bluuebunny/crossref_metadata_2025 huggingface dataset:
Angular Response of Photomultiplier Tubes: Photon-to-Electron Conversion Efficiency and Reflectance
Authors: Shibamura Eido , Sasaki Shinichi , Tawara Hiroko , Saito Kiwamu , Miyajima Mitsuhiro
Published: July 2006

Reflectance and photon-to-electron conversion efficiency have been measured for photomultiplier tubes (PMTs; Hamamatsu R878 and 7696) using three-color light-emitting diode (LED) emitting photons with central wavelengths of 470, 525, and 640 nm. The use of a light guide with a refractive index similar to that of a photomultiplier window enabled the measurement at the angle of incidence to a photocathode up to 75°. An appreciably large reflectance and conversion efficiency were obtained at the angles of approximately 45 and 60°, respectively. It was shown that these PMTs work with a higher photon-to-electron conversion efficiency than the quantum efficiency given by the manufacturer in many cases of scintillation counting. The reflectance measured in this study is consistent with that calculated using an optical model, where the photocathode was a thin film with a complex refractive index.
Very High Rate and Uniform Glass Etching with HF/HCl Spray for Transferring Thin-Film Transistor Arrays to Flexible Substrates
Authors: Takechi Kazushige , Kanoh Hiroshi , Otsuki Shigeyoshi
Published: July 2006

We report on very high rate and uniform glass etching with HF/HCl spray for transferring thin-film transistor (TFT) arrays from a glass substrate to a flexible substrate. Using HF/HCl spray etching, we achieved both high etch rates of over 20 µm/min and satisfactory etch-rate uniformity over a 150 mm□ area with an approximately 5% variation. Using spray etching, we have successfully fabricated flexible TFT substrates that have satisfactory electrical characteristics.
Millimeter-Wave GaAs Surface Micromachined Bandpass Filters Using the External Quality Factor
Authors: Lee Myeong-Gil , Yun Tae-Soon , Nam Hee , Shin Dong-Hoon , Baek Tae-Jong , Rhee Jin-Koo , Lee Jong-Chul
Published: July 2006

In this paper, millimeter-wave bandpass filters with λg/4 short stubs made by surface micromachining on a GaAs substrate are presented. These filters show flexible bandwidth by variation of the position of the short stub using the external quality factor, Q
e without changing the impedance value at millimeter-wave range. The bandpass filters can be realized with a wide (50%) or narrow (10%) bandwidth simply by adjusting the positions of the short stubs. They show insertion losses of 2.3 and 6.8 dB, and return losses of 15 and 16 dB, respectively at a center frequency of 60 GHz.
Numerical Compensation of Dispersion Mismatch in Discretely Swept Optical-Frequency-Domain-Reflectometry Optical Coherence Tomography
Authors: Choi Donghak , Hiro-Oka Hideaki , Amano Takuji , Furukawa Hiroyuki , Kano Fumiyoshi , Nakanishi Motoi , Shimizu Kimiya , Ohbayashi Kohji
Published: July 2006

We propose a numerical method to compensate dispersion mismatch in optical coherence tomography (OCT) based on optical-frequency-domain reflectyometry (OFDR). Dispersion mismatch causes phase distortion in interferograms depending on wavelength and results in a loss of resolution. We introduce a method to perform the numerical compensation directly to experimental interferograms in real space. Experimental tests are performed for the case of the Mach–Zehnder type OFDR-OCT using a super-structured-grating distributed-Bragg-reflector (SSG-DBR) laser, in which the wavenumber of the optical source is swept discretely by equal interval. It is shown that the method is effective to improve images for layered transparency sheets. We also apply the method to OFDR-OCT imaging of a human nail.
Axonal Wiring in the Mouse Olfactory System
Authors: Mombaerts Peter
Published: July 2006

The main olfactory epithelium of the mouse is a mosaic of 2000 populations of olfactory sensory neurons (OSNs). Each population expresses one allele of one of the 1000 intact odorant receptor (OR) genes. An OSN projects a single unbranched axon to a single glomerulus, from an array of 1600–1800 glomeruli in the main olfactory bulb. Within a glomerulus the OSN axon synapses with the dendrites of second-order neurons and interneurons. Axons of OSNs that express the same OR project to the same glomeruli—typically one glomerulus per half-bulb and thus four glomeruli per mouse. These glomeruli are located at characteristic positions within the glomerular layer of the bulb. ORs determine both the odorant response profile of the OSN and the projection of its axon to a specific glomerulus. I focus on genetic approaches to the axonal wiring problem, particularly on how ORs may function in axonal wiring.
What Mouse Mutants Teach Us About Extracellular Matrix Function
Authors: Aszódi A. , Legate Kyle R. , Nakchbandi I. , Fässler R.
Published: July 2006

For many years the extracellular matrix was viewed as a benign scaffold for arranging cells within connective tissues, but it is now being redefined as a dynamic, mobile, and flexible key player in defining cellular behavior. Gene targeting, transgene expression, and spontaneous mutations of extracellular matrix proteins in mice have greatly accelerated our mechanistic view of the structural and instructive functions of the extracellular matrix in developmental and regenerative processes. This review summarizes the phenotypes of genetic mouse models carrying mutations in extracellular matrix proteins, with specific emphasis on recent advances. The application of reverse genetics has demonstrated the multifunctionality of matrix proteins in a biological context and, in addition, has brought a novel perspective to the understanding of human pathologies.
Mitochondrial Fusion and Fission in Mammals
Authors: Chan David C.
Published: July 2006

Eukaryotic cells maintain the overall shape of their mitochondria by balancing the opposing processes of mitochondrial fusion and fission. Unbalanced fission leads to mitochondrial fragmentation, and unbalanced fusion leads to mitochondrial elongation. Moreover, these processes control not only the shape but also the function of mitochondria. Mitochondrial dynamics allows mitochondria to interact with each other; without such dynamics, the mitochondrial population consists of autonomous organelles that have impaired function. Key components of the mitochondrial fusion and fission machinery have been identified, allowing initial dissection of their mechanisms of action. These components play important roles in mitochondrial function and development as well as programmed cell death. Disruption of the fusion machinery leads to neurodegenerative disease.
Abrupt Change in Earth's Climate System
Authors: Overpeck Jonathan T. , Cole Julia E.
Published: July 2006

▪ Abstract  Many aspects of Earth's climate system have changed abruptly in the past and are likely to change abruptly in the future. Although abrupt shifts in temperature are most dramatic in glacial climates, abrupt changes, resulting in an altered probability of drought, large floods, tropical storm landfall, and monsoon rainfall, are all important concerns even in the absence of significant anthropogenic climate forcing. Continued climate change will likely increase the probability of these types of abrupt change and also make abrupt changes in ocean circulation and sea level more likely. Although global warming may have already triggered abrupt change, current understanding and modeling capability is not sufficient to specify details of future abrupt climate change. Improved adaptation strategies are warranted, as well as efforts to avoid crossing climate change thresholds beyond which large abrupt changes in sea level, ocean circulation, and methane-clathrate release could greatly amplify the impacts of climate change.
Water Markets and Trading
Authors: Chong Howard , Sunding David
Published: July 2006

▪ Abstract  Since the 1970s, supply augmentation strategies to meet water needs have waned, and governments have increasingly focused on demand management measures, including voluntary water transfers. Water demands have also changed as expanding urban growth, changes in agriculture, and increasing concern for the environment compete for water. Water rights regimes based on queuing principles lead to an inefficient allocation of water resources and may also result in other inefficiencies, such as overuse of land and inadequate adoption of capital-intensive conservation technologies. Water trading based on transferable water rights has been advanced as a solution to these problems. Trading helps equalize the marginal prices faced by various water users, thereby providing information about the value of water in alternative uses and creating compatible incentives. Putting water markets into practice introduces real-world complications of transaction costs and third-party externalities. We present these complications along with some major criticisms of water markets, and actual cases of water trading are discussed. We conclude with avenues of potential future research.
The Ciliopathies: An Emerging Class of Human Genetic Disorders
Authors: Badano Jose L. , Mitsuma Norimasa , Beales Phil L. , Katsanis Nicholas
Published: July 2006

Cilia and flagella are ancient, evolutionarily conserved organelles that project from cell surfaces to perform diverse biological roles, including whole-cell locomotion; movement of fluid; chemo-, mechano-, and photosensation; and sexual reproduction. Consistent with their stringent evolutionary conservation, defects in cilia are associated with a range of human diseases, such as primary ciliary dyskinesia, hydrocephalus, polycystic liver and kidney disease, and some forms of retinal degeneration. Recent evidence indicates that ciliary defects can lead to a broader set of developmental and adult phenotypes, with mutations in ciliary proteins now associated with nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome. The molecular data linking seemingly unrelated clinical entities are beginning to highlight a common theme, where defects in ciliary structure and function can lead to a predictable phenotypic pattern that has potentially predictive and therapeutic value.
Structural Variation of the Human Genome
Authors: Sharp Andrew J. , Cheng Ze , Eichler Evan E.
Published: July 2006

There is growing appreciation that the human genome contains significant numbers of structural rearrangements, such as insertions, deletions, inversions, and large tandem repeats. Recent studies have defined approximately 5% of the human genome as structurally variant in the normal population, involving more than 800 independent genes. We present a detailed review of the various structural rearrangements identified to date in humans, with particular reference to their influence on human phenotypic variation. Our current knowledge of the extent of human structural variation shows that the human genome is a highly dynamic structure that shows significant large-scale variation from the currently published genome reference sequence.
Transcriptional Regulatory Elements in the Human Genome
Authors: Maston Glenn A. , Evans Sara K. , Green Michael R.
Published: July 2006

The faithful execution of biological processes requires a precise and carefully orchestrated set of steps that depend on the proper spatial and temporal expression of genes. Here we review the various classes of transcriptional regulatory elements (core promoters, proximal promoters, distal enhancers, silencers, insulators/boundary elements, and locus control regions) and the molecular machinery (general transcription factors, activators, and coactivators) that interacts with the regulatory elements to mediate precisely controlled patterns of gene expression. The biological importance of transcriptional regulation is highlighted by examples of how alterations in these transcriptional components can lead to disease. Finally, we discuss the methods currently used to identify transcriptional regulatory elements, and the ability of these methods to be scaled up for the purpose of annotating the entire human genome.
Genetic Disorders of Adipose Tissue Development, Differentiation, and Death
Authors: Agarwal Anil K. , Garg Abhimanyu
Published: July 2006

Lack of adipose tissue, either complete or partial, is the hallmark of disorders known as lipodystrophies. Patients with lipodystrophies suffer from metabolic complications similar to those associated with obesity, including insulin resistance, type 2 diabetes, hypertriglyceridemia, and hepatic steatosis. The loss of body fat in inherited lipodystrophies can be caused by defects in the development and/or differentiation of adipose tissue as a consequence of mutations in a number of genes, including PPARG (encoding a nuclear hormone receptor), AGPAT2 (encoding an enzyme involved in the biosynthesis of triglyceride and phospholipids), AKT2 (encoding a protein involved in insulin signal transduction), and BSCL2 (encoding seipin, whose role in the adipocyte biology remains unclear). The loss of body fat can also be caused by the premature death of adipocytes due to mutations in lamin A/C, nuclear lamina proteins, and ZMPSTE24, which modifies the prelamin A post-translationally. In this review, we focus on the molecular basis of inherited lipodystrophies as they relate to adipocyte biology and their associated phenotypic manifestations.
The Killer Immunoglobulin-Like Receptor Gene Cluster: Tuning the Genome for Defense
Authors: Bashirova Arman A. , Martin Maureen P. , McVicar Daniel W. , Carrington Mary
Published: July 2006

Killer immunoglobulin-like receptors (KIRs) are molecules expressed on the surface of natural killer (NK) cells, which play an important role in innate immunity. KIR recognition of major histocompatability complex (MHC) class I allotypes represents one component of the complex interactions between NK cells and their targets in determining NK cell reactivity. KIRs are encoded by a gene cluster at human chromosome 19q13.4. Despite their high degree of sequence identity, KIR genes encode proteins that have diverse recognition patterns (specific HLA class I allotypes) and confer opposing signals (activating or inhibitory) to the NK cell. The KIR gene cluster is highly polymorphic, with individual genes exhibiting allelic variability and individual haplotypes differing in gene content. The polymorphism of the KIR locus parallels that of the MHC, facilitating the adaptation of the immune system to a dynamic, challenging environment. This variation is associated with a growing number of human diseases, which is likely to extend to levels observed for the HLA loci. Here we review current progress in understanding KIR biology and genetics.
Francisella tularensis:Taxonomy, Genetics, and Immunopathogenesis of a Potential Agent of Biowarfare
Authors: McLendon Molly K. , Apicella Michael A. , Allen Lee-Ann H.
Published: July 2006

Tularemia is a zoonosis of humans caused by infection with the facultative intracellular bacterium Francisella tularensis. Interest in F. tularensis has increased markedly in the past few years because of its potential use as an agent of bioterrorism. Five subspecies of this organism are found in the Northern hemisphere, but only F. tularensis subsp. tularensis and subsp. holarctica cause disease in humans. This review summarizes what is known about the pathogenesis of tularemia with a focus on bacterial surface components such as lipopolysaccharide and capsule as well as information obtained from the F. tularensis subsp. tularensis SCHU S4 genome. In particular, the mechanisms of action of recently identified virulence factors are discussed in the context of bacterial replication in macrophages and manipulation of the host inflammatory response. Throughout this report, shared and unique features of F. tularensis subsp. tularensis, subsp. holarctica, and subsp. novicida are discussed.
Manganese Transport and the Role of Manganese in Virulence
Authors: Papp-Wallace Krisztina M. , Maguire Michael E.
Published: July 2006

Two areas of research have recently converged to highlight important roles for Mn2+ in pathogenesis: the recognition that both bacterial Nramp homologs and members of LraI family of proteins are Mn2+ transporters. Their mutation is associated with decreased virulence of various bacterial species. Thus, Mn2+ appears to be essential for bacterial virulence. This review describes what is currently known about Mn2+ transport in prokaryotes and how prokaryotic Mn2+ transport is regulated. Some of the phenotypes that arise when microorganisms lack Mn2+ are then discussed, with an emphasis on those phenotypes involving pathogenesis. The concluding section describes possible enzymatic roles for Mn2+ that might help explain why Mn2+ is necessary for virulence.
A Microbial Genetic Journey
Authors: Kaiser Dale
Published: July 2006

Fortunately, I began research in 1950 when the basic concepts of microbial genetics could be explored experimentally. I began with bacteriophage λ and tried to establish the colinearity of its linkage map with its DNA molecule. My students and I worked out the regulation of λ repressor synthesis for the establishment and maintenance of lysogeny. We also investigated the proteins responsible for assembly of the phage head. Using cell extracts, we discovered how to package DNA inside the head in vitro. Around 1972, I began to use molecular genetics to understand the developmental biology of Myxococcus xanthus. In particular, I wanted to learn how myxococcus builds its multicellular fruiting body within which it differentiates spores. We identified two cell-to-cell signals used to coordinate development. We have elucidated, in part, the signal transduction pathway for C-signal that directs the morphogenesis of a fruiting body.
The Bacterial Twin-Arginine Translocation Pathway
Authors: Lee Philip A. , Tullman-Ercek Danielle , Georgiou George
Published: July 2006

The twin-arginine translocation (Tat) pathway is responsible for the export of folded proteins across the cytoplasmic membrane of bacteria. Substrates for the Tat pathway include redox enzymes requiring cofactor insertion in the cytoplasm, multimeric proteins that have to assemble into a complex prior to export, certain membrane proteins, and proteins whose folding is incompatible with Sec export. These proteins are involved in a diverse range of cellular activities including anaerobic metabolism, cell envelope biogenesis, metal acquisition and detoxification, and virulence. The Escherichia coli translocase consists of the TatA, TatB, and TatC proteins, but little is known about the precise sequence of events that leads to protein translocation, the energetic requirements, or the mechanism that prevents the export of misfolded proteins. Owing to the unique characteristics of the pathway, it holds promise for biotechnological applications.
Environmental Stress and Lesion-Bypass DNA Polymerases
Authors: Nohmi Takehiko
Published: July 2006

In nature, microbes live under a variety of harsh conditions, such as excess DNA damage, starvation, pH shift, or high temperatures. Microbial cells respond to such stressful conditions mostly by switching global patterns of gene expression to relieve the environmental stress. The SOS response, which is induced by DNA damage, is one such global network of gene expression that plays a crucial role in balancing the genomic stability and flexibility that are necessary to adapt to harsh environments. Here, I review the roles of SOS-inducible and noninducible lesion-bypass DNA polymerases in mutagenesis induced by environmental stress, and discuss how these polymerases are coordinated for the replication of damaged chromosomes. Possible contributions of lesion-bypass DNA polymerase in hyperthermophilic archaea, e.g., Sulfolobus solfataricus, to genome maintenance are also discussed.
A vH+-ATPase is present in cultured sheep ruminal epithelial cells
Authors: Etschmann Benjamin , Heipertz Katrin Sophie , von der Schulenburg Annabelle , Schweigel Monika
Published: July 2006

In this study, the existence and functional activity of a vacuolar-type H+-ATPase (vH+-ATPase) was explored in primary cultures of sheep ruminal epithelial cells (REC). The mRNA transcripts of the E and B subunits of vH+-ATPase were detectable in RNA from REC samples by RT-PCR. Immunoblotting of REC protein extractions with antibodies directed against the B subunit of yeast vH+-ATPase revealed a protein band of the expected size (60 kDa). Using the fluorescent indicator BCECF and selective inhibitors (foliomycin, HOE 694, S3226), the contribution of vH+-ATPase and Na+/H+exchanger (NHE) subtype 1 and 3 activity to the regulation of intracellular pH (pHi) was determined in nominally HCO3−-free, HEPES-buffered NaCl medium containing 20 mM of the short-chain fatty acid butyrate as well as after reduction of the extracellular Cl−concentration ([Cl−]e) from 136 to 36 mM. The initial pHiof REC was 7.4 ± 0.1 in nominally HCO3−-free, HEPES-buffered NaCl medium and 7.0 ± 0.1 after acid loading with butyrate. Selective inhibition of the vH+-ATPase with foliomycin decreased pHiby 0.19 ± 0.03 pH units. On the basis of the observed decreases in pHiresulting from inhibition of vH+-ATPase as well as of subtypes 1 and 3 of NHE, vH+-ATPase activity appears to account for ∼30% of H+extrusion, whereas the activities of NHE subtypes 3 and 1 account for 20 and 50% of H+extrusion, respectively. Lowering of [Cl−]einduced a pHidecrease (−0.51 ± 0.03 pH units) and impaired pHirecovery from butyrate-induced acid load. Moreover, reduction of [Cl−]eabolished the inhibitory effect of foliomycin and markedly reduced the HOE 694- and S3226-sensitive components of pHi, indicating a role of Cl−in the function of these H+extrusion mechanisms. We conclude that a vH+-ATPase is expressed in ovine REC and plays a considerable role in the pHiregulation of these cells.
Estrogen and salt sensitivity in the female mRen(2).Lewis rat
Authors: Chappell Mark C. , Yamaleyeva Liliya M. , Westwood Brian M.
Published: July 2006

The present study determined whether early loss of estrogen influences salt-sensitive changes in blood pressure, renal injury, and cardiac hypertrophy as well as the effects on the circulating renin-angiotensin-aldosterone system (RAAS) in the hypertensive female mRen( 2 ).Lewis strain. Ovariectomy (OVX) of heterozygous mRen( 2 ).Lewis rats on a normal salt (NS) diet (0.5% sodium) increased systolic blood pressure from 137 ± 3 to 177 ± 5 mmHg ( P < 0.01) by 15 wk but did not show any changes in cardiac-to-body weight index (CI), proteinuria, or creatinine clearance. Maintenance with a high-sodium (HS) diet (4%) increased blood pressure (203 ± 4 mmHg, P < 0.01), proteinuria (3.5 ± 0.3 vs. 6.4 ± 0.7 mg/day, P < 0.05), and CI (4.0 ± 0.1 vs. 5.2 ± 0.1 mg/kg, P < 0.01) but decreased creatinine clearance (0.89 ± 0.15 vs. 0.54 ± 0.06 ml/min, P < 0.05). OVX exacerbated the effects of salt on the degree of hypertension (230 ± 5 mmHg), CI (5.6 ± 0.2 mg/kg), and proteinuria (13 ± 3.0 mg/day). OVX increased the urinary excretion of aldosterone approximately twofold in animals on the NS diet (3.8 ± 0.5 vs. 6.6 ± 0.5 ng·mg creatinine−1·day−1, P < 0.05) and HS diet (1.4 ± 0.2 vs. 4.5 ± 1.0 ng·mg creatinine−1·day−1, P < 0.05). Circulating renin, angiotensin-converting enzyme, and angiotensin II were also significantly increased in the OVX group fed a HS diet. These results reveal that the protective effects of estrogen apart from the increase in blood pressure were only manifested in the setting of a chronic HS diet and suggest that the underlying sodium status may have an important influence on the overall effect of reduced estrogen.
Central venous pressure and mean circulatory filling pressure in the dogfishSqualus acanthias: adrenergic control and role of the pericardium
Authors: Sandblom Erik , Axelsson Michael , Farrell Anthony P.
Published: July 2006

Subambient central venous pressure (Pven) and modulation of venous return through cardiac suction (vis a fronte) characterizes the venous circulation in sharks. Venous capacitance was estimated in the dogfish S qualus acanthias by measuring the mean circulatory filling pressure (MCFP) during transient occlusion of cardiac outflow. We tested the hypothesis that venous return and cardiac preload can be altered additionally through adrenergic changes of venous capacitance. The experiments involved the surgical opening of the pericardium to place a perivascular occluder around the conus arteriosus. Another control group was identically instrumented, but lacked the occluder, and was subjected to the same pharmacological protocol to evaluate how pericardioectomy affected cardiovascular status. Routine Pvenwas negative (−0.08 ± 0.02 kPa) in control fish but positive (0.09 ± 0.01 kPa) in the pericardioectomized group. Injections of 5 μg/kg body mass ( Mb) of epinephrine and phenylephrine (100 μg/kg Mb) increased Pvenand MCFP, whereas isoproterenol (1 μg/kg Mb) decreased both variables. Thus, constriction and relaxation of the venous vasculature were mediated through the respective stimulation of α- and β-adrenergic receptors. α-Adrenergic blockade with prazosin (1 mg/kg Mb) attenuated the responses to phenylephrine and decreased resting Pvenin pericardioectomized animals. Our results provide convincing evidence for adrenergic control of the venous vasculature in elasmobranchs, although the pericardium is clearly an important component in the modulation of venous function. Thus active changes in venous capacitance have previously been underestimated as an important means of modulating venous return and cardiac performance in this group.
Anatomic consequences of intrinsic tongue muscle activation
Authors: Bailey E. Fiona , Huang Yu-Hsien , Fregosi Ralph F.
Published: July 2006

We recently showed respiratory-related coactivation of both extrinsic and intrinsic tongue muscles in the rat. Here, we test the hypothesis that intrinsic tongue muscles contribute importantly to changes in velopharyngeal airway volume. Spontaneously breathing anesthetized rats were placed in a MRI scanner. A catheter was placed in the hypopharynx and connected to a pressure source. Axial and sagittal images of the velopharyngeal airway were obtained, and the volume of each image was computed at airway pressures ranging from +5.0 to −5.0 cmH2O. We obtained images in the hypoglossal intact animal (i.e., coactivation of intrinsic and extrinsic tongue muscles) and after selective denervation of the intrinsic tongue muscles, with and without electrical stimulation. Denervation of the intrinsic tongue muscles reduced velopharyngeal airway volume at atmospheric and positive airway pressures. Electrical stimulation of the intact hypoglossal nerve increased velopharyngeal airway volume; however, when stimulation was repeated after selective denervation of the intrinsic tongue muscles, the increase in velopharyngeal airway volume was significantly attenuated. These findings support our working hypothesis that intrinsic tongue muscles play a critical role in modulating upper airway patency.
Regional pulmonary blood flow in dogs by 4D-X-ray CT
Authors: Chon Deokiee , Beck Kenneth C. , Larsen Ranae L. , Shikata Hidenori , Hoffman Eric A.
Published: July 2006

ECG-triggered computed tomography (CT) was used during passage of iodinated contrast to determine regional pulmonary blood flow (PBF) in anesthetized prone/supine dogs. PBF was evaluated as a function of height within the lung (supine and prone) as a function of various normalization methods: raw unit volume data (PBFraw) or PBF normalized to regional fraction air (PBFair), fractional non-air (PBFgm), or relative number of alveoli (PBFalv). The coefficient of variation of PBFraw, PBFair, PBFalv, and PBFgm ranged between 30 and 50% in both lungs and both body postures. The position of maximal flow along the height of the lung (MFP) was calculated for PBFraw, PBFair, PBFalv, and PBFgm. Only PBFgm showed a significantly different MFP height supine vs. prone (whole lung: 2.60 ± 1.08 cm supine vs. 5.08 ± 1.61 cm prone, P < 0.01). Mean slopes (ml/min/gm water content/cm) of PBFgm were steeper supine vs. prone in the right (RL) but not left lung (LL) (RL: −0.65 ± 0.29 supine vs. −0.26 ± 0.25 prone, P < 0.02; LL: −0.47 ± 0.21 supine vs. −0.32 ± 0.26 prone, P > 0.10). Mean slopes of PBFgm vs. vertical lung height were not different prone vs. supine above this vertical height of MFP (VMFP), but PBFgm slopes were steeper in the supine position below the VMFP in the RL. We conclude that PBFgm distribution was posture dependent in RL but not LL. Support of the heart may play a role. We demonstrate that normalization factors can lead to differing attributions of gravitational effects on PBF heterogeneity.
Toll-Like Receptor 9 Agonists Promote Cellular Invasion by Increasing Matrix Metalloproteinase Activity
Authors: Merrell Melinda A. , Ilvesaro Joanna M. , Lehtonen Niko , Sorsa Timo , Gehrs Bradley , Rosenthal Eben , Chen Dongquan , Shackley Brit , Harris Kevin W. , Selander Katri S.
Published: July 2006

Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 μmol/L) dramatically increased their in vitro invasion in both Matrigel assays and three-dimensional collagen cultures. Similar effects on invasion were seen in TLR9-expressing astrocytoma and glioblastoma cells and in the immortalized human breast epithelial cell line MCF-10A. This effect was not, however, dependent on the CpG content of the TLR9 ligands because the non-CpG oligonucleotides induced invasion of TLR9-expressing cells. CpG or non-CpG oligonucleotide-induced invasion in MDA-MB-231 cells was blunted by chloroquine and they did not induce invasion of TLR9− breast cancer cells. Treatment of MDA-MB-231 cells with CpG or non-CpG oligonucleotides induced the formation of ∼50-kDa gelatinolytic band in zymograms. This band and the increased invasion were abolished by a matrix metalloproteinase (MMP) inhibitor GM6001 but not by a serine proteinase inhibitor aprotinin. Furthermore, CpG oligonucleotide treatment decreased tissue inhibitor of metalloproteinase-3 expression and increased levels of active MMP-13 in TLR9-expressing but not TLR9− breast cancer cells without affecting MMP-8. Neutralizing anti-MMP-13 antibodies inhibited the CpG oligonucleotide-induced invasion. These findings suggest that infections may promote cancer progression through a novel TLR9-mediated mechanism. They also propose a new molecular target for cancer therapy, because TLR9 has not been associated with cancer invasiveness previously. (Mol Cancer Res 2006;4(7):437–47)
“Translating” Tumor Hypoxia: Unfolded Protein Response (UPR)–Dependent and UPR-Independent Pathways
Authors: Koumenis Constantinos , Wouters Bradly G.
Published: July 2006

Poor oxygenation (hypoxia) is present in the majority of human tumors and is associated with poor prognosis due to the protection it affords to radiotherapy and chemotherapy. Hypoxia also elicits multiple cellular response pathways that alter gene expression and affect tumor progression, including two recently identified separate pathways that strongly suppress the rates of mRNA translation during hypoxia. The first pathway is activated extremely rapidly and is mediated by phosphorylation and inhibition of the eukaryotic initiation factor 2α. Phosphorylation of this factor occurs as part of a coordinated endoplasmic reticulum stress response program known as the unfolded protein response and activation of this program is required for hypoxic cell survival and tumor growth. Translation during hypoxia is also inhibited through the inactivation of a second eukaryotic initiation complex, eukaryotic initiation factor 4F. At least part of this inhibition is mediated through a Redd1 and tuberous sclerosis complex 1/2–dependent inhibition of the mammalian target of rapamycin kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia-induced proteins. Consequently, both arms of translational control during hypoxia influence gene expression and phenotype. These hypoxic response pathways show differential activation requirements that are dependent on the level of oxygenation and duration of hypoxia and are themselves highly dynamic. Thus, the severity and duration of hypoxia can lead to different biological and therapeutic consequences. (Mol Cancer Res 2006;4(7):423–36)
Botryoid-Type Pleomorphic Rhabdomyosarcoma of the Renal Pelvis in an Adult
Authors: Tsai Wen-Chiuan , Lee Shang-Sen , Cheng Ming-Fang , Lee Herng-Sheng
Published: July 2006

Rhabdomyosarcoma of the renal pelvis is an extremely rare lesion for which only two reports are available. Here, we report another case of botryoid-type pleomorphic rhabdomyosarcoma in the renal pelvis. The tumor produced mild hydroureteronephrosis and right nephrectomy was performed after the needle aspiration cytology revealed abnormal epithelial clusters. The surgical specimen disclosed a polypoid mass attached to the wall of the lower pole of the renal pelvis. Light microscopy examination revealed a large polypoid tumor protruding from the inner surface of the renal pelvis with intact surface urothelium. Immunohistochemical stains for actin, myoglobin, and vimentin were positive. Although rhabdomyosarcoma has formerly been reported to occur at the renal pelvis, to our knowledge, this is the first case of renal pelvis botryoid-type pleomorphic rhabdomyosarcoma diagnosed by light microscopy and immunohistochemical stains.
Elimination of chromosomes in Hordeum vulgare × H. bulbosum crosses at mitosis and interphase involves micronucleus formation and progressive heterochromatinization
Authors: Gernand D. , Rutten T. , Pickering R. , Houben A.
Published: July 2006

Uniparental chromosome elimination occurs in several interspecific hybrids of plants. We studied the mechanism underlying selective elimination of the paternal chromosomes during the development of Hordeum vulgare × H. bulbosum hybrid embryos that is restricted to an early stage of development. In almost all embryos most of the H. bulbosum chromatin undergoes a fast rate of elimination within nine days after pollination. There are differences in the mitotic behaviour between the parental chromosomes, with H. bulbosum chromatids segregating asymmetrically at anaphase. We provide evidence for a chromosome elimination pathway that involves the formation of nuclear extrusions during interphase in addition to postmitotically formed micronuclei. The chromatin structure of nuclei and micronuclei differs and heterochromatinization and disintegration of the nuclear envelope of micronuclei are the final steps of chromosome elimination.
Effects of Heptad Repeat Regions of F Protein on the Specific Membrane Fusion in Paramyxoviruses
Authors: Ren Guijie , Wang Zhiyu , Wang Guiting , Song Yanyan , Yao Ping , Xu Hongzhi , Wen Hongling , Zhang Wenqiang
Published: July 2006

Objectives: To identify the effects of heptad repeat regions (HR1 and HR2) of F on the specific membrane fusion in paramyxoviruses. Methods: Site-directed mutagenesis was used to create same enzyme sites on the F genes of Newcastle disease virus (NDV) and human parainfluenza virus (hPIV). Gene recombination was used to get chimeric F proteins NDV C-HR1 and hPIV C-HR1 by exchanging HR1 fragments each other; NDV C-HR2 and hPIV C-HR2 were also obtained by the same way. All the chimeric F proteins were co-expressed with their homologous or heterogeneous HN in eukaryocytes. Cell fusion functions were assayed by Giemsa staining and reporter gene method. The expression efficiencies of F proteins were assayed with fluorescence-activated cell sorter (FACS). Results: NDV C-HR1 and hPIV C-HR1 had 53.91 and 83.15% of fusion activities, and NDV C-HR2 and hPIV C-HR2 had 107.23 and 12.01% of fusion activities, respectively, as compared with their relevant wild types. The analysis of FACS indicated that the expression efficiencies of all the chimeric F proteins except NDV C-HR2 were lower than those of their relevant wild types. Conclusions: HR1 of NDV F might be important for its specific membrane fusion, but HR2 of NDV F may not; both HR1 and HR2 of hPIV F may be important for its specific membrane fusion.
An Approach for Precise Three-Dimensional Modeling of the Human Inner Ear
Authors: Li Shu-Feng , Zhang Tian-Yu , Wang Zheng-Min
Published: July 2006

For further morphological and physiological research, it is vital to establish precise three-dimensional models of the whole inner ear including the details of the membranous components. With the system of a projector and a high-resolution digital camera, 2 complete serial unstained celloidin sections of fresh human temporal bones were digitized as high-resolution images which were then sorted, calibrated, aligned and segmented using the 3D-Doctor software. Finally, 2 precise three-dimensional models of the inner ear were generated by simple surface rendering. The contours of tiny structures such as the crista ampullaris, the macula utriculi and the macula sacculi could be observed clearly. Our study suggests that it is technically feasible to employ complete serial unstained celloidin sections for precise three-dimensional reconstruction and that this helps reduce errors and laboratory workload. Moreover, the use of a high-resolution digital camera and the autoalignment function of 3D-Doctor further increase the accuracy of the models.
Adiponectin and Cardiovascular Remodeling in End-Stage Renal Disease and Co-Morbid Diabetes Mellitus
Authors: Karakitsos Dimitrios , De Groot Eric , Patrianakos Alexandros P. , Parthenakis Frangiscos , Boletis John , Karabinis Andreas , Kyriazis John , Vardas Panos , Daphnis Eugene
Published: July 2006

Objectives and Methods: Altered plasma high-sensitivity C-reactive protein (hs-CRP) and adiponectin (ADP) may contribute to increased vascular inflammation and accelerated atherosclerosis in patients with end-stage renal disease (ESRD) and co-morbid diabetes. Common carotid artery intima-media thickness (CCA-IMT) and atherosclerotic plaque occurrence, left-ventricular mass index (LVMI), and pulse wave velocity of the proximal aorta (PWVr) were determined by ultrasound imaging in 120 ESRD (55 diabetic) patients, and 83 age-, sex-, and blood pressure-matched controls. Also, plasma levels of ADP and hs-CRP were determined and their relationships with the above cardiovascular alterations were analyzed. Results: LVMI, PWVr, CCA-IMT and atherosclerotic plaque occurrence were all increased in ESRD patients compared to controls (all p < 0.001). LVMI (p < 0.05), PWVr (p < 0.001), CCA-IMT (p < 0.001) and atherosclerotic plaque occurrence (p < 0.001) were increased in diabetic compared to nondiabetic ESRD patients. Hs-CRP levels were increased and ADP levels were decreased in diabetic compared to nondiabetic ESRD patients (both p < 0.001). ADP levels correlated inversely with hs-CRP (r = –0.473, p < 0.0001) in ESRD patients. Hs-CRP was positively correlated with LVMI (r = 0.365, p < 0.0001), PWVr (r = 0.42, p < 0.0001) and CCA-IMT (r = 0.18, p = 0.047) while ADP inversely correlated with PWVr (r = –0.263, p = 0.0035) and CCA-IMT (r = –0.207, p = 0.022) in ESRD patients. Conclusion: The present results indicate diabetic disease-specific alterations in the biochemical parameters of hs-CRP and ADP in ESRD patients. The above biochemical parameters were intimately linked to the cardiovascular measurements of LVMI, PWVr and CCA-IMT in patients with ESRD and co-morbid diabetes mellitus.
Mutational and LOH Analyses of the Chromosome 4q Region in Esophageal Adenocarcinoma
Authors: Sterian Anca , Kan Takatsugu , Berki Agnes T. , Mori Yuriko , Olaru Andreea , Schulmann Karsten , Sato Fumiaki , Wang Suna , Paun Bogdan , Cai Kun , Hamilton James P. , Abraham John M. , Meltzer Stephen J.
Published: July 2006

Objective: Mortality due to esophageal adenocarcinoma has risen markedly, but the molecular mechanisms underlying this carcinogenesis are still incompletely understood. Findings from loss of heterozygosity (LOH) studies have suggested that the long arm of chromosome 4 might harbor tumor suppressor genes relevant to esophageal adenocarcinoma. Methods: We performed LOH analysis of 4q in esophageal adenocarcinomas. Regions of LOH were further evaluated by studying two candidate tumor suppressor genes, hCDC4 and CARF, located within them. Results: 54% of the adenocarcinomas examined showed allelic deletion. LOH was observed in 53, 40, 32, 38, and 27% of tumors at positions D4S1554 (the locus of CARF), D4S1572, D4S1548, D4S2934, and D4S3021, respectively. An area of allelic deletion (spanning 3 million bases) was identified at 4q31.1–3 in 37% of tumors. This region harbors a candidate tumor suppressor gene: hCDC4. However, sequencing of the coding regions of CARF and hCDC4 at 4q35 and 4q31, respectively, did not identify mutations. Conclusions: Our findings demonstrate frequent LOH in esophageal adenocarcinoma at several loci including a novel area of allelic deletion at 4q31.1–3. The results imply that mutational or other alterations at these loci may be involved in the pathogenesis of esophageal adenocarcinoma. Candidate tumor suppressor genes located within these regions merit further study.
Reduced Capacity of Mononuclear Cells to Synthesize Cytokines against an Inflammatory Stimulus in Uremic Patients
Authors: Ando Minoru , Shibuya Asuka , Tsuchiya Ken , Akiba Takashi , Nitta Kosaku
Published: July 2006

Background: The local production of cytokines and phagocytosis is pivotal in innate immunity. Uremic patients have a high infectious morbidity, but it remains unclear if this arises from incompetence of these local cellular functions. Methods: In 30 predialysis uremic patients and 20 controls, we studied the intracellular cytokine synthesis by mononuclear cells in response to stimulation. Moreover, phagocytic activity by leukocytes was tested. Lipopolysaccharide- or mitogen-stimulated peripheral blood cells were labeled with anti-CD14 and -CD4 antibodies, respectively and subjected to intracellular cytokine staining and flow cytometry. Tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8 synthesis was examined in CD14+ monocytes. IFN-γ and IL-4 synthesis was examined in CD4+ helper T cells to determine their Th1 or Th2 phenotype. The flow cytometric analysis of phagocytosis of opsonized bacteria was performed in whole blood. Results: Uremic patients exhibited a significantly reduced monokine response and inhibited development of helper T cells into Th1 or Th2 phenotypes compared with control subjects. Their phagocytic activity was comparable to control subjects. No clinical parameters were linked to in vitro cytokine production and phagocytic activity. Conclusions: Mononuclear cells in uremic patients are hyporeactive to inflammatory challenge and this may be one reason why uremic patients are vulnerable to infections.
Cholesterol Primes Vascular Smooth Muscle to Induce Ca
2
Sensitization Mediated by a Sphingosylphosphorylcholine–Rho-Kinase Pathway
Authors: Morikage Noriyasu , Kishi Hiroko , Sato Masafumi , Guo Fengling , Shirao Satoshi , Yano Takashi , Soma Masaaki , Hamano Kimikazu , Esato Kensuke , Kobayashi Sei
Published: July 2006

Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase–mediated Ca
2+
sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase–mediated Ca
2+
sensitization. Here we report the strong linkage between cholesterol and the Ca
2+
sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by β-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca
2+
sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca
2+
sensitization of VSM mediated by a SPC/Src-TK/Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia.
Essential Role of ICAM-1/CD18 in Mediating EPC Recruitment, Angiogenesis, and Repair to the Infarcted Myocardium
Authors: Wu Yaojiong , Ip James E. , Huang Jing , Zhang Lunan , Matsushita Kenichi , Liew Choong-Chin , Pratt Richard E. , Dzau Victor J.
Published: July 2006

Bone marrow–derived endothelial progenitor cells (EPCs) have the ability to migrate to ischemic organs. However, the signals that mediate trafficking and recruitment of these cells are not well understood. Using a functional genomics strategy, we determined the genes that were upregulated in the ischemic myocardium and might be involved in EPC recruitment. Among them, CD18 and its ligand ICAM-1 are particularly intriguing because CD18 and its heterodimer binding chains CD11a and CD11b were correspondingly expressed in ex vivo–expanded EPCs isolated from rat and murine bone marrows. To further verify the functional role of CD18 in mediating EPC recruitment and repair to the infarcted myocardium, we used neutralizing antibody to block CD18. Blockade of CD18 in EPCs significantly inhibited their attachment capacity in vitro and reduced their recruitment to the ischemic myocardium in vivo by 95%. Moreover, mice receiving EPCs that were treated with control isotype IgG exhibited significantly increased capillary density in the infarct border zone, reduced cardiac dilatation, ventricular wall thinning, and fibrosis when compared with myocardial infarction mice receiving PBS and CD18 blockade reversed the EPC-mediated improvements to the infarcted heart. Thus, our results suggest an essential role of CD18 in mediating EPC recruitment and the subsequent functional effects on the infarcted heart.