bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison between longitudinal shedding patterns of Salmonella Typhimurium and Salmonella Dublin on dairy farms
Authors: Kirchner M. , McLaren I. , Clifton‐Hadley F. A. , Liebana E. , Wales A. D. , Davies R. H.
Published: August 2012

Salmonella

in cattle herds may behave as epidemic or endemic infections. An intensive longitudinal sampling study across all management groups and ages on six dairy farms in the UK was used to examine patterns of Salmonella shedding, following the prior identification of either Salmonella Dublin (SD) (three farms) or Salmonella Typhimurium (ST) (three farms) on the premises in the context of clinical salmonellosis. Individual faeces, pooled faeces and environmental samples (total 5711 samples), taken approximately every six weeks for 15–24 weeks, were cultured for Salmonella. SD was detected at low frequency (on any visit, 0.5–18.3 per cent of samples positive) and most consistently in calves. By contrast, ST was isolated at higher frequency (on any visit, 6.8–75 per cent of samples positive), and in higher numbers, up to 107 cfu/g faeces. Significantly more samples from calves were positive for ST than were positive for SD (50.6 per cent v 3.1 per cent; P < 0.001), which was also true for milking cows (46.3 per cent v 4.4 per cent; P < 0.001). The differences could help to explain the different patterns of bovine infection classically associated with these two serovars in the UK. No consistent effect upon shedding was seen among the ST‐infected herds following vaccination.
CHRISTOFFEL FUNCTIONS AND UNIVERSALITY LIMITS FOR ORTHOGONAL RATIONAL FUNCTIONS
Authors: DECKERS KARL , LUBINSKY DORON S.
Published: August 2012

We establish limits for Christoffel functions associated with orthogonal rational functions, whose poles remain a fixed distance away from the interval of orthogonality [-1, 1], and admit a suitable asymptotic distribution. The measure of orthogonality μ is assumed to be regular on [-1, 1], and to satisfy a local condition such as continuity of μ′. As a consequence, we deduce universality limits in the bulk for reproducing kernels associated with orthogonal rational functions.
UNIFORM ASYMPTOTIC APPROXIMATIONS FOR THE MEIXNER–SOBOLEV POLYNOMIALS
Authors: KHWAJA S. FARID , OLDE DAALHUIS A. B.
Published: August 2012

We obtain uniform asymptotic approximations for the monic Meixner–Sobolev polynomials Sn(x). These approximations for n → ∞, are uniformly valid for x/n restricted to certain intervals, and are in terms of Airy functions. We also give asymptotic approximations for the location of the zeros of Sn(x), especially the small and the large zeros are discussed. As a limit case, we also give a new asymptotic approximation for the large zeros of the classical Meixner polynomials.

The method is based on an integral representation in which a hypergeometric function appears in the integrand. After a transformation, the hypergeometric functions can be uniformly approximated by unity, and all that remains are simple integrals for which standard asymptotic methods are used. As far as we are aware, this is the first time that standard uniform asymptotic methods have been used for the Sobolev-class of orthogonal polynomials.
CAN PLANNERS TAKE THE LEADERSHIP IN LOCAL ENVIRONMENTAL MANAGEMENT?
Authors: TANG ZHENGHONG , ZHAO NAN , ZHANG LEI
Published: August 2012

There is an increasing demand for environmental leadership in the planning process. In collaborative planning models, planners have a distinct role as a bridge between citizens, politicians, and scientists. However, there is limited research evaluating the leadership role of planners in the process of creating high quality environmental plans for local jurisdictions. This study proposes and tests a conceptual model with measurable indicators of planners' use of leadership to facilitate the creation of plans that can benefit the environment. This paper examined two distinct roles for planners: as an information source and as a facilitator. The descriptive results suggest that planners are exercising limited environmental leadership in local land use planning. The explanatory results highlight that the key to improve planners' leadership abilities lies with increasing planning capacity. Several policy recommendations are provided to improve planner's use of leadership processes in environmental planning and management.
FISHING FROM THE SAME POOL: THE INFLUENCE OF ENVIRONMENTAL GOVERNANCE ON LOCAL CLIMATE CHANGE ACTIONS IN SCOTLAND AND THE US PACIFIC NORTHWEST
Authors: JACKSON ANTHONY , ILLSLEY BARBARA , LYNCH WILLIAM
Published: August 2012

The impact of environmental governance on the delivery of local climate change plans is examined by comparing two transatlantic sub-national jurisdictions which have adopted stringent targets for reducing greenhouse gas emissions: Scotland and the Pacific Northwest region of the United States of America. The former relies on dirigiste top-down environmental governance, through which central government sets targets and imposes statutory duties that apply equally to all local councils. In the latter, a bottom-up multi-level form of environmental governance has emerged to compensate for the absence of a federal mandate. Specific action plans from a climate change pioneer in each location are assessed to test the strengths and limitations of these alternative modes of environmental governance: Portland in Oregon and Fife in Scotland. The Scottish dirigiste approach offers its local councils a consistent policy framework, allowing them to focus on specific measures to reduce greenhouse gas emissions, while avoiding concerns about free-rider effects from non-participating councils. The asymmetrical uptake of climate change measures by United States municipalities exposes their domestic market to the risks of carbon leakage that America sought to avoid in global markets during negotiations over the Kyoto Protocol.
UNNECESSARILY NEGLECTED IN PLANNING: ILLUSTRATION OF A PRACTICAL APPROACH TO IDENTIFY HUMAN DIMENSION IMPACTS OF MARINE OIL SPILLS
Authors: LORD FABIENNE , TULER SETH , WEBLER THOMAS , DOW KIRSTIN
Published: August 2012

Technological hazards research, including that on oil spills and their aftermath, is giving greater attention to human dimension impacts resulting from events and response. While oil spill contingency planners recognize the importance of human dimension impacts, little systematic attention is given to them in contingency plans. We introduce an approach to identifying human dimensions impacts using concepts from hazard and vulnerability assessment and apply it to the Bouchard-120 oil spill in Buzzards Bay, MA. Our assessment covers the spill, emergency response, clean-up, damage assessment, and mid-term recovery. This approach, while still exploratory, did demonstrate that the spill produced a range of positive and negative impacts on people and institutions and that these were mediated by vulnerabilities. We suggest ways in which the framework may help spill managers to learn from events and improve contingency planning by anticipating risks to social systems and identifying strategies to reduce impacts.
BRAZILIAN GMO REGULATION: DOES IT HAVE AN ENVIRONMENTAL APPROACH?
Authors: PIZELLA DENISE GALLO , DE SOUZA MARCELO PEREIRA
Published: August 2012

Brazil is the second largest producer of genetically modified crops (GM crops) and the National Technical Commission on Biosafety (CTNBio) the decision making agency on this matter. The country uses Risk Analysis (RA) and project EIA as tools for biosafety evaluation. This paper aims to review the appropriateness of these tools for evaluating the environmental impacts of GM crops, also considering institutional aspects. An overview of the process of release of GM crops in Brazil along with important operational and institutional aspects is provided. The results indicate that project EIA could be applied to GM crops in specific sites and RA could give support to the evaluation of GM crop itself. Regarding institutional issues, it is concluded that decisions should be made by the environmental bodies, and not by the CTNBio.
INTEGRATION OF FORESTRY DECISION SUPPORT SYSTEMS IN GIS
Authors: PIZZIRANI STEFANIA , BATHGATE STEPHEN
Published: August 2012

Landscape characteristics underpin the ability of the forestry industry to deliver in an increasingly complex operational environment. However, the range of site types within the British public forest estate includes many with soil or exposure constraints. Until recently it was not possible to effectively assess the scale of constraints and spatially allocate land appropriately to the objectives suggested by policy makers. Stand level forestry decision support systems have been developed to address these issues but it is difficult to incorporate their outputs into the spatial forest plans, limiting their operational use. The MOTIVE project (EU 7th Framework Programme) provided an opportunity to integrate stand level tools with spatial inventory data. The output is a comprehensive GIS layer containing silvicultural, geophysical and climate data, and site-specific decision support system outputs. This paper describes the climate and inventory data, models, GIS methods, the visualisation of outputs, and the impact on stakeholders.
Spatial Distribution of Photocurrent in Si Stripes under Tilted Illumination Measured by Multimode Scanning Probe Microscopy
Authors: Bolotov Leonid , Tada Tetsuya , Poborchii Vladimir , Fukuda Koichi , Kanayama Toshihiko
Published: August 2012

Spatial distribution of photocurrent in Si stripes of 50–1000 nm in width were investigated as a function of optical excitation wavelength by multimode scanning probe microscopy (MSPM). Inhomogeneous distribution of the MSPM photocurrent in the Si stripe interior was attributed to the light intensity profile. A model that included light absorption depth profile and the probe-induced band-bending region reproduced the photocurrent profile for tilted illumination of the stripes. An effective spatial resolution of ∼10 nm was deduced from the photocurrent measurements with multimode SPM in the constant-force mode.
Loss of intracellular lipid binding proteins differentially impacts saturated fatty acid uptake and nuclear targeting in mouse hepatocytes
Authors: Storey Stephen M. , McIntosh Avery L. , Huang Huan , Martin Gregory G. , Landrock Kerstin K. , Landrock Danilo , Payne H. Ross , Kier Ann B. , Schroeder Friedhelm
Published: August 2012

The liver expresses high levels of two proteins with high affinity for long-chain fatty acids (LCFAs): liver fatty acid binding protein (L-FABP) and sterol carrier protein-2 (SCP-2). Real-time confocal microscopy of cultured primary hepatocytes from gene-ablated (L-FABP, SCP-2/SCP-x, and L-FABP/SCP-2/SCP-x null) mice showed that the loss of L-FABP reduced cellular uptake of 12- N-methyl-(7-nitrobenz-2-oxa-1,3-diazo)-aminostearic acid (a fluorescent-saturated LCFA analog) by ∼50%. Importantly, nuclear targeting of the LCFA was enhanced when L-FABP was upregulated (SCP-2/SCP-x null) but was significantly reduced when L-FABP was ablated (L-FABP null), thus impacting LCFA nuclear targeting. These effects were not associated with a net decrease in expression of key membrane proteins involved in LCFA or glucose transport. Since hepatic LCFA uptake and metabolism are closely linked to glucose uptake, the effect of glucose on L-FABP-mediated LCFA uptake and nuclear targeting was examined. Increasing concentrations of glucose decreased cellular LCFA uptake and even more extensively decreased LCFA nuclear targeting. Loss of L-FABP exacerbated the decrease in LCFA nuclear targeting, while loss of SCP-2 reduced the glucose effect, resulting in enhanced LCFA nuclear targeting compared with control. Simply, ablation of L-FABP decreases LCFA uptake and even more extensively decreases its nuclear targeting.
Body fat loss and compensatory mechanisms in response to different doses of aerobic exercise—a randomized controlled trial in overweight sedentary males
Authors: Rosenkilde Mads , Auerbach Pernille , Reichkendler Michala Holm , Ploug Thorkil , Stallknecht Bente Merete , Sjödin Anders
Published: August 2012

The amount of weight loss induced by exercise is often disappointing. A diet-induced negative energy balance triggers compensatory mechanisms, e.g., lower metabolic rate and increased appetite. However, knowledge about potential compensatory mechanisms triggered by increased aerobic exercise is limited. A randomized controlled trial was performed in healthy, sedentary, moderately overweight young men to examine the effects of increasing doses of aerobic exercise on body composition, accumulated energy balance, and the degree of compensation. Eighteen participants were randomized to a continuous sedentary control group, 21 to a moderate-exercise (MOD; 300 kcal/day), and 22 to a high-exercise (HIGH; 600 kcal/day) group for 13 wk, corresponding to ∼30 and 60 min of daily aerobic exercise, respectively. Body weight (MOD: −3.6 kg, P < 0.001; HIGH: −2.7 kg, P = 0.01) and fat mass (MOD: −4.0 kg, P < 0.001 and HIGH: −3.8 kg, P < 0.001) decreased similarly in both exercise groups. Although the exercise-induced energy expenditure in HIGH was twice that of MOD, the resulting accumulated energy balance, calculated from changes in body composition, was not different (MOD: −39.6 Mcal, HIGH: −34.3 Mcal, not significant). Energy balance was 83% more negative than expected in MOD, while it was 20% less negative than expected in HIGH. No statistically significant changes were found in energy intake or nonexercise physical activity that could explain the different compensatory responses associated with 30 vs. 60 min of daily aerobic exercise. In conclusion, a similar body fat loss was obtained regardless of exercise dose. A moderate dose of exercise induced a markedly greater than expected negative energy balance, while a higher dose induced a small but quantifiable degree of compensation.
Acute regulation of activin A and its binding protein, follistatin, in serum and tissues following lipopolysaccharide treatment of adult male mice
Authors: Wu Hui , Chen Yi , Winnall Wendy R. , Phillips David J. , Hedger Mark P.
Published: August 2012

Activin A, a member of the transforming growth factor-β family, increases in the circulation within 1 h after administration of bacterial LPS. To clarify the origins of this rapid increase, the distribution of activin A and its binding protein, follistatin, and their production following LPS treatment, were assessed in adult male mice. In untreated mice, activin A was detectable in all 23 tissues examined, with highest mRNA expression (as measured by quantitative RT-PCR) was found in the liver, and the largest concentration of activin A protein (by ELISA) was found in the bone marrow. Likewise, follistatin mRNA and protein were present in all tissues, with highest expression in the vas deferens. Activin A and follistatin mRNA did not increase significantly in any tissue within the first hour after LPS, but activin A protein decreased by 35% in the bone marrow and increased 5-fold in the lung. No significant changes were observed in any other tissue. Activin A reached a peak in the circulation 1 h following LPS, and then declined. Cycloheximide, an inhibitor of protein translation, reduced this increase of activin A by more than 50%. Actinomycin D, an inhibitor of mRNA transcription, had no effect. Circulating follistatin did not increase until 4 h after LPS and was not affected by either inhibitor. These data indicate that the rapid increase in circulating activin A during LPS-induced inflammation is regulated at the posttranscriptional level, apparently from newly translated and stored protein, and implicate bone marrow-derived cells, and, in particular, neutrophils, as a significant source of this preformed activin A.
Increased oxidative stress and anaerobic energy release, but blunted Thr172-AMPKα phosphorylation, in response to sprint exercise in severe acute hypoxia in humans
Authors: Morales-Alamo David , Ponce-González Jesús Gustavo , Guadalupe-Grau Amelia , Rodríguez-García Lorena , Santana Alfredo , Cusso Maria Roser , Guerrero Mario , Guerra Borja , Dorado Cecilia , Calbet José A. L.
Published: August 2012

AMP-activated protein kinase (AMPK) is a major mediator of the exercise response and a molecular target to improve insulin sensitivity. To determine if the anaerobic component of the exercise response, which is exaggerated when sprint is performed in severe acute hypoxia, influences sprint exercise-elicited Thr172-AMPKα phosphorylation, 10 volunteers performed a single 30-s sprint (Wingate test) in normoxia and in severe acute hypoxia (inspired Po2: 75 mmHg). Vastus lateralis muscle biopsies were obtained before and immediately after 30 and 120 min postsprint. Mean power output and O2 consumption were 6% and 37%, respectively, lower in hypoxia than in normoxia. O2 deficit and muscle lactate accumulation were greater in hypoxia than in normoxia. Carbonylated skeletal muscle and plasma proteins were increased after the sprint in hypoxia. Thr172-AMPKα phosphorylation was increased by 3.1-fold 30 min after the sprint in normoxia. This effect was prevented by hypoxia. The NAD+-to-NADH.H+ ratio was reduced (by 24-fold) after the sprints, with a greater reduction in hypoxia than in normoxia ( P < 0.05), concomitant with 53% lower sirtuin 1 (SIRT1) protein levels after the sprint in hypoxia ( P < 0.05). This could have led to lower liver kinase B1 (LKB1) activation by SIRT1 and, hence, blunted Thr172-AMPKα phosphorylation. Ser485-AMPKα1/Ser491-AMPKα2 phosphorylation, a known negative regulating mechanism of Thr172-AMPKα phosphorylation, was increased by 60% immediately after the sprint in hypoxia, coincident with increased Thr308-Akt phosphorylation. Collectively, our results indicate that the signaling response to sprint exercise in human skeletal muscle is altered in severe acute hypoxia, which abrogated Thr172-AMPKα phosphorylation, likely due to lower LKB1 activation by SIRT1.
Adhesion of malignant mammary tumor cells MDA-MB-231 to microvessel wall increases microvascular permeability via degradation of endothelial surface glycocalyx
Authors: Cai Bin , Fan Jie , Zeng Min , Zhang Lin , Fu Bingmei M.
Published: August 2012

To investigate the effect of tumor cell adhesion on microvascular permeability ( P) in intact microvessels, we measured the adhesion rate of human mammary carcinoma MDA-MB-231, the hydraulic conductivity (Lp), the P, and reflection coefficient (σ) to albumin of the microvessels at the initial tumor cell adhesion and after ∼45 min cell perfusion in the postcapillary venules of rat mesentery in vivo. Rats (Sprague-Dawley, 250–300 g) were anesthetized with pentobarbital sodium given subcutaneously. A midline incision was made in the abdominal wall, and the mesentery was gently taken out and arranged on the surface of a glass coverslip for the measurement. An individual postcapillary venule was perfused with cells at a rate of ∼1 mm/s, which is the mean blood flow velocity in this type of microvessels. At the initial tumor cell adhesion, which was defined as one adherent cell in ∼100- to 145-μm vessel segment, Lp was 1.5-fold and P was 2.3-fold of their controls, and σ decreased from 0.92 to 0.64; after ∼45-min perfusion, the adhesion increased to ∼5 adherent cells in ∼100- to 145-μm vessel segment, while Lp increased to 2.8-fold, P to 5.7-fold of their controls, and σ decreased from 0.92 to 0.42. Combining these measured data with the predictions from a mathematical model for the interendothelial transport suggests that tumor cell adhesion to the microvessel wall degrades the endothelial surface glycocalyx (ESG) layer. This suggestion was confirmed by immunostaining of heparan sulfate of the ESG on the microvessel wall. Preserving of the ESG by a plasma glycoprotein orosomucoid decreased the P to albumin and reduced the tumor cell adhesion.
Muscarinic acetylcholine receptors enhance neonatal mouse hypoglossal motoneuron excitability in vitro
Authors: Ireland Matthew F. , Funk Gregory D. , Bellingham Mark C.
Published: August 2012

In brain stem slices from neonatal ( postnatal days 0–4) CD-1 mice, muscarinic ACh receptors (MAChRs) increased rhythmic inspiratory-related and tonic hypoglossal nerve discharge and depolarized single hypoglossal motoneurons (HMs) via an inward current without changing input resistance. These responses were blocked by the MAChR antagonist 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP; 100 nM). MAChRs shifted voltage-dependent activation of the hyperpolarization-activated cation current to more positive levels. MAChRs increased the HM repetitive firing rate and decreased rheobase, with both effects being blocked by 4-DAMP. Muscarinic agonists reduced the afterhyperpolarization of single action potentials (APs), suggesting that small-conductance Ca2+-dependent K+ current inhibition increased the HM firing rate. Muscarinic agonists also reduced the AP amplitude and slowed its time course, suggesting that MAChRs inhibited voltage-gated Na+ channels. To compare muscarinic excitation of single HMs to muscarinic excitatory effects on motor output in thicker brain stem slices requiring higher extracellular K+ for rhythmic activity, we tested the effects of muscarinic agonists on single HM excitability in high-K+ artificial cerebrospinal fluid (aCSF). In high-K+ aCSF, muscarinic agonists still depolarized HMs and altered AP size and shape, as in standard aCSF, but did not increase the steady-state firing rate, decrease afterhyperpolarization, or alter threshold potential. These results indicate that the basic cellular response of HMs to muscarinic receptors is excitatory, via a number of distinct mechanisms, and that this excitatory response will be largely preserved in rhythmically active brain stem slices.
Exercise delays neutrophil apoptosis by a G-CSF-dependent mechanism
Authors: Mooren Frank C. , Völker Klaus , Klocke Rainer , Nikol Sigrid , Waltenberger Johannes , Krüger Karsten
Published: August 2012

The aim of the study was to determine whether exercise affects neutrophil apoptosis and to characterize the underlying mechanisms. Using annexin V labeling, neutrophil apoptosis was measured using flow cytometry after various bouts of exercise (marathon run, concentric/eccentric treadmill exercise, moderate/intensive resistance training) and in vitro conditions. Similarly, apoptosis-related markers as death receptors/ligands and mitochondrial membrane potential were detected. Furthermore, concentrations of intracellular free calcium and glutathione were measured using spectrofluorometry. After both marathon run and intensive laboratory exercise tests, neutrophil apoptosis was delayed. Furthermore, neutrophils mitochondrial membrane potential and death receptor/ligand expression were not affected by exercise. Apoptosis delay was accompanied under some exercise conditions by enhanced intracellular calcium transients and decreased glutathione levels. A delay of spontaneous apoptosis in vitro could be induced by incubation of neutrophils in postexercise serum. Heating of postexercise serum abolished the apoptosis delaying effect. In vitro stimulation of resting neutrophils with granulocyte-colony-stimulating factor (G-CSF) and C-reactive protein resulted in apoptosis delay too. Addition of anti-G-CSF antibody to postexercise serum was also effective in reversing its apoptosis-delaying effect. Exercise-induced mobilization of neutrophils is associated with a delay of apoptosis. This fundamental process seems to maintain exercise-induced neutrophilia and to contribute to the alerting and activation of the nonadaptive immune system known from other inflammatory conditions. An important extracellular trigger of apoptosis delay during exercise conditions seems to be G-CSF; intracellular processes may include calcium and redox signaling.
Chemopreventive and Chemotherapeutic Actions of mTOR Inhibitor in Genetically Defined Head and Neck Squamous Cell Carcinoma Mouse Model
Authors: Sun Zhi-Jun , Zhang Lu , Hall Bradford , Bian Yansong , Gutkind J. Silvio , Kulkarni Ashok B.
Published: August 2012

Purpose: To assess the efficacy of rapamycin treatment in chemoprevention and chemotherapy of tumorigenesis in a genetically defined mouse model of head and neck squamous cell carcinoma (HNSCC).

Experimental design: Knockdown of Tgfbr1 and/or Pten using siRNA-mediated RNA interference was carried out in human HNSCC cell lines to analyze molecular changes in the mTOR pathway. Tgfbr1flox/flox; Ptenflox/flox; K14-CreERtam mice were treated with oral gavage of tamoxifen for the conditional deletion of Tgfbr1 and Pten in oral mucosa, resulting in HNSCC. Tgfbr1 and Pten conditonal deletion (2cKO) mice were treated with rapamycin before or after the onset of HNSCC, and the efficacy of this treatment was assessed by determining tumor burden, longevity, and molecular analysis of the mTOR pathway. Molecular changes observed in human HNSCC cell lines and 2cKO mice were compared to identify key alterations in the mTOR pathway.

Results: Knockdown of Tgfbr1 and/or Pten in human HNSCC cell lines resulted in activation of mTOR activity complex 1 and increased levels of survivin. Furthermore, we observed similar changes in HNSCC of the 2cKO mouse. In the human HNSCC tissue array, a loss of Tgfbr1 expression correlated with increased survivin levels. Chemopreventive rapamycin treatment significantly delayed the onset of the HNSCC tumors and prolonged survival in 2cKO mice. In addition, we also found that rapamycin had a therapeutic effect on squamous cell carcinomas in these mice. In 2cKO HNSCC tongue tumors, rapamycin treatment induced apoptosis, inhibited cell proliferation and phosphorylation of Akt and S6, and decreased survivin expression.

Conclusions: These findings indicate that tumorigenesis in 2cKO HNSCC is associated with activation of the Akt/mTOR/survivin pathway, and inhibition of this pathway by rapamycin treatment successfully ameliorates the onset and progression of tumorigenesis. Clin Cancer Res; 18(19); 5304–13. ©2012 AACR.
Zeroing in on ROS1 Rearrangements in Non–Small Cell Lung Cancer
Authors: Stumpfova Magda , Jänne Pasi A.
Published: August 2012

Rimkunas and colleagues report on the development and validation of an immunohistochemical assay evaluating non–small cell lung cancers (NSCLC) for the presence of ROS1 fusions. The diagnostic was validated in a screen of 556 NSCLCs, identifying 9 (1.6%) tumors with oncogenic ROS1 rearrangements. These patients are candidates for ROS1-targeted therapies. Clin Cancer Res; 18(16); 4222–4. ©2012 AACR.
Hepatocyte Growth Factor Enhances Alternative Splicing of the Krüppel-like Factor 6 (KLF6) Tumor Suppressor to Promote Growth through SRSF1
Authors: Muñoz Úrsula , Puche Juan E. , Hannivoort Rebekka , Lang Ursula E. , Cohen-Naftaly Michal , Friedman Scott L.
Published: August 2012

Alternative splicing of the Krüppel-like factor 6 (KLF6) tumor suppressor into an antagonistic splice variant 1 (SV1) is a pathogenic event in several cancers including hepatocellular carcinoma (HCC) because elevated SV1 is associated with increased tumor metastasis and mortality. Ras activation is one factor that can enhance KLF6 splicing in cancer cells, however pathways driving KLF6 splicing are unknown. Splice site selection is regulated by splice factors that include serine/arginine-rich (SR) proteins such as SRSF1 (ASF-SF2), which in turn is controlled by phosphoinositide 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) signaling pathway. Because signaling pathways downstream of the liver mitogen hepatocyte growth factor (HGF) include Akt, we explored whether HGF induces KLF6 alternative splicing. In HepG2 cells, HGF (25 ng/mL) significantly increases the ratio of SV1/KLF6 full by 40% through phosphorylation of Akt and subsequent downregulation of two splicing regulators, SRSF3 (SRp20) and SRSF1. Decreased SRSF3 levels regulate SRSF1 levels by alternative splicing associated with the nonsense-mediated mRNA decay pathway (AS-NMD), which stimulates cell growth by decreasing p21 levels. Enhanced cell replication through increased KLF6 alternative splicing is a novel growth-promoting pathway of HGF that could contribute to the molecule's mitogenic activity in physiologic liver growth and hepatocellular carcinoma. Mol Cancer Res; 10(9); 1216–27. ©2012 AACR.
Dry Eye Symptoms in Patients after Eyelid Reconstruction with Full-Thickness Eyelid Defects: Using the Tomey TG-1000 Thermographer
Authors: Gonnermann Johannes , Klein Julian P. , Klamann Matthias K.J. , Maier Anna-Karina , Pleyer Uwe , Joussen Antonia M. , Bertelmann Eckart
Published: August 2012

Background: Large full-thickness eyelid defects are conventionally reconstructed by either a Hughes flap or Cutler-Beard bridge flap. Since the structure of the eyelid and its components are necessary for the tear film production and stability, we investigated the outcome after eyelid reconstruction focusing on dry eye symptoms using a new thermographic device, the TG-1000. Methods: Seventeen eyes of patients formerly treated with Hughes flaps (n = 16) and a Cutler-Beard bridge flap (n = 1) were compared to untreated healthy eyes (n = 17) regarding the functional and aesthetic outcome. The follow-up ranged from 3 to 63 months (mean 24.88 ± 17.86). Results: There was no significant difference in Schirmer’s test, break-up time and ocular surface temperature (p > 0.05) between patients after full-thickness eyelid reconstruction and a control group. Eleven patients had minor postoperative complications such as notching of the lid margin (11/17), epiphora (1/17), superficial punctate keratitis (6/17), trichiasis (2/17) and a mild tendency to eversion of the lid margin (6/17). More than 75% of the patients rated their postoperative aesthetic outcome as good or even excellent. Conclusion: The new TG-1000 device is a simple and quick tool for screening of dry eye. This study shows that tarsoconjunctival grafts offer good aesthetic and functional outcome with sufficient tear film composition and stability.
Association between Angiotensin II Type 2 Receptor Gene A/C3123 Polymorphism and High-Density Lipoprotein Cholesterol with Hypertension in Asymptomatic Women
Authors: Kotani Kazuhiko , Sakane Naoki , Taniguchi Nobuyuki
Published: August 2012

Objective: The present study investigated the association between the angiotensin II type 2 receptor (AT2R) gene adenine/cytosine (A/C)-3123 polymorphism and cardiometabolic variables in subjects with and without hypertension. Methods: Cardiometabolic variables, in addition to genotyping by an allele-specific DNA assay, were measured in 161 asymptomatic community-dwelling Japanese women (age range 30–83 years). They were divided into hypertensive (n = 82, age 50–81 years) and nonhypertensive (n = 79, age 30–83 years) subjects. Results: The A-allele carriers (n = 53) showed significantly lower high-density lipoprotein cholesterol (HDL-C) levels than the non-A-allele carriers (n = 26) among nonhypertensive subjects (1.45 ± 0.38 vs. 1.66 ± 0.33 mmol/l, p = 0.02). Even when multiple-adjusted analyses were performed, the HDL-C levels continued to differ significantly and independently of other variables, including the body mass index and insulin resistance index, between A-allele and non-A-allele carriers. However, this association was not observed among hypertensive subjects. Conclusion: The present study demonstrated that A-allele carriers had significantly lower HDL-C levels than did non-A-allele carries among nonhypertensive women, while this association was not observed among hypertensive women. This indicates that the A/C3124 polymorphism may be a marker associated with HDL metabolism by hypertension. This was a small study, so further research is warranted to confirm the observed association.
Prevalence, Incidence and Obstetric Factors’ Impact on Female Urinary Incontinence in Europe: A Systematic Review
Authors: Cerruto Maria Angela , D’Elia Carolina , Aloisi Alberto , Fabrello Miriam , Artibani Walter
Published: August 2012

Objectives: A systematic review of the published data on the prevalence, incidence and risk factors of female urinary incontinence (UI) and obstetric treatment of UI in Europe. Data Sources: Epidemiologic studies were sought via PubMed to identify articles published in English, French, Spanish, German and Italian between 2000 and September 30, 2010, in Europe. Results: The prevalence of UI ranged from 14.1 to 68.8% and increased with increasing age. Significant risk factors for UI in pregnancy were maternal age ≥35 years and initial body mass index, a family history of UI and parity. UI in women who delivered ‘at term’ ranged from 26 to 40.2%, with a remission rate of 3 months after childbirth of up to 86.4%. Pelvic floor muscle training may help to prevent postpartum UI in primiparous women without UI during pregnancy. Conclusion: UI definition, outcome measures, survey methods and validation criteria are still heterogeneous, and thus it is difficult to compare data and impossible to draw definite conclusions.
The Methyl Xanthine Caffeine Inhibits DNA Damage Signaling and Reactive Species and Reduces Atherosclerosis in ApoE
−/−
Mice
Authors: Mercer John R. , Gray Kelly , Figg Nichola , Kumar Sheetal , Bennett Martin R.
Published: August 2012

Objective—

Caffeine remains one of the most widely consumed drugs in the world. Caffeine has multiple actions, including inhibition of the DNA damage response, and its metabolites, 1-methylxanthine and 1-methyluric acid, are potent antioxidants. Combined, these properties can exert direct effects on cell proliferation, cell death, inflammation, and DNA repair, all important processes that occur in atherosclerosis.

Methods and Results—

We first examined the effects of caffeine on mouse vascular smooth muscle cells. Caffeine inhibited activation of the DNA damage response regulator ataxia telangiectasia mutated protein and its downstream targets. Caffeine delayed DNA repair, had a concentration-dependent effect on cell proliferation, and protected against apoptosis. In vitro caffeine reduced oxygen consumption and decreased generation of reactive oxygen species. In vivo caffeine reduced DDR activation in vascular and nonvascular tissues, reduced reactive nitrogen species and serum levels of the DNA adduct 8-oxo-guanine, and inhibited atherogenesis in fat−fed ApoE
−/−
mice. Reduction in atherosclerosis was independent of the effects on blood pressure and serum lipids but associated with reduced cell proliferation and ataxia telangiectasia mutated protein activation.

Conclusion—

The Methyl Xanthine caffeine inhibits the DNA damage response in vitro and in vivo, regulates both cell proliferation and apoptosis after DNA damage, inhibits reactive species, and reduces atherogenesis in ApoE
−/−
mice.
Modulation of the Cochaperone AHA1 Regulates Heat-Shock Protein 90 and Endothelial NO Synthase Activation by Vascular Endothelial Growth Factor
Authors: Desjardins Fanny , Delisle Chantal , Gratton Jean-Philippe
Published: August 2012

Objective—

Vascular endothelial growth factor (VEGF) signaling to endothelial NO synthase (eNOS) plays a central role in angiogenesis. In endothelial cells (ECs), heat-shock protein 90 (Hsp90) is also a regulator of eNOS activity. Our study is designed to determine whether modulation of the activator of Hsp90 ATPase 1 (AHA1) regulates the function of Hsp90 in ECs.

Methods and Results—

We show that eNOS phosphorylation on Ser-1179 after VEGF stimulation is significantly reduced in ECs transfected with a small interfering RNA against AHA1. Accordingly, VEGF-stimulated NO production, endothelial permeability, cell migration, and EC invasion in Matrigel implants in mice are reduced in small interfering RNA against AHA1-treated conditions. Furthermore, the induction of eNOS association with Hsp90 after VEGF stimulation is decreased in AHA1-downregulated cells. We also demonstrate that modulation of Hsp90 activity by AHA1 regulates phosphorylation of Hsp90 on Tyr-300. Interestingly, the association of AHA1 with Hsp90 is increased after c-Src–mediated phosphorylation of Hsp90 on Tyr-300. Finally, we show that overexpression of AHA1 in ECs promotes association of eNOS and Hsp90, phosphorylation of Ser-1179 of eNOS, increases NO production, and cell migration.

Conclusion—

These results reveal that modulation of Hsp90 activity by AHA1 regulates VEGF signaling to eNOS and angiogenesis.
IL1B
and
VWF
Variants Are Associated With Fibrinolytic Early Recanalization in Patients With Ischemic Stroke
Authors: Fernández-Cadenas Israel , del Río-Espínola Alberto , Giralt Dolors , Domingues-Montanari Sophie , Quiroga Adoracion , Mendióroz Maite , Ruíz Agustin , Ribó Marc , Serena Joaquin , Obach Victor , Freijo Mari Mar , Martí-Fábregas Joan , Delgado Pilar , Montaner Joan
Published: August 2012

Background and Purpose—

There is a great interindividual variability among patients with acute ischemic stroke regarding the response to intravenous tissue-type plasminogen activator treatment. The aim of this study was to identify genetic variants associated with recanalization, and thus treatment efficacy, after tissue-type plasminogen activator administration.

Methods—

A total of 140 single nucleotide polymorphisms from 97 candidate genes were successfully genotyped by SNPlex in 2 cohorts, accounting for 497 prospectively recruited tissue-type plasminogen activator-treated patients, of whom 33% recanalized during tissue-type plasminogen activator infusion. Functional studies were then performed, including assessment of interleukin 1B mRNA levels and von Willebrand factor, FIII, FVII, FVIII, and FX protein activity.

Results—

After replication, the following single nucleotide polymorphisms were associated with early recanalization: rs1143627 in
IL1B
gene (CC: 53.1% of recanalization, A-carriers: 32.7%;
P
=0.022; replication cohort:
P
=0.046), rs16944 in
IL1B
gene (AA: 50% of recanalization, G-carriers: 32%;
P
=0.038; replication cohort:
P
=0.049), and rs1063856 in the
vWF
gene (GG: 53.8% of recanalization, A-carriers: 31.5%;
P
=0.006; replication cohort:
P
=0.046). The functional studies revealed an association between the rs1063856 single nucleotide polymorphisms in
vWF
and FVIII activity (AA: 115.93%, AG: 156.07%, GG: 83.42%;
P
=0.005).

Conclusions—

Three single nucleotide polymorphisms were associated with tissue-type plasminogen activator efficacy in the Spanish population, and their mechanism of action might be associated with the activity of coagulation factors.
Comparison of Computed Tomography Perfusion and Magnetic Resonance Imaging Perfusion-Diffusion Mismatch in Ischemic Stroke
Authors: Campbell Bruce C.V. , Christensen Søren , Levi Christopher R. , Desmond Patricia M. , Donnan Geoffrey A. , Davis Stephen M. , Parsons Mark W.
Published: August 2012

Background and Purpose—

Perfusion imaging has the potential to select patients most likely to respond to thrombolysis. We tested the correspondence of computed tomography perfusion (CTP)-derived mismatch with contemporaneous perfusion-diffusion magnetic resonance imaging (MRI).

Methods—

Acute ischemic stroke patients 3 to 6 hours after onset had CTP and perfusion-diffusion MRI within 1 hour, before thrombolysis. Relative cerebral blood flow (relCBF) and time to peak of the deconvolved tissue residue function (Tmax) were calculated. The diffusion lesion (diffusion-weighted imaging) was registered to the CTP slabs and manually outlined to its maximal visual extent. Volumetric accuracy of CT-relCBF infarct core (compared with diffusion-weighted imaging) was tested. To reduce false-positive low CBF regions, relCBF core was restricted to voxels within a relative time-to-peak (relTTP) >4 seconds for lesion region of interest. The MR-Tmax >6 seconds perfusion lesion was automatically segmented and registered to CTP. Receiver-operating characteristic analysis determined the optimal CT-Tmax threshold to match MR-Tmax >6 seconds. Agreement of these CT parameters with MR perfusion-diffusion mismatch in coregistered slabs was assessed (mismatch ratio >1.2, absolute mismatch >10 mL, infarct core <70 mL).

Results—

In analysis of 49 patients (mean onset to CT, 213 minutes; mean CT to MR, 31 minutes), constraining relCBF <31% within the automated relTTP perfusion lesion region of interest reduced the median magnitude of volumetric error (vs diffusion-weighted imaging) from 47.5 mL to 15.8 mL (
P
<0.001). The optimal CT-Tmax threshold to match MR-Tmax >6 seconds was 6.2 seconds (95% confidence interval, 5.6–7.3 seconds; sensitivity, 91%; specificity, 70%; area under the curve, 0.87). Using CT-Tmax >6 seconds “penumbra” and relTTP-constrained relCBF “core,” CT-based and MRI-based mismatch status was concordant in 90% (kappa=0.80).

Conclusions—

Quantitative CTP mismatch classification using relCBF and Tmax is similar to perfusion-diffusion MRI. The greater accessibility of CTP may facilitate generalizability of mismatch-based selection in clinical practice and trials.
Open Source Architecture: An Exploration of Source Code and Access in Architectural Design
Authors: Vardouli Theodora , Buechley Leah
Published: August 2012

The term open source is increasingly applied to architecture, yet there is little consensus about what it means in this context. This paper explores how different literal and metaphoric interpretations of the “access to source code” principle, set by the founders of the Free and Open Source Software movements, are being applied to architecture. The authors explore several challenges that have arisen in the translation of open source rhetoric from cyberspace to architectural space and discuss paths for new conceptual and programmatic agendas promoting user empowerment and democratization in architectural design.
Turbulence and Diapycnal Mixing in Drake Passage
Authors: St. Laurent L. , Naveira Garabato A. C. , Ledwell J. R. , Thurnherr A. M. , Toole J. M. , Watson A. J.
Published: August 2012

Direct measurements of turbulence levels in the Drake Passage region of the Southern Ocean show a marked enhancement over the Phoenix Ridge. At this site, the Antarctic Circumpolar Current (ACC) is constricted in its flow between the southern tip of South America and the northern tip of the Antarctic Peninsula. Observed turbulent kinetic energy dissipation rates are enhanced in the regions corresponding to the ACC frontal zones where strong flow reaches the bottom. In these areas, turbulent dissipation levels reach 10−8 W kg−1 at abyssal and middepths. The mixing enhancement in the frontal regions is sufficient to elevate the diapycnal turbulent diffusivity acting in the deep water above the axis of the ridge to 1 × 10−4 m2 s−1. This level is an order of magnitude larger than the mixing levels observed upstream in the ACC above smoother bathymetry. Outside of the frontal regions, dissipation rates are O(10−10) W kg−1, comparable to the background levels of turbulence found throughout most mid- and low-latitude regions of the global ocean.
The Evolution of Financial Structure in the G-7 Over 1997–2010
Authors: Davis E. Philip
Published: August 2012

As background for this special issue of the Review, this article provides an overview of recent developments in financial structure in the major industrial countries using national flow of funds balance sheet data. We focus in particular on changes in the size and composition of the balance sheet for the major sectors — households, companies, general government, foreign and financial as well as banks and institutional investors separately. Two recent subperiods are distinguished, namely the ‘great moderation’ of high growth and low inflation from roughly 1997–2006 and then the crisis period 2007–10. We discern elements of convergence — notably in corporate leverage — but also some continuing contrasts — such as household debt — between market- and bank-dominated financial systems, while highlighting that short-run changes arising from the conjuncture may blur longer-term trends in financial structure. Looking ahead, the data highlight common challenges from public and household debt, albeit to an extent that varies markedly between countries. Bank deleveraging and recapitalisation appear slow, while a subsector including shadow banks continues to grow except in the US. There are contrasts between France and Italy on the one hand and Germany on the other which underline the vulnerability of the former in the ongoing Euro Area crisis.
Planning a Future for Phnom Penh: Mega Projects, Aid Dependence and Disjointed Governance
Authors: Paling Willem
Published: August 2012

This paper presents an analysis of the growth and diversification of international involvement in urban planning and development in Phnom Penh, Cambodia. Over the past decade, a multiplicity of mainly intra-Asian connections have emerged alongside the continued involvement of Western donor aid. The paper shows how various forms of international finance capital, development capital and local capital vie for influence amongst a loose assemblage of alliances and conflicts linking elements of the Cambodian government, international donors and Cambodian and intra-Asian private-sector actors. The paper highlights the on-going efforts of government–private-sector alliances to ‘world’ Phnom Penh and to assert a greater claim to its significance in the world. These desires are seen to have overridden plans produced in partnership with the development sector. Attention is drawn to the intra-Asian mobilities through which these processes operate and which, in doing so, contribute to the on-going unsettling of existing geographies of urban knowledge.
Chief Executive Officer departures and market uncertainty
Authors: Cheung W Jane , Jackson Andrew B
Published: August 2012

This study investigates the effect on stock return volatility of a significant event in the life of a firm, a change in its Chief Executive Officer (CEO). Citing weaknesses in the prior literature, we bring a new approach to re-examine the issue. Firstly, we use a relatively unbiased classification system using both company announcements and media reports. Secondly, we use short-term stock return volatility as a more accurate estimator to isolate the effect of a single disclosure. We find strong evidence that the level of stock return volatility increases following announcements of CEO departures, and that the increase is significantly higher following announcements of forced departures compared to voluntary departures. The results are consistent with signalling effect theory in that forced dismissals convey previously unknown information to the market. Signed cumulative abnormal returns are also more negative for a forced CEO departure.
Effects of fenofibrate, a PPAR-α ligand, on the haemodynamics of glycerol-induced renal failure in rats
Authors: Adedapo AA , Oyekan AO
Published: August 2012

The modulating effect of peroxisome proliferator-activated receptor α ligand on haemodynamic effects of phenylepherine (PE), angiotensin II (AII), endothelin 1 (ET1), acetylcholine (Ach), sodium nitroprusside (SNP) and isoproterenol (ISO) were evaluated in glycerol-induced acute kidney injury in rats. The effect of PE on fenofibrate-treated animals was a dose-dependent increase in mean arterial blood pressure (MAP). For AII and ET1, MAP was also increased for the fenofibrate group but not in a dose-dependent fashion. On the medullary blood flow (MBF), while the lower doses of PE and AII increased the perfusion unit on the fenofibrate-treated group, the higher doses decreased the perfusion unit. The ET1 increased the perfusion unit on this group but not in dose-dependent fashion. The effects of PE and AII on the cortical blood flow (CBF) of fenofibrate-treated group is similar to that of MBF for the same group but not for ET1. The effect of Ach, SNP and ISO in all the groups was the decrease in MAP. ISO caused dose-dependent increase in MBF of fenofibrate-treated group. The effect of Ach, SNP and ISO on the CBF perfusion unit was that of the increase for the fenofibrate-treated group. The study showed that fenofibrate did not attenuate increased blood pressure induced by PE, AII and ET1 but caused enhanced vasodilation by Ach, SNP and ISO.