bluuebunny/crossref_metadata_2025 huggingface dataset:
Compact high-resolution differential interference contrast soft x-ray microscopy
Authors: Bertilson Michael C. , von Hofsten Olov , Lindblom Magnus , Wilhein Thomas , Hertz Hans M. , Vogt Ulrich
Published: February 2008

We demonstrate high-resolution x-ray differential interference contrast (DIC) in a compact soft x-ray microscope. Phase contrast imaging is enabled by the use of a diffractive optical element objective which is matched to the coherence conditions in the microscope setup. The performance of the diffractive optical element objective is evaluated in comparison with a normal zone plate by imaging of a nickel siemens star pattern and linear grating test objects. Images obtained with the DIC optic exhibit typical DIC enhancement in addition to the normal absorption contrast. Contrast transfer functions based on modulation measurements in the obtained images show that the DIC optic gives a significant increase in contrast without reducing the spatial resolution. The phase contrast operation mode now available for our compact soft x-ray microscope will be a useful tool for future studies of samples with low absorption contrast.
Formation of stable direct current microhollow cathode discharge by venturi gas flow system for remote plasma source in atmosphere
Authors: Park Ki Wan , Lee Tae Il , Hwang Hyeon Seok , Noh Joo Hyon , Baik Hong Koo , Song Kie Moon
Published: February 2008

We introduce a microhollow cathode configuration with venturi gas flow to ambient air in order to obtain glow discharge at atmospheric pressure. Stable microhollow cathode discharge was formed in a 200μm diameter at 9mA and the optimum value of gas velocity×diameter for hollow cathode effect was obtained in our system. In order to confirm hollow cathode effect, we measured the enhancement of E∕N strength for 200μm (0.31m2∕s) and 500μm (0.78m2∕s) air discharge at 8mA under the velocity of 156m∕s. As a result, an increase of 46.7% in E∕N strength of the discharge of 200μm hole was obtained compare to that of 500μm.
Bias stress instability in pentacene thin film transistors: Contact resistance change and channel threshold voltage shift
Authors: Wang S. D. , Minari T. , Miyadera T. , Aoyagi Y. , Tsukagoshi K.
Published: February 2008

Bias stress instability in top-contact pentacene thin film transistors was observed to be correlated not only to the channel but also to the metal/organic contact. The drain current decay under bias stress results from the combination of the contact resistance change and the threshold voltage shift in the channel. The contact resistance change is contact-metal dependent, though the corresponding channel threshold voltage shifts are similar. The results suggest that the time-dependent charge trapping into the deep trap states in both the contact and channel regions is responsible for the bias stress effect in organic thin film transistors.
Strain induced magnetoelectric coupling between magnetite and BaTiO3
Authors: Tian H. F. , Qu T. L. , Luo L. B. , Yang J. J. , Guo S. M. , Zhang H. Y. , Zhao Y. G. , Li J. Q.
Published: February 2008

Magnetite (Fe3O4) thin films have been grown on ferroelectric BaTiO3 (BTO) single crystal substrates by pulsed laser deposition. Transmission-electron microscope observations demonstrate the orientation relationship between Fe3O4 and BTO as [400]Fe3O4∥[200]BTO and [004]Fe3O4∥[002]BTO. Experimental measurements of magnetization, coercivity and remanent magnetization of the films show abrupt jumps at around phase transition temperatures of BTO and opposite jump signs are observed for the in-plane and out-of-plane measurements. The magnetization jumps can be suppressed by a strong external magnetic field. These results were discussed in terms of the interface strain induced changes of magnetic domain structure in the Fe3O4 film. This work demonstrates the presence of strong magnetoelectric coupling between Fe3O4 and BTO.
Electroluminescence emission from polariton states in GaAs-based semiconductor microcavities
Authors: Khalifa A. A. , Love A. P. D. , Krizhanovskii D. N. , Skolnick M. S. , Roberts J. S.
Published: February 2008

The authors report the observation of electroluminescence from GaAs-based semiconductor microcavities in the strong coupling regime. At low current densities, the emission consists of two peaks, which exhibit anticrossing behavior as a function of detection angle and thus originate from polariton states. With increasing carrier injection, we observe a progressive transition from strong to weak coupling due to screening of the exciton resonance by free carriers. The demonstration that polariton emission can be excited by electrical injection is encouraging for future development of polariton lasers.
Fullerene (C60) decoration in oxygen plasma treated multiwalled carbon nanotubes for photovoltaic application
Authors: Kalita Golap , Adhikari Sudip , Aryal Hare Ram , Umeno Masayoshi , Afre Rakesh , Soga Tetsuo , Sharon Maheshwar
Published: February 2008

Multiwalled carbon nanotubes (MWNTs) were functionalized by oxygen plasma treatment. Photoelectron spectroscopy study of oxygen plasma treated MWNTs (O-MWNTs) shows surface modification with hydroxyl and carboxyl groups. C60 decoration of MWNTs were carried out by thermal evaporation and more dense distribution of C60 was achieved on O-MWNTs. C60 decorated MWNTs were combined with poly(3-octylthiophene) for photovoltaic device fabrication. The device with C60 decorated O-MWNTs shows short circuit current density (Jsc), open circuit voltage (Voc), fill factor, and power conversion efficiency (η) as 1.68mA∕cm2, 0.245V, 27%, and 0.11%, respectively. It is expected that C60 provide large surface area for photoexcitons dissociation and efficient electron transportation, whereas MWNTs provide efficient hole transportation.
Two-dimensional electrostatic force field measurements with simultaneous topography measurement on embedded interdigitated nanoelectrodes using a force distance curve based method
Authors: Jenke Martin Günter , Santschi Christian , Hoffmann Patrik
Published: February 2008

Accurate simultaneous measurements on the topography and electrostatic force field of 500nm pitch interdigitated electrodes embedded in a thin SiO2 layer in a plane perpendicular to the orientation of the electrodes are shown for the first time. A static force distance curve (FDC) based method has been developed, which allows a lateral and vertical resolution of 25 and 2nm, respectively. The measured force field distribution remains stable as result of the well controlled fabrication procedure of Pt cantilever tips that allows thousands of FDC measurements. A numerical model is established as well which demonstrates good agreement with the experimental results.
Positronium reemission yield from mesostructured silica films
Authors: Liszkay L. , Corbel C. , Perez P. , Desgardin P. , Barthe M.-F. , Ohdaira T. , Suzuki R. , Crivelli P. , Gendotti U. , Rubbia A. , Etienne M. , Walcarius A.
Published: February 2008

The reemission yield of ortho-positronium (o-Ps) into vacuum outside mesoporous silica films on glass is measured in reflection mode with a specially designed lifetime (LT) spectrometer. Values as high as 40% are found. The intensity of the 142ns vacuum LT is recorded as a function of reemission depth. The LT depth profiling is correlated to the 2γ and 3γ energy ones to determine the annihilation characteristics inside the films. Positron lifetime in capped films is used to determine the pore size. For the first time, a set of consistent fingerprints for positronium annihilation, o-Ps reemission into vacuum, and pore size, is directly determined in surfactant-templated mesoporous silica films.
Screening dynamics of intrinsic electric field in AlGaN quantum wells
Authors: Pinos A. , Marcinkevičius S. , Liu K. , Shur M. S. , Kuokštis E. , Tamulaitis G. , Gaska R. , Yang J. , Sun W.
Published: February 2008

Shift of the transition energy after pulsed optical excitation in Al0.35Ga0.65N∕Al0.49Ga0.51N quantum well (QW) structures with varying well width has been studied by time-resolved photoluminescence. The shift dynamics, which is due to descreening of the intrinsic electric field, has characteristic times similar to carrier lifetimes revealing negligible influence of trapped carriers on screening. Comparison of the experimental spectral shifts with the calculations has shown that the intrinsic field in our AlGaN QWs is about 0.4–0.5MV∕cm, which is about a factor of two smaller than the value calculated using the theoretical polarization constants.
Electroviscous effects in capillary filling of nanochannels
Authors: Mortensen Niels Asger , Kristensen Anders
Published: February 2008

We theoretically examine the widespread hypothesis of an electroviscous origin of the increase in apparent viscosity observed in recent experiments on capillary filling of nanochannels. Including Debye-layer corrections to the hydraulic resistance, we find that the apparent viscosity reaches a maximum in the mesoscopic regime where the channel height (or more generally the hydraulic radius) is comparable to the screening length. However, for realistic estimates of central parameters, we find that the electroviscous contribution to the apparent viscosity is at most a 1% effect.
Stochastic data processing circuit based on single electrons using nanoscale field-effect transistors
Authors: Nishiguchi K. , Ono Y. , Fujiwara A. , Inokawa H. , Takahashi Y.
Published: February 2008

A circuit utilizing single electrons is demonstrated at room temperature using a silicon-on-insulator metal-oxide-semiconductor field-effect transistor (MOSFET). Individual electrons randomly passing through the nanoscale MOSFET, which are the origin of shot noise, are monitored by an electrometer in real time. This random behavior of single electrons is used as a random number for a stochastic associative memory for image-pattern matching, in which the most preferable pattern is extracted with the largest probability. The use of electron transport in the MOSFET provides high controllability of the randomness as well as fast generation of random numbers. The present result promises single-electron applications using nanoscale MOSFETs.
Expanded CTG repeats within the
DMPK
3′ UTR causes severe skeletal muscle wasting in an inducible mouse model for myotonic dystrophy
Authors: Orengo James P. , Chambon Pierre , Metzger Daniel , Mosier Dennis R. , Snipes G. Jackson , Cooper Thomas A.
Published: February 2008

Severe skeletal muscle wasting is the most debilitating symptom experienced by individuals with myotonic dystrophy type 1 (DM1). We present a DM1 mouse model with inducible and skeletal muscle-specific expression of large tracts of CTG repeats in the context of
DMPK
exon 15. These mice recapitulate many findings associated with DM1 skeletal muscle, such as CUG RNA foci with Muscleblind-like 1 (MBNL1) protein colocalization, misregulation of developmentally regulated alternative splicing events, myotonia, characteristic histological abnormalities, and increased CUGBP1 protein levels. Importantly, this DM1 mouse model recapitulates severe muscle wasting, which has not been reported in models in which depletion of MBNL1 is the main feature. Using these mice, we discovered previously undescribed alternative splicing events that are responsive to CUGBP1 and not MBNL, and these events were found to be misregulated in individuals with DM1. Our results indicate that increased CUGBP1 protein levels are associated with DMPK-CUG RNA expression, suggesting a role for CUGBP1-specific splicing or cytoplasmic functions in muscle wasting.
Crystal structure of tetrameric form of human lysyl-tRNA synthetase: Implications for multisynthetase complex formation
Authors: Guo Min , Ignatov Michael , Musier-Forsyth Karin , Schimmel Paul , Yang Xiang-Lei
Published: February 2008

In mammals, many aminoacyl-tRNA synthetases are bound together in a multisynthetase complex (MSC) as a reservoir of procytokines and regulation molecules for functions beyond aminoacylation. The α
2
homodimeric lysyl-tRNA synthetase (LysRS) is tightly bound in the MSC and, under specific conditions, is secreted to trigger a proinflammatory response. Results by others suggest that α
2
LysRS is tightly bound into the core of the MSC with homodimeric β
2
p38, a scaffolding protein that itself is multifunctional. Not understood is how the two dimeric proteins combine to make a presumptive α
2
β
2
heterotetramer and, in particular, the location of the surfaces on LysRS that would accommodate the p38 interactions. Here we present a 2.3-Å crystal structure of a tetrameric form of human LysRS. The relatively loose (as seen in solution) tetramer interface is assembled from two eukaryote-specific sequences, one in the catalytic- and another in the anticodon-binding domain. This same interface is predicted to provide unique determinants for interaction with p38. The analyses suggest how the core of the MSC is assembled and, more generally, that interactions and functions of synthetases can be built and regulated through dynamic protein–protein interfaces. These interfaces are created from small adaptations to what is otherwise a highly conserved (through evolution) polypeptide sequence.
Discovering gapped binding sites of yeast transcription factors
Authors: Chen Chien-Yu , Tsai Huai-Kuang , Hsu Chen-Ming , May Chen Mei-Ju , Hung Hao-Geng , Huang Grace Tzu-Wei , Li Wen-Hsiung
Published: February 2008

A gapped transcription factor-binding site (TFBS) contains one or more highly degenerate positions. Discovering gapped motifs is difficult, because allowing highly degenerate positions in a motif greatly enlarges the search space and complicates the discovery process. Here, we propose a method for discovering TFBSs, especially gapped motifs. We use ChIP-chip data to judge the binding strength of a TF to a putative target promoter and use orthologous sequences from related species to judge the degree of evolutionary conservation of a predicted TFBS. Candidate motifs are constructed by growing compact motif blocks and by concatenating two candidate blocks, allowing 0–15 degenerate positions in between. The resultant patterns are statistically evaluated for their ability to distinguish between target and nontarget genes. Then, a position-based ranking procedure is proposed to enhance the signals of true motifs by collecting position concurrences. Empirical tests on 32 known yeast TFBSs show that the method is highly accurate in identifying gapped motifs, outperforming current methods, and it also works well on ungapped motifs. Predictions on additional 54 TFs successfully discover 11 gapped and 38 ungapped motifs supported by literature. Our method achieves high sensitivity and specificity for predicting experimentally verified TFBSs.
Atbf1 is required for the Pit1 gene early activation
Authors: Qi Yingchuan , Ranish Jeffrey A. , Zhu Xiaoyan , Krones Anna , Zhang Jie , Aebersold Ruedi , Rose David W. , Rosenfeld Michael G. , Carrière Catherine
Published: February 2008

Enhancers have been functionally described for >35 years, but the molecular principles underlying the integration of regulatory inputs to alternate gene enhancers used during mammalian organogenesis remain incompletely understood. Using a combination ofin vivoenhancer mapping and proteomics approaches, we have established that two distant and distinct early enhancers, each requiring different transcription complexes, are required for full activation of the gene encoding the pituitary lineage determining factor, Pit1. A transcription factor belonging to the “giant, multiple-homeodomain and zinc finger family,” Atbf1, serves as a novel pituitary regulator for one of the two required enhancers as shown by genetic andin vitroanalysis.
Pentachlorophenol (but not Phenobarbital) Promotes Intrahepatic Biliary Cysts Induced by Diethylnitrosamine to Cholangio Cystic Neoplasms in B6C3F1 Mice Possibly Due to Oxidative Stress
Authors: Umemura Takashi , Kodama Yukio , Kanki Keita , Iatropoulos Michael J. , Nishikawa Akiyoshi , Hirose Masao , Williams Gary M.
Published: February 2008

Administration of diethylnitrosamine (DEN) to B6C3F1 mice at low dose (20 ppm) in drinking water for long duration resulted in formation of multifocal cystic biliary lesions in the liver. To investigate the potential of the lesions to be promoted to neoplasias by chemicals, we examined the effects of 2 different types of hepatocarcinogenesis promoters, pentachlorophenol (PCP) and phenobarbital (PB) in B6C3F1 mice. Two weeks' exposure to PCP at a concentration of 600 ppm in the diet increased 8-oxodeoxyguanosine (8-oxodG) levels in liver nuclear DNA, and cell proliferation quantified by bromodeoxyuridine (BrdU) incorporation in epithelial cells of intrahepatic bile ducts as well as hepatocytes. In mice initiated with DEN at 20 ppm in the drinking water for the first 13 weeks followed, after a 4-week recovery interval, by PCP at a concentration of 600 ppm in the diet for 25 weeks, cystic atypical hyperplasias, cholangiomas, and cholangiocarcinomas were present at statistically significant higher incidences. In contrast, neoplasia did not occur in animals treated with 500 ppm PB, and there were no elevations in 8-oxodG levels or increases in the proliferation of biliary epithelium, although proliferation was increased in hepatocytes. These findings suggest that oxidative stress due to PCP might exert a promoting action on the biliary cystic lesions produced by DEN.
Safety Evaluation of Recombinant Staphylokinase in Rhesus Monkeys
Authors: Qiujun Lu  , Yuanmin Li  , Liqing Wen  , Shaoming Guo  , Yuanyuan Chen  , Weijing Liu  , Yue Gao  , Lingmao Ding
Published: February 2008

Recombinant staphylokinase (rSTAR) is a profibrinolytic agent of bacterial origin. The objective of this study was to assess the toxicity of rSTAR administered with bolus intravenous infusion in rhesus monkeys (2/sex/group) at the dosages of 0, 4, 14, and 49 mg/kg/day for 2 weeks. The clinical signs were thickening of the skin in all animals and mild hematoma formation in three dosage groups at the injection sites. There were no effects on body weight, absolute or relative organ weights, ophthalmology, or electrocardiogram. Urinalysis indicated that 2 monkeys in 14 or 49 mg/kg/day group developed proteinuria and mild hematuria. Increases in serum BUN levels (14 and 49 mg/kg/day), ALT activity, and bilirubin levels (49 mg/kg/day), and decreases in red blood cell counts, hemoglobin concentrations and Hct values (49 mg/kg/day) were observed at week 2. Significant prolongation of APTT, PT, and TT (14 and 49 mg/kg/day), and decreases in circulating plasminogen levels (3 treatment groups) were noted. Dose-dependent increases in the titers of anti-rSTAR antibodies and neutralizing rSTAR activity were observed in the three treated groups. Increased neutralizing rSTAR activity diminished the pharmacologic effects of rSTAR (ie, prolonged APTT, PT, and TT approaching baseline levels at week 2). Histopathological findings included hemorrhage, and perivascular inflammatory cell infiltration at the injection sites, heptocellular degeneration characterized as cytoplasmic eosinophilia, vacuolation and condensed nuclei (49 mg/kg/day), effusion of RBCs and plasma within some Bowman's capsules and hyaline casts within the lumen of some renal tubules in the kidneys (14 and 49 mg/day/kg), and mild to moderate megakaryocyte hypoplasia with varying levels of pyknotic nuclei at all dose levels. Immune deposits in glomeruli in the kidneys from the three treated groups were detected. These changes were reversible following a 4-week recovery period. In the present preclinical evaluation of toxicity in monkeys, rSTAR is well tolerated at doses up to 49 mg/kg/day. The toxic target organs are the liver, kidney, and bone marrow.
Slowing Tumorigenic Progression in TRAMP Mice and Prostatic Carcinoma Cell Lines Using Natural Anti-Oxidant from Spinach, NAO—A Comparative Study of Three Anti-Oxidants
Authors: Nyska Abraham , Suttie Andrew , Bakshi Shlomo , Lomnitski Liat , Grossman Sholomo , Bergman Margalit , Ben-Shaul Varda , Crocket Patrick , Haseman Joseph K. , Moser Glenda , Goldsworthy Thomas L. , Maronpot Robert R.
Published: February 2008

The TRAMP model and human prostatic cancer (PCA) cell lines DU145 and PC3 are useful for chemopreventive studies. We compared the efficacy of 3 anti-oxidants [a water-soluble natural anti-oxidant, NAO (200 mg/kg), found in spinach leaves; epigallocatechin-3 gallate, EGCG (200 mg/kg), a major green tea polyphenol; and N-acetylcysteine, NAC (125 mg/kg)] plus vehicle in slowing spontaneous tumorigenic progression in TRAMP and wild-type male mice. Sacrifices occurred on weeks 5, 9, and 13. Prostatic histopathology and oxidative-stress blood markers were evaluated. Hyperplasias were ranked by a combination of severity grade and distribution (focal, multifocal, and diffuse). The effectivity of each tested compound in reducing the severity/focalness of hyperplasia varied from lobe to lobe. NAO exerted a significant effect on the dorsal and lateral lobes; NAC, on the anterior and ventral lobes, and EGCG, on the ventral lobe. When the most severe hyperplasia in all 4 lobes of TRAMPs was evaluated, only NAO reduced hyperplasia at weeks 9 and 13. Plasma peroxide levels in TRAMPs were reduced following oral administration of NAO or NAC for 13 weeks; EGCG only slightly reduced these levels. In NAO-treated DU145 and PC3 PCA cells, inhibition of cellular proliferation occurred in a dose-dependent manner, increasing numbers of G1 cells and reducing ROS levels. The anti-oxidative and antiproliferative properties of NAO may explain its efficacy in slowing the spontaneous prostatic carcinogenic process in the TRAMP and its effects in the cell lines.
A Grading Scheme for the Assessment of Proliferative Lesions of the Mouse Prostate in the TRAMP Model
Authors: Suttie Andrew , Nyska Abraham , Haseman Joseph K. , Moser Glenda J. , Hackett Theleria R. , Goldsworthy Thomas L.
Published: February 2008

To improve the precision and consistency of experimental results, we have developed a scoring system for proliferative epithelial lesions in the mouse prostate based on histological growth patterns observed in individual lobes. Severity of proliferative lesions was divided into 6 categories; the grade of the most advanced lesion was identified for each lobe and its distribution estimated semiquantitatively. A numerical score combining grade and distribution of the most advanced lesion in each lobe was assigned and termed the “distribution-adjusted lesion grade”; the mean of these scores was calculated for each treatment group. Using this grading scheme, we assessed lesion development in ad libitum-fed and 20%-diet-restricted groups of TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice that were started on study at 7 weeks of age and sacrificed when 11 and 20 weeks old. The anterior, dorsal, lateral, and ventral prostate lobes showed clear reductions in lesion severity in diet-restricted TRAMPs at 11 and 20 weeks. This method for scoring the epithelial pathology of the prostate in the TRAMP model with minimal to severe proliferative lesions utilizes the natural history of lesion development for assessing the effects of chemical and dietary interventions.
Different Effects of the Liver Mitogens Triiodo-Thyronine and Ciprofibrate on the Development of Rat Hepatocellular Carcinoma
Authors: Ledda-Columbano Giovanna M. , Perra Andrea , Concas Danilo , Cossu Costanza , Molotzu Francesca , Sartori Claudia , Shinozuka Hisashi , Columbano Amedeo
Published: February 2008

Previous work has shown that treatment with thyroid hormone (T3) decreased the incidence of rat hepatocellular carcinoma (HCC). The present study was designed to determine whether the inhibitory effect of T3 on HCC development was limited to early steps of the carcinogenetic process or, whether a similar effect could also be exerted by starting T3 treatment at later stages. Hepatic nodules were induced in Fischer rats by a single dose of DENA, followed by a 2-week exposure of the animals to 2-AAF and partial hepatectomy. Rats were then divided into 3 groups: group 1 was maintained on basal diet; group 2 was fed a diet containing 4 mg/kg T3 for a week, every month/7 months, starting 9 weeks after DENA administration; group 3 was exposed to cycles of T3 starting 8 months after initiation. Results demonstrate that inhibition of HCC development was essentially similar in rats exposed to T3 starting either 9 weeks or 8 months after initiation (50% inhibition compared to control rats). We have previously shown that T3-induced nodule regression and HCC inhibition occurred in spite of its mitogenic effect. Therefore, we next wished to determine whether a similar antitumoral effect could be exerted by other liver mitogens, such as peroxisome proliferators. Rats exposed to the initiation-promotion protocol described previously, were subjected to 11 cycles of a T3 or a ciprofibrate-supplemented diet, each cycle consisting of 7 days/month; the incidence of HCC and lung metastases was determined 13.5 months after initiation. Results showed that although treatment with T3 strongly inhibited HCC development (only 31% of T3+ rats showed HCC vs 91% of controls), rats given ciprofibrate developed the same number of HCC as T3-untreated rats. In conclusion, the results of this study showed that the anticarcinogenic effect of T3 is maintained also when treatment begins late in the process, and its antitumoral property appears to be specific and may not be shared by other liver mitogens.
Biostatistical Evaluation of Focal Hepatic Preneoplasia
Authors: Kopp-Schneider Annette
Published: February 2008

Qualitative analyses of focal hepatic preneoplasia are relatively easy and fast but hypothesis tests based on these analyses often lack statistical power. Evaluating focal hepatic preneoplasia quantitatively, on the other hand, requires more effort but is rewarded by an increased ability to detect differences between treatment groups and by the possibility to investigate the mechanism of a treatment under study. Due to the stereological problems inherent in the data a statistical analysis that concentrates on the evaluation of area fraction will provide clear results whereas the analysis of focal transection density and size distribution can produce misleading results. In addition, the area fraction is a valid variable even in the presence of confluent foci. The number and size distribution of focal transections in liver sections cannot be directly translated to the number and sizes of foci in the liver. As no general statements about the relationship between focal transection density and foci density as well as between focal transection size and foci size distribution can be made, there is need for a parametric mechanistic model to link the number and size distribution of focal transections to those of the underlying foci. The stereological problem therefore can be avoided by introducing a model for foci appearance and change of volume that then can be used to conclude whether the treatment induces foci and whether it changes their volume.
Prevalidation of a Rat Liver Foci Bioassay (RLFB) Based on Results from 1600 Rats: A Study Report
Authors: Ittrich Carina , Deml Erhard , Oesterle Doris , Küttler Karin , Mellert Werner , Brendler-Schwaab Susanne , Enzmann Harald , Schladt Ludwig , Bannasch Peter , Haertel Thomas , Mönnikes Oliver , Schwarz Michael , Kopp-Schneider Annette
Published: February 2008

A rat liver foci bioassay (RLFB) based on an initiation-promotion protocol employing preneoplastic foci of altered hepatocytes (FAH) as an endpoint, was prevalidated in 5 different laboratories. FAH were identified by immunohistochemical demonstration of glutathione- S-transferase (placental form, GSTP) and by staining with hematoxilin/eosin (H&E), and their area fraction was quantified morphometrically. The four model hepatocarcinogens N-nitrosomorpholine, 2-acetylaminofluoren, phenobarbital, and clofibrate were selected according to characteristic differences in their presumed mode of action, and tested in a total of 1,600 male and female rats at 2 different dose levels. The chemicals were found to differ characteristically in their potency and dose-response relationship to induce FAH when given alone or when administered following initiation with diethylnitrosamine. The interlaboratory variation was small for results obtained with the GSTP-stain and somewhat larger with respect to H&E. The assessment of the carcinogenic potential of the four chemicals by the different laboratories was in the same range and the nature of their dose-response relationships did not differ essentially between laboratories. Our results suggest that this RLFB is a sensitive bioassay, providing potentially valuable information for risk assessment including the classification of carcinogenic chemicals according to their mode of action.
Significance of Hepatic Preneoplasia in Risk Identification and Early Detection of Neoplasia *
Authors: Bannasch Peter , Haertel Thomas , Qin Su
Published: February 2008

Among the different types of liver tumor, hepatocellular neoplasms predominate by far in both animals and man. Consequently, preneoplastic foci of altered hepatocytes (FAH), preceding both hepatocellular adenomas and carcinomas, represent the most prevalent form of hepatic preneoplasia observed in animals for a long time, and identified in human chronic liver diseases associated with, or predisposing to, hepatocellular carcinomas more recently. Morphological, microbiochemical, and molecular biological approaches in situ revealed striking similarities in specific changes of the cellular phenotype of preneoplastic FAH developing in experimental and human hepatocarcinogenesis, irrespective of whether this was elicited by chemicals, hormones, viruses or radiation. The advantage of using FAH for risk identification (aiming at primary cancer prevention) in long-term and medium-term carcinogenesis bioassays has been well documented, but quantitative morphometric approaches appear to be indispensable for an appropriate evaluation of both bioassays. The detection of phenotypically similar FAH in various animal models and in humans prone to develop or bearing hepatocellular carcinomas favors the extrapolation from data obtained in animals to humans. Moreover, the recently reported frequent finding of FAH in fine-needle biopsies of patients suffering from chronic liver diseases opens new perspectives for secondary prevention of human hepatocellular carcinoma.
Role of Connexin32 and β-Catenin in Tumor Promotion in Mouse Liver
Authors: Schwarz Michael , Wanke Ines , Wulbrand Ulrich , Moennikes Oliver , Buchmann Albrecht
Published: February 2008

Tumor promoters are nonmutagenic chemicals that increase the probability of cancer by accelerating the clonal expansion of cells transformed during tumor initiation. The molecular mechanisms underlying this process are only partly understood but interference with signaling pathways regulating cell division and/or cell death is likely to be important. Ras- and β-Catenin-dependent signaling is important for both of these processes and ras and β-catenin genes are known mutational targets in mouse hepatocarcinogenesis. About 80% of liver tumors generated in mice by a promotional regimen including phenobarbital (PB) as tumor promoter and N-nitrosodiethylamine (DEN) as initiator showed β-catenin mutations whereas Ha-ras mutations were not detected. By contrast, tumors from mice treated with DEN alone showed a ~30% Ha-ras mutation prevalence but no β-catenin mutations. This result suggests that PB-mediated promotion in mouse liver consists in a positive selection for hepatocytes harboring mutations in β-catenin. The gap junction protein connexin 32 (Cx32) was also found to be involved in tumor promotion by PB because Cx32 gene knockout mice were almost entirely resistent to the promotional effects of the barbiturate. The link between β-catenin-signaling and Cx32-dependent gap junctional intercellular communication, if existent, remains obscure.
Activation of Srk1 by the Mitogen-activated Protein Kinase Sty1/Spc1 Precedes Its Dissociation from the Kinase and Signals Its Degradation
Authors: López-Avilés Sandra , Lambea Eva , Moldón Alberto , Grande Maribel , Fajardo Alba , Rodríguez-Gabriel Miguel A. , Hidalgo Elena , Aligue Rosa
Published: February 2008

Control of cell cycle progression by stress-activated protein kinases (SAPKs) is essential for cell adaptation to extracellular stimuli. The Schizosaccharomyces pombe SAPK Sty1/Spc1 orchestrates general changes in gene expression in response to diverse forms of cytotoxic stress. Here we show that Sty1/Spc1 is bound to its target, the Srk1 kinase, when the signaling pathway is inactive. In response to stress, Sty1/Spc1 phosphorylates Srk1 at threonine 463 of the regulatory domain, inducing both activation of Srk1 kinase, which negatively regulates cell cycle progression by inhibiting Cdc25, and dissociation of Srk1 from the SAPK, which leads to Srk1 degradation by the proteasome.
SoxE Proteins Are Differentially Required in Mouse Adrenal Gland Development
Authors: Reiprich Simone , Stolt C. Claus , Schreiner Silke , Parlato Rosanna , Wegner Michael
Published: February 2008

Sry-box (Sox)8, Sox9, and Sox10 are all strongly expressed in the neural crest. Here, we studied the influence of these closely related transcription factors on the developing adrenal medulla as one prominent neural crest derivative. Whereas Sox9 was not expressed, both Sox8 and Sox10 occurred widely in neural crest cells migrating to the adrenal gland and in the gland itself, and they were down-regulated in cells expressing catecholaminergic traits. Sox10-deficient mice lacked an adrenal medulla. The adrenal anlage was never colonized by neural crest cells, which failed to specify properly at the dorsal aorta and died apoptotically during migration. Furthermore, mutant neural crest cells did not express Sox8. Strong adrenal phenotypes were also observed when the Sox10 dimerization domain was inactivated or when a transactivation domain in the central portion was deleted. Sox8 in contrast had only minimal influence on adrenal gland development. Phenotypic consequences became only visible in Sox8-deficient mice upon additional deletion of one Sox10 allele. Replacement of Sox10 by Sox8, however, led to significant rescue of the adrenal medulla, indicating that functional differences between the two related Sox proteins contribute less to the different adrenal phenotypes of the null mutants than dependence of Sox8 expression on Sox10.
The Utility of the 6‐Minute Walk Test as a Measure of Frailty in Older Adults with Heart Failure
Authors: Boxer Rebecca S. , Wang Zhu , Walsh Stephen J. , Hager David , Kenny Anne M.
Published: February 2008

Patients with heart failure (HF) are at increased risk for frailty, and identification is challenging. The authors assessed the distance on the 6‐minute walk test (6MWT) as a measure of frailty in 60 older HF patients (ejection fraction ≤40%) compared with frailty phenotype (FP). Scores were dichotomized to frail (F) or nonfrail (NF), and the results of 6MWT were dichotomized to low endurance (LE) or normal endurance (NE). FP and 6MWT results were in moderate agreement (κ=0.57, confidence interval [CI], 0.36–0.79; age‐adjusted κ=0.54, 95% CI, 0.33–0.76);25% of participants were classified as F/LE, and 55% were classified as NF/NE. Discordance was asymmetric (McNemar P=.006); 18% of participants were NF/LE. There were no differences between the NF/LE and other groups in age, sex, body mass index, or physical activity level. Results in the NF/LE group differed from those in the NF/NE group by a slower 8‐foot walking speed (P=.02), weaker grip strength (P=.056), and worse renal function (P=.01) and from those in the F/LE group by faster 8‐foot walking speed (P<.001). The 6MWT may be useful to identify frailty and those in transition to frailty.
Impact of Combination Evidence‐Based Medical Therapy on Mortality Following Myocardial Infarction in Elderly Patients
Authors: Tay Edgar Lik‐Wui , Chan Mark , Tan Virlynn , Sim Ling Ling , Tan Huay‐Cheem , Cheng Yeo Tiong
Published: February 2008

Antiplatelet drugs, β‐blockers, statins, and angiotensinogen‐converting enzyme inhibitors reduce mortality following myocardial infarction (MI). The data on the impact of combination evidence‐based medications on mortality following acute MI in elderly patients are limited. In this study, 5529 patients with MI admitted between January 2000 and December 2003 were assessed. Based on discharge use of evidence‐based medications, the patients were divided into those using 0, 1, 2, 3, or 4 medications. The impact of medications on 1‐year mortality was assessed for patients younger than 75 years and 75 years and older. Mean age of the patients was 63±13 years (71% male). The unadjusted 1‐year mortality post‐MI was 18.3% and 52.7% for young and elderly patients, respectively. Compared with patients with 0 medications, the adjusted odds ratio for 1‐year mortality was lower in patients with 1, 2, 3, and 4 medications in both groups. Use of combination evidence‐based medications was independently associated with lower 1‐year post‐MI mortality irrespective of age.
A systematic review of commonly used medical treatments for hirsutism in women
Authors: Koulouri Olympia , Conway Gerard S.
Published: February 2008

Objective  To evaluate the efficacy of various drug treatments in common use for hirsutism in women.

Design  A systematic review of published randomized controlled trials (RCTs). We included RCTs that tested commonly prescribed pharmaceutical treatments for hirsutism and the most common outcome measure, a decrease in Ferriman–Gallwey (F–G) score for hirsutism after 6 months of treatment. We excluded trials using unconventional treatments, alternative treatment outcomes, and trials referring to women with conditions other than polycystic ovary syndrome or idiopathic hirsutism.

Results  We identified 79 RCTs of which 28 were eligible for analysis. A significant reduction in hirsutism was found for flutamide, spironolactone, cyproterone acetate combined with an oral contraceptive, thiazolidinediones, oral contraceptive pills (OCPs), finasteride and metformin but not for placebo. Reduction in F–G score in response to treatment was negatively associated with body mass index (BMI) (r = –0·38; P = 0·004).

Conclusions  Seven different drug groups result in improvement in hirsutism and creative use of these will open new options for women with hirsutism. Obesity has a negative impact on the efficacy of treatments for hirsutism, thus appropriate lifestyle advice is necessary for a successful treatment programme.
A non‐native invasive grass increases soil carbon flux in a Hawaiian tropical dry forest
Authors: LITTON CREIGHTON M. , SANDQUIST DARREN R. , CORDELL SUSAN
Published: February 2008

Non‐native plants are invading terrestrial ecosystems across the globe, yet little is known about how invasions impact carbon (C) cycling or how these impacts will be influenced by climate change. We quantified the effect of a non‐native C4 grass invasion on soil C pools and fluxes in a Hawaiian tropical dry forest over 2 years in which annual precipitation was average (Year 1) and ∼60% higher than average (Year 2). Work was conducted in a series of forested plots where the grass understory was completely removed (removal plots) or left intact (grass plots) for 3 years before experiment initiation. We hypothesized that grass invasion would: (i) not change total soil C pools, (ii) increase the flux of C into and out of soils, and (iii) increase the sensitivity of soil C flux to variability in precipitation. In grass plots, grasses accounted for 25–34% of litter layer C and ∼70% of fine root C. However, no differences were observed between treatments in the size of any soil C pools. Moreover, grass‐derived C constituted a negligible fraction of the large mineral soil C pool (< 3%) despite being present in the system for ≥50 years. Tree litterfall was ∼45% lower in grass plots, but grass‐derived litterfall more than compensated for this reduction in both years. Annual cumulative soil‐surface CO2 efflux (Rsoil) was ∼40% higher in grass plots in both years, and increased in both treatments by ∼36% in the wetter Year 2. Despite minimal grass‐derived mineral soil C, > 75% of Rsoil in grass plots was of C4 (i.e. grass) origin. These results demonstrate that grass invasion in forest ecosystems can increase the flux of C into and out of soils without changing total C pools, at least over the short term and as long as the native tree canopy remains intact, and that invasion‐mediated changes in belowground C cycling are sensitive to precipitation.
Thirty‐five years of synchrony in the organic matter concentrations of Swedish rivers explained by variation in flow and sulphate
Authors: ERLANDSSON MARTIN , BUFFAM ISHI , FÖLSTER JENS , LAUDON HJALMAR , TEMNERUD JOHAN , WEYHENMEYER GESA A. , BISHOP KEVIN
Published: February 2008

Increasing concentrations of organic matter (OM) in surface waters have been noted over large parts of the boreal/nemoral zone in Europe and North America. This has raised questions about the causes and the likelihood of further increases. A number of drivers have been proposed, including temperature, hydrology, as well as ‐ and Cl− deposition. The data reported so far, however, have been insufficient to define the relative importance of different drivers in landscapes where they interact. Thirty‐five years of monthly measurements of absorbance and chemical oxygen demand (COD), two common proxies for OM, from 28 large Scandinavian catchments provide an unprecedented opportunity to resolve the importance of hypothesized drivers. For 21 of the catchments, there are 18 years of total organic carbon (TOC) measurements as well. Despite the heterogeneity of the catchments with regards to climate, size and land use, there is a high degree of synchronicity in OM across the entire region. Rivers go from widespread trends of decreasing OM to increasing trends and back again three times in the 35‐year record. This synchronicity in decadal scale oscillations and long‐term trends suggest a common set of dominant OM drivers in these landscapes. Here, we use regression models to test the importance of different potential drivers. We show that flow and together can predict most of the interannual variability in OM proxies, up to 88% for absorbance, up to 78% for COD. Two other candidate drivers, air temperature and Cl−, add little explanatory value. Declines in anthropogenic since the mid‐1970s are thus related to the observed OM increases in Scandinavia, but, in contrast to many recent studies, flow emerges as an even more important driver of OM variability. Stabilizing levels also mean that hydrology is likely to be the major driver of future variability and trends in OM.
The paradoxical association between inherited factor VII deficiency and venous thrombosis
Authors: MARTY S. , BARRO C. , CHATELAIN B. , FIMBEL B. , TRIBOUT B. , REYNAUD J. , SCHVED J.‐F. , GIANSILY‐BLAIZOT M.
Published: February 2008

Summary.  Inherited factor VII (FVII) deficiency is considered to be a haemorrhagic disease. Nonetheless, some patients paradoxically present with venous thrombosis. We assessed whether there was a link between phenotype and genotype in seven patients with inherited FVII deficiency and thrombosis (eleven venous thrombotic events). For each patient (FVII:C < 50%), clinical data were collected, aetiological assessment of risk factors for thrombosis was investigated, and direct sequencing of the nine exons and promoter of the FVII gene (F7) was performed. We present the second series ever published on FVII patients with thrombosis. In nine of the eleven thrombotic events, there was at least one classical triggering risk factor; clinical (n = 4), familial antecedent (n = 2), or biological, defined by phospholipid‐binding antibodies or elevated FVIII:C levels (n = 7). In contrast to a previous series, only two events occurred after surgery, performed both with and without replacement therapy. The thrombotic event remained unexplained in one young patient, highlighting the lack of ‘protection’ against venous thrombosis by low FVII:C levels. Genetic mutations were found to be heterogeneous. Among the seven F7 sequence alterations identified in the present study, only two (p.Ala354Val and p.Arg364Gln) have previously been reported in FVII‐deficient patients presenting with venous thrombosis. Our genetic analyses of the F7 mutations in these patients show the complexity of FVII deficiency associated with thrombosis. These data justify a holistic, clinical and biological approach for patients with these specific symptoms. This series also strongly suggest that mild FVII deficiency should not prevent physicians from using antithrombotic prophylaxis in FVII‐deficient patients.
Biogeographical patterns of Chinese spiders (Arachnida: Araneae) based on a parsimony analysis of endemicity
Authors: Meng Kaibaryer , Li Shuqiang , Murphy Robert W.
Published: February 2008

Aim  The distributions of Chinese spiders are used to form biotic regions and to infer biogeographical patterns.

Location  China.

Methods  China was initially divided into 294 quadrats of 2° latitude by 2° longitude. The distributions of 958 species of spiders were summarized for each quadrat. Subsequently, these quadrats were pooled into 28 areas based on topographical characteristics and to a lesser extent on the distributions of spiders. Parsimony analysis of endemicity (PAE) was used to classify the 28 areas based on the shared distributional patterns of spiders.

Results  China was found to have seven major biogeographical regions based on the distributional patterns of spiders: Western Northern region (clade B2: Tibetan Plateau and Inner Mongolia‐Xinjiang subregions), Central Northern region (clade B3), Eastern Northern region (clade B4), Central region (clade C2), Eastern Southern region (clade C3), Western Southern region (clade C4), and Central Southern region (clade C5).

Main conclusions  The distributional patterns of Chinese spiders correspond broadly to geological provinces. A comparison of the geological provinces and the distributional patterns of spiders reveals that the spiders occur south of the geological provinces. Furthermore, a general biogeographical classification with five natural areas is suggested as follows: Tibetan Plateau, Central Northern, Eastern Northern, Western Northern (excluding Tibetan Plateau), and Southern regions.