At the end of adenine loading, whole metanephroi from embryonic day 15 rats were transplanted into the omentum and epididymis of the transplantation group. Vascular calcification was evaluated 2 weeks after metanephroi transplantation. Results: Metanephros transplantation significantly reduced vascular calcium and phosphorus content and suppressed the progression of vascular calcification as indicated by von Kossa staining of the media of the thoracic aorta. However, no significant differences between the adenine-fed control and transplantation groups were found regarding the serum levels of 1,25(OH)2D3, calcium or phosphorus or the calcium × phosphorus product. Conclusion: The present study has shown that transplantation of metanephroi suppresses the progression of vascular calcification via a mechanism that is independent of calcium-phosphorus dynamics.
Regulation of Physiologic Actions of LRRK2: Focus on Autophagy
Authors: Ferree Andrew , Guillily Maria , Li Hu , Smith Katelyn , Takashima Aki , Squillace Rachel , Weigele Manfred , Collins James J. , Wolozin Benjamin
Published: December 2011

Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson’s disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown. Objectives: To investigate mechanisms by which LRRK2 might cause PD. Methods: We used systems biology to investigate the transcriptomes from human brains, human blood cells and Caenorhabditis elegans expressing wild-type LRRK2. The role of autophagy was tested in lines of C. elegans expressing LRRK2, V337M tau or both proteins. Neuronal function was measured by quantifying thrashing. Results: Genes regulating autophagy were coordinately regulated with LRRK2. C. elegans expressing V337M tau showed reduced thrashing, as has been noted previously. Coexpressing mutant LRRK2 (R1441C or G2019S) with V337M tau increased the motor deficits. Treating the lines of C. elegans with an mTOR inhibitor that enhances autophagic flux, ridaforolimus, increased the thrashing behavior to the same level as nontransgenic nematodes. Conclusion: These data support a role for LRRK2 in autophagy, raise the possibility that deficits in autophagy contribute to the pathophysiology of LRRK2, and point to a potential therapeutic approach addressing the pathophysiology of LRRK2 in PD.
Mechanism-Based Therapeutics for Autosomal Dominant Polycystic Kidney Disease: Recent Progress and Future Prospects
Authors: Chang Ming-Yang , Ong Albert C.M.
Published: December 2011

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, accounting for up to 10% of patients on renal replacement therapy. There are presently no proven treatments for ADPKD and an effective disease-modifying drug would have significant implications for patients and their families. Since the identification of PKD1 and PKD2, there has been an explosion in knowledge identifying new disease mechanisms and testing new drugs. Currently, the three major treatment strategies are to: (1) reduce cAMP levels; (2) inhibit cell proliferation, and (3) reduce fluid secretion. Several compounds shown to be effective in preclinical models have already undergone clinical trials and more are planned. In addition, a whole raft of other compounds have been developed from preclinical studies. The purpose of this paper is to evaluate the results of recent published trials, review current trials and highlight the most promising compounds in the pipeline. There appears to be no shortage of potential candidates, but several key issues need to be addressed to facilitate clinical translation.
Adjusting for Urinary Creatinine Overestimates Arsenic Concentrations in Diabetics
Authors: Yassine Hussein , Kimzey Michael J. , Galligan Michael A. , Gandolfi A. Jay , Stump Craig S. , Lau Serrine S.
Published: December 2011

Background/Aims: Arsenic (As) is linked to insulin resistance in animal studies, but the effect of low-level As exposure on the prevalence of diabetes in humans is uncertain. An optimal method to report inorganic As in humans has not been established. Measurements of As in spot urine are usually adjusted to creatinine (Cr). However, urinary Cr is an independent variable in diabetes. Our aims are to optimize reporting of urinary As in the setting of diabetes and insulin resistance. Methods: Urinary inorganic As was measured in 24-hour or first-void spot urine from diabetic (n = 31) and non-diabetic (n = 12) subjects and normalized to Cr or specific gravity (SG). The relation of normalized urinary inorganic As to glycemia and surrogate measures of insulin resistance was investigated. Blood pressure, waist circumference, and glycated hemoglobin were also assessed. Homeostasis model assessment was used to determine insulin resistance. Results: A strong correlation was found between spot urinary As adjusted to Cr (R2 = 0.82) or SG (R2 = 0.61) to 24-hour urinary As (p < 0.001), while non-adjusted urinary As did not correlate well (R2 = 0.03, p = 0.46). Adjusting for Cr revealed significant differences in total 24-hour urinary As when comparing diabetic to normal subjects. In contrast, no differences were found when As was adjusted to SG using either 24-hour or spot urine. Moreover, adjusted urinary spot or 24-hour As measures did not correlate with measures of glycemia or insulin resistance. Conclusions: Urinary Cr is an independent variable in diabetes, therefore adjusting spot As for SG is preferred.
Investigative Clinical Study on Prostate Cancer Part VI: Follicle-Stimulating Hormone and the Pituitary-Testicular-Prostate Axis at the Time of Initial Diagnosis and Subsequent Cluster Selection of the Patient Population
Authors: Porcaro Antonio B. , Migliorini Filippo , Petrozziello Aldo , Sava Teodoro , Romano Mario , Caruso Beatrice , Cocco Claudio , Ghimenton Claudio , Zecchinini Antoniolli Stefano , Lacola Vincenzo , Rubilotta Emanuele , Monaco Carmelo , Comunale Luigi
Published: December 2011

Aim: To evaluate the physiopathology of follicle-stimulating hormone (FSH) along the pituitary-testicular-prostate axis at the time of initial diagnosis of prostate cancer in relation to the available clinical variables and to the subsequent cluster selection of the patient population. Patients and Methods: The study included 98 patients who were diagnosed with prostate cancer. Age, percentages of positive cores (P+) at transrectal ultrasound scan biopsy, biopsy Gleason score (bGS), luteinizing hormone (LH), FSH, total testosterone, free testosterone (FT) and prostate-specific antigen (PSA) were the continuous clinical variables. All patients had not previously received hormonal manipulations. FSH correlation and multiple linear analyses were computed in the population. The FSH/PSA ratio was computed and then ranked for clustering the population as groups A (0.13≤FSH/PSA≤0.57), B (0.57<FSH/PSA≤1.61) and C (1.61<FSH/PSA≤19.4). The model was assessed by simple linear and multiple linear regression analysis and differences between the groups were assessed by analysis of variance. Results: In the patient population, FSH correlated to LH (p < 0.0001), FT (p = 0.007) and age (p = 0.004). FSH was independently predicted by both LH (p < 0.0001) and PSA (p = 0.04). PSA predicted FSH/PSA A (p < 0.0001), B (p < 0.0001) and C (p = 0.04). On multiple regression analysis, FSH/PSA A was predicted by PSA (p < 0.0001), P+ (p = 0.03) and bGS (p = 0.04); FSH/PSA B by LH (p = 0.002) and PSA (p < 0.0001); FSH/PSA C by LH (p < 0.0001) and PSA (p < 0.0001). Moreover, FSH/PSA A, B and C differed for mean values of FSH (p < 0.0001), LH (p < 0.0001), PSA (p < 0.0001) and PSA/FT ratio (p < 0.0001). FSH/PSA clusters showed features of decreasing aggressive disease as the FSH/PSA ratio progressed from A to C. Conclusion:At the diagnosis of prostate cancer and along the pituitary-testis-prostate axis in a patient population FSH significantly correlated to LH, FT and age, and FSH was independently and significantly predicted by both LH and PSA. Because of the independent prediction of PSA by FSH, the prostate cancer population at diagnosis was clustered and ranked according to the FSH/PSA ratio in groups A, B and C. Also, the predictive model of PSA on FSH for the different groups proved to be effective at selecting potential prognostic clusters in which the risk of progression might be assessed as low (group C), intermediate (group B) and high (group A). The FSH/PSA model might be considered as a tool for prostate cancer study and for use in individualized, risk-adapted approaches. However, confirmatory studies are needed.
Vascular Incorporation of Endothelial Colony-Forming Cells Is Essential for Functional Recovery of Murine Ischemic Tissue Following Cell Therapy
Authors: Schwarz Theresa M. , Leicht Simon F. , Radic Tamara , Rodriguez-Arabaolaza Iker , Hermann Patrick C. , Berger Frank , Saif Jaimy , Böcker Wolfgang , Ellwart Joachim W. , Aicher Alexandra , Heeschen Christopher
Published: December 2011

Objective—

Cord blood–derived human endothelial colony-forming cells (ECFCs) bear a high proliferative capacity and potently enhance tissue neovascularization in vivo. Here, we investigated whether the leading mechanism for the functional improvement relates to their physical vascular incorporation or perivascular paracrine effects and whether the effects can be further enhanced by dual-cell–based therapy, including mesenchymal stem cells (MSCs).

Methods and Results—

ECFCs or MSCs were lentivirally transduced with thymidine kinase suicide gene driven by the endothelial-specific vascular endothelial growth factor 2 (kinase insert domain receptor) promoter and evaluated in a hindlimb ischemia model. ECFCs and MSCs enhanced neovascularization after ischemic events to a similar extent. Dual therapy using ECFCs and MSCs further enhanced neovascularization. Mechanistically, 3 weeks after induction of ischemia followed by cell therapy, ganciclovir-mediated elimination of kinase insert domain receptor
+
cells completely reversed the therapeutic effect of ECFCs but not that of MSCs. Histological analysis revealed that ganciclovir effectively eliminated ECFCs incorporated into the vasculature.

Conclusion—

Endothelial-specific suicide gene technology demonstrates distinct mechanisms for ECFCs and MSCs, with complete abolishment of ECFC-mediated effects, whereas MSC-mediated effects remained unaffected. These data strengthen the notion that a dual-cell–based therapy represents a promising approach for vascular regeneration of ischemic tissue.
Matrix Metalloproteinase-2 Proteolysis of Calponin-1 Contributes to Vascular Hypocontractility in Endotoxemic Rats
Authors: Castro Michele M. , Cena Jonathan , Cho Woo Jung , Walsh Michael P. , Schulz Richard
Published: December 2011

Objective—

Matrix metalloproteinase (MMP)-2 is activated in aorta during endotoxemia and plays a role in the hypocontractility to vasoconstrictors. Calponin-1 is a regulator of vascular smooth muscle tone with similarities to troponin, a cardiac myocyte protein that is cleaved by MMP-2 in myocardial oxidative stress injuries. We hypothesized that calponin-1 may be proteolyzed by MMP-2 in endotoxemia-induced vascular hypocontractility.

Methods and Results—

Rats were given a nonlethal dose of bacterial lipopolysaccharide (LPS) or vehicle. Some rats were given the MMP inhibitors ONO-4817 or doxycycline. Six hours later, plasma nitrate+nitrite increased >15-fold in LPS-treated rats, an effect unchanged by doxycycline. Both ONO-4817 and doxycycline prevented LPS-induced aortic hypocontractility to phenylephrine. LPS activated MMP-2 in the aorta by S-glutathiolation. Calponin-1 levels decreased by 25% in endotoxemic aortae, which was prevented by doxycycline. Calponin-1 and MMP-2 coimmunoprecipitated and both exhibited uniform cytosolic staining in medial vascular smooth muscle cells. In vitro incubation of calponin-1 with MMP-2 led to calponin-1 degradation and appearance of its cleavage product.

Conclusion—

Calponin-1 is a target of MMP-2, which contributes to endotoxemia-induced vascular hypocontractility.
Integrin-Linked Kinase Regulates Vasomotor Function by Preventing Endothelial Nitric Oxide Synthase Uncoupling
Authors: Herranz Beatriz , Marquez Susana , Guijarro Brenda , Aracil Enrique , Aicart-Ramos Clara , Rodriguez-Crespo Ignacio , Serrano Isabel , Rodríguez-Puyol Manuel , Zaragoza Carlos , Saura Marta
Published: December 2011

Rationale:

Atherosclerotic lesions develop in regions of disturbed flow, whereas laminar flow protects from atherogenesis; however, the mechanisms involved are not completely elucidated. Integrins are mechanosensors of shear stress in endothelial cells, and integrin-linked kinase (ILK) is important for blood vessel integrity and cardiovascular development.

Objectives:

To explore the role of ILK in vascular function by studying conditionally ILK-deficient (cKO) mice and human atherosclerotic arteries.

Results:

ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofolate reductase expression, and increased eNOS-dependent generation of superoxide accompanied by extensive vascular protein nitration. ILK reexpression prevented eNOS uncoupling in cKO cells, whereas superoxide formation was unaffected by ILK depletion in eNOS-KO cells, indicating eNOS as a primary source of superoxide anion. eNOS and ILK coimmunoprecipitated in aortic lysates from control animals, and eNOS-ILK–shock protein 90 interaction was detected in human normal mammary arteries but was absent from human atherosclerotic carotid arteries. eNOS-ILK interaction in endothelial cells was prevented by geldanamycin, suggesting heat shock protein 90 as a binding partner.

Conclusions:

Our results identify ILK as a regulatory partner of eNOS in vivo that prevents eNOS uncoupling, and suggest ILK as a therapeutic target for prevention of endothelial dysfunction related to shear stress–induced vascular diseases.
Gene selection and classification for cancer microarray data based on machine learning and similarity measures
Authors: Liu Qingzhong , Sung Andrew H , Chen Zhongxue , Liu Jianzhong , Chen Lei , Qiao Mengyu , Wang Zhaohui , Huang Xudong , Deng Youping
Published: December 2011

Background

Microarray data have a high dimension of variables and a small sample size. In microarray data analyses, two important issues are how to choose genes, which provide reliable and good prediction for disease status, and how to determine the final gene set that is best for classification. Associations among genetic markers mean one can exploit information redundancy to potentially reduce classification cost in terms of time and money.

Results

To deal with redundant information and improve classification, we propose a gene selection method, Recursive Feature Addition, which combines supervised learning and statistical similarity measures. To determine the final optimal gene set for prediction and classification, we propose an algorithm, Lagging Prediction Peephole Optimization. By using six benchmark microarray gene expression data sets, we compared Recursive Feature Addition with recently developed gene selection methods: Support Vector Machine Recursive Feature Elimination, Leave-One-Out Calculation Sequential Forward Selection and several others.

Conclusions

On average, with the use of popular learning machines including Nearest Mean Scaled Classifier, Support Vector Machine, Naive Bayes Classifier and Random Forest, Recursive Feature Addition outperformed other methods. Our studies also showed that Lagging Prediction Peephole Optimization is superior to random strategy; Recursive Feature Addition with Lagging Prediction Peephole Optimization obtained better testing accuracies than the gene selection method varSelRF.
Changes in predicted protein disorder tendency may contribute to disease risk
Authors: Hu Yang , Liu Yunlong , Jung Jeesun , Dunker A Keith , Wang Yadong
Published: December 2011

Background

Recent studies suggest that many proteins or regions of proteins lack 3D structure. Defined as intrinsically disordered proteins, these proteins/peptides are functionally important. Recent advances in next generation sequencing technologies enable genome-wide identification of novel nucleotide variations in a specific population or cohort.

Results

Using the exonic single nucleotide variations (SNVs) identified in the 1,000 Genomes Project and distributed by the Genetic Analysis Workshop 17, we systematically analysed the genetic and predicted disorder potential features of the non-synonymous variations. The result of experiments suggests that a significant change in the tendency of a protein region to be structured or disordered caused by SNVs may lead to malfunction of such a protein and contribute to disease risk.

Conclusions

After validation with functional SNVs on the traits distributed by GAW17, we conclude that it is valuable to consider structure/disorder tendencies while prioritizing and predicting mechanistic effects arising from novel genetic variations.
Parallel progressive multiple sequence alignment on reconfigurable meshes
Authors: Nguyen Ken D , Pan Yi , Nong Ge
Published: December 2011

Background

One of the most fundamental and challenging tasks in bio-informatics is to identify related sequences and their hidden biological significance. The most popular and proven best practice method to accomplish this task is aligning multiple sequences together. However, multiple sequence alignment is a computing extensive task. In addition, the advancement in DNA/RNA and Protein sequencing techniques has created a vast amount of sequences to be analyzed that exceeding the capability of traditional computing models. Therefore, an effective parallel multiple sequence alignment model capable of resolving these issues is in a great demand.

Results

We design O(1) run-time solutions for both local and global dynamic programming pair-wise alignment algorithms on reconfigurable mesh computing model. To align m sequences with max length n, we combining the parallel pair-wise dynamic programming solutions with newly designed parallel components. We successfully reduce the progressive multiple sequence alignment algorithm's run-time complexity from O(m × n
4) to O(m) using O(m × n
3) processing units for scoring schemes that use three distinct values for match/mismatch/gap-extension. The general solution to multiple sequence alignment algorithm takes O(m × n
4) processing units and completes in O(m) time.

Conclusions

To our knowledge, this is the first time the progressive multiple sequence alignment algorithm is completely parallelized with O(m) run-time. We also provide a new parallel algorithm for the Longest Common Subsequence (LCS) with O(1) run-time using O(n
3) processing units. This is a big improvement over the current best constant-time algorithm that uses O(n
4) processing units.
Maximizing biomarker discovery by minimizing gene signatures
Authors: Chang Chang , Wang Junwei , Zhao Chen , Fostel Jennifer , Tong Weida , Bushel Pierre R , Deng Youping , Pusztai Lajos , Symmans W Fraser , Shi Tieliu
Published: December 2011

Background

The use of gene signatures can potentially be of considerable value in the field of clinical diagnosis. However, gene signatures defined with different methods can be quite various even when applied the same disease and the same endpoint. Previous studies have shown that the correct selection of subsets of genes from microarray data is key for the accurate classification of disease phenotypes, and a number of methods have been proposed for the purpose. However, these methods refine the subsets by only considering each single feature, and they do not confirm the association between the genes identified in each gene signature and the phenotype of the disease. We proposed an innovative new method termed Minimize Feature's Size (MFS) based on multiple level similarity analyses and association between the genes and disease for breast cancer endpoints by comparing classifier models generated from the second phase of MicroArray Quality Control (MAQC-II), trying to develop effective meta-analysis strategies to transform the MAQC-II signatures into a robust and reliable set of biomarker for clinical applications.

Results

We analyzed the similarity of the multiple gene signatures in an endpoint and between the two endpoints of breast cancer at probe and gene levels, the results indicate that disease-related genes can be preferably selected as the components of gene signature, and that the gene signatures for the two endpoints could be interchangeable. The minimized signatures were built at probe level by using MFS for each endpoint. By applying the approach, we generated a much smaller set of gene signature with the similar predictive power compared with those gene signatures from MAQC-II.

Conclusions

Our results indicate that gene signatures of both large and small sizes could perform equally well in clinical applications. Besides, consistency and biological significances can be detected among different gene signatures, reflecting the studying endpoints. New classifiers built with MFS exhibit improved performance with both internal and external validation, suggesting that MFS method generally reduces redundancies for features within gene signatures and improves the performance of the model. Consequently, our strategy will be beneficial for the microarray-based clinical applications.
Global host metabolic response to Plasmodium vivax infection: a 1H NMR based urinary metabonomic study
Authors: Sengupta Arjun , Ghosh Soumita , Basant Angika , Malusare Suhas , Johri Parul , Pathak Sulabha , Sharma Shobhona , Sonawat Haripalsingh M
Published: December 2011

Background

Plasmodium vivax is responsible for the majority of malarial infection in the Indian subcontinent. This species of the parasite is generally believed to cause a relatively benign form of the disease. However, recent reports from different parts of the world indicate that vivax malaria can also have severe manifestation. Host response to the parasite invasion is thought to be an important factor in determining the severity of manifestation. In this paper, attempt was made to determine the host metabolic response associated with P. vivax infection by means of NMR spectroscopy-based metabonomic techniques in an attempt to better understand the disease pathology.

Methods

NMR spectroscopy of urine samples from P. vivax- infected patients, healthy individuals and non-malarial fever patients were carried out followed by multivariate statistical analysis. Two data analysis techniques were employed, namely, Principal Component Analysis [PCA] and Orthogonal Projection to Latent Structure Discriminant Analysis [OPLS-DA]. Several NMR signals from the urinary metabolites were further selected for univariate comparison among the classes.

Results

The urine metabolic profiles of P. vivax- infected patients were distinct from those of healthy individuals as well as of non-malarial fever patients. A highly predictive model was constructed from urine profile of malarial and non-malarial fever patients. Several metabolites were found to be varying significantly across these cohorts. Urinary ornithine seems to have the potential to be used as biomarkers of vivax malaria. An increasing trend in pipecolic acid was also observed. The results suggest impairment in the functioning of liver as well as impairment in urea cycle.

Conclusions

The results open up a possibility of non-invasive analysis and diagnosis of P. vivax using urine metabolic profile. Distinct variations in certain metabolites were recorded, and amongst these, ornithine may have the potential of being used as biomarker of malaria. Pipecolic acid also showed increasing trend in the malaria patient compared to the other groups.
Effect of yoghurt containing Bifidobacterium lactis Bb12®on faecal excretion of secretory immunoglobulin A and human beta-defensin 2 in healthy adult volunteers
Authors: Kabeerdoss Jayakanthan , Devi R Shobana , Mary R Regina , Prabhavathi D , Vidya R , Mechenro John , Mahendri NV , Pugazhendhi Srinivasan , Ramakrishna Balakrishnan S
Published: December 2011

Background

Probiotics are used to provide health benefits. The present study tested the effect of a probiotic yoghurt on faecal output of beta-defensin and immunoglobulin A in a group of young healthy women eating a defined diet.

Findings

26 women aged 18-21 (median 19) years residing in a hostel were given 200 ml normal yoghurt every day for a week, followed by probiotic yoghurt containing Bifidobacterium lactis Bb12® (109 in 200 ml) for three weeks, followed again by normal yoghurt for four weeks. Stool samples were collected at 0, 4 and 8 weeks and assayed for immunoglobulin A and human beta-defensin-2 by ELISA. All participants tolerated both normal and probiotic yoghurt well. Human beta-defensin-2 levels in faeces were not altered during the course of the study. On the other hand, compared to the basal sample, faecal IgA increased during probiotic feeding (P = 0.0184) and returned to normal after cessation of probiotic yoghurt intake.

Conclusions

Bifidobacterium lactis Bb12® increased secretory IgA output in faeces. This property may explain the ability of probiotics to prevent gastrointestinal and lower respiratory tract infections.
The peroxisome proliferator-activated receptor delta +294T > C polymorphism and alcohol consumption on serum lipid levels
Authors: Wei Xian-Liang , Yin Rui-Xing , Miao Lin , Wu Dong-Feng
Published: December 2011

Background

The single nucleotide polymorphism (SNP) of peroxisome proliferator-activated receptor delta (PPARD) gene affects serum lipid profiles, but to what extent alcohol consumption interferes with this association remains unknown. The present study was undertaken to compare the association of PPARD +294T > C (rs2016520) polymorphism and serum lipid levels in the nondrinkers and drinkers.

Methods

A total of 685 unrelated nondrinkers and 497 drinkers aged 15-82 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the PPARD +294T > C was performed by polymerase chain reaction and restriction fragment length polymorphism. Interactions of the PPARD +294T > C genotypes and alcohol consumption on serum lipid levels were detected by using a factorial regression analysis after controlling for potential confounders.

Results

The levels of triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) A1, and the ratio of ApoA1 to ApoB were higher in drinkers than in nondrinkers (P < 0.05-0.001). There were no significant differences in the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and ApoB between the two groups (P > 0.05 for all). The frequencies of TT, TC and CC genotypes were 56.0%, 36.4% and 7.6% in nondrinkers, and 57.2%, 38.0% and 4.8% in drinkers (P > 0.05); respectively. The frequencies of T and C alleles were 74.2% and 25.8% in nondrinkers, and 76.2% and 23.8% in drinkers (P > 0.05); respectively. There was also no significant difference in the genotypic and allelic frequencies between males and females in both groups (P > 0.05 for all). The levels of TC in nondrinkers were different among the three genotypes (P = 0.01), the C allele carriers had higher serum TC levels than the C allele noncarriers. The levels of all seven lipid traits in drinkers were not different among the three genotypes (P > 0.05 for all). The interactions of PPARD +294T > C genotypes and alcohol consumption on serum lipid levels were not detected in the drinkers (P > 0.05 for all). Multiple linear regression analysis showed that serum TC, HDL-C, LDL-C, ApoA1, and ApoB levels were correlated with genotypes in drinkers but not in nondrinkers (P < 0.05-0.01).

Conclusions

These results suggest that the great majority of our study populations are beneficial from alcohol consumption. But there is no interaction between the PPARD +294T > C genotypes and alcohol consumption on serum lipid levels in the drinkers.
Polytomy identification in microbial phylogenetic reconstruction
Authors: Lin Guan Ning , Zhang Chao , Xu Dong
Published: December 2011

Background

A phylogenetic tree, showing ancestral relations among organisms, is commonly represented as a rooted tree with sets of bifurcating branches (dichotomies) for simplicity, although polytomies (multifurcating branches) may reflect more accurate evolutionary relationships. To represent the true evolutionary relationships, it is important to systematically identify the polytomies from a bifurcating tree and generate a taxonomy-compatible multifurcating tree. For this purpose we propose a novel approach, "PolyPhy", which would classify a set of bifurcating branches of a phylogenetic tree into a set of branches with dichotomies and polytomies by considering genome distances among genomes and tree topological properties.

Results

PolyPhy employs a machine learning technique, BLR (Bayesian logistic regression) classifier, to identify possible bifurcating subtrees as polytomies from the trees resulted from ComPhy. Other than considering genome-scale distances between all pairs of species, PolyPhy also takes into account different properties of tree topology between dichotomy and polytomy, such as long-branch retraction and short-branch contraction, and quantifies these properties into comparable rates among different sub-branches. We extract three tree topological features, 'LR' (Leaf rate), 'IntraR' (Intra-subset branch rate) and 'InterR' (Inter-subset branch rate), all of which are calculated from bifurcating tree branch sets for classification. We have achieved F-measure (balanced measure between precision and recall) of 81% with about 0.9 area under the curve (AUC) of ROC.

Conclusions

PolyPhy is a fast and robust method to identify polytomies from phylogenetic trees based on genome-wide inference of evolutionary relationships among genomes. The software package and test data can be downloaded from http://digbio.missouri.edu/ComPhy/phyloTreeBiNonBi-1.0.zip.