bluuebunny/crossref_metadata_2025 huggingface dataset:
Improvement on the photorefractive performance of a monolithic molecular material by introducing electron traps
Authors: Zhang Jie , Chen Zhijian , Liu Yihong , Huang Maomao , Wei Qun , Gong Qihuang
Published: August 2004

The electron-injecting material, tris(8-hydroxyquinoline) aluminum (Alq3), was introduced into photorefractive (PR) samples containing the (9-ethyl-9H-carbazol-3-ylmethylent)-(4-nitrophenyl)-amine (ECYENPA) molecule, which has been proved to possess the fine functions of both electro-optic effect and hole transportation. A small amount of Alq3 forms quantum dots in ECYENPA, serving as electron traps and leading to a great enhancement of the PR effect. A large two-beam coupling coefficient of 424cm−1 (at 44.6V∕μm) was observed in a sample doped with 2wt% of Alq3, in contrast to a value of 232cm−1 for a sample without Alq3. Moreover, the measured response time was one order of magnitude shorter than that of the undoped sample.
Thick and adherent cubic boron nitride films grown on diamond interlayers by fluorine-assisted chemical vapor deposition
Authors: Zhang W. J. , Bello I. , Lifshitz Y. , Chan K. M. , Wu Y. , Chan C. Y. , Meng X. M. , Lee S. T.
Published: August 2004

Using plasma-enhanced chemical vapor deposition (PECVD) based on fluorine chemistry, the limitations hindering the practical use of cubic boron nitride (cBN) films in mechanical applications have been overcome. The CVD method presented is characteristic with (a) the direct cBN growth on diamond without soft, noncubic BN interface layers, (b) the synthesis of cBN films with extraordinary adhesion to the substrates and high mechanical properties, and (c) the scalable process providing thick, large-area cBN films at high deposition rate even on rough and untreated surfaces. These prime technological properties open the route to the mechanical exploitation of cBN films, particularly in tribological and tool applications. The reduction of the bias voltage in the PECVD process presented to a value of −20V not only provides high-quality films, but also gives physical insight into the cBN growth mechanism.
Influence of pressure and ion bombardment on the growth and properties of nanocrystalline silicon materials
Authors: Dalal Vikram L. , Graves Joshua , Leib Jeffrey
Published: August 2004

We report on the growth and properties of nanocrystalline silicon:H films deposited using plasma discharge at 45MHz under varying pressure regimes from 50 to 500mTorr. X-ray diffraction data revealed that the primary orientation in these films was ⟨111⟩. The amount of hydrogen dilution needed to crystallize the films was found to be a strong function of deposition pressure, with a significantly higher hydrogen dilution needed to crystallize films at higher pressures. Langmuir probe data showed that these results could be attributed to the increase in density of low-energy hydrogen ions impinging on the substrate at lower pressures.
Measurement of phosphorus segregation in silicon at the atomic scale using scanning tunneling microscopy
Authors: Oberbeck L. , Curson N. J. , Hallam T. , Simmons M. Y. , Bilger G. , Clark R. G.
Published: August 2004

In order to fabricate precise atomic-scale devices in silicon using a combination of scanning tunneling microscopy (STM) to position dopant atoms and molecular beam epitaxy to encapsulate the dopants it is necessary to minimize the segregation∕diffusion of dopant atoms during silicon encapsulation. We characterize the surface segregation∕diffusion of phosphorus atoms from a δ-doped layer in silicon after encapsulation at 250°C and room temperature using secondary ion mass spectrometry (SIMS) and STM. We show that the surface phosphorus density can be reduced to a few percent of the initial δ-doped density if the phosphorus atoms are encapsulated with 5 monolayers of epitaxial silicon at room temperature. We highlight the limitations of SIMS to determine phosphorus segregation at the atomic scale and the advantage of using STM directly.
Incipient plasticity during nanoindentation at elevated temperatures
Authors: Lund Alan C. , Hodge Andrea M. , Schuh Christopher A.
Published: August 2004

The onset of plastic deformation during nanoindentation is studied, focusing upon the effects of temperature variation. Indentations on pure (100)-oriented platinum at 20, 100, and 200°C reveal that the transition from elastic to plastic deformation occurs at progressively lower stress levels as temperature is increased. Additionally, it is shown that during plastic deformation, higher temperatures promote the discretization of plasticity into sharp bursts of activity. These results are in line with expectations for stress-biased, thermally activated deformation processes such as the nucleation of dislocations or the abrupt release of dislocation entanglements.
Ecology of Nassella neesiana, Chilean needle grass, in pastures on the Northern Tablelands of New South Wales. II. Seedbank dynamics, seed germination, and seedling recruitment
Authors: Gardener M. R. , Whalley R. D. B. , Sindel B. M.
Published: August 2004

This is the second in a series of papers investigating the ecology of Nassella neesiana (Trin. & Rupr.) Barkworth (Chilean needle grass) in pastures on the Northern Tablelands of New South Wales. The reasons for its success as a pasture weed are discussed. Nassella neesiana has a large and persistent soil seedbank. After 3 years without seed input, the seedbank declined from 4676 to 1323 seeds/m2. When an exponential decay curve was fitted to the data it was predicted that the seedbank would reach 10 seeds/m2 after 12.4 years. When seed production was large in 1996, 41.6% of seeds produced were incorporated into the seedbank, whereas in 1995 and 1997 the smaller seed production was only sufficient to maintain seedbank numbers. Furthermore, it is likely that the seedbank numbers were underestimated because they did not include basal cleistogenes. In a separate experiment, basal cleistogenes were found to contribute a further 20% to the seedbank.A small proportion of the viable seeds in a natural seedbank emerged from bare ground over 2 years. Seedling survival was high, with 78% of those germinating from bare ground surviving for at least 20 months. Several experiments were designed to investigate the mechanisms of this germination and survival. It appears that the seeds of N. neesiana have an after-ripening requirement of between 3 months and 1 year for maximum germination. Lemma removal from seeds stored for 8 months increased germination from 49 to 82%. The rate of germination and the total percentage of seeds germinating also increased with time of burial in the ground. Of seeds that had been buried for 2 years, 90% germinated after laboratory incubation compared with 48% of seeds stored in the laboratory as controls. Depth of seed burial appears to affect seedling emergence and survival. A smaller number of seedlings emerged from 0–10 mm and they had lower survival than those from seed buried at 10–20 mm.
Relating arsenic and phosphorus remobilisation to sediment formation mechanisms using fractionation and trends in elemental composition
Authors: Linge Kathryn L. , Oldham Carolyn E.
Published: August 2004

Shallow lakes are frequently characterised by a consolidated sediment that is covered by an overlying floc layer. Arsenic and P remobilisation was related to differences in contaminant binding and sediment formation for two such sediments from Lake Yangebup, Western Australia. Chemical fractionation data, statistical relationships between total elemental concentrations, and mineralogy data highlighted differences in As and P binding in each sediment. The results showed that As and P are bound in a common Fe oxide fraction in the consolidated sediment, whereas in the floc As is mostly bound by adsorption and P is scavenged during Fe or natural organic matter sedimentation. The disparity between As and P binding in floc can be accounted for by differences in As and P oxidation state (As(III) v. P(V)), the incorporation of P but not As into natural organic matter, and the short time scale of floc formation. Arsenic and P behavior is closer in the consolidated sediment because As(III) gradually oxidizes to As(V) during consolidated sediment formation. The results demonstrate that, despite sediment heterogeneity and chemical complexity, contaminant binding and remobilisation mechanisms can be determined using a suite of simple chemical tests. This is important if remediation strategies are to be evaluated properly.
Induction of metamorphosis in larvae of the brooding corals Acropora palifera and Stylophora pistillata
Authors: Baird Andrew H. , Morse Aileen N. C.
Published: August 2004

Many coral larvae require surface contact with crustose red algae (CRA) to induce metamorphosis; however, many features of the ecology of pocilloporid corals, such as their ability to colonize primary substrata, suggest that their larvae respond to different cues. We compared the metamorphosis of larvae of the brooding corals Stylophora pistillata (family Pocilloporidae) and Acropora palifera (family Acroporidae) in response to a variety of environmental cues. Acropora palifera metamorphosed only in the presence of three species of CRA. In contrast, S. pistillata metamorphosed in all assays, except those containing the brown alga Lobophora sp. Metamorphosis was highest (80 ± 20%) in unfiltered sea water; however, metamorphosis also occurred in 0.2-μm filtered sea water. These results suggest that S. pistillata larvae respond to both large and small water-borne molecular cues. The lack of a stringent requirement for surface contact with CRA will allow S. pistillata larvae to pre-empt species that require a more developed fouling community to induce metamorphosis and this feature of larval ecology may be the key to understanding the success of many opportunistic benthic species.
Sizes and ages in commercial landings with estimates of growth, mortality and yield per recruit of yellowtail kingfish (Seriola lalandi) from New South Wales, Australia
Authors: Stewart John , Ferrell Douglas J. , van der Walt Bryan
Published: August 2004

The size and age compositions of yellowtail kingfish (Seriola lalandi) were studied in commercial landings in New South Wales, Australia between 1998 and 2000. The fishery was dominated by fish smaller than 65 cm fork length and these fish were estimated to be 2 and 3 year olds. Estimates of growth rates were made using size-at-age data from sectioned otoliths. The oldest yellowtail kingfish found was 21 years and measured 136 cm fork length. There were no differences in the growth rates between regions or between sexes. Yellowtail kingfish grow rapidly and reach their minimum legal length of 60 cm total length at around 2 years of age. These estimates showed that previous studies, which estimated ages using whole otoliths, may have underestimated the ages of older yellowtail kingfish. Total instantaneous mortality rates generated from catch curves ranged between 0.43 and 0.79. Yield per recruit models suggest that the population is currently growth overfished. The information provided is used to discuss the suitability of the current minimum legal length for yellowtail kingfish in New South Wales.
Nonspecific hydrophobic interactions stabilize an equilibrium intermediate of apomyoglobin at a key position within the AGH region
Authors: Bertagna Angela M. , Barrick Doug
Published: August 2004

Acid-induced unfolding of apomyoglobin (apoMb) proceeds in a multistate process involving at least one equilibrium intermediate (I) at pH 4.2. The structure of the I form has been investigated thoroughly, with significant effort devoted to identifying potentially stabilizing native contacts. Here, we test whether rigid side-chain packing interactions like those in holomyoglobin persist at a buried position, Met-131, within the low-pH apoMb intermediate. We have measured the urea-induced unfolding transitions of overpacking, underpacking, and polar substitutions of Met-131 to determine the effect on the stability of the native and intermediate states of apoMb. Whereas underpacking substitutions should destabilize the I form irrespective of the degree of native side-chain-packing interactions, we anticipate that overpacking replacements might show opposite effects in a tightly packed environment, compared with a region lacking native side-chain packing interactions. We observe that, whereas underpacking and polar substitutions destabilize the I form, overpacking substitutions are stabilizing, implying that I is structurally plastic. We also report a strong correlation between the I state unfolding free energies and side-chain transfer free energies from water to octanol. Our results suggest that, whereas side-chain hydrophobicity is important for the stability of the I form, specific side-chain packing interactions are not.
A small molecule inhibitor of β-catenin/cyclic AMP response element-binding protein transcription
Authors: Emami Katayoon H. , Nguyen Cu , Ma Hong , Kim Dae Hoon , Jeong Kwang Won , Eguchi Masakatsu , Moon Randall T. , Teo Jia-Ling , Oh Se Wong , Kim Hak Yeop , Moon Sung Hwan , Ha Jong Ryul , Kahn Michael
Published: August 2004

Inherited and somatic mutations in the adenomatous polyposis coli occur in most colon cancers, leading to activation of β-catenin-responsive genes. To identify small molecule antagonists of this pathway, we challenged transformed colorectal cells with a secondary structure-templated chemical library, looking for compounds that inhibit a β-catenin-responsive reporter. We identified ICG-001, a small molecule that down-regulates β-catenin/T cell factor signaling by specifically binding to cyclic AMP response element-binding protein. ICG-001 selectively induces apoptosis in transformed cells but not in normal colon cells, reducesin vitrogrowth of colon carcinoma cells, and is efficacious in the Min mouse and nude mouse xenograft models of colon cancer.
Metabonomic investigations in mice infected with
Schistosoma mansoni
: An approach for biomarker identification
Authors: Wang Yulan , Holmes Elaine , Nicholson Jeremy K. , Cloarec Olivier , Chollet Jacques , Tanner Marcel , Singer Burton H. , Utzinger Jürg
Published: August 2004

Schistosomiasis, a chronic and debilitating parasitic disease, affects ≈200 million people in the developing world and imposes a substantial public health and economic impact. Accurately diagnosing at the individual level, monitoring disease progression, and assessing the impact of pharmacological interventions at the population level are of prime importance for controlling schistosomiasis. Using a
Schistosoma mansoni
-mouse model, we present a characterization of a parasitic infection by metabolic profiling, employing
1
H NMR spectroscopy and multivariate pattern recognition techniques. We infected 10 mice with 80
S. mansoni
cercariae each and collected urine samples 49 and 56 days postinfection. Urine samples were also obtained from 10 uninfected control mice at the same time. The metabolic signature of an
S. mansoni
infection consists of reduced levels of the tricarboxylic acid cycle intermediates, including citrate, succinate, and 2-oxoglutarate, and increased levels of pyruvate, suggesting stimulated glycolysis. A disturbance of amino acid metabolism was also associated with an
S. mansoni
infection, as indicated by depletion of taurine, 2-oxoisocaproate, and 2-oxoisovalerate and elevation of tryptophan in the urine. A range of microbial-related metabolites, i.e., trimethylamine, phenylacetylglycine, acetate,
p
-cresol glucuronide, butyrate, propionate, and hippurate, were also coupled with an
S. mansoni
infection, indicating disturbances in the gut microbiota. Our work highlights the potential of metabolic profiling to enhance our understanding of biological responses to parasitic infections. It also holds promise as a basis for novel diagnostic tests with high sensitivity and specificity and for improved disease surveillance and control.
Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling
Authors: Sanchez Pilar , Hernández Ana Maria , Stecca Barbara , Kahler Andrea J. , DeGueme Amy M. , Barrett Andrea , Beyna Mercedes , Datta Milton W. , Datta Sumana , Ruiz i Altaba Ariel
Published: August 2004

Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)–GLI signaling pathway is implicated in prostate cancer. We report expression of SHH–GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of
GLI1
+
/
PSA
+
primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through
GLI1
RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH–GLI function and suggest a novel therapeutic approach.
Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis
Authors: Castriconi Roberta , Dondero Alessandra , Augugliaro Raffaella , Cantoni Claudia , Carnemolla Barbara , Sementa Angela Rita , Negri Francesca , Conte Romana , Corrias Maria Valeria , Moretta Lorenzo , Moretta Alessandro , Bottino Cristina
Published: August 2004

In this study, in an attempt to identify neuroblastoma-associated surface antigens, we generated mAbs against the ACN neuroblastoma cell line. A mAb was selected (5B14) that reacted with all neuroblastoma cell lines analyzed and allowed detection of tumor cell infiltrates in bone marrow aspirates from neuroblastoma patients. In cytofluorimetric analysis, unlike anti-disialoganglioside mAb, 5B14 mAb did not display reactivity with normal bone marrow hematopoietic cell precursors, thus representing a highly specific marker for identifying neuroblastoma cells. Molecular analysis revealed that the 5B14 mAb-reactive surface glycoprotein corresponded to the recently identified 4Ig-B7-H3 molecule. Remarkably, mAb-mediated masking of the 4Ig-B7-H3 molecule on cell transfectants or on freshly isolated neuroblastoma cells resulted in enhancement of natural killer-mediated lysis of these target cells. These data suggest that 4Ig-B7-H3 molecules expressed at the tumor cell surface can exert a protective role from natural killer-mediated lysis by interacting with a still undefined inhibitory receptor expressed on natural killer cells.
Developmentally regulated mannose 6-phosphate receptor-mediated transport of a lysosomal enzyme across the blood-brain barrier
Authors: Urayama Akihiko , Grubb Jeffrey H. , Sly William S. , Banks William A.
Published: August 2004

Mucopolysaccharidosis type VII is a lysosomal storage disorder resulting from inherited deficiency of β-glucuronidase (GUS). Mucopolysaccharidosis type VII is characterized by glycosaminoglycan storage in most tissues, including brain. In these disorders, enzyme delivery across the blood-brain barrier (BBB) is the main obstacle to correction of lysosomal storage in the CNS. Prior studies suggested mouse brain is accessible to GUS in the first 2 weeks of life but not later. To explore a possible role for the mannose 6-phosphate/insulin-like growth factor II receptor in GUS transport across the BBB in neonatal mice, we compared brain uptake of phosphorylated GUS (P-GUS) and nonphosphorylated GUS (NP-GUS) in newborn and adult mice.131I-P-GUS was transported across the BBB after i.v. injection in 2-day-old mice. The brain influx rate (Kin) of131I-P-GUS in 2-day-old mice was 0.21 μl/g·min and decreased with age. By 7 weeks of age, transport of131I-P-GUS was not significant. Capillary depletion revealed that 62% of the131I-P-GUS in brain was in brain parenchyma in 2-day-old mice. In addition, uptake of131I-P-GUS into brain was significantly reduced by coinjection of unlabeled P-GUS or M6P in a dose-dependent manner. In contrast, theKinof131I-NP-GUS (0.04 μl/g·min) was significantly lower than131I-P-GUS in 2-day-old mice. Transcardiac brain perfusion confirmed that neither131I-P-GUS nor131I-NP-GUS crossed the BBB in adult mice. These results indicate that131I-P-GUS transport into brain parenchyma in early postnatal life is mediated by the mannose 6-phosphate/insulin-like growth factor II receptor. This receptor-mediated transport is not observed in adult mice.
Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren's syndrome
Authors: Shim Gil-Jin , Warner Margaret , Kim Hyun-Jin , Andersson Sandra , Liu Lining , Ekman Jenny , Imamov Otabek , Jones Margaret E. , Simpson Evan R. , Gustafsson Jan-Åke
Published: August 2004

Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-α and -β-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of α-fodrin in the salivary glands and anti-α-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.
Binding between the Niemann–Pick C1 protein and a photoactivatable cholesterol analog requires a functional sterol-sensing domain
Authors: Ohgami Nobutaka , Ko Dennis C. , Thomas Matthew , Scott Matthew P. , Chang Catherine C. Y. , Chang Ta-Yuan
Published: August 2004

Niemann–Pick type C (NPC) 1 protein plays important roles in moving cholesterol and other lipids out of late endosomes by means of vesicular trafficking, but it is not known whether NPC1 directly interacts with cholesterol. We performed photoaffinity labeling of intact cells expressing fluorescent protein (FP)-tagged NPC1 by using [3H]7,7-azocholestanol ([3H]AC). After immunoprecipitation,3H-labled NPC1-GFP appeared as a single band. Including excess unlabeled sterol to the labeling reaction significantly diminished the labeling. Altering the NPC1 sterol-sensing domain (SSD) with loss-of-function mutations (P692S and Y635C) severely reduced the extent of labeling. To further demonstrate the specificity of labeling, we show that NPC2, a late endosomal/lysosomal protein that binds to cholesterol with high affinity, is labeled, whereas mutant NPC2 proteins inactive in binding cholesterol are not. Vamp7, an abundant late endosomal membrane protein without an SSD but with one transmembrane domain, cannot be labeled. Binding between [3H]AC and NPC1 does not require NPC2. Treating cells with either U-18666A, a compound that creates an NPC-like phenotype, or with bafilomycin A1, a compound that raises late endosomal pH, has no effect on labeling of NPC1-YFP, suggesting that both drugs affect processes other than NPC1 binding to cholesterol. We also developed a procedure to label the NPC1-YFP by [3H]ACin vitroand showed that cholesterol is more effective in protection against labeling than its analogs epicholesterol or 5-α-cholestan. Overall, the results demonstrate that there is direct binding between NPC1 and azocholestanol; the binding does not require NPC2 but requires a functional SSD within NPC1.
An aminoacyl-tRNA synthetase that specifically activates pyrrolysine
Authors: Polycarpo Carla , Ambrogelly Alexandre , Bérubé Amélie , Winbush SusAnn M. , McCloskey James A. , Crain Pamela F. , Wood John L. , Söll Dieter
Published: August 2004

Pyrrolysine, the 22nd cotranslationally inserted amino acid, was found in the
Methanosarcina barkeri
monomethylamine methyltransferase protein in a position that is encoded by an in-frame UAG stop codon in the mRNA.
M. barkeri
encodes a special amber suppressor tRNA (tRNA
Pyl
) that presumably recognizes this UAG codon. It was reported that Lys-tRNA
Pyl
can be formed by the aminoacyl-tRNA synthetase-like
M. barkeri
protein PylS [Srinivasan, G., James, C. M. & Krzycki, J. A. (2002)
Science
296, 1459–1462], whereas a later article showed that Lys-tRNA
Pyl
is synthesized by the combined action of LysRS1 and LysRS2, the two different
M. barkeri
lysyl-tRNA synthetases. Pyrrolysyl-tRNA
Pyl
formation was presumed to result from subsequent modification of lysine attached to tRNA
Pyl
. To investigate whether pyrrolysine can be directly attached to tRNA
Pyl
we chemically synthesized pyrrolysine. We show that PylS is a specialized aminoacyl-tRNA synthetase for charging pyrrolysine to tRNA
Pyl
; lysine and tRNA
Lys
are not substrates of the enzyme. In view of the properties of PylS we propose to name this enzyme pyrrolysyl-tRNA synthetase. In contrast, the LysRS1:LysRS2 complex does not recognize pyrrolysine and charges tRNA
Pyl
with lysine. These
in vitro
data suggest that
Methanosarcina
cells have two pathways for acylating the suppressor tRNA
Pyl
. This would ensure efficient translation of the in-frame UAG codon in case of pyrrolysine deficiency and safeguard the biosynthesis of the proteins whose genes contain this special codon.
Infiltrating CD8+ T Lymphocytes, Natural Killer Cells, and Expression of IL-10 and TGF-β1 in Chemically Induced Neoplasms in Male Wistar Rats
Authors: Tozzi Spinardi-Barbisan Ana Lúcia , Barbisan Luís Fernando , Lauro Viana De Camargo João , Aparecida Marchesan Rodrigues Maria
Published: August 2004

The present study aimed to estimate the number of CD8+ T and natural killer (NK) infiltrating cells and the expression of interleukin-10 (IL-10) and transforming growth factor beta 1 (TGF- β1) in chemically induced neoplasms in an initiation-promotion bioassay for carcinogenesis. Male Wistar rats were treated with N-nitrosodiethylamine, N-methyl- N-nitrosourea, N-butyl- N-(4-hydroxybutyl)nitrosamine, dihydroxy-di- N-propylnitrosamine, and 1,2-dimethylhydrazine for 4 weeks. Two groups were subsequently exposed through diet to phenobarbital (0.05%) or 2-acetylaminofluorene (0.01%) for 25 weeks. An untreated group was used as a control. Immune cells and cytokines were immunohistochemically evaluated in neoplasms and in surrounding normal tissues at the liver, kidneys, lung, and small and large intestines. When compared to the respective normal tissues, an increased number of NK cells was verified infiltrating the colon, lung, and kidney neoplasms, while the number of CD8+ T cells decreased in the intestine and lung neoplasms. Expression of IL-10 was found mainly in kidney tumors. TGF- β1 was expressed mainly in the liver and kidneys tumors. The results indicate that the differential occurrence of immune cells between neoplastic and normal tissues could be dependent upon tumor microenvironment.
Maintenance of T Cell Specification and Differentiation Requires Recurrent Notch Receptor–Ligand Interactions
Authors: Schmitt Thomas M. , Ciofani Maria , Petrie Howard T. , Zúñiga-Pflücker Juan Carlos
Published: August 2004

Notch signaling has been shown to play a pivotal role in inducing T lineage commitment. However, T cell progenitors are known to retain other lineage potential long after the first point at which Notch signaling is required. Thus, additional requirements for Notch signals and the timing of these events relative to intrathymic differentiation remain unknown. Here, we address this issue by culturing subsets of CD4 CD8 double negative (DN) thymocytes on control stromal cells or stromal cells expressing Delta-like 1 (Dll1). All DN subsets were found to require Notch signals to differentiate into CD4+ CD8+ T cells. Using clonal analyses, we show that CD44+ CD25+ (DN2) cells, which appeared committed to the T cell lineage when cultured on Dll1-expressing stromal cells, nonetheless gave rise to natural killer cells with a progenitor frequency similar to that of CD44+ CD25− (DN1) thymocytes when Notch signaling was absent. These data, together with the observation that Dll1 is expressed on stromal cells throughout the thymic cortex, indicates that Notch receptor–ligand interactions are necessary for induction and maintenance of T cell lineage specification at both the DN1 and DN2 stages of T cell development, suggesting that the Notch-induced repression of the B cell fate is temporally separate from Notch-induced commitment to the T lineage.
Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia
Authors: Messmer Bradley T. , Albesiano Emilia , Efremov Dimitar G. , Ghiotto Fabio , Allen Steven L. , Kolitz Jonathan , Foa Robin , Damle Rajendra N. , Fais Franco , Messmer Davorka , Rai Kanti R. , Ferrarini Manlio , Chiorazzi Nicholas
Published: August 2004

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.
Mechanism of Arachidonic Acid Modulation of the T-type Ca2+ Channel α1G
Authors: Talavera Karel , Staes Mik , Janssens Annelies , Droogmans Guy , Nilius Bernd
Published: August 2004

Arachidonic acid (AA) modulates T-type Ca2+ channels and is therefore a potential regulator of diverse cell functions, including neuronal and cardiac excitability. The underlying mechanism of modulation is unknown. Here we analyze the effects of AA on the T-type Ca2+ channel α1G heterologously expressed in HEK-293 cells. AA inhibited α1G currents within a few minutes, regardless of preceding exposure to inhibitors of AA metabolism (ETYA and 17-ODYA). Current inhibition was also observed in cell-free inside-out patches, indicating a membrane-delimited interaction of AA with the channel. AA action was consistent with a decrease of the open probability without changes in the size of unitary currents. AA shifted the inactivation curve to more negative potentials, increased the speed of macroscopic inactivation, and decreased the extent of recovery from inactivation at −80 mV but not at −110 mV. AA induced a slight increase of activation near the threshold and did not significantly change the deactivation kinetics or the rectification pattern. We observed a tonic current inhibition, regardless of whether the channels were held in resting or inactivated states during AA perfusion, suggesting a state-independent interaction with the channel. Model simulations indicate that AA inhibits T-type currents by switching the channels into a nonavailable conformation and by affecting transitions between inactivated states, which results in the negative shift of the inactivation curve. Slow-inactivating α1G mutants showed an increased affinity for AA with respect to the wild type, indicating that the structural determinants of fast inactivation are involved in the AA–channel interaction.
The broaden–and–build theory of positive emotions
Authors: Fredrickson Barbara L.
Published: August 2004

The broaden–and–build theory describes the form and function of a subset of positive emotions, including joy, interest, contentment and love. A key proposition is that these positive emotionsbroadenan individual's momentary thought–action repertoire: joy sparks the urge to play, interest sparks the urge to explore, contentment sparks the urge to savour and integrate, and love sparks a recurring cycle of each of these urges within safe, close relationships. The broadened mindsets arising from these positive emotions are contrasted to the narrowed mindsets sparked by many negative emotions (i.e. specific action tendencies, such as attack or flee). A second key proposition concerns the consequences of these broadened mindsets: by broadening an individual's momentary thought–action repertoire—whether through play, exploration or similar activities—positive emotions promote discovery of novel and creative actions, ideas and social bonds, which in turnbuildthat individual's personal resources; ranging from physical and intellectual resources, to social and psychological resources. Importantly, these resources function as reserves that can be drawn on later to improve the odds of successful coping and survival. This chapter reviews the latest empirical evidence supporting the broaden–and–build theory and draws out implications the theory holds for optimizing health and well–being.
Conjugation-specific small RNAs in Tetrahymena have predicted properties of scan (scn) RNAs involved in genome rearrangement
Authors: Mochizuki Kazufumi , Gorovsky Martin A.
Published: August 2004

We proposed a scan-RNA model for genome rearrangement based on finding small RNAs that hybridized preferentially to micronuclear-specific sequences and on the properties of Twi1p, a PPD protein required for both sequence elimination and small RNA accumulation in Tetrahymena. Here we show that Twi1p interacts with the small RNAs in both the old and the developing macronucleus, and is required for their stability. We show that the specificity of the small RNAs for micronuclear-limited sequences increases during conjugation. These results indicate that the small RNAs observed in conjugating cells have the properties predicted for scan RNAs.
A novel nuclear receptor/coregulator complex controls C. elegans lipid metabolism, larval development, and aging
Authors: Ludewig Andreas H. , Kober-Eisermann Corinna , Weitzel Cindy , Bethke Axel , Neubert Kerstin , Gerisch Birgit , Hutter Harald , Antebi Adam
Published: August 2004

Environmental cues transduced by an endocrine network converge on Caenorhabditis elegans nuclear receptor DAF-12 to mediate arrest at dauer diapause or continuous larval development. In adults, DAF-12 selects long-lived or short-lived modes. How these organismal choices are molecularly specified is unknown. Here we show that coregulator DIN-1 and DAF-12 physically and genetically interact to instruct organismal fates. Homologous to human corepressor SHARP, DIN-1 comes in long (L) and short (S) isoforms, which are nuclear localized but have distinct functions. DIN-1L has embryonic and larval developmental roles. DIN-1S, along with DAF-12, regulates lipid metabolism, larval stage-specific programs, diapause, and longevity. Epistasis experiments reveal that din-1S acts in the dauer pathways downstream of lipophilic hormone, insulin/IGF, and TGFβ signaling, the same point as daf-12. We propose that the DIN-1S/DAF-12 complex serves as a molecular switch that implements slow life history alternatives in response to diminished hormonal signals.
Terlipressin increased the concentration of l‐lactate in the rectal lumen in a patient with septic shock
Authors: Perner A. , JØrgensen V. L. , Waldau T.
Published: August 2004

Terlipressin – a long‐acting analogue of vasopressin – has been described to restore blood pressure in patients with catecholamine‐resistant septic shock without obvious complications. We administered low‐dose terlipressin (a single i.v.‐bolus of 0.5 mg) to a patient with severe, hyperdynamic septic shock requiring high dosage of noradrenalin. After terlipressin the dose of noradrenalin could be reduced by 2/3 to obtain the same blood pressure. Two hours after terlipressin, the cardiac index had decreased from 6.2 to 3.3 l min−1 m−2 and the concentration of L‐lactate in the rectal lumen, as assessed by equilibrium dialysis, increased from 3.6 to 7.2 mmol l−1. In contrast, the systemic concentration of L‐lactate was unaffected around 2.8 mmol l−1. After 8 h the effect of terlipressin started to decline, and after an additional 12 h the systemic haemodynamics, dose of noradrenalin and concentrations of rectal and systemic L‐lactate were the same as prior to the administration of terlipressin. As a strong vasopressor, terlipressin may have further impaired the metabolic dysfunction in the rectal mucosa either directly via vasoconstriction of mucosal vessels or through decreased cardiac output in this patient with noradrenalin‐treated septic shock.
Estimation of myocardial performance in CABG patients
Authors: Poelaert J. , Heerman J. , Schüpfer G. , Moerman A. , Reyntjens K. , Roosens C.
Published: August 2004

Myocardial performance index (MPI) permits a relative easy estimation of global left ventricular (LV) systolic and diastolic function. It was shown that MPI inversely correlated strongly with the maximum derivative of LV pressure with respect to time (+dP/dtmax). The current study evaluated the change of MPI during and immediately after coronary artery bypass surgery (CABG) surgery and analyzed the relationship between MPI and hydraulic energy (exemplified by preload adjusted maximal power – PAMP) during that same period. The study was conducted in 45 patients undergoing CABG. After induction of anaesthesia, 10 min after revascularization and 2 h postoperatively, haemodynamics were assessed. Preload was characterized by LV end‐diastolic area indexed for BSA (LVEDAI); afterload was estimated by arterial elastance (Ea) and indexed systemic vascular resistance (SVRI). Global myocardial performance was indicated in terms of MPI and contractility was achieved by PAMP. Myocardial performance index increased postoperatively (0.44 ± 0.13, 0.37 ± 0.17 and 0.50 ± 0.16, respectively; P < 0.001). Preload adjusted maximal power did not alter significantly (1.90 ± 1.24, 2.02 ± 1.34 and 2.12 ± 1.00 W cm−2*104, respectively). Left ventricular enddiastolic area indexed did not change. Arterial elastance augmented to 0.76  ±  0.39, 0.80 ± 0.40 and 1.01 ± 0.43 mmHg ml−1, respectively; P < 0.001. Systemic vascular resistance did not change. A relationship was found between 1‐MPI/LVEDAI2 and PAMP (R2 = 0.50).

 This study shows that in the setting of CABG surgery, MPI appears to be a good measure of global LV function.
Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients
Authors: Calvo R. , Telletxea S. , Leal N. , Aguilera L. , Suarez E. , De La Fuente L. , Martin‐Suarez A. , Lukas J. C.
Published: August 2004

Background:  In anesthesia with propofol, variability persists besides sophisticated effect targeting. Drug formulation may be another factor. We have analyzed, retrospectively, the pharmacokinetics (PK) and pharmacodynamics (PD) in monitored surgery patients anesthetized with one each of five formulations of propofol.

Methods:  Propofol 1% (‘form’ 1: Diprivan®(Zeneca Limited, Macclesfield, UK), 2: Recofol®(Schering Espan̄a, Madrid, Spain), 3: Ivofol®(Juste, Madrid, Spain), 4: Propofol Abbott® (Abbott Laboratories, Madrid, Spain), 5: Fresenius® (Fresenius Kabi Espan̄a, Barcelona, Spain)) was administered to 77 ASA I–II patients of age [mean (range) 44 (18–65) years]. Induction of anesthesia was with varying propofol doses up to endpoints of either 60 on the Bispectral Index™ system (BIS) in group I (n = 48, model development) or standard clinical signs in group II (n = 29, validation). Maintenance was with three 10‐min infusions of 10, 8 and 6 mg kg−1 h−1. Three blood samples were obtained from each subject, immediately after induction, and at 15 and 30 min on maintenance, with BIS and hemodynamic variables recorded at these times also. Total and free blood concentrations (Cb) of propofol were determined with HPLC. Pharmacokinetic and PD models with link equilibration rate ke0, were studied with a mixed‐effects procedure (NONMEM).

Results:  The induction dose (group I) showed large interindividual variability [mean (range) 163 (90–290 mg)] that correlated significantly with age, basal systolic blood pressure and formulation. The PK of propofol (basic model) was described by a one‐compartment model with (typical value [interindividual coefficient of variation percent (CV%)]) CL=2.30 l min−1 (27%) and V=8.40 l (80%). Weight (WT) and formulation, within NONMEM, were found to be significant covariates for CL and V, reducing their CV% to 25% and 74%, respectively. The final PK/PD model, which includes formulation, showed a 50% reduction in the CV% for both the ke0 and the residual error. This PK/PD model was validated in group II with 33% precision and no bias.

Conclusion:  The PK and PD are not equal for all formulations, which contributes to an increase in variability of the observed effect.
Anaesthesia in patients with Brugada syndrome
Authors: Kim J. S. , Park S. Y. , Min S. K. , Kim J. H. , Lee S. Y. , Moon B. K. , Chae Y. J.
Published: August 2004

Brugada syndrome is characterized by right bundle branch block, ST segment elevation in the precordial leads and sudden death caused by ventricular fibrillation. We present two successful anaesthetic management cases in patients with Brugada syndrome.
Beliefs and reality: detection and prevention of high alcohol consumption in Swedish antenatal clinics
Authors: Göransson Mona , Faxelid Elisabeth , Heilig Markus
Published: August 2004

Background.  Public antenatal care (ANC) clinics in Sweden contribute to low prenatal mortality and morbidity, through early detection of somatic risk factors, and referral to appropriate specialized care. Available statistics indicate, however, that this system is ineffective in dealing with psychosocial health problems, such as hazardous drug and alcohol use. Factors underlying this failure have not been explored.

Methods.  An anonymous survey was carried out among all 207 ANC midwives in Stockholm County to establish their level of training within this problem area, clinical experience, theoretical clinical strategies, and actual clinical actions.

Findings.  Responses indicate that ANC midwives:

1. are well aware of the health hazards of drug and alcohol use during pregnancy;

2. confirm having met and cared for subjects with hazardous substance use;

3. are familiar with specialized care resources available for this patient category;

4. make adequate choices regarding clinical action, i.e. problem identification and referral to specialized care, in hypothetical situations of encountering this patient category;

5. report consistent failure to actually exercise these choices in real clinical situations.

Conclusions.  A structured, clinically acceptable methodology needs to be developed in order for ANC clinics to fulfill their mission in the area of hazardous substance use in pregnant women.
Impact of recombinant FSH dose adjustments on ovarian response in the second treatment cycle with IVF or ICSI in “standard” patients treated with 150 IU/day during the first cycle
Authors: Popovic‐Todorovic B. , Loft A. , Ziebe S. , Andersen A. Nyboe
Published: August 2004

Background.  A dose of 150 IU/day of recombinant follicle stimulating hormone (rFSH) is commonly used as a “standard” dose for “standard” patients in the first in vitro fertilization (IVF) treatment cycle. In the second cycle, the starting dose is adjusted in those patients who had an inappropriate response during the first cycle. The purpose of the study was to assess the impact of dose adjustments on ovarian response.

Materials and methods.  Retrospective study including 567 first IVF/intracytoplasmic sperm injection (ICSI) cycles using the long agonist protocol in “standard” patients. In the second cycle 385 patients who had failed to achieve an ongoing pregnancy were included. The starting dose in the second cycle was adjusted according to the response in the first cycle.

Results.  A total of 215 patients (55.8%) had altered starting dose in the second cycle: 193 (50.1%) received >150 IU/day, whereas 22 (5.7%) had <150 IU/day. In the group given >150 IU/day, significantly more follicles (9.8 vs. 8.3, p = 0.002) and oocytes (8.4 vs. 6.7, p <0.0001) were obtained in the second cycle. In the group given <150 IU/day, there were significantly fewer follicles (20.4 vs. 13.5, p <0.0001) and oocytes (16.4 vs. 11.4, p = 0.005) in the second cycle. In the group given <150 IU/day in the second cycle, six (27.3%) had an appropriate ovarian response (5–14 oocytes) in the first cycle compared to 14 (63.6%) women in the second cycle (p = 0.01). The ongoing pregnancy rates in all of the first (32.1%) and second cycles (27%) were similar (p = NS).

Conclusion.  In a “standard” patient population, 55.8% needed an altered starting dose in the second cycle and rFSH dose adjustments had a significant impact on the ovarian response.
Comprehensive Care of the Epilepsy Patient—Control, Comorbidity, and Cost
Authors: W. Bazil Carl
Published: August 2004

Summary:  Traditionally, control of seizures in patients with epilepsy is viewed as the most important clinical outcome. Yet, current antiepileptic drugs (AEDs) do not always achieve this. Around 30–40% of patients remain uncontrolled despite pharmacological intervention. Poor tolerability of AEDs is a large part of the problem and contributes as much to the overall effectiveness of therapy as efficacy. Comorbid conditions are present in many patients, and appropriate management of these can further improve seizure control and quality of life. Patients with epilepsy often experience—among other disorders—neuropsychological effects, migraines, and psychological problems (especially anxiety and depression). Sleep disturbances are also common and have been shown to contribute to the intractability of seizures in some patients. Many anticonvulsant treatments have the potential to improve—or in some cases worsen—these concurrent conditions, and these properties should therefore be considered in the total care of the patient. Finally, the costs of uncontrolled epilepsy are measured not only in terms of direct healthcare‐related costs, but also in terms of lost productivity and opportunity. The indirect costs of epilepsy are substantial and account for 70–85% of total disease‐related costs. Patients with uncontrolled seizures contribute disproportionately to healthcare costs, reinforcing the need for the development of newer AEDs with improved profiles of efficacy and tolerability, but with minimal adverse effects on behavior, cognition, and sleep.