bluuebunny/crossref_metadata_2025 huggingface dataset:
Biosynthesis of riboflavin
Authors: Lehmann Martin , Degen Simone , Hohmann Hans‐Peter , Wyss Markus , Bacher Adelbert , Schramek Nicholas
Published: July 2009

GTP cyclohydrolase II catalyzes the first dedicated step in the biosynthesis of riboflavin and appears to be a limiting factor for the production of the vitamin by recombinant Bacillus subtilis overproducer strains. Using error‐prone PCR amplification, we generated a library of the B. subtilis ribA gene selectively mutated in the GTP cyclohydrolase II domain. The ratio of the GTP cyclohydrolase II to 3,4‐dihydroxy‐2‐butanone synthase activities of the mutant proteins was measured. A mutant designated Construct E, carrying seven point mutations, showed a two‐fold increase in GTP cyclohydrolase II activity and a four‐fold increase in the Km value with GTP as the substrate. Using the analog 2‐amino‐5‐formylamino‐6‐ribosylamino‐4(3H)‐pyrimidinone 5′‐triphosphate as the substrate, the mutant showed a rate enhancement by a factor of about two and an increase in the Km value by a factor of about 5. A series of UV absorption spectra obtained in stopped‐flow experiments using the wild‐type and mutant enzymes revealed isosbestic points indicative of apparently perfect reactions, which were similar to the findings obtained with GTP cyclohydrolase II of Escherichia coli. Initial burst velocities obtained for the mutant and wild‐type proteins were similar. The data suggest that the mutations present in Construct E are jointly conducive to the acceleration of a late step in the reaction trajectory, most probably the release of product from the enzyme.
Structural and mechanistic aspects of flavoproteins: probes of hydrogen tunnelling
Authors: Hay Sam , Pudney Christopher R. , Scrutton Nigel S.
Published: July 2009

At least half of all enzyme‐catalysed reactions are thought to involve a hydrogen transfer. In the last 10 years, it has become apparent that many of these reactions will occur, in part, or in full, by quantum mechanical tunnelling. We are particularly interested in the role of promoting vibrations on H transfer, and the Old Yellow Enzyme family of flavoproteins has proven to be an excellent model system with which to examine such reactions. In this minireview, we describe new and established experimental methods used to study H‐tunnelling in these enzymes and we consider some practical issues important to such studies. The application of these methods has provided strong evidence linking protein dynamics and H‐tunnelling in biological systems.
Subcellular compartmentalization of FADD as a new level of regulation in death receptor signaling
Authors: Föger Niko , Bulfone‐Paus Silvia , Chan Andrew C. , Lee Kyeong‐Hee
Published: July 2009

Fas‐associated protein with death domain (FADD) is an essential adaptor protein in death receptor‐mediated signal transduction. During apoptotic signaling, FADD functions in the cytoplasm, where it couples activated receptors with initiator caspase‐8. However, in resting cells, FADD is predominantly stored in the nucleus. In this study, we examined the modalities of FADD intracellular trafficking. We demonstrate that, upon CD95 activation, FADD redistributes from the nucleus to the cytoplasm. This inducible nuclear–cytoplasmic translocation of FADD is independent of CD95 internalization, formation of the death‐inducing signaling complex, and caspase‐8 activation. In contrast to nuclear export of FADD, its subsequent recruitment and accumulation at endosomes containing internalized CD95 requires a caspase‐8‐dependent feedback loop. These data indicate the existence of differential pathways directing FADD nuclear export and cytoplasmic trafficking, and identify subcellular compartmentalization of FADD as a novel regulatory mechanism in death receptor signaling.
SAF‐3, a novel splice variant of the SAF‐1/MAZ/Pur‐1 family, is expressed during inflammation
Authors: Ray Alpana , Dhar Srijita , Shakya Arvind , Ray Papiya , Okada Yasunori , Ray Bimal K.
Published: July 2009

The Cys2His2‐type zinc finger transcription factor serum amyloid A activating factor 1 [SAF‐1, also known as MAZ (myc‐associated zinc finger protein) or Pur‐1 (purine binding factor‐1)] plays an important role in regulation of a variety of inflammation‐responsive genes. An SAF‐2 splice variant acting as a negative regulator of SAF‐1 was identified previously, and the present study reports the identification of a novel SAF‐3 splice variant that is expressed during inflammation. SAF‐3 mRNA, isolated from a cDNA library produced from IL‐1β‐induced cells, originates from a previously unknown first coding exon, and thereby contains a unique N‐terminal domain but shares the same six zinc finger DNA‐binding domains as present in SAF‐1. In addition, a negatively functioning domain present at the N‐terminus of SAF‐1 and SAF‐2 is spliced out in SAF‐3. The expression of SAF‐3 is very low in normal tissues and in cells grown under normal conditions. However, RT‐PCR analysis of mRNAs from cytokine and growth factor‐induced cells as well of mRNAs isolated from several diseased tissues revealed abundant expression of SAF‐3. The transactivation potential of SAF‐3 is much greater than that of the predominantly expressed splice variant SAF‐1. These findings show that transcriptional regulation of downstream inflammation‐responsive genes by SAF/MAZ/Pur‐1 is likely to be more complex than previously assumed. In addition, we show that SAF‐3 expression initiates from an upstream novel promoter. This is the first report of the existence of multiple promoters regulating expression of the SAF/MAZ/Pur‐1 family of proteins.
CTLA‐4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients
Authors: Ulker M. , Yazisiz V. , Sallakci N. , Avci A. B. , Sanlioglu S. , Yegin O. , Terzioglu E.
Published: July 2009

Cytotoxic T lymphocyte‐associated antigen‐4 is a cell‐surface molecule providing a negative signal for T cell activation. CTLA‐4 gene polymorphisms are known to be related with genetic susceptibility to various autoimmune diseases, including systemic lupus erythematosus (SLE). However, the effects of this polymorphism on clinical features of SLE have not been defined. We analysed the CTLA‐4 gene +49 A/G polymorphisms in patients with SLE by using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and investigated the effect of polymorphisms on clinical outcomes. Blood was collected from 47 unrelated Turkish SLE patients, all fulfilling the American College of Rheumatology criteria for SLE, and 100 ethnically matched healthy volunteers. The AA genotype was a predominant genotype in the Turkish population and genotype frequencies of CTLA‐4 AA were significantly higher in SLE patients (70%) than healthy controls (47%) (P = 0.015). There was a statistically significant difference in the AA genotype [odds ratio (OR): 2.66, confidence interval (CI) 95%: 1.27–5.56, P = 0.014] distribution among patients and controls. There was also an increase in A allele frequency in SLE and controls, but the difference was not statistically significant (81% vs. 70%, P = 0.068, OR = 1.8, CI 95%: 0.99–3.28). Interestingly, mean age and mean age of onset disease was higher in AA homozygote SLE patients compared to non‐AA (39.2 ± 11.5 vs. 31.6 ± 10.6, P = 0.044; 32.38 vs. 24.31, P = 0.046, respectively). There was no association between genotype and the other clinical features of SLE. Our results suggested that CTLA‐4 +49 AA genotype might be a risk factor for the development of SLE in Turkish population and G allele might be involved in early development of SLE. No association with clinical features was found for polymorphism of the promoter region in CTLA‐4 +49.
Variation in genes of the epidermal differentiation complex in German atopic dermatitis patients
Authors: Stemmler S. , Nothnagel M. , Parwez Q. , Petrasch‐Parwez E. , Epplen J. T. , Hoffjan S.
Published: July 2009

The filaggrin (FLG) gene is one of the most widely replicated susceptibility genes for atopic dermatitis (AD) so far. Yet, FLG mutations cannot fully account for the original linkage peak on chromosome 1q21, a region comprising the so‐called epidermal differentiation complex (EDC). Since the EDC contains numerous genes relevant for epidermal differentiation, we sought to evaluate variation in other genes located in this region in a German AD case–control cohort. Thirty‐two single nucleotide polymorphisms (SNPs) in 21 genes across the EDC were genotyped in 402 unrelated AD patients and 325 non‐atopic controls by means of restriction enzyme digestion or TaqMan assays. Allele and genotype frequencies were tested for differences between patients and controls by logistic regression. Haplotype frequencies were evaluated using the famhap software. Except for the already known association with FLG, we did not identify any additional significant associations of EDC genes with AD.

Thus, in this German cohort, there is no evidence that additional genes in the EDC region apart from FLG contribute substantially to AD pathogenesis.
Prediction of heavy metal concentrations in urban stormwater
Authors: May Daniel B. , Sivakumar Muttucumaru
Published: July 2009

Heavy metals in urban stormwater runoff can adversely impact aquatic ecosystems. Successful management of such systems requires the accurate prediction of contaminant concentrations. This has created the need for simplistic statistical models. In this study, models were constructed to predict three of the most prevalent heavy metal constituents in urban stormwater: copper (Cu), lead (Pb) and zinc (Zn). Data from the United States, obtained during the Nationwide Urban Runoff Program (NURP), were used to calibrate and verify the models. A comparison of the models revealed that regression models were more accurate than the landuse‐based or metropolitan area averages of event mean concentration (EMC). The regression models also provided insight into important stormwater processes. It was found that pollutant accumulation on the catchment surface was essentially supply limited, and that significant portions of heavy metals originate from highly impervious areas.
Quantifying six decades of fishery selection for size and age at maturity in sockeye salmon
Authors: Kendall Neala W. , Hard Jeffrey J. , Quinn Thomas P.
Published: July 2009

Life history traits of wild animals can be strongly influenced, both phenotypically and evolutionarily, by hunting and fishing. However, few studies have quantified fishery selection over long time periods. We used 57 years of catch and escapement data to document the magnitude of and trends in gillnet selection on age and size at maturity of a commercially and biologically important sockeye salmon stock. Overall, the fishery has caught larger fish than have escaped to spawn, but selection has varied over time, becoming weaker and less consistent recently. Selection patterns were strongly affected by fish age and sex, in addition to extrinsic factors including fish abundance, mesh size regulations, and fish length variability. These results revealed a more complex and changing pattern of selective harvest than the ‘larger is more vulnerable’ model, emphasizing the need for quantified, multi‐year studies before conclusions can be drawn about potential evolutionary and ecological effects of fishery selection. Furthermore, the results indicate that biologically robust escapement goals and prevention of harvest of the largest individuals may help prevent negative effects of size‐selective harvest.
Hieracium (Asteraceae) of sub‐alpine Dalarna, Sweden, revisited: decline in species richness attributable to both forestry and overgrowth
Authors: Tyler Torbjörn , Bertilsson Anders
Published: July 2009

The Hieracium flora of westernmost Dalarna, comprising the southern fringe of the Scandes alps (central Scandinavia), is extremely rich in species. The area is dominated by species‐poor coniferous sub‐alpine and taiga forest, but within this matrix there are small and isolated sites with high species richness of both Hieracium and other plants. Both steep mountain slopes with outcrops of base‐rich bedrock and moving ground water, and old seasonal or permanant human settlements constitute such biodiversity hotspots. However, today the former are threatened by modern forestry practices and/or exploitation for winter tourism and the latter are commonly abandoned and subjected to severe overgrowth or dramatically changed land‐use. The area was thorougly surveyed in 1897–1921. In 2007, the same region and partly the same sites, were revisited. In 1897–1921, 15 Hieracium species were on average recorded from each site, but when the same sites were revisited in 2007 significantly fewer, only about 6 (40%) species per site, were refound. As far as the total species pool of the study area is concerned, it consisted of 168 species in 1897–1921, whereof only 117 (67%) were found in 2007. This remarkable reduction in species richness at both the local and the regional scale is attributable to both modern forestry practices and to the cessation of traditional agricultural practices like hay‐making on semi‐natural grasslands and extensive cattle‐grazing in the forests. It is concluded that to reduce the on‐going severe loss of biodiversity in the sub‐alpine and taiga regions, conservation efforts in these areas ought to be enhanced and concentrated not only on saving what still remains of old‐growth forest but also on managing remnants of grasslands and formerly grazed or mowed open forests around former settlements.
Working criteria of mild cognitive impairment in community: findings from Gwangju Dementia and Mild Cognitive Impairment Study (GDEMCIS)
Authors: Lee Kang Soo , Cheong Hae Kwan , Oh Byoung Hoon , Na Duk L. , Hong Chang Hyung
Published: July 2009

Introduction:The clinical determination of relative severity of impairment along the spectrum of mild cognitive impairment (MCI) may be valuable for the prediction of dementia. The purpose of the present study is to suggest the working criteria of MCI based on severity in the community sample.

Methods:The MCI group was divided into three groups by severity according to cognitive and functional status. The grade I MCI group was based on the original concept of Petersen's MCI. The grade II MCI group was in the same condition as grade I MCI, except that the general cognitive function was not intact. The grade III MCI group was defined as the condition not essentially preserved instrumental to the activity of daily living, but not definite in dementia regardless of general cognitive and functional state.

Results:A total of 38.5% of the subjects were classified as not cognitively impaired (NCI), 41.4% as MCI, and 10.3% as having dementia. Preliminary results showed that the grades I, II, and III MCI groups had a tendency to lie between the NCI and dementia groups.

Discussion:Prospective cohort studies with clinical correlations are needed to determine whether our working criteria of MCI considering characteristics of the rural elderly, such as low education and less comprehensive activities of daily living (ADL), would be useful.
Sympathetic‐mediated hypertension of awake juvenile rats submitted to chronic intermittent hypoxia is not linked to baroreflex dysfunction
Authors: Zoccal Daniel B. , Bonagamba Leni G. H. , Paton Julian F. R. , Machado Benedito H.
Published: July 2009

In the present study, we evaluated the mechanisms underpinning the hypertension observed in freely moving juvenile rats submitted to chronic intermittent hypoxia (CIH). Male juvenile Wistar rats (20–21 days old) were submitted to CIH (6% O2for 40 s every 9 min, 8 h day−1) for 10 days while control rats were maintained in normoxia. Prior to CIH, baseline systolic arterial pressure (SAP), measured indirectly, was similar between groups (86 ± 1versus87 ± 1 mmHg). After exposure to CIH, SAP recorded directly was higher in the CIH (n= 28) than in the control group (n= 29; 131 ± 3versus115 ± 2 mmHg,P< 0.05). This higher SAP of CIH rats presented an augmented power of oscillatory components at low (10.05 ± 0.91versus5.02 ± 0.63 mmHg2,P< 0.05) and high (respiratory‐related) frequencies (12.42 ± 2.46versus3.28 ± 0.61 mmHg2,P< 0.05) in comparison with control animals. In addition, rats exposed to CIH also exhibited an increased cardiac baroreflex gain (−3.11 ± 0.08versus−2.1 ± 0.10 beats min−1mmHg−1,P< 0.0001), associated with a shift to the right of the operating point, in comparison with control rats. Administration of hexamethonium (ganglionic blocker,i.v.), injected after losartan (angiotensin II type 1 receptor antagonist) and [β‐mercapto‐β,β‐cyclopenta‐methylenepropionyl1,O‐Me‐Tyr2, Arg8]‐vasopressin (vasopressin type 1a receptor antagonist), produced a larger depressor response in the CIH (n= 8) than in the control group (n= 9; −49 ± 2versus−39 ± 2 mmHg,P< 0.05). Fifteen days after the cessation of exposure to CIH, the mean arterial pressure of CIH rats returned to normal levels. The data indicate that the sympathetic‐mediated hypertension observed in conscious juvenile rats exposed to CIH is not secondary to a reduction in cardiac baroreflex gain and exhibits a higher respiratory modulation, indicating that an enhanced respiratory–sympathetic coupling seems to be the major factor contributing to hypertension in rats exposed to CIH.
GENERATION OF OSCILLATORS BASED ON GROUNDED CAPACITOR CURRENT CONVEYORS WITH MINIMUM PASSIVE COMPONENTS
Authors: SOLIMAN AHMED M.
Published: July 2009

In this paper, eight new Frequency Dependent Negative Resistance (FDNR) circuits using two current conveyors or inverting current conveyors or a combination of the two types are introduced. The proposed circuits are canonic and they use two grounded capacitors and one floating resistor. The generation of grounded capacitor minimum passive component oscillators from the FDNR circuits is also considered. It is found that two of the recently reported attractive oscillators are among the family of the generated oscillator circuits. Additional six new oscillator circuits based on the FDNR circuits are introduced in this paper. Spice simulation results using technology: SCN 05 feature size 0.5 μm, MOSIS Vendor: AGILENT to demonstrate the practicality of the proposed oscillators are included.
THE DESIGN OF A LI-ION BATTERY CHARGER BASED ON MULTIMODE LDO TECHNOLOGY
Authors: TSAI CHIA-CHUN , LIN CHIN-YEN , HWANG YUH-SHYAN , LEE TRONG-YEN
Published: July 2009

In this paper, we design a CMOS Li-Ion battery charger using the multimode low dropout (LDO) voltage regulator associated with a current sense to supply trickle current, constant current, and constant voltage for charging the battery in order. The protections from over charging and discharging are also considered by monitoring the charging current, reverse voltage, and battery temperature. The whole charger has been verified by HSPICE with TSMC 0.35 μm 2P4M CMOS process. The charger provides the trickle current of 150 mA, maximum charging current of 312 mA, and charging voltage of 4.2 V at the input voltage of 4.5 V. The power efficiency of 72.3% is acceptable under the power consumption of 1.28 W. The chip occupies an area of 1.78 mm × 1.77 mm including 2955 transistors.
DYNAMICS OF MATTER IN A COMPACTIFIED KALUZA–KLEIN MODEL
Authors: LACQUANITI VALENTINO , MONTANI GIOVANNI
Published: July 2009

A long-standing problem in Kaluza–Klein models is the description of matter dynamics. Within the 5D model, the dimensional reduction of the geodesic motion for a 5D free test particle formally restores electrodynamics, but the reduced 4D particle shows a charge–mass ratio that is upper-bounded, such that it cannot fit in with any kind of elementary particle. At the same time, from the quantum dynamics viewpoint, there is the problem of the generation of huge massive modes. We present a criticism against the 5D geodesic approach and face the hypothesis that in Kaluza–Klein space the geodesic motion does not deal with the real dynamics of the test particle. We propose a new approach: starting from the conservation equation for the 5D matter tensor, within the Papapetrou multipole expansion, we prove that the 5D dynamical equation differs from the 5D geodesic one. Our new equation provides right coupling terms without bounding and in such a scheme the tower of massive modes is removed.
CAN THE PIONEER ANOMALY BE INDUCED BY VELOCITY-DEPENDENT FORCES? TESTS IN THE OUTER REGIONS OF THE SOLAR SYSTEM WITH PLANETARY DYNAMICS
Authors: IORIO LORENZO
Published: July 2009

We analyze the impact of some velocity-dependent forces recently proposed to explain the Pioneer anomaly on the orbital motions of the outer planets of the solar system from Jupiter to Pluto, and compare their predictions (secular variations of the longitude of perihelion ϖ or of the semimajor axis a and the eccentricity e) with the latest observational determinations by E. V. Pitjeva with the EPM2006 ephemerides. It turns out that while the predicted centennial shifts of a are so huge that they would have been easily detected for all planets with the exception of Neptune, the predicted anomalous precessions of ϖ are too small, with the exception of Jupiter, so that they are still compatible with the estimated corrections to the standard Newton–Einstein perihelion precessions. As a consequence, we are inclined to discard those extra forces predicting secular variations of a and e, also for some other reasons, and to give a chance, at least observationally, to those models yielding perihelion precessions. Of course, adequate theoretical foundations for them should be found.
A SEARCH FOR NEW PHYSICS WITH THE BEACON MISSION
Authors: TURYSHEV SLAVA G. , SHAO MICHAEL , GIRERD ANDRÉ , LANE BENJAMIN
Published: July 2009

The primary objective of the Beyond Einstein Advanced Coherent Optical Network (BEACON) mission is a search for new physics beyond general relativity by measuring the curvature of relativistic space–time around the Earth. This curvature is characterized by the Eddington parameter γ — the most fundamental relativistic gravity parameter and a direct measure for the presence of new physical interactions. BEACON will achieve an accuracy of 1 × 10-9 in measuring the parameter γ, thereby going a factor of 30,000 beyond the present best result involving the Cassini spacecraft. Secondary mission objectives include: (i) a direct measurement of the "frame-dragging" and geodetic precessions in the Earth's rotational gravitomagnetic field, to 0.05% and 0.03% accuracy respectively, (ii) the first measurement of gravity's nonlinear effects on light and the corresponding second order spatial metric's effects to 0.01% accuracy. BEACON will lead to robust advances in tests of fundamental physics — this mission could discover a violation or extension of general relativity and/or reveal the presence of an additional long range interaction in physics. It will provide crucial information to separate modern scalar–tensor theories of gravity from general relativity, probe possible ways for gravity quantization, and test modern theories of cosmological evolution.
The Biology of Paternal Care in Human and Nonhuman Primates
Authors: Fernandez-Duque Eduardo , Valeggia Claudia R. , Mendoza Sally P.
Published: July 2009

Among primates, intense paternal care is manifested in only a few distantly related species, including humans. Thus, neither purely phylogenetic nor socioecological hypotheses can explain its presence or the variability in the expression of paternal behaviors. Traditional theoretical models for the evolution of paternal care can now be reexamined, focusing on male-female interactions as a possible key to understanding parental strategies. At a proximate level, the existing evidence implies a common physiological substrate for both paternal behavior and pair-bonds. Vasopressin, and perhaps prolactin and testosterone, apparently underlies the endocrinological bases of paternal care, and neuroanatomical reward pathways may be involved in the formation of attachment bonds. Understanding of the genetic structure of primate populations and the neurogenetics of social behavior is also emerging. A multidisciplinary approach that also considers epigenetic and transgenerational effects promises to open new avenues to explain the flexible nature of paternal care in primates.
New Paths in the Linguistic Anthropology of Oceania
Authors: Tomlinson Matt , Makihara Miki
Published: July 2009

The linguistic anthropology of Oceania has seen vigorous and productive analysis of language ideologies, ritual performance, personhood, and agency. This article points to three related paths of inquiry that are especially promising. First, language ideologies are analyzed for the ways they shape expectations and interpretations of effective action and social identity. Second, processes of entextualization are examined with reference to Bible translation because Christianity is a dominant social force in contemporary Oceania. Third, prominent recent work on personhood and agency is reviewed, and scholars are urged to reconsider the classic Oceanic term mana in relation to changing understandings of power, including those wrought by religious transformations. These paths of inquiry are intertwined and cross-cutting and can lead to productive new understandings of ideologies and practices of stability and transformation.
Archaeology and Anthropology: A Personal Overview of the Past Half-Century
Authors: Watson Patty Jo
Published: July 2009

Having begun graduate work in anthropology and prehistoric archaeology at a time (early 1950s) and place (University of Chicago) where the two were closely linked, I subsequently participated in work devoted to early agricultural economies in Western Asia and Eastern North America; to the relations among archaeology, history, and science; and to the place of anthropological archaeology in the contemporary world. In this article I discuss my personal experiences within each of these areas of endeavor.
Tobacco
Authors: Kohrman Matthew , Benson Peter
Published: July 2009

Anthropologists have long studied tobacco, what is today the world's greatest cause of preventable death. Their publications have garnered modest attention, however, even as the academy is increasingly interested in global health, transnational commoditization, pharmaceuticals, and the politics of life and death. We take stock of anthropology's tobacco literature and our discipline's broader appetites. We review how colleagues have studied health issues related to tobacco and engaged with theory and policy pertaining to the production, consumption, and regulation of drugs. We assess ways scholars working at the interface of anthropology and cigarettes have analyzed gender and ethnicity, corporate predation and industry-related harm, governmental management of disease, and the semiotics of misinformation. We discuss why anthropology has not more broadly and ardently engaged the study of tobacco. And we identify areas for further research capable of illuminating more fully tobacco's analytical potential and toxic effects.
Social Reproduction in Classrooms and Schools
Authors: Collins James
Published: July 2009

Social reproduction theory argues that schools are not institutions of equal opportunity but mechanisms for perpetuating social inequalities. This review discusses the emergence and development of social reproduction analyses of education and examines three main perspectives on reproduction: economic, cultural, and linguistic. Reproduction analyses emerged in the 1960s and were largely abandoned by the 1990s; some of the conceptual and political reasons for this turning away are addressed. New approaches stress concepts such as agency, identity, person, and voice over the structural constraints of political economy or code, but results have been mixed. Despite theoretical and methodological advances—including new approaches to multilevel analysis and alertness to temporal processes—the difficult problem remains to understand how social inequality results from the interplay of classrooms, schools, and the wider society.
Hemoglobin vesicles improve wound healing and tissue survival in critically ischemic skin in mice
Authors: Plock Jan A. , Rafatmehr Nassim , Sinovcic Dubravko , Schnider Jonas , Sakai Hiromi , Tsuchida Eishun , Banic Andrej , Erni Dominique
Published: July 2009

Local hypoxia, as due to trauma, surgery, or arterial occlusive disease, may severely jeopardize the survival of the affected tissue and its wound-healing capacity. Initially developed to replace blood transfusions, artificial oxygen carriers have emerged as oxygen therapeutics in such conditions. The aim of this study was to target primary wound healing and survival in critically ischemic skin by the systemic application of left-shifted liposomal hemoglobin vesicles (HbVs). This was tested in bilateral, cranially based dorsal skin flaps in mice treated with a HbV solution with an oxygen affinity that was increased to a P50 (partial oxygen tension at which the hemoglobin becomes 50% saturated with oxygen) of 9 mmHg. Twenty percent of the total blood volume of the HbV solution was injected immediately and 24 h after surgery. On the first postoperative day, oxygen saturation in the critically ischemic middle flap portions was increased from 23% (untreated control) to 39% in the HbV-treated animals ( P < 0.05). Six days postoperatively, flap tissue survival was increased from 33% (control) to 57% ( P < 0.01) and primary healing of the ischemic wound margins from 6.6 to 12.7 mm ( P < 0.05) after HbV injection. In addition, higher capillary counts and endothelial nitric oxide synthase expression (both P < 0.01) were found in the immunostained flap tissue. We conclude that left-shifted HbVs may ameliorate the survival and primary wound healing in critically ischemic skin, possibly mediated by endothelial nitric oxide synthase-induced neovascularization.
Adipose-derived stem cells are an effective cell candidate for treatment of heart failure: an MR imaging study of rat hearts
Authors: Wang Lei , Deng Jixian , Tian Weichen , Xiang Bo , Yang Tonghua , Li Gang , Wang Jian , Gruwel Marco , Kashour Tarek , Rendell John , Glogowski Miriam , Tomanek Boguslaw , Freed Darren , Deslauriers Roxanne , Arora Rakesh C. , Tian Ganghong
Published: July 2009

This study assessed the potential therapeutic efficacy of adipose-derived stem cells (ASCs) on infarcted hearts. Myocardial infarction was induced in rat hearts by occlusion of the left anterior descending artery (LAD). One week after LAD occlusion, the rats were divided into three groups and subjected to transplantation of ASCs or transplantation of cell culture medium (CCM) or remained untreated. During a 1-mo recovery period, magnetic resonance imaging showed that the ASC-treated hearts had a significantly greater left ventricular (LV) ejection fraction and LV wall thickening than did the CCM-treated and untreated hearts. The capillary density in infarct border zone was significantly higher in the ASC-treated hearts than in the CCM-treated and untreated hearts. However, only 0.5% of the ASCs recovered from the ASC-treated hearts were stained positive for cardiac-specific fibril proteins. It was also found that ASCs under a normal culture condition secreted three cardiac protective growth factors: vascular endothelial growth factor, hepatocyte growth factor, and insulin-like growth factor-1. Results of this study suggest that ASCs were able to improve cardiac function of infarcted rat hearts. Paracrine effect may be the mechanism underlying the improved cardiac function and increased capillary density.
Vestibular evoked myogenic potentials evoked by brief interaural head acceleration: properties and possible origin
Authors: Rosengren Sally M. , Todd Neil P. M. , Colebatch James G.
Published: July 2009

The vestibular system responds to head acceleration by producing compensatory reflexes in the eyes and postural muscles. In this study, we investigated the effect of brief interaural acceleration on the vestibular evoked myogenic potential (VEMP) in 10 normal subjects and 10 patients with bilateral (bVL) or unilateral vestibular loss (uVL). The stimuli were delivered with a handheld minishaker and tendon hammer over the mastoid and produced relatively pure interaural head acceleration with little rotation (mean peak acceleration: 0.14 g at 3.3 ms). VEMPs were recorded from the neck muscles and were characterized in normal subjects by a positive/negative potential ipsilateral to the stimulated side (peak latencies: 15.1 and 22.6 ms) and a positive response contralaterally (20.3 ms), which was sometimes preceded by a negativity (14.5 ms). These peaks were absent in patients with bVL, confirming their vestibular dependence. In the patients with uVL, medial acceleration of the intact ear produced bilateral responses, an initial positivity on the intact side, and a negativity on the affected side, whereas lateral acceleration produced only a late positivity on the intact side. As the acceleration was primarily in the horizontal plane, it is likely to have activated utricular receptors. Consistent with this, we found that VEMPs are very sensitive to the direction of head acceleration and have features consistent with the utriculocollic projections demonstrated in animals.
Hormone therapy attenuates exercise-induced skeletal muscle damage in postmenopausal women
Authors: Dieli-Conwright Christina M. , Spektor Tanya M. , Rice Judd C. , Schroeder E. Todd
Published: July 2009

Hormone therapy (HT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation [serum creatine kinase (CK), serum lactate dehydrogenase (LDH), and skeletal muscle mRNA expression of IL-6, IL-8, IL-15, and TNF-α] in postmenopausal women after a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: women not using HT (control; n = 6, 59 ± 4 yr, 63 ± 17 kg) and women using traditional HT (HT; n = 8, 59 ± 4 yr, 89 ± 24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60°/s with 20-s rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 h after the exercise bout. Gene expression was determined by RT-PCR for IL-6, IL-8, IL-15, and TNF-α. Blood draws were performed at baseline and 3 days after exercise to measure CK and LDH. Independent t-tests were performed to test group differences (control vs. HT). A probability level of P ≤ 0.05 was used to determine statistical significance. We observed significantly greater changes in mRNA expression of IL-6, IL-8, IL-15, and TNF-α ( P ≤ 0.01) in the control group compared with the HT group after the exercise bout. CK and LDH levels were significantly greater after exercise ( P ≤ 0.01) in the control group. Postmenopausal women not using HT experienced greater muscle damage after maximal eccentric exercise, indicating a possible protective effect of HT against exercise-induced skeletal muscle damage.
Transient influence of end-tidal carbon dioxide tension on the postural restraint in cerebral perfusion
Authors: Immink Rogier V. , Truijen Jasper , Secher Niels H. , Van Lieshout Johannes J.
Published: July 2009

In the upright position, cerebral blood flow is reduced, maybe because arterial carbon dioxide partial pressure (PaCO2) decreases. We evaluated the time-dependent influence of a reduction in PaCO2, as indicated by the end-tidal Pco2 tension (PetCO2), on cerebral perfusion during head-up tilt. Mean arterial pressure, cardiac output, middle cerebral artery mean flow velocity (MCA Vmean), and dynamic cerebral autoregulation at supine rest and 70° head-up tilt were determined during free breathing and with PetCO2 clamped to the supine level. The postural changes in central hemodynamic variables were equivalent, and the cerebrovascular autoregulatory capacity was not significantly affected by tilt or by clamping PetCO2. In the first minute of tilt, the decline in MCA Vmean (10 ± 4 vs. 3 ± 4 cm/s; mean ± SE; P < 0.05) and PetCO2 (6.8 ± 4.3 vs. 1.7 ± 1.6 Torr; P < 0.05) was larger during spontaneous breathing than during isocapnic tilt. However, after 2 min in the head-up position, the reduction in MCA Vmean was similar (7 ± 5 vs. 6 ± 3 cm/s), although the spontaneous decline in PetCO2 was maintained ( P < 0.05 vs. isocapnic tilt). These results suggest that the potential contribution of PaCO2 to the postural reduction in MCA Vmean is transient, leaving the mechanisms for the sustained restrain in MCA Vmean to be identified.
Increased serum levels of the brain damage marker S100B after apnea in trained breath-hold divers: a study including respiratory and cardiovascular observations
Authors: Andersson Johan P. A. , Linér Mats H. , Jönsson Henrik
Published: July 2009

The concentration of the protein S100B in serum is used as a brain damage marker in various conditions. We wanted to investigate whether a voluntary, prolonged apnea in trained breath-hold divers resulted in an increase of S100B in serum. Nine trained breath-hold divers performed a protocol mimicking the procedures they use during breath-hold training and competition, including extensive preapneic hyperventilation and glossopharyngeal insufflation, in order to perform a maximum-duration apnea, i.e., “static apnea” (average: 335 s, range: 281–403 s). Arterial blood samples were collected and cardiovascular variables recorded. Arterial partial pressures of O2 and CO2 (PaO2 and PaCO2) were 128 Torr and 20 Torr, respectively, at the start of apnea. The degree of asphyxia at the end of apnea was considerable, with PaO2 and PaCO2 reaching 28 Torr and 45 Torr, respectively. The concentration of S100B in serum transiently increased from 0.066 μg/l at the start of apnea to 0.083 μg/l after the apnea ( P < 0.05). The increase in S100B is attributed to the asphyxia or to other physiological responses to apnea, for example, increased blood pressure, and probably indicates a temporary opening of the blood-brain barrier. It is not possible to conclude that the observed increase in S100B levels in serum after a maximal-duration apnea reflects a serious injury to the brain, although the results raise concerns considering negative long-term effects. At the least, the results indicate that prolonged, voluntary apnea affects the integrity of the central nervous system and do not preclude cumulative effects.
Impact of preinduced quadriceps fatigue on exercise response in chronic obstructive pulmonary disease and healthy subjects
Authors: Gagnon Philippe , Saey Didier , Vivodtzev Isabelle , Laviolette Louis , Mainguy Vincent , Milot Julie , Provencher Steeve , Maltais François
Published: July 2009

Exercise intolerance in chronic obstructive pulmonary disease (COPD) results from a complex interaction between central (ventilatory) and peripheral (limb muscles) components of exercise limitation. The purpose of this study was to evaluate the influence of quadriceps muscle fatigue on exercise tolerance and ventilatory response during constant-workrate cycling exercise testing (CWT) in patients with COPD and healthy subjects. Fifteen patients with COPD and nine age-matched healthy subjects performed, 7 days apart, two CWTs up to exhaustion at 80% of their predetermined maximal work capacity. In a randomized order, one test was performed with preinduced quadriceps fatigue and the other in a fresh state. Quadriceps fatigue was produced by electrostimulation-induced contractions and quantified by maximal voluntary contraction and potentiated twitch force (TwQpot). Endurance time and ventilatory response during CWT were compared between fatigued and fresh state. Endurance time significantly decreased in the fatigued state compared with the fresh condition in COPD (356 ± 69 s vs. 294 ± 45 s, P < 0.05) and controls (450 ± 74 s vs. 340 ± 45 s, P < 0.05). Controls showed significantly higher ventilation and end-exercise dyspnea scores in the fatigued condition, whereas, in COPD, fatigue did not influence ventilation or dyspnea during exercise. The degree of ventilatory limitation, as expressed by the V̇e/maximum voluntary ventilation ratio, was similar in both conditions in patients with COPD. We conclude that it is possible to induce quadriceps fatigue by local electrostimulation-induced contractions. Our findings demonstrate that peripheral muscle fatigue is an additional important factor, besides intense dyspnea, that limits exercise tolerance in COPD.
Junctional Adhesion Molecule-C Mediates Leukocyte Infiltration in Response to Ischemia Reperfusion Injury
Authors: Scheiermann Christoph , Colom Bartomeu , Meda Paolo , Patel Nimesh S.A. , Voisin Mathieu-Benoit , Marrelli Alessandra , Woodfin Abigail , Pitzalis Costantino , Thiemermann Christoph , Aurrand-Lions Michel , Imhof Beat A. , Nourshargh Sussan
Published: July 2009

Objective—

Junctional adhesion molecule-C (JAM-C) is an adhesion molecule that has multiple roles in inflammation and vascular biology, but many aspects of its functions under pathological conditions are unknown. Here we investigated the role of JAM-C in leukocyte migration in response to ischemia reperfusion (I/R) injury.

Methods and Results—

Pretreatment of mice with soluble JAM-C (sJAM-C), used as a pharmacological blocker of JAM-C-mediated reactions, significantly suppressed leukocyte migration in models of kidney and cremaster muscle I/R injury (39 and 51% inhibition, respectively). Furthermore, in the cremaster muscle model (studied by intravital microscopy), both leukocyte adhesion and transmigration were suppressed in JAM-C-deficient mice (JAM-C
−/−
) and enhanced in mice overexpressing JAM-C in their endothelial cells (ECs). Analysis of JAM-C subcellular expression by immunoelectron microscopy indicated that in I/R-injured tissues, EC JAM-C was redistributed from cytoplasmic vesicles and EC junctional sites to nonjunctional plasma membranes, a response that may account for the role of JAM-C in both leukocyte adhesion and transmigration under conditions of I/R injury.

Conclusions—

The findings demonstrate a role for EC JAM-C in mediating leukocyte adhesion and transmigration in response to I/R injury and indicate the existence of a novel regulatory mechanism for redistribution and hence function of EC JAM-C in vivo.
Nox2-Containing NADPH Oxidase Deficiency Confers Protection From Hindlimb Ischemia in Conditions of Increased Oxidative Stress
Authors: Haddad Paola , Dussault Sylvie , Groleau Jessika , Turgeon Julie , Michaud Sophie-Elise , Ménard Catherine , Perez Gemma , Maingrette Fritz , Rivard Alain
Published: July 2009

Objective—

Because Nox2-containing NADPH oxidase is a major source of ROS in the vasculature, we investigated its potential role for the modulation of ischemia-induced neovascularization in conditions of increased oxidative stress.

Methods and Results—

To mimic a clinical situation of increased oxidative stress, mice were exposed to cigarette smoke before and after the surgical induction of hindlimb ischemia. Nox2 expression and oxidative stress in ischemic tissues were significantly increased in wild-type mice, but not in mice deficient for the Nox2-containing NADPH oxidase (Nox2
−/−
). Nox2
−/−
mice demonstrated faster blood flow recovery, increased capillary density in ischemic muscles, and improved endothelial progenitor cell functional activities compared to Nox2
+/+
mice. In addition, Nox2 deficiency was associated with increased antioxidant and nitrite concentrations in plasma, together with a preserved expression of eNOS in ischemic tissues. In vitro, Nox2
−/−
endothelial cells exhibit resistance against superoxide induction and improved VEGF-dependent angiogenic activities compared to Nox2
+/+
endothelial cells. Importantly, the beneficial effects of Nox2 deficiency on neovascularization in vitro and in vivo were lost after treatment with the NO inhibitor L-NAME.

Conclusions—

Nox2-containing NADPH oxidase deficiency protects against ischemia in conditions of increased oxidative stress. The mechanism involves improved neovascularization through a reduction of ROS formation, preserved activation of the VEGF/NO angiogenic pathway, and improved functional activities of endothelial progenitor cells.
Functional Characterization of a Putative Serine Carboxypeptidase in Vascular Smooth Muscle Cells
Authors: Lee Ting-Hein , Chen Jiyuan , Miano Joseph M.
Published: July 2009

Rationale:

We previously identified a novel serine carboxypeptidase, SCPEP1, that undergoes cleavage across all tissues where it is expressed. SCPEP1 bears the signature catalytic triad found in all serine carboxypeptidases, but its biological function is completely unknown.

Objective:

To begin elucidating the functions of SCPEP1 in vitro and in the vessel wall after injury.

Methods and Results:

Cultured smooth muscle cells were transduced with adenovirus carrying wild-type
Scpep1
, a short hairpin RNA to
Scpep1
, or variants of
Scpep1
with mutations that disrupt the catalytic triad domain or SCPEP1 cleavage. Western blotting of key growth regulators or growth and migratory responses were assessed following SCPEP1 gain- or loss-of-function in smooth muscle cells. Vascular injury-induced remodeling and cell proliferation were evaluated in wild-type or newly created
Scpep1
knockout mice. Overexpression of wild-type or cleavage-defective SCPEP1, but not a catalytic triad mutant SCPEP1, promotes smooth muscle cell proliferation and migration in vitro. A short hairpin RNA to
Scpep1
blunts endogenous growth, which is rescued on concurrent expression of
Scpep1
carrying silent mutations that evade knockdown. SCPEP1 protein is highly expressed in the neointima of 2 models of vascular remodeling.
Scpep1
-null mice show decreases in medial and intimal cell proliferation as well as vessel remodeling following arterial injury.

Conclusions:

SCPEP1 promotes smooth muscle cell proliferation and migration in a catalytic triad-dependent, cleavage-independent manner. SCPEP1 represents a new mediator of vascular remodeling and a potential therapeutic target for the treatment of vascular occlusive diseases.
Evidence From Human Myectomy Samples That
MYBPC3
Mutations Cause Hypertrophic Cardiomyopathy Through Haploinsufficiency
Authors: Marston Steven , Copeland O‘Neal , Jacques Adam , Livesey Karen , Tsang Victor , McKenna William J. , Jalilzadeh Shapour , Carballo Sebastian , Redwood Charles , Watkins Hugh
Published: July 2009

Rationale:

Most sarcomere gene mutations that cause hypertrophic cardiomyopathy are missense alleles that encode dominant negative proteins. The potential exceptions are mutations in the
MYBPC3
gene (encoding cardiac myosin-binding protein-C [MyBP-C]), which frequently encode truncated proteins.

Objective:

We sought to determine whether there was evidence of haploinsufficiency in hypertrophic cardiomyopathy caused by
MYBPC3
mutations by comparing left ventricular muscle from patients undergoing surgical myectomy with samples from donor hearts.

Methods and Results:

MyBP-C protein and mRNA levels were quantitated using immunoblotting and RT-PCR. Nine of 37 myectomy samples had mutations in
MYBPC3
: 2 missense alleles (Glu258Lys, Arg502Trp) and 7 premature terminations. No specific truncated MyBP-C peptides were detected in whole muscle homogenates of hypertrophic cardiomyopathy tissue. However, the overall level of MyBP-C in myofibrils was significantly reduced (
P
<0.0005) in tissue containing either a truncation or missense
MYBPC3
mutation: 0.76±0.03 compared with 1.00±0.05 in donor and 1.01±0.06 in non-
MYBPC3
mutant myectomies.

Conclusions:

The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense
MYBPC3
mutations argues strongly that haploinsufficiency is sufficient to cause the disease.
Introduction
Authors: Berman Constance
Published: July 2009

This introduction describes the changing assumptions about medieval religious women that have allowed increasing research in their often unpublished archives, which has revealed continued power and authority among secular women who were often patrons of such religious communities.