bluuebunny/crossref_metadata_2025 huggingface dataset:
FUNDAMENTAL STRUCTURE OF LOOP QUANTUM GRAVITY
Authors: HAN MUXIN , MA YONGGE , HUANG WEIMING
Published: October 2007

In the recent twenty years, loop quantum gravity, a background independent approach to unify general relativity and quantum mechanics, has been widely investigated. The aim of loop quantum gravity is to construct a mathematically rigorous, background independent, non-perturbative quantum theory for a Lorentzian gravitational field on a four-dimensional manifold. In the approach, the principles of quantum mechanics are combined with those of general relativity naturally. Such a combination provides us a picture of, so-called, quantum Riemannian geometry, which is discrete on the fundamental scale. Imposing the quantum constraints in analogy from the classical ones, the quantum dynamics of gravity is being studied as one of the most important issues in loop quantum gravity. On the other hand, the semi-classical analysis is being carried out to test the classical limit of the quantum theory.

In this review, the fundamental structure of loop quantum gravity is presented pedagogically. Our main aim is to help non-experts to understand the motivations, basic structures, as well as general results. It may also be beneficial to practitioners to gain insights from different perspectives on the theory. We will focus on the theoretical framework itself, rather than its applications, and do our best to write it in modern and precise langauge while keeping the presentation accessible for beginners. After reviewing the classical connection dynamical formalism of general relativity, as a foundation, the construction of the kinematical Ashtekar–Isham–Lewandowski representation is introduced in the content of quantum kinematics. The algebraic structure of quantum kinematics is also discussed. In the content of quantum dynamics, we mainly introduce the construction of a Hamiltonian constraint operator and the master constraint project. At last, some applications and recent advances are outlined. It should be noted that this strategy of quantizing gravity can also be extended to obtain other background-independent quantum gauge theories. There is no divergence within this background-independent and diffeomorphism-invariant quantization program of matter coupled to gravity.
MECHANICAL BEHAVIORS OF QUENCHED IRON FILM SPUTTERING DEPOSITED ON GLASS SUBSTRATE
Authors: ZHANG YONG-JU , YU SEN-JIANG , CAI PING-GEN , ZHOU HONG
Published: October 2007

A characteristic wedge-shaped iron ( Fe ) film system, deposited on glass substrate by a DC-magnetron sputtering method and quenched by silicone oil during deposition, has been successfully fabricated. The mechanical behaviors of the quenched and non-quenched Fe films have been compared and analyzed. The internal stress is found to transform from tension to compression in nature after quenching, which results in the formation of buckling pattern in the quenched Fe film while crack pattern in the non-quenched film. It is proposed that the origin of the compressive stress is mainly due to freezing of the Fe atoms (or clusters) with high kinetic energy and doping of the oil molecules into the Fe film defects.
EFFECTS OF OXYGEN CONTENT ON THE TRANSPORT PROPERTIES OF La0.7Ca0.3MnO3-δ THIN FILMS
Authors: JIANG H. C. , ZHANG W. L. , CHEN Z. C. , ZHANG W. X. , PENG B.
Published: October 2007

We report the effects of oxygen content on the transport properties of La 0.7 Ca 0.3 MnO 3-δ thin films grown epitaxially on LaAlO 3 (001) substrates by RF magnetron sputtering. The as-deposited thin films were annealed and treated by oxygen plasma to improve the oxygen content. We observe that the La 0.7 Ca 0.3 MnO 3-δ films annealed at 850°C is highly oriented growth on (001) LAO substrate. However, the XRD patterns of the samples annealed at lower than 850°C show no distinct diffraction peaks. This evidence indicates that the samples annealed at lower than 850°C are still amorphous or nanocrystalline. The La 0.7 Ca 0.3 MnO 3-δ films without oxygen plasma do not suffer insulator to metal transition at the temperature range from 213 to 293 K. But, at the same temperature range, for the 650°C, 750°C, and 850°C annealed samples with oxygen plasma treatment show an insulator to metal transition at 239 K, 239 K, and 257 K, respectively. Moreover, compared to without oxygen plasma treatment, the resistivity of the sample with oxygen plasma treatment is dramatically decreased. These results imply that the insulator to metal transition is strongly determined by the ratio of Mn 4+/ Mn 3+ and the oxygen content of the films. The increases of the ratio of Mn 4+/ Mn 3+ and the oxygen content lead to a higher insulator to metal transition temperature.
Hepcidin inhibits apical iron uptake in intestinal cells
Authors: Mena Natalia P. , Esparza Andrés , Tapia Victoria , Valdés Pamela , Núñez Marco T.
Published: October 2007

Hepcidin (Hepc) is considered a key mediator in iron trafficking. Although the mechanism of Hepc action in macrophages is fairly well established, much less is known about its action in intestinal cells, one of the main targets of Hepc. The current study investigated the effects of physiologically generated Hepc on iron transport in Caco-2 cell monolayers and rat duodenal segments compared with the effects on the J774 macrophage cell line. Addition of Hepc to Caco-2 cells or rat duodenal segments strongly inhibited apical 55Fe uptake without apparent effects on the transfer of 55Fe from the cells to the basolateral medium. Concurrently, the levels of divalent metal transporter 1 (DMT1) mRNA and protein in Caco-2 cells decreased while the mRNA and protein levels of the iron export transporter ferroportin did not change. Plasma membrane localization of ferroportin was studied by selective biotinylation of apical and basolateral membrane domains; Hepc induced rapid internalization of ferroportin in J774 cells but not in Caco-2 cells These results indicate that the effect of Hepc is cell dependent: in macrophages it inhibits iron export by inducing ferroportin degradation, whereas in enterocytes it inhibits apical iron uptake by inhibiting DMT1 transcription. Our results highlight the crucial role of Hepc in the control of intestinal iron absorption.
Functional characterization and sex differences in small mesenteric arteries of the estrogen receptor-β knockout mouse
Authors: Douglas Gillian , Natalia Cruz M. , Poston Lucilla , Gustafsson Jan-Åke , Kublickiene Karolina
Published: October 2007

The role of the estrogen receptor (ER) subtypes in the modulation of vascular function is poorly understood. The aim of this study was to characterize ex vivo the functional properties of small arteries and their response to estrogens in the mesenteric circulation of female and male ER-β knockout mice (β-ERKO) and their wild-type (WT) littermates. Responses to changes in intraluminal flow and pressure were obtained before and after incubation with 17β-estradiol or ER-α agonist propyl-pyrazole-triol (3 h; 10 nM). Cumulative concentration-response curves to acetylcholine, norepinephrine, and passive distensibility were compared with respect to sex and genotype. The collagen and elastin content within the vascular wall and ER expression were also determined. Endothelial morphology was visualized by scanning electron microscopy. 17β-Estradiol and propyl-pyrazole-triol-treated arteries from female β-ERKO and WT mice showed enhanced flow-mediated dilation, but this was not evident in males. Distensibility was decreased in arteries from β-ERKO females. Sex differences in myogenic tone were observed in 17β-estradiol-treated arteries, but were similar between β-ERKO and WT mice. Acetylcholine- and norepinephrine-induced responses were similar between groups and sexes. ER-α was similarly expressed in the endothelium and media of arteries from all groups studied, as well as ER-β in WT animals. Endothelial morphology was similar in arteries from animals of both sexes and genotype; however, arterial elastin content was decreased, and collagen content was increased in β-ERKO male compared with WT male and with β-ERKO female. We suggest that ERs play a sex-specific role in estrogen-mediated flow responses and distensibility, and that deletion of ER-β affects artery structure but only in male animals. Further studies in β-ERKO mice with established hypertension and in α-ERKO mice are warranted.
Chronic hypoxia aggravates renal injury via suppression of Cu/Zn-SOD: a proteomic analysis
Authors: Son Daisuke , Kojima Ichiro , Inagi Reiko , Matsumoto Makiko , Fujita Toshiro , Nangaku Masaomi
Published: October 2007

Accumulating evidence suggests a pathogenic role of chronic hypoxia in various kidney diseases. Chronic hypoxia in the kidney was induced by unilateral renal artery stenosis, followed 7 days later by observation of tubulointerstitial injury. Proteomic analysis of the hypoxic kidney found various altered proteins. Increased proteins included lipocortin-5, calgizzarin, ezrin, and transferrin, whereas the decreased proteins were α2u-globulin PGCL1, eukaryotic translation elongation factor 1α2, and Cu/Zn superoxide dismutase (SOD1). Among these proteins, we focused on Cu/Zn-SOD, a crucial antioxidant. Western blot analysis and real-time quantitative PCR analysis confirmed the downregulation of Cu/Zn-SOD in the chronic hypoxic kidney. Furthermore, our laser capture microdissection system showed that the expression of Cu/Zn-SOD was predominant in the tubulointerstitium and was decreased by chronic hypoxia. The tubulointerstitial injury estimated by histology and immunohistochemical markers was ameliorated by tempol, a SOD mimetic. This amelioration was associated with a decrease in levels of the oxidative stress markers 4-hydroxyl-2-nonenal and nitrotyrosine. Our in vitro studies utilizing cultured tubular cells revealed a role of TNF-α in downregulation of Cu/Zn-SOD. Since the administration of anti-TNF-α antibody ameliorated Cu/Zn-SOD suppression, TNF-α seems to be one of the suppressants of Cu/Zn-SOD. In conclusion, our proteomic analysis revealed a decrease in Cu/Zn-SOD, at least partly by TNF-α, in the chronic hypoxic kidney. This study, for the first time, uncovered maladaptive suppression of Cu/Zn-SOD as a mediator of a vicious cycle of oxidative stress and subsequent renal injury induced by chronic hypoxia.
Promoter methylation is associated with the age-dependent loss of N-cadherin in the rat kidney
Authors: Akintola Adebayo D. , Crislip Zachary L. , Catania Jeffrey M. , Chen Gang , Zimmer Warren E. , Burghardt Robert C. , Parrish Alan R.
Published: October 2007

The cadherins are cell adhesion molecules required for cellular homeostasis, and N-cadherin is the predominant cadherin expressed in proximal tubular epithelial cells in humans and rats. Our laboratory previously reported an age-dependent decrease in renal N-cadherin expression; the levels of N-cadherin mRNA and protein expression decreased in parallel, implicating a transcriptional mechanism in the age-dependent loss of expression ( 19 ). In this study, we examined the hypothesis that promoter hypermethylation underlies the loss of N-cadherin expression in aging rat kidney. We cloned the 5′ flanking region of the rat N-cadherin gene and observed basic promoter activity in a 3,992-bp region localized immediately upstream of the ATG start site. Nucleotide analysis revealed 87% identity with the human N-cadherin minimal promoter region. Consistent with a role for regulation by DNA methylation, we found that a dense CpG island, which spans 1,104 bp (−1,158 to −55), flanks the rat N-cadherin gene; a similar CpG profile was found in the human N-cadherin 5′ flanking region. Methylation-specific PCR analysis demonstrated that the promoter region of N-cadherin is heavily methylated in aged, but not young, rat kidney. Interestingly, the promoter is not methylated in age-matched, calorically restricted animals. In contrast, the promoter region is not methylated in either young or aged rat liver; this corresponds to the finding that aging is not associated with decreased N-cadherin expression in the liver. In addition, N-cadherin expression is markedly induced in NRK-52E cells treated with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine, further suggesting that methylation at CpG in the promoter region may underlie the age-dependent decrease in renal N-cadherin expression.
Muscle mechanosensitive reflex is suppressed in the conscious condition: effect of anesthesia
Authors: Matsukawa Kanji , Nakamoto Tomoko
Published: October 2007

To test the hypothesis that a muscle mechanosensitive reflex is suppressed in the conscious condition, we examined the effect of anesthesia on the cardiovascular responses to passive mechanical stretch of the hindlimb triceps surae muscle in six conscious cats. The triceps surae muscle was manually stretched for 30 s by extending the hip and knee joints and subsequently by dorsiflexing the ankle joint; the lateral gastrocnemius muscle was lengthened by 19 ± 2.6 mm. Heart rate (HR) and mean arterial blood pressure (MAP) did not change significantly during passive stretch of the muscle in the conscious condition. At 10–40 min after intravenously administering pentobarbital sodium (20–25 mg/kg), the identical passive stretch of the triceps surae muscle was able to induce the cardiovascular responses; HR and MAP were increased by 14 ± 1.3 beats/min and 14 ± 1.4 mmHg, respectively, and the cardiovascular responses were sustained throughout the passive stretch. In contrast, stretching skin on the triceps surae muscle evoked no significant changes in HR and MAP in the anesthetized condition. When anesthesia became light 40–90 min after injection of pentobarbital and the animals started to show spontaneous body movement, the cardiovascular response to passive muscle stretch tended to be blunted again. It is therefore concluded that passive mechanical stretch of skeletal muscle is capable of evoking the reflex cardiovascular response, which is suppressed in the conscious condition but exaggerated by anesthesia.
Relations between Sequences and Selection Properties
Authors: Djurcic D. , Kocinac Lj. D. R. , Žižovic M. R.
Published: October 2007

We consider the set𝕊of sequences of positive real numbers and show that some subclasses of𝕊have certain nice selection and game theoretic properties.
Molecular Characterization of Intrinsic and Acquired Antibiotic Resistance in Lactic Acid Bacteria and Bifidobacteria
Authors: Ammor Mohammed Salim , Flórez Ana Belén , van Hoek Angela H.A.M. , de los Reyes-Gavilán Clara G. , Aarts Henk J.M. , Margolles Abelardo , Mayo Baltasar
Published: October 2007

The minimum inhibitory concentrations (MICs) of 6 different antibiotics (chloramphenicol, clindamycin, erythromycin, streptomycin, tetracycline and vancomycin) were determined for 143 strains of lactic acid bacteria and bifidobacteria using the Etest. Different MICs were found for different species and strains. Based on the distribution of these MIC values, most of the strains were either susceptible or intrinsically resistant to these antibiotics. However, the MIC range of some of these antibiotics showed a bimodal distribution, which suggested that some of the tested strains possess acquired antibiotic resistance. Screening for resistance genes was performed by PCR using specific primers, or using a DNA microarray with around 300 nucleotide probes representing 7 classes of antibiotic resistance genes. The genes identified encoded resistance to tetracycline [tet(M), tet(W), tet(O) and tet(O/W)], erythromycin and clindamycin [erm(B)] and streptomycin [aph(E) and sat(3)]. Internal portions of some of these determinants were sequenced and found to be identical to genes described in other bacteria. All resistance determinants were located on the bacterial chromosome, except for tet(M), which was identified on plasmids in Lactococcus lactis. The contribution of intrinsic multidrug transporters to the antibiotic resistance was investigated by cloning and measuring the expression of Bifidobacterium breve genes in L. lactis.
Regulation of Excision of Integrative and Potentially Conjugative Elements from Streptococcus thermophilus: Role of the arp1 Repressor
Authors: Bellanger Xavier , Morel Catherine , Decaris Bernard , Guédon Gérard
Published: October 2007

The integrative and conjugative elements (ICEs) excise by site-specific recombination between attL and attR flanking sites, self-transfer the resulting circular form and integrate into the genome of the recipient cell. Two putative ICEs, ICESt1 and ICESt3, are integrated in the same locus in 2 strains of Streptococcusthermophilus. ICESt1 is a composite element harbouring an internal recombination site, attL’. The recombination between attL’ and attR leads to the excision of a shorter putative ICE, ICESt2. ICESt1/ICESt2 and ICESt3 carry related regulation modules sharing the open reading frame arp1 that encodes a protein related to the cI repressor of the phage λ. The repressors belonging to this family autoproteolyse in the presence of damaged DNA. Treatments with mitomycin C induce an increase in the excision of ICESt1, ICESt2 and ICESt3. Furthermore, the arp1 deletion leads to a 1,000-fold increase in the excision of ICESt1 and ICESt2 and to a decrease in the excision induction by mitomycin C. Thus, all together, these results suggest that the autocleavage of the arp1 repressor is involved in derepression of the S. thermophilus putative ICE excision by mitomycin C.
Development of Software Facilities to Characterize Regulatory Binding Motifs and Application to Streptococcaceae
Authors: Pons Nicolas , Batto Jean-Michel , Ehrlich Stanislav Dusko , Renault Pierre
Published: October 2007

Gene expression regulation often involves the recognition of particular DNA or RNA sequences, called motifs. Detection and characterization of such motifs together with biological expertise allow to build gene expression regulatory maps that facilitate the comprehension of complex cellular processes. In this frame, we developed a software integrating relevant information for the detection and characterization of conserved motifs in genomic sequences. A relational database was built up to host data related to genomic information and transcriptional experiments. A user-friendly interface was designed to allow a convenient representation of these data and to run the detection motif program. A set of complementary utilities was also developed to improve the determination of motif consensus sequences and the detection of additional potential regulator targets in the genome.
Preliminary Study of the Effects of Commercial Lactobacilli Preparations on Digestive Metabolism of Juvenile Sea Bass (Dicentrarchus labrax)
Authors: Frouël S. , Le Bihan E. , Serpentini A. , Lebel J.M. , Koueta N. , Nicolas J.L.
Published: October 2007

Two forms of the same commercial product (SORBIAL, Allonnes, France), one with live bacteria (PSA) and the other with heat-inactivated bacteria (PSI), containing a mixture of 2 strains of lactobacilli and their growth medium were tested as a diet complement for juvenile sea bass (Dicentrarchus labrax) during a 103-day experiment. In addition to zootechnical parameters (survival, growth, conformation), some effects on digestive metabolism were studied, including enzymatic, ultrastructural and microbial aspects. Microbial preparations improved survival rate. The ventral, dorsal and operculum malformations which usually occur in juveniles did not appear in those receiving PSA and PSI. Furthermore, they stimulated, but not constantly, trypsin and acid phosphatase activities. Intestinal ultrastructure showed an increase in the number of endocytosis vesicles at the apical pole of enterocytes in fishes receiving enrichments. Bacterial flora was not modified in terms of quantity, especially the lactic acid bacteria counts, which were not changed in fishes receiving live lactobacilli (PSA). The mode of action of these multiple beneficial effects appears complex and could be caused by different molecules inside the bacterial cell or excreted into their medium.
Metabolic Adaptation of Lactococcus lactis in the Digestive Tract: The Example of Response to Lactose
Authors: Roy Karine , Anba Jamila , Corthier Gérard , Rigottier-Gois Lionel , Monnet Véronique , Mistou Michel-Yves
Published: October 2007

Lactococcus lactis is a model of food-grade lactic acid bacterium, which can durably colonize the digestive tract of germ-free mice. To study in vivo the bacterial adaptation to a novel nutritional resource brought by alimentation, the lactose-catabolizing strain IL2661 of L. lactis was established in monoxeny in mice. Half of the mice then received a lactose-rich diet. The mouse has no efficient intestinal lactase and is well adapted to a follow-up of the metabolic activity of microbial origin. The analysis of lactose and lactate in the feces suggested that L. lactis was able to use lactose in vivo. We developed a proteomic approach to evaluate in deeper details the metabolic response of the bacterium. We observed that L. lactis switched its metabolism to use the novel carbon source and reduced the level of proteins involved in an alternative mode of ATP production. In parallel, we also found that the amount of proteins involved in transcriptional regulation, transport and catabolism decreased in the presence of lactose. The proteome analysis informed us about the resources used by the bacteria in absence of lactose. In competition experiments, we found that the metabolic adaptation gives a strong ecological advantage to the bacteria able to efficiently utilize lactose.
Low Carbamoyl Phosphate Pools May Drive Lactobacillus plantarum CO2-Dependent Growth Phenotype
Authors: Bringel Françoise , Vuilleumier Stéphane , Arsène-Ploetze Florence
Published: October 2007

Lactobacillus plantarum is often found in nutrient-rich habitats with elevated levels of inorganic carbon (IC), and IC-dependent growth is commonly encountered in natural isolates of this species. High CO2-requiring (HCR) prototrophs are unable to grow under conditions of low IC unless arginine and pyrimidines are provided. Prototrophy is restored under high IC conditions, that is in 4% CO2-enriched air or bicarbonate-supplemented medium. Bicarbonate is required for the synthesis of carbamoyl phosphate (CP), a precursor of both arginine and pyrimidine biosynthesis. We hypothesize that at low IC levels, intracellular CP pools limit growth through the limitation of arginine and nucleotide supplies. HCR mutants obtained in the laboratory can be classified into 3 functional groups: mutants with impaired CP synthesis, increased CP consumption or increased CP requirements relative to wild type. This classification provides a framework for investigating the origin of the HCR phenotype in natural environmental isolates of Lactobacillus species, and to investigate the hypothesis that a low level of carbamoyl phosphate is a major determinant of the CO2-dependent growth phenotype often observed in L. plantarum isolates.
MCAT Elements and the TEF-1 Family of Transcription Factors in Muscle Development and Disease
Authors: Yoshida Tadashi
Published: October 2007

MCAT elements are located in the promoter-enhancer regions of cardiac, smooth, and skeletal muscle-specific genes including cardiac troponin T, β-myosin heavy chain, smooth muscle α-actin, and skeletal α-actin, and play a key role in the regulation of these genes during muscle development and disease. The binding factors of MCAT elements are members of the transcriptional enhancer factor-1 (TEF-1) family. However, it has not been fully understood how these transcription factors confer cell-specific expression in muscle, because their expression patterns are relatively broad. Results of recent studies revealed multiple mechanisms whereby TEF-1 family members control MCAT element-dependent muscle-specific gene expression, including posttranslational modifications of TEF-1 family members, the presence of muscle-selective TEF-1 cofactors, and cell-selective control of TEF-1 accessibility to MCAT elements. In addition, of particular interest, recent studies regarding MCAT element-dependent transcription of the myocardin gene and the smooth muscle α-actin gene in muscle provide evidence for the transcriptional diversity among distinct cell types and subtypes. This article summarizes the role of MCAT elements and the TEF-1 family of transcription factors in muscle development and disease, and reviews recent progress in our understanding of the transcriptional regulatory mechanisms involved in MCAT element-dependent muscle-specific gene expression.
Arterial Stiffness Is Associated With Regional Ventricular Systolic and Diastolic Dysfunction
Authors: Fernandes Verônica Rolim S. , Polak Joseph F. , Cheng Susan , Rosen Boaz D. , Carvalho Benilton , Nasir Khurram , McClelland Robyn , Hundley Gregory , Pearson Greg , O’Leary Daniel H. , Bluemke David A. , Lima João A.C.
Published: October 2007

Objective—

The pathophysiology of left ventricular (LV) dysfunction, particularly in the setting of a preserved ejection fraction (EF), remains unclear. Few studies have investigated the relationship between arterial compliance and LV function in humans, and none used cardiovascular MRI.

Methods and Results—

We sought to determine whether arterial compliance is related to regional myocardial function among participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Arterial compliance was assessed using carotid ultrasound measurements to calculate the distensibility coefficient (DC) and Young’s modulus (YM). Circumferential systolic (SR
S
) and diastolic (SR
E
) strain rates were calculated by harmonic phase (HARP) from tagged MRI. Associations between arterial compliance and indices of ventricular function were adjusted for cardiovascular risk factors. We found a significant association between arterial compliance and SR
S
in all myocardial regions (
P
<0.05); arterial compliance was also associated with SR
E
in the lateral and septal wall regions (
P
<0.05). Multiple linear regression analyses demonstrated a direct linear relationship between the carotid artery DC and SR
S
across all LV segments and slices, even after adjustment for cardiovascular risk factors and LV mass. In regression analyses, a significant relationship between arterial compliance and SR
E
in the septal and antero-apical walls was also found and remained significant after multivariable adjustment.

Conclusion—

Arterial stiffness is associated with early and asymptomatic impairment of systolic as well as diastolic myocardial function. Further studies are needed to elucidate role of vascular compliance in the development of ventricular dysfunction and failure.
Pitavastatin, an HMG-CoA Reductase Inhibitor, Exerts eNOS-Independent Protective Actions Against Angiotensin II–Induced Cardiovascular Remodeling and Renal Insufficiency
Authors: Yagi Shusuke , Aihara Ken-ichi , Ikeda Yasumasa , Sumitomo Yuka , Yoshida Sumiko , Ise Takayuki , Iwase Takashi , Ishikawa Kazue , Azuma Hiroyuki , Akaike Masashi , Matsumoto Toshio
Published: October 2007

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II–induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II–induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II–induced oxidative stress, cardiac TGFβ-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II–induced cardiac remodeling and diastolic dysfunction in eNOS
−/−
mice as in wild-type mice. In eNOS
−/−
mice, the Ang II–induced cardiac oxidative stress and TGF-β–Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II–treated eNOS
−/−
mice, with suppression of glomerular oxidative stress and TGF-β-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II–induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-β-Smad 2/3 signaling pathway by suppression of oxidative stress.
Transcription Factor Nrf2 Protects the Brain From Damage Produced by Intracerebral Hemorrhage
Authors: Zhao Xiurong , Sun Guanghua , Zhang Jie , Strong Roger , Dash Pramod K. , Kan Yuet Wai , Grotta James C. , Aronowski Jaroslaw
Published: October 2007

Background and Purpose—

Intracerebral hemorrhage (ICH) remains a major medical problem for which there is no effective treatment. Oxidative and cytotoxic damage plays an important role in ICH pathogenesis and may represent a target for treatment of ICH. Recent studies have suggested that nuclear factor–erythroid 2–related factor 2 (Nrf2), a pleiotropic transcription factor, may play a key role in protecting cells from cytotoxic/oxidative damage. This study evaluated the role of Nrf2 in protecting the brain from ICH-mediated damage.

Methods—

Sprague-Dawley rats and Nrf2-deficient or control mice received intracerebral injection of autologous blood to mimic ICH. Sulforaphane was used to activate Nrf2. Oxidative stress, the presence of myeloperoxidase-positive cells (neutrophils) in ICH-affected brains, and behavioral dysfunction were assessed to determine the extent of ICH-mediated damage.

Results—

Sulforaphane activated Nrf2 in ICH-affected brain tissue and reduced neutrophil count, oxidative damage, and behavioral deficits caused by ICH. Nrf2-deficient mice demonstrated more severe neurologic deficits after ICH and did not benefit from the protective effect of sulforaphane.

Conclusions—

Nrf2 may represent a strategic target for ICH therapies.
Decreased Glomerular Filtration Rate Is a Risk Factor for Hemorrhagic But Not for Ischemic Stroke
Authors: Bos Michiel J. , Koudstaal Peter J. , Hofman Albert , Breteler Monique M.B.
Published: October 2007

Background and Purpose—

Persons with early stages of chronic kidney disease, defined by a decreased glomerular filtration rate (GFR), have an increased risk of cardiovascular disease. It is unclear whether decreased GFR is a risk factor for stroke. We assessed the association between GFR and stroke in a prospective population-based cohort study.

Methods—

The study was based on 4937 participants of the Rotterdam Study who at baseline (1990 to 1993) were aged 55 years or over, free from stroke, and had serum creatinine assessment. GFR was estimated with the Cockcroft-Gault equation. Follow-up for incident cerebrovascular disease was complete until January 1, 2005. Data were analyzed with Cox proportional hazards models with adjustment for relevant confounders and results were expressed as hazard ratios with 95% CIs.

Results—

During an average follow-up of 10.2 years, 586 strokes (338 ischemic, 44 hemorrhagic, and 204 unspecified strokes) occurred. We found no association between GFR and risk of overall stroke or risk of ischemic stroke. In contrast, with decreasing GFR, the risk of hemorrhagic stroke strongly increased; the age- and sex-adjusted hazard ratio for hemorrhagic stroke was 4.10 (95% CI, 1.25 to 13.42) for lowest versus highest quartile of GFR, and there was a clear and highly significant dose–effect relationship. Adjustment for other vascular risk factors only slightly attenuated this association.

Conclusions—

Decreased GFR is a strong risk factor for hemorrhagic, but not ischemic stroke.
Haptoglobin 2-2 Genotype Determines Chronic Vasospasm After Experimental Subarachnoid Hemorrhage
Authors: Chaichana Kaisorn L. , Levy Andrew P. , Miller-Lotan Rachel , Shakur Sophia , Tamargo Rafael J.
Published: October 2007

Background and Purpose—

Chronic cerebral arterial vasospasm is the leading cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Not all cases of SAH, however, develop chronic vasospasm. Inflammation, specifically leukocyte–endothelial cell interactions, appears to be critical in vasospasm development. Haptoglobin (Hp) is a serum protein that limits the extent of inflammation after a hemorrhagic event. An individual’s Hp genotype may predict the severity of the inflammatory response during a hemorrhagic event, and consequently modulate the risk for vasospasm.

Methods—

Sixty mice (Hp 1-1, n=30; Hp 2-2, n=30) underwent injection of either autologous blood or normal saline solution into the cisterna magna. An additional 30 mice (15 per genotype) served as controls. The extent and manifestations of vasospasm were assessed by measuring lumen patency, quantifying activity levels, and counting the number of vessel-infiltrated macrophages/neutrophils at 24 hours after injection, which corresponds to the time of peak vasospasm in mice.

Results—

Genetically modified Hp 2-2 mice with SAH had significantly lower basilar artery lumen patencies (mean±SEM; 52.9±1.9% vs 82.3±1.3%;
P
<0.01), reduced activity levels (0.8±0.3 vs 2.4±0.2;
P
<0.01), and increased macrophage/neutrophil counts in the subarachnoid space (31.2±6.3 vs 8.8±1.7,
P
<0.01) as compared with wild-type Hp 1-1 mice.

Conclusions—

These findings suggest that the Hp 2-2 genotype is critical for the development of severe vasospasm, which typically occurs 24 hours after SAH in mice.
Population-Based Analysis of the Impact of Expanding the Time Window for Acute Stroke Treatment
Authors: Juhl Majersik Jennifer , Smith Melinda A. , Zahuranec Darin B. , Sánchez Brisa N. , Morgenstern Lewis B.
Published: October 2007

Background and Purpose—

Currently, a major focus on expanding acute ischemic stroke treatment opportunities centers on the development of drugs and devices with longer time windows for use. We sought to determine the time intervals within which stroke patients present to establish whether time window expansion will translate into more treatment.

Methods—

Data were derived from the Brain Attack Surveillance in Corpus Christi project, a population-based stroke surveillance study in an urban, southeast Texas county. This community does not contain an academic medical center, thus providing a “real-world” setting to capture patient arrival times. Onset time was recorded from the chart according to a prespecified methodology.

Results—

From January 2000 to June 2005, 2347 patients with acute ischemic stroke were validated. The mean age was 71 years, and 53% were female. Thirty-one percent presented within 3 hours of symptom onset; 13% between 3 and 6 hours; and 15% between 6 and 12 hours. Forty-one percent presented beyond 12 hours from symptom onset. Nearly half of patients with moderate and severe strokes presented in the 0- to 3-hour time window, whereas only 28% of mildly affected patients presented early.

Conclusions—

This population-based study provides estimates of time to presentation in a representative community without tertiary referral bias. These data are useful for planning acute stroke therapy interventions and suggest that in addition to developing therapies with expanded time windows, research resources should also be devoted to reducing hospital presentation delays.
Neural Correlates of Verb Argument Structure Processing
Authors: Thompson Cynthia K. , Bonakdarpour Borna , Fix Stephen C. , Blumenfeld Henrike K. , Parrish Todd B. , Gitelman Darren R. , Mesulam M.-Marsel
Published: October 2007

Neuroimaging and lesion studies suggest that processing of word classes, such as verbs and nouns, is associated with distinct neural mechanisms. Such studies also suggest that subcategories within these broad word class categories are differentially processed in the brain. Within the class of verbs, argument structure provides one linguistic dimension that distinguishes among verb exemplars, with some requiring more complex argument structure entries than others. This study examined the neural instantiation of verbs by argument structure complexity: one-, two-, and three-argument verbs. Stimuli of each type, along with nouns and pseudowords, were presented for lexical decision using an event-related functional magnetic resonance imaging design. Results for 14 young normal participants indicated largely overlapping activation maps for verbs and nouns, with no areas of significant activation for verbs compared to nouns, or vice versa. Pseudowords also engaged neural tissue overlapping with that for both word classes, with more widespread activation noted in visual, motor, and peri-sylvian regions. Examination of verbs by argument structure revealed activation of the supramarginal and angular gyri, limited to the left hemisphere only when verbs with two obligatory arguments were compared to verbs with a single argument. However, bilateral activation was noted when both two- and three-argument verbs were compared to one-argument verbs. These findings suggest that posterior peri-sylvian regions are engaged for processing argument structure information associated with verbs, with increasing neural tissue in the inferior parietal region associated with increasing argument structure complexity. These findings are consistent with processing accounts, which suggest that these regions are crucial for semantic integration.
Temporal Characteristics of Top-Down Modulations during Working Memory Maintenance: An Event-related Potential Study of the N170 Component
Authors: Sreenivasan Kartik K. , Katz Jennifer , Jha Amishi P.
Published: October 2007

We investigated the top-down influence of working memory (WM) maintenance on feedforward perceptual processing within occipito-temporal face processing structures. During event-related potential (ERP) recordings, subjects performed a delayed-recognition task requiring WM maintenance of faces or houses. The face-sensitive N170 component elicited by delay-spanning task-irrelevant grayscale noise probes was examined. If early feedforward perceptual activity is biased by maintenance requirements, the N170 ERP component elicited by probes should have a greater N170 amplitude response during face relative to house WM trials. Consistent with this prediction, N170 elicited by probes presented at the beginning, middle, and end of the delay interval was greater in amplitude during face relative to house WM. Thus, these results suggest that WM maintenance demands may modulate early feedforward perceptual processing for the entirety of the delay duration. We argue based on these results that temporally early biasing of domain-specific perceptual processing may be a critical mechanism by which WM maintenance is achieved.
Neural Substrates of Contextual Interference during Motor Learning Support a Model of Active Preparation
Authors: Cross Emily S. , Schmitt Paul J. , Grafton Scott T.
Published: October 2007

When individuals acquire new skills, initial performance is typically better and tasks are judged to be easier when the tasks are segregated and practiced by block, compared to when different tasks are randomly intermixed in practice. However, subsequent skill retention is better for a randomly practiced group, an effect known as contextual interference (CI). The present study examined the neural substrates of CI using functional magnetic resonance imaging (fMRI). Individuals learned a set of three 4-element sequences with the left hand according to a block or random practice schedule. Behavioral retest for skill retention confirmed the presence of a typical CI effect with the random group outperforming the block group. Using a go/no-go fMRI paradigm, sequence preparation during the premovement study period was separated from movement execution. Imaging data for the two groups were compared for the first 1/3 and final 1/3 of training trials. Toward the end of training, behavioral performance between the two groups was similar, although the random group would later display a performance advantage on retention testing. During study time, the random group showed greater activity in sensorimotor and premotor regions compared to the block group. These areas are associated with motor preparation, sequencing, and response selection. This pattern of recruitment is consistent with the hypothesis that CI benefits in a sequencing task are due to improved capacity to actively prepare motor responses.
The Contribution of the Inferior Parietal Lobe to Auditory Spatial Working Memory
Authors: Alain Claude , He Yu , Grady Cheryl
Published: October 2007

There is strong evidence for dissociable “what” and “where” pathways in the auditory system, but considerable debate remains regarding the functional role of these pathways. The sensory-motor account of spatial processing posits that the dorsal brain regions (e.g., inferior parietal lobule, IPL) mediate sensory-motor integration required during “where” responding. An alternative account suggests that the IPL plays an important role in monitoring sound location. To test these two models, we used a mixed-block and event-related functional magnetic resonance imaging (fMRI) design in which participants responded to occasional repetitions in either sound location (“where” task) or semantic category (“what” task). The fMRI data were analyzed with the general linear model using separate regressors for representing sustained and transient activity in both listening conditions. This analysis revealed more sustained activity in right dorsal brain regions, including the IPL and superior frontal sulcus, during the location than during the category task, after accounting for transient activity related to target detection and the motor response. Conversely, we found greater sustained activity in the left superior temporal gyrus and left inferior frontal gyrus during the category task compared to the location task. Transient target-related activity in both tasks was associated with enhanced signal in the left pre- and postcentral gyrus, prefrontal cortex and bilateral IPL. These results suggest dual roles for the right IPL in auditory working memory—one involved in monitoring and updating sound location independent of motor responding, and another that underlies the integration of sensory and motor functions.
Odd Sound Processing in the Sleeping Brain
Authors: Ruby Perrine , Caclin Anne , Boulet Sabrina , Delpuech Claude , Morlet Dominique
Published: October 2007

How does the sleeping brain process external stimuli, and in particular, up to which extent does the sleeping brain detect and process modifications in its sensory environment? In order to address this issue, we investigated brain reactivity to simple auditory stimulations during sleep in young healthy subjects. Electroencephalogram signal was acquired continuously during a whole night of sleep while a classical oddball paradigm with duration deviance was applied. In all sleep stages, except Sleep Stage 4, a mismatch negativity (MMN) was unquestionably found in response to deviant tones, revealing for the first time preserved sensory memory processing during almost the whole night. Surprisingly, during Sleep Stage 2 and paradoxical sleep, both P3a-like and P3b-like components were identified after the MMN, whereas a P3a alone followed the MMN in wakefulness and in Sleep Stage 1. This totally new result suggests elaborated processing of external stimulation during sleep. We propose that the P3b-like response could be associated to an active processing of the deviant tone in the dream's consciousness.
The Role of the Right Prefrontal Cortex in Self-evaluation of the Face: A Functional Magnetic Resonance Imaging Study
Authors: Morita Tomoyo , Itakura Shoji , Saito Daisuke N. , Nakashita Satoshi , Harada Tokiko , Kochiyama Takanori , Sadato Norihiro
Published: October 2007

Individuals can experience negative emotions (e.g., embarrassment) accompanying self-evaluation immediately after recognizing their own facial image, especially if it deviates strongly from their mental representation of ideals or standards. The aim of this study was to identify the cortical regions involved in self-recognition and self-evaluation along with self-conscious emotions. To increase the range of emotions accompanying self-evaluation, we used facial feedback images chosen from a video recording, some of which deviated significantly from normal images. In total, 19 participants were asked to rate images of their own face (SELF) and those of others (OTHERS) according to how photogenic they appeared to be. After scanning the images, the participants rated how embarrassed they felt upon viewing each face. As the photogenic scores decreased, the embarrassment ratings dramatically increased for the participant's own face compared with those of others. The SELF versus OTHERS contrast significantly increased the activation of the right prefrontal cortex, bilateral insular cortex, anterior cingulate cortex, and bilateral occipital cortex. Within the right prefrontal cortex, activity in the right precentral gyrus reflected the trait of awareness of observable aspects of the self; this provided strong evidence that the right precentral gyrus is specifically involved in self-face recognition. By contrast, activity in the anterior region, which is located in the right middle inferior frontal gyrus, was modulated by the extent of embarrassment. This finding suggests that the right middle inferior frontal gyrus is engaged in self-evaluation preceded by self-face recognition based on the relevance to a standard self.
Fractionation of the Component Processes Underlying Successful Episodic Encoding: A Combined fMRI and Divided-attention Study
Authors: Uncapher Melina R. , Rugg Michael D.
Published: October 2007

Considerable evidence suggests that attentional resources are necessary for the encoding of episodic memories, but the nature of the relationship between attention and neural correlates of encoding is unclear. Here we address this question using functional magnetic resonance imaging and a divided-attention paradigm in which competition for different types of attentional resources was manipulated. Fifteen volunteers were scanned while making animacy judgments to visually presented words and concurrently performing one of three tasks on auditorily presented words: male/female voice discrimination (control task), 1-back voice comparison (1-back task), or indoor/outdoor judgment (semantic task). The 1-back and semantic tasks were designed to compete for task-generic and task-specific attentional resources, respectively. Using the “remember/know” procedure, memory for the study words was assessed after 15 min. In the control condition, subsequent memory effects associated with later recollection were identified in the left dorsal inferior frontal gyrus and in the left hippocampus. These effects were differentially attenuated in the two more difficult divided-attention conditions. The effects of divided attention seem, therefore, to reflect impairments due to limitations at both task-generic and task-specific levels. Additionally, each of the two more difficult divided-attention conditions was associated with subsequent memory effects in regions distinct from those showing effects in the control condition. These findings suggest the engagement of alternative encoding processes to those engaged in the control task. The overall pattern of findings suggests that divided attention can impact later memory in different ways, and accordingly, that different attentional resources, including task-generic and task-specific resources, make distinct contributions to successful episodic encoding.