bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutualism or parasitism? The variable outcome of cleaning symbioses
Authors: Cheney Karen L , Côté Isabelle M
Published: May 2005

The exact nature of many interspecific interactions remains unclear, with some evidence suggesting mutualism and other evidence pointing to parasitism for the same pair of interacting species. Here, we show spatial variation in the outcome of the cleaning relationship between Caribbean cleaning gobies (
Elacatinus evelynae
) and longfin damselfish (
Stegastes diencaeus
) over the distribution range of these species, and link this variation to the availability of ectoparasites. Cleaning interactions at sites with more ectoparasites were characterized by greater reductions in ectoparasite loads on damselfish clients and lower rates of removal of scales and mucus (i.e. cheating) by cleaning gobies, whereas the opposite was observed at sites where ectoparasite abundance was lower. For damselfish clients, cleaning was therefore clearly mutualistic in some locations, but sometimes neutral or even parasitic in others. Seasonal variability in ectoparasite abundance may ensure that locally low parasite availability, which promotes cleanerfish cheating, may be a transient condition at any given site. Conflicting conclusions about the nature of cleaning symbioses may, therefore, be explained by variation in ectoparasite abundance.
Carotenoids need structural colours to shine
Authors: Shawkey Matthew D , Hill Geoffrey E
Published: May 2005

The bright colours of feathers are among the most striking displays in nature and are frequently used as sexual signals. Feathers can be coloured by pigments or by ordered tissue, and these mechanisms have traditionally been treated as distinct modes of display. Here we show that some yellow plumage colour is created both by reflection of light from white structural tissue and absorption of light by carotenoids. Thus, structural components of feathers contribute substantially to yellow ‘carotenoid’ displays, but the effect of variation in structural components on variation in colour displays is, to our knowledge, unstudied. The presence of structural colour in some carotenoid-based colour displays will have to be considered in studies of colour signalling.
Phylogeny can make the mid-domain effect an inappropriate null model
Authors: Jonathan Davies T , Grenyer Richard , Gittleman John L
Published: May 2005

The mid-domain effect (MDE), a bias in species richness towards the midpoint of a given geographical dimension, has been used as a null model in macro-ecological studies. Departures from a MDE are often thought of as interesting. The MDE is a product of the interaction between geometric boundaries and range locations, with species being forced to occupy more central positions in proportion to their range size. We criticize this mechanism for assuming species' locations to be wholly independent from their evolutionary past. We present a simple simulation model that shows how range locations arising as part of a phylogenetic process depart from a MDE. The amount of departure is positively correlated with phylogenetic imbalance (tree shape), but a deviation from an equal-rates Markov speciation model is not necessary to negate a MDE. We suggest that the MDE is an appropriate ecological null model only when phylogenetic influence on range location is demonstrably low or non-existent.
Male mate choice and sperm allocation in a sexual/asexual mating complex of
Poecilia
(Poeciliidae, Teleostei)
Authors: Schlupp I , Plath M
Published: May 2005

Male mate choice is critical for understanding the evolution and maintenance of sexual/asexual mating complexes involving sperm-dependent, gynogenetic species. Amazon mollies (
Poecilia formosa
) require sperm to trigger embryogenesis, but the males (e.g.
Poecilia mexicana
) do not contribute genes. Males benefit from mating with Amazon mollies, because such matings make males more attractive to conspecific females, but they might control the cost of such matings by providing less sperm to Amazon mollies. We examined this at the behavioural and sperm levels.
P. mexicana
males preferred to mate with, and transferred more sperm to conspecific females. However, if males mated with
P. formosa
, sperm was readily transferred. This underscores the importance of male choice in this system.
Surface plasmon resonance shows that type IV pili are important in surface attachment by
Pseudomonas aeruginosa
Authors: Jenkins A. Toby A , Buckling Angus , McGhee Marsha , ffrench-Constant Richard H
Published: May 2005

Type IV pili have been shown to play a role in the early stages of bacterial biofilm formation, but not in initial bacterial attachment. Here, using the surface analytical technique, surface plasmon resonance (SPR), we follow the attachment of the bacterium
Pseudomonas aeruginosa
in real time. In contrast to previous studies, we show that type IV pili mutants are defective in attachment. Both mutants lacking pili (
pilA
), and those possessing an overabundance of pili (
pilT
), showed reduced SPR measured attachment compared with the wild-type PAO1 strain. Both
pil
mutants also showed reduced pathogenicity in a model insect host, as measured by percentage mortality after 24 h. SPR revealed differences in the kinetics of attachment between
pilA
and
pilT
, differences obscured by endpoint assays using crystal violet stain. These results highlight the power of SPR in monitoring bacterial attachment in real time and also demonstrate an additional role for type IV pili beyond bacterial aggregation and micro-colony formation.
Preliminary comparative study of small amplitude helical and conventional ePTFE arteriovenous shunts in pigs
Authors: Caro Colin G , Cheshire Nick J , Watkins Nick
Published: May 2005

Intimal hyperplasia (IH), which causes occlusion of arterial bypass grafts and arteriovenous (A-V) shunts, develops preferentially in low wall shear, or stagnation, regions. Arterial geometry is commonly three-dimensional, generating swirling flows, the characteristics of which include in-plane mixing and inhibition of stagnation. Clinical arterial bypass grafts are commonly two-dimensional, favouring extremes of wall shear. We have developed small amplitude helical technology (SwirlGraft) devices and shown them to generate physiological-type swirling flows. Expanded polytetrafluorethylene (ePTFE) grafts, although widely used as A-V shunts for renal dialysis access, are prone to thrombosis and IH. In a small preliminary study in pigs, we have implanted SwirlGraft ePTFE carotid artery-to-jugular vein shunts on one side and conventional ePTFE carotid artery-to-jugular vein shunts contralaterally. There was consistently less thrombosis and IH in the SwirlGraft than conventional shunts. At eight weeks (two animals), the differences were marked, with virtually no disease in the SwirlGraft devices and occlusion of the conventional grafts by thrombosis and IH. The study had limitations, but the lesser pathology in the SwirlGraft devices is likely to have resulted from their geometry and the associated swirling flow. The results could have implications for vascular biology and prolongation of the patency of arterial bypass grafts and A-V shunts.
Universal oscillations of high derivatives
Authors: Berry M.V
Published: May 2005

Differentiation generates oscillations. For the
n
th derivative
f
(
n
, 
t
) of a function
f
(
t
) that is analytic in a strip, including the real
t
-axis, the oscillations occupy a
t
interval that gets larger as
n
increases. The oscillations are studied in detail using integral representations and large-
n
asymptotics. For functions with singularities (poles or branch-points) in the complex
t
-plane, the oscillations of high derivatives are determined by the singularities; for entire functions, the oscillations originate in complex saddle-points. In a wide class of cases, the oscillations are contained in a Gaussian envelope in the
t
interval where
f
(
n
, 
t
) is largest, with the envelope including about

oscillations. Examples of the universal oscillations are given for
f
(
t
) with a simple pole, competing branch-points, a single saddle, competing pole and saddle and where the zeros are confined to half the real axis.
Phylogenetics of modern birds in the era of genomics
Authors: Edwards Scott V , Bryan Jennings W , Shedlock Andrew M
Published: May 2005

In the 14 years since the first higher-level bird phylogenies based on DNA sequence data, avian phylogenetics has witnessed the advent and maturation of the genomics era, the completion of the chicken genome and a suite of technologies that promise to add considerably to the agenda of avian phylogenetics. In this review, we summarize current approaches and data characteristics of recent higher-level bird studies and suggest a number of as yet untested molecular and analytical approaches for the unfolding tree of life for birds. A variety of comparative genomics strategies, including adoption of objective quality scores for sequence data, analysis of contiguous DNA sequences provided by large-insert genomic libraries, and the systematic use of retroposon insertions and other rare genomic changes all promise an integrated phylogenetics that is solidly grounded in genome evolution. The avian genome is an excellent testing ground for such approaches because of the more balanced representation of single-copy and repetitive DNA regions than in mammals. Although comparative genomics has a number of obvious uses in avian phylogenetics, its application to large numbers of taxa poses a number of methodological and infrastructural challenges, and can be greatly facilitated by a ‘community genomics’ approach in which the modest sequencing throughputs of single PI laboratories are pooled to produce larger, complementary datasets. Although the polymerase chain reaction era of avian phylogenetics is far from complete, the comparative genomics era—with its ability to vastly increase the number and type of molecular characters and to provide a genomic context for these characters—will usher in a host of new perspectives and opportunities for integrating genome evolution and avian phylogenetics.
Roles and regulation of theDrosophilacentromere cohesion protein MEI-S332 family
Authors: Lee Janice Y , Hayashi-Hagihara Aki , Orr-Weaver Terry L
Published: May 2005

In meiosis, a physical attachment, or cohesion, between the centromeres of the sister chromatids is retained until their separation at anaphase II. This cohesion is essential for ensuring accurate segregation of the sister chromatids in meiosis II and avoiding aneuploidy, a condition that can lead to prenatal lethality or birth defects. TheDrosophilaMEI-S332 protein localizes to centromeres when sister chromatids are attached in mitosis and meiosis, and it is required to maintain cohesion at the centromeres after cohesion along the sister chromatid arms is lost at the metaphase I/anaphase I transition. MEI-S332 is the founding member of a family of proteins that protect centromeric cohesion but whose members also affect kinetochore behaviour and spindle microtubule dynamics. We compare theDrosophilaMEI-S332 family members, evaluate the role of MEI-S332 in mitosis and meiosis I, and discuss the regulation of localization of MEI-S332 to the centromere and its dissociation at anaphase. We analyse the relationship between MEI-S332 and cohesin, a protein complex that is also necessary for sister-chromatid cohesion in mitosis and meiosis. In mitosis, centromere localization of MEI-S332 is not dependent upon the cohesin complex, and cohesin retains its association with mitotic chromosomes even in the absence of MEI-S332.
Lateral prefrontal cortex: architectonic and functional organization
Authors: Petrides Michael
Published: May 2005

A comparison of the architecture of the human prefrontal cortex with that of the macaque monkey showed a very similar architectonic organization in these two primate species. There is no doubt that the prefrontal cortical areas of the human brain have undergone considerable development, but it is equally clear that the basic architectonic organization is the same in the two species. Thus, a comparative approach to the study of the functional organization of the primate prefrontal cortex is more likely to reveal the essential aspects of the various complex control processes that are the domain of frontal function. The lateral frontal cortex appears to be functionally organized along both a rostral–caudal axis and a dorsal–ventral axis. The most caudal frontal region, the motor region on the precentral gyrus, is involved in fine motor control and direct sensorimotor mappings, whereas the caudal lateral prefrontal region is involved in higher order control processes that regulate the selection among multiple competing responses and stimuli based on conditional operations. Further rostrally, the mid-lateral prefrontal region plays an even more abstract role in cognitive control. The mid-lateral prefrontal region is itself organized along a dorsal–ventral axis of organization, with the mid-dorsolateral prefrontal cortex being involved in the monitoring of information in working memory and the mid-ventrolateral prefrontal region being involved in active judgments on information held in posterior cortical association regions that are necessary for active retrieval and encoding of information.
Vax genes ventralize the embryonic eye
Authors: Mui Stina H. , Kim Jin Woo , Lemke Greg , Bertuzzi Stefano
Published: May 2005

The vertebrate retina and optic nerve are strikingly different in terms of their size, organization, and cellular diversity, yet these two structures develop from the same embryonic neuroepithelium. Precursor cells in the most ventral domain of this epithelium give rise only to the astrocytes of the optic nerve, whereas immediately adjacent, more dorsal precursors give rise to the myriad cell types of the retina. We provide genetic evidence that two closely related, ventrally expressed homeodomain proteins—Vax1 and Vax2—control this neuroepithelial segregation. In the absence of both proteins, we find that the optic nerve is transformed in its entirety into fully differentiated retina. We demonstrate that this transformation results from the loss of ventralizing actvity in the developing eye field, and that ventralization is mediated, at least in part, via Vax repression of the Pax6 gene, a potent inducer of retinal development.
Zebrafish Hairy/Enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites
Authors: Kawamura Akinori , Koshida Sumito , Hijikata Hiroko , Sakaguchi Takuya , Kondoh Hisato , Takada Shinji
Published: May 2005

Notch and fibroblast growth factor (FGF) signaling pathways have been implicated in the establishment of proper periodicity of vertebrate somites. Here, we show evidence that a Hes6-related hairy/Enhancer of split-related gene, her13.2, links FGF signaling to the Notch-regulated oscillation machinery in zebrafish. Expression of her13.2 is induced by FGF-soaked beads and decreased by an FGF signaling inhibitor. her13.2 is required for periodic repression of the Notch-regulated genes her1 and her7, and for proper somite segmentation. Furthermore, Her13.2 augments autorepression of her1 in association with Her1 protein. Therefore, FGF signaling appears to maintain the oscillation machinery by supplying a binding partner, Her13.2, for Her1.
Embryonic stem cell differentiation: emergence of a new era in biology and medicine
Authors: Keller Gordon
Published: May 2005

The discovery of mouse embryonic stem (ES) cells >20 years ago represented a major advance in biology and experimental medicine, as it enabled the routine manipulation of the mouse genome. Along with the capacity to induce genetic modifications, ES cells provided the basis for establishing an in vitro model of early mammalian development and represented a putative new source of differentiated cell types for cell replacement therapy. While ES cells have been used extensively for creating mouse mutants for more than a decade, their application as a model for developmental biology has been limited and their use in cell replacement therapy remains a goal for many in the field. Recent advances in our understanding of ES cell differentiation, detailed in this review, have provided new insights essential for establishing ES cell-based developmental models and for the generation of clinically relevant populations for cell therapy.
Developmentally induced changes in transcriptional program alter spatial organization across chromosomes
Authors: Casolari Jason M. , Brown Christopher R. , Drubin David A. , Rando Oliver J. , Silver Pamela A.
Published: May 2005

Although the spatial location of genes within the nucleus has been implicated in their transcriptional status, little is known about the dynamics of gene location that accompany large-scale changes in gene expression. The mating of haploid yeast Saccharomyces cerevisiae is accompanied by a large-scale change in transcription and developmental program. We examined changes in nuclear organization that accompany stimulus by the mating pheromone α factor and found that most α-factor-induced genes become associated with components of the nuclear envelope. The myosin-like protein Mlp1, which has been implicated in mRNA export, was further shown to exhibit RNA dependence in its association with α-factor-induced genes. High-resolution mapping of association of chromosome III with Mlp1 revealed α-factor-dependent determinants of nuclear pore association, including origins of replication, specific intergenic regions, and the 3′ ends of transcriptionally activated genes. Taken together, these results reveal RNA- and DNA-dependent determinants of nuclear organization as well as a detailed picture of how an entire chromosome alters its spatial conformation in response to a developmental cue.
BRCA1/BARD1 inhibition of mRNA 3′ processing involves targeted degradation of RNA polymerase II
Authors: Kleiman Frida E. , Wu-Baer Foon , Fonseca Danae , Kaneko Syuzo , Baer Richard , Manley James L.
Published: May 2005

Mammalian cells exhibit a complex response to DNA damage. The tumor suppressor BRCA1 and associated protein BARD1 are thought to play an important role in this response, and our previous work demonstrated that this includes transient inhibition of the pre-mRNA 3′ processing machinery. Here we provide evidence that this inhibition involves proteasomal degradation of a component necessary for processing, RNA polymerase II (RNAP II). We further show that RNAP IIO, the elongating form of the enzyme, is a specific in vitro target of the BRCA1/BARD1 ubiquitin ligase activity. Significantly, siRNA-mediated knockdown of BRCA1 and BARD1 resulted in stabilization of RNAP II after DNA damage. In addition, inhibition of 3′ cleavage induced by DNA damage was reverted in extracts of BRCA1-, BARD1-, or BRCA1/BARD1-depleted cells. We also describe corresponding changes in the nuclear localization and/or accumulation of these factors following DNA damage. Our results support a model in which a BRCA1/BARD1-containing complex functions to initiate degradation of stalled RNAP IIO, inhibiting the coupled transcription-RNA processing machinery and facilitating repair.
The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions
Authors: Berset Thomas A. , Hoier Erika Fröhli , Hajnal Alex
Published: May 2005

Protein phosphorylation by kinases and the subsequent dephosphorylation by phosphatases are key mechanisms that regulate intracellular signal transduction during development. Here, we report the identification of the receptor protein tyrosine phosphatase DEP-1 as a negative regulator of the Caenorhabditis elegans EGF receptor. DEP-1 amplifies in the developing vulva and the excretory system the small differences in the amount of EGF signal received by equivalent precursor cells to achieve binary cell fate decisions. During vulval development, DEP-1 inhibits EGFR signaling in the secondary cell lineage in parallel with the NOTCH-mediated lateral inhibition, while EGFR signaling simultaneously down-regulates DEP-1 and NOTCH expression in the primary cell lineage. This regulatory network of inhibitors results in the full activation of the EGFR/RAS/MAPK pathway in the primary vulval cells and at the same time keeps the EGFR/RAS/MAPK pathway inactive in the adjacent secondary cells. Mammalian Dep-1/Scc1 functions as a tumor-suppressor gene in the intestinal epithelium. Thus, mutations in human Dep-1 may promote tumor formation through a hyperactivation of the EGF receptor.
Spontaneous rDNA copy number variation modulates Sir2 levels and epigenetic gene silencing
Authors: Michel Agnès H. , Kornmann Benoît , Dubrana Karine , Shore David
Published: May 2005

We show that in budding yeast large rDNA deletions arise frequently and cause an increase in telomeric and mating-type gene silencing proportional to repeat loss. Paradoxically, this increase in silencing is correlated with a highly specific down-regulation of SIR2, which encodes a deacetylase enzyme required for silencing. These apparently conflicting observations suggest that a large nucleolar pool of Sir2 is released upon rDNA loss and made available for telomeric and HM silencing, as well as down-regulation of SIR2 itself. Indeed, we present evidence for a reduction in the fraction of Sir2 colocalizing with the nucleolar marker Nop1, and for SIR2 autoregulation. Despite a decrease in the fraction of nucleolar Sir2, and in overall Sir2 protein levels, short rDNA strains display normal rDNA silencing and a lifespan indistinguishable from wild type. These observations reveal an unexpectedly large clonal variation in rDNA cluster size and point to the existence of a novel regulatory circuit, sensitive to rDNA copy number, that balances nucleolar and nonnucleolar pools of Sir2 protein.
The Dewey-Lippmann Debate Today: Communication Distortions, Reflective Agency, and Participatory Democracy
Authors: Whipple Mark
Published: May 2005

In this article, I introduce the Dewey-Lippmann democracy debate of the 1920s as a vehicle for considering how social theory can enhance the empirical viability of participatory democratic theory within the current context of advanced capitalism. I situate within this broad theoretical framework the theories of Habermas and Dewey. In the process, I argue (a) that while Dewey largely failed to reconcile his democratic ideal with the empirical constraint of large-scale organizations, Habermas, in particular his work on the public sphere, provides an important starting point for considering the state of public participation within the communication distortions of advanced capitalism; (b) that to fully understand the relation between communication distortions and public participation, social theorists must look beyond Habermas and return to Dewey to mobilize his bi-level view of habitual and reflective human agency; and, finally, (c) that the perspective of a Deweyan political theory of reflective agency best furthers our understanding of potential communication distortions and public participation, particularly in the empirical spaces of media centralization and intellectual property rights.
Seeing Invisible Religion: Religion as a Societal Conversation about Transcendent Meaning
Authors: Besecke Kelly
Published: May 2005

Contemporary sociology conceptualizes religion along two dimensions: the institutional and the individual. Lost in this dichotomy is religion's noninstitutional, but collective and public, cultural dimension. As a result, theories of religious modernity, including both sides of the secularization debate, are unable to recognize or evaluate the social power of noninstitutionalized religious communication. This article offers a reconceptualization of religion that highlights its cultural, communicative dimension. Original research on religious talk provides an empirical ground for a theoretical discussion that highlights: (1) the “invisible” nature of religion in modern societies, as theorized by Thomas Luckmann and (2) the social power attributed to communication by contemporary cultural sociologists and cultural theorists. I argue that conceptualizing religion as an evolving societal conversation about transcendent meaning broadens the empirical and theoretical grasp of the religion concept.
Overexpression of MUC13 is associated with intestinal‐type gastric cancer
Authors: Shimamura Takahiro , Ito Hirotaka , Shibahara Junji , Watanabe Akira , Hippo Yoshitaka , Taniguchi Hirokazu , Chen Yongxin , Kashima Takeshi , Ohtomo Toshihiko , Tanioka Fumihiko , Iwanari Hiroko , Kodama Tatsuhiko , Kazui Teruhisa , Sugimura Haruhiko , Fukayama Masashi , Aburatani Hiroyuki
Published: May 2005

Mucins are secreted or transmembrane glycoproteins that are expressed mainly in the digestive tract. This family of proteins has been the focus of much gastric cancer research as some transmembrane mucins are implicated in tumorigenesis and make attractive targets for cancer diagnosis and therapeutics. Mucins have also been utilized to classify gastric cancer by differentiating between gastric and intestinal phenotypes. Here we show that transmembrane mucin MUC13 is upregulated in gastric cancer. By quantitative real‐time reverse transcription‐polymerase chain reaction and immunoblot analysis, overexpression of MUC13 was verified in more than half of the samples examined. In immunohistochemical analysis, MUC13 staining was observed in 74 of 114 cases of gastric cancer (64.9%), predominantly in intestinal type (P < 0.001), and in 9 of 10 cases of intestinal metaplasia, precancerous lesions of intestinal‐type gastric cancer, but not observed in normal gastric mucosa. Moreover, MUC13 staining patterns characteristic of histological type were identified: staining was on the apical side of tubular glands in intestinal type and on the cytoplasm in diffuse type. These results suggest that MUC13 is a good differentiation marker for gastrointestinal mucosa and that it may have a causal role that correlates with two distinct gastric tumorigenesis pathways. (Cancer Sci 2005; 96: 265 –274)
Charcoal cigarette filters and lung cancer risk in Aichi Prefecture, Japan
Authors: Muscat Joshua E. , Takezaki Toshiro , Tajima Kazuo , Stellman Steven D.
Published: May 2005

The lung cancer mortality rate has been lower in Japan than in the United States for several decades. We hypothesized that this difference is due to the Japanese preference for cigarettes with charcoal‐containing filters, which efficiently absorb selected gas phase components of mainstream smoke including the carcinogen 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone. We analyzed a subset of smokers (396 cases and 545 controls) from a case‐control study of lung cancer conducted in Aichi Prefecture, Japan. The risk associated with charcoal filters (73% of all subjects) was evaluated after adjusting for age, sex, education and smoking dose. The odds ratio (OR) associated with charcoal compared with ‘plain’ cigarette filters was 1.2 (95% confidence intervals [CI] 0.9, 1.6). The histologic‐specific risks were similar (e.g. OR = 1.3, 95% CI 0.9, 2.1 for adenocarcinoma). The OR was 1.7 (95% CI 1.1, 2.9) in smokers who switched from ‘plain’ to charcoal brands. The mean daily number of cigarettes smoked in subjects who switched from ‘plain’ to charcoal brands was 22.5 and 23.0, respectively. The findings from this study did not indicate that charcoal filters were associated with an attenuated risk of lung cancer. As the detection of a modest benefit or risk (e.g. 10–20%) that can have significant public health impact requires large samples, the findings should be confirmed or refuted in larger studies. (Cancer Sci2005; 96: 283 –287)
Possible antitumor activity of 1‐(3‐C‐ethynyl‐β‐d‐ribo‐pentofuranosyl)cytosine (ECyd, TAS‐106) against an established gemcitabine (dFdCyd)‐resistant human pancreatic cancer cell line
Authors: Kazuno Hiromi , Sakamoto Kazuki , Fujioka Akio , Fukushima Masakazu , Matsuda Akira , Sasaki Takuma
Published: May 2005

We established a variant of MIAPaCa‐2 human pancreatic cancer cells that is resistant to 2′,2′‐difluorodeoxycytidine (gemcitabine, dFdCyd), MIAPaCa‐2/dFdCyd, and elucidated the biochemical characteristics and mechanism of dFdCyd‐resistance in these cells. We also evaluated 1‐(3‐C‐ethynyl‐β‐d‐ribo‐pentofuranosyl)cytosine (ECyd, TAS‐106, RNA polymerase inhibitor), a new anticancer ribonucleoside, for antitumor activity against the resistant cells in vitro and in vivo. MIAPaCa‐2/dFdCyd cells were 2541‐fold more resistant to dFdCyd than parental MIAPaCa‐2 cells, and the major mechanism of the dFdCyd‐resistance was found to be a decrease in the intracellular pool of dFdCyd and its active metabolites, which would result in a decrease in incorporation of dFdCyd triphosphate into DNA. This finding was confirmed by the discovery of decreased deoxycytidine kinase activity, increased cytidine deaminase and ribonucleotide reductase activity, and increased 5′‐nucleotidase mRNA expression in the MIAPaCa‐2/dFdCyd cells. The cytotoxicity of TAS‐106 as an antitumor nucleoside analog was similar in both parental and dFdCyd‐resistant cells, with IC50 values of 6.25 and 6.27 nM, respectively, and this finding was supported by similar intracellular uptake and metabolism of TAS‐106 in both cell lines. We also evaluated the in vivo antitumor activity of TAS‐106 against MIAPaCa‐2 and dFdCyd‐resistant MIAPaCa‐2/dFdCyd tumors implanted into nude mice. The tumor growth inhibition rate of weekly additions of TAS‐106 (7 mg/kg, iv) against parental and dFdCyd‐resistant tumors was 73% and 76%, respectively, while that of dFdCyd administered twice a week (240 mg/kg, iv) was 84% and 34%, respectively. These results suggest that TAS‐106 would contribute to the treatment of patients with advanced pancreatic carcinomas in whom dFdCyd‐based chemotherapy has failed. (Cancer Sci 2005; 96: 295 –302)
Suppression of azoxymethane‐induced colon cancer development in rats by a prostaglandin E receptor EP1‐selective antagonist
Authors: Niho Naoko , Mutoh Michihiro , Kitamura Tomohiro , Takahashi Mami , Sato Hidetaka , Yamamoto Hiroshi , Maruyama Takayuki , Ohuchida Shuichi , Sugimura Takashi , Wakabayashi Keiji
Published: May 2005

Prostaglandin E2 is involved in colon carcinogenesis through its binding to the PGE2 receptor subtypes EP1, EP2, EP3 and EP4. We have demonstrated that administration of ONO‐8711, an EP1‐selective antagonist, suppresses development of AOM‐induced ACF in C57BL/6 mice and F344 rats. ONO‐8711 also reduced the numbers of intestinal polyps in Min mice. In the present study, we investigated the long‐term effects of ONO‐8711 on colon cancer development in rats treated with AOM. Male F344 rats were injected subcutaneously with AOM (15 mg/kg body weight) once a week for the first 2 weeks to develop colon cancer. Administration of 400 or 800 p.p.m. ONO‐8711 in their diets for 32 weeks reduced the incidence, multiplicity and volume of colon carcinomas. The incidence of colon adenocarcinomas in AOM‐treated rats was 97, 83 and 76% (P < 0.05) in the 0, 400 and 800 p.p.m. of ONO‐8711 groups, respectively. The multiplicity of adenocarcinomas was also decreased significantly, being 3.31 ± 0.33, 2.34 ± 0.27 (P < 0.05) and 2.06 ± 0.34 (P < 0.01) with 0, 400 and 800 p.p.m. of ONO‐8711, respectively. Moreover, treatment with 800 p.p.m. ONO‐8711 reduced the mean volume of adenocarcinomas to 49% (P < 0.05) of the value for the AOM treatment alone. Furthermore, the BrdU labeling index was decreased significantly in colon cancer cells by 800 p.p.m. ONO‐8711. These results confirm that EP1 is involved in colon carcinogenesis and that EP1‐selective antagonists might be promising candidates for colon cancer chemopreventive agents. (Cancer Sci 2005; 96: 260 –264)
Notch1 oncoprotein antagonizes TGF‐β/Smad‐mediated cell growth suppression via sequestration of coactivator p300
Authors: Masuda Shigeo , Kumano Keiki , Shimizu Kiyoshi , Imai Yoichi , Kurokawa Mineo , Ogawa Seishi , Miyagishi Makoto , Taira Kazunari , Hirai Hisamaru , Chiba Shigeru
Published: May 2005

The Notch proteins constitute a family of transmembrane receptors that play a pivotal role in cellular differentiation, proliferation and apoptosis. Although it has been recognized that excess Notch signaling is potentially tumorigenic, little is known about precise mechanisms through which dysregulated Notch signaling induces neoplastic transformation. Here we demonstrate that Notch signaling has a transcriptional cross‐talk with transforming growth factor‐β (TGF‐β) signaling, which is well characterized by its antiproliferative effects. TGF‐β‐mediated transcriptional responses are suppressed by constitutively active Notch1, and this inhibitory effect is canceled by introduction of transcriptional coactivator p300. We further show that this blockade of TGF‐β signaling is executed by the sequestration of p300 from Smad3. Moreover, in a human cervical carcinoma cell line, CaSki, in which Notch1 is spontaneously activated, suppression of Notch1 expression with small interfering RNA significantly restores the responsiveness to TGF‐β. Taken together, we propose that Notch oncoproteins promote cell growth and cancer development partly by suppressing the growth inhibitory effects of TGF‐β through sequestrating p300 from Smad3. (Cancer Sci 2005; 96: 274 –283)
Dendritic cell immunotherapy with poly(d,l‐2,4‐diaminobutyric acid)‐mediated intratumoral delivery of the interleukin‐12 gene suppresses tumor growth significantly
Authors: Iwashita Yukio , Goto Shigeru , Tominaga Masayuki , Sasaki Atsushi , Ohmori Naoya , Goto Takeshi , Sato Syuji , Ohta Masayuki , Kitano Seigo
Published: May 2005

A conventional DC‐based immunotherapy has been tested clinically for treatment of patients with advanced cancer but requires modification to further improve the clinical results. In this study, we evaluated the in vivo antitumor effects of DC therapy, non‐viral‐mediated IL‐12 gene therapy, and a combination of the two in a murine bilateral subcutaneous tumor model. DC therapy alone and IL‐12 gene therapy alone suppressed tumor growth at the injected sites. However, the antitumor effect on the distant contralateral tumor was insufficient. When DC therapy and IL‐12 gene therapy were carried out simultaneously, tumor growth was significantly suppressed bilaterally (P < 0.001). Cytolytic activity was augmented significantly in mice given the combination treatment compared to in mice treated with either DC or IL‐12 gene therapy alone (P < 0.05). Microvessel density of both tumors was significantly lower in mice subjected to the combination therapy than in mice treated otherwise (P < 0.05). Furthermore, no side‐effects were observed in the treated mice. DC therapy combined with non‐viral‐mediated intratumoral IL‐12 gene delivery has a synergistic antitumor effect not only on targeted tumors but also on contralateral distant tumors and may be of great potential as a therapeutic treatment for patients with advanced cancer. (Cancer Sci 2005; 96: 303 –308)
Tumor immunity against adult T‐cell leukemia
Authors: Kannagi Mari , Harashima Nanae , Kurihara Kiyoshi , Ohashi Takashi , Utsunomiya Atae , Tanosaki Ryuji , Masuda Masato , Tomonaga Masao , Okamura Jun
Published: May 2005

Human T‐cell leukemia virus type‐I (HTLV‐I) causes adult T‐cell leukemia (ATL) in a small population of infected individuals after a long incubation period. Although the process of clonal evolution of ATL cells may involve multiple steps, ATL cells from half of the ATL cases still retain the ability to express HTLV‐I Tax, a key molecule of HTLV‐I leukemogenesis. A recent finding of reactivation of Tax‐specific cytotoxic T lymphocytes (CTL) in ATL patients after hematopoietic stem cell transplantation suggests the presence of Tax expression in vivo and potential contribution of the CTL to antitumor immunity. This is consistent with the results of a series of animal experiments indicating that Tax‐specific CTL limit the growth of HTLV‐I‐infected cells in vivo, although the animal model mimics only an early phase of HTLV‐I infection and leukemogenesis. Establishment of an insufficient HTLV‐I‐specific T‐cell response and an increased viral load in orally HTLV‐I‐infected rats suggests that host HTLV‐I‐specific T‐cell response at a primary HTLV‐I infection can be a critical determinant of persistent HTLV‐I levels thereafter. These findings indicate that Tax‐targeted vaccines may be effective for prophylaxis of ATL in a high‐risk group, and also for therapy of ATL in at least half the cases. (Cancer Sci 2005; 96: 249 –255)
A11 Tetramer‐assisted characterization of Rta‐specific CD8+ T‐cell responses in healthy virus carriers
Authors: Yu H.X. , Srinivasan N. , Ren E.E. , Chan S.H.
Published: May 2005

Abstract:  HLA Class I‐restricted CD8+ T‐cell responses are believed to play an important role in controlling Epstein–Barr virus (EBV) infection, which has been consistently associated with nasopharyngeal carcinoma (NPC). Immediate early transactivator Rta of EBV has been shown to be associated with the reactivation of EBV from latency and drive the lytic cascade of EBV and comprise an important target for EBV‐specific cellular cytotoxicity. Furthermore, BRLF1 is specifically expressed in NPC tumor cells. The protein product of BRLF1, Rta, could then be considered as a NPC tumor antigen. Therefore, cellular immunity against Rta represents a very important part of the immunity against NPC, as they should prevent the replication of EBV. In the present study, Rta‐specific CD8+ T‐cell responses in healthy virus carriers were characterized by using A1101 tetramer containing the known Rta epitope ATIGTAMYK (134–142). We clearly showed A1101/ATIGTAMYK tetramer‐reactive CD8+ T cells in the circulation of healthy virus carriers, ranging from 2.13 to 9.03%. We then studied the expression of perforin and interferon‐γ (IFN‐γ) secretion in these Rta‐specific T cells. Our study demonstrated that Rta‐specific T cells are capable of IFN‐γ production and nearly 90% of the Rta‐specific CD8+ T cells expressed perforin. Presumably, these are the cells that play an important role in determining the initiation of the lytic cycle or the clearance of EBV.
Role of NK cells in mismatched unrelated haematopoietic stem‐cell transplantation: fact or fiction?
Authors: Claas F.H.J. , Oudshoorn M.
Published: May 2005

Abstract:  The role of alloreactive NK cells in haematopoietic stem‐cell transplantation is a controversial topic. Different studies come up with different conclusions. This is mainly due to heterogeneous patient populations, differences in the sources of haematopoietic stem cells and various conditioning regimens. International collaboration is essential to reveal in which situation NK cell alloreactivity plays a role and, if so, whether it is beneficial or detrimental for patient survival.
Complete coding sequences and haplotypic associations of HLA‐B*0707, ‐B*1524, ‐B*4405, ‐B*4802, ‐DRB1*0409, ‐DRB1*0411, ‐DRB1*1115, ‐DRB1*1305, and the novel allele ‐DRB1*0709. Group‐specific amplification of cDNA from DRB1 alleles associated to DRB3 and DRB4
Authors: Vilches C. , Sepúlveda S. , Balas A. , Solís R. , Avilés M.J. , Estefanía E. , Gómez‐Lozano N. , Vicario J. L. , DePablo R.
Published: May 2005

Abstract:  We present here the characterization of the complete coding sequences, previously unavailable, of the human leukocyte antigen (HLA) alleles B*0707, B*1524, B*4405, B*4802, DRB1*0409, DRB1*0411, DRB1*1115, DRB1*1305, and that of a new allele, DRB1*0709. For the isolation of cDNA from the DRB1 gene, we designed a novel set of polymerase chain reaction (PCR) primers that makes it possible to amplify separately the groups of DRB1 alleles associated to each of the DRB3 and DRB4 loci. The primary structures, functional features, evolutionary relationships, haplotypic associations, and population distributions of each of the nine HLA‐B and ‐DRB1 alleles reported here are reviewed.
Characterization of a novel HLA‐Cw*02 variant, Cw*0208, in a Caucasian individual
Authors: Canossi A. , Aureli A. , Piancatelli D. , Liberatore G. , Del Beato T. , Ozzella G. , Tessitore A. , Piazza A. , Papola F. , Casciani C.U. , Adorno D.
Published: May 2005

Abstract:  We describe an additional HLA‐Cw*02 variant, HLA‐Cw*0208, which has been identified in a renal transplant recipient of Caucasian origin (Italy). After performing preliminary serological typing, we analyzed exons 2 and 3 of the HLA‐C locus polymorphism by cloning the amplified DNA and using a sequence‐based typing method. The new allele differs from Cw*020202 by one nucleotide substitution at nucleotide 61 (G→A) of exon 2, which translates to a difference of one amino acid at residue 21 (His→Arg) of the HLA‐C heavy chain. We propose that Cw*0208 was generated by a random point mutation in codon 21 from the Cw*020202 allele, or through gene conversion of Cw*020202 with another allele, probably the Cw*1205 and Cw*1602 alleles.
Identification of a new HLA‐DRB1 allele, HLA‐DRB1*1212, and confirmation of HLA‐B*1586*
Authors: Yan L.‐X. , Zhu F.‐M. , Lv Q.‐F. , Zhang W.
Published: May 2005

Abstract:  A novel allele, HLA‐DRB1*1212, was identified by sequence‐based typing. DRB1*1212 was identical to DRB*120101 at exon 2 except for a single nucleotide at position 199 from A to C, leading to amino acidic substitution from Ile to Leu at codon 67. We also confirmed the HLA‐B*1586 in another Chinese person.
Geropsychiatric consultation in a general hospital in Taiwan
Authors: JUANG YEONG‐YUH , LIU CHIA‐YIH , CHEN CHING‐YEN , HSU SHIH‐CHIEH , HSIAO MEI‐CHUN , HUNG CHING‐I , YEH ENG‐KUNG
Published: May 2005

Abstract  The aim of this study was to characterize clinically significant issues in a psychiatric consultation service for geriatric inpatients in a general hospital in Taiwan. This was a case‐control study. During a 5‐month period, 100 geriatric (age ≥65 years) inpatients consecutively referred for consultation‐liaison psychiatric service from non‐psychiatric departments formed the study group. Another 100 medical inpatients, also referred for consultation‐liaison to the psychiatric service, but aged 17–50, formed the control (non‐geriatric) group. The diagnosis, demography, reason for referral, symptomatology, and other clinical characteristics were determined by consensus between two psychiatrists. Psychiatric diagnosis was made according to criteria in the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders. The geropsychiatric consultation rate was 0.9%. Geriatric patients constituted 20.1% of all psychiatric referrals. Common reasons for referral of geriatric inpatients were confusion (32%), depression (17%), disturbing behaviors (14%), and psychosis (14%). The most common psychiatric disorder among geriatric patients was an organic mental disorder (79%), followed by a depressive disorder (13%). More geriatric patients suffered from cancers and cerebrovascular diseases than non‐geriatric patients. The geriatric group was more likely to have multiple physical illnesses. Organic mental disorder and depressive disorders are the most common psychiatric diagnoses in the geropsychiatric consultation service of the authors. In the authors’ experience, both psychotropic medication treatment and psychosocial intervention are important in geropsychiatric consultation.
Gender differences in association of plasma adiponectin with obesity reflect resultant insulin resistance in non‐diabetic Japanese patients with schizophrenia
Authors: MATSUDA YUKIHIKO , TANIOKA TETSUYA , YOSHIOKA TAKAOKI , NAGANO TAKAMASA , HIROI TADASHI , YOSHIKAWA KENICHI , OKABE KEN‐ICHIRO , NAGAMINE ISAO , TAKASAKA YOICHIRO
Published: May 2005

Abstract  Adipose tissues poorly produce adiponectin in the population with increased body fat mass and diabetes mellitus. It was investigated whether hypoadiponectinemia is associated with obesity and insulin resistance in patients with chronically medicated schizophrenia. A cross‐sectional study was designed for 73 non‐diabetic Japanese patients with schizophrenia. The patients aged <70 years with body mass index (BMI) ≥18.5 were selected. Anthropometrics and blood parameters including fat‐derived cytokines were measured, and then the BMI and homeostasis model assessment – insulin resistance (HOMA‐IR) was calculated. The variables were compared between the non‐obesity (BMI, 18.5–24.9) and obesity (≥25.0) groups, and between genders. Plasma adiponectin negatively correlated with BMI (r = −0.554, P < 0.0003) and HOMA‐IR (r = −0.380, P = 0.007) in men, but not in women. The obesity group in men, as compared with the non‐obesity group, showed significantly lower plasma adiponectin (P = 0.008) and higher HOMA‐IR (P < 0.05), but not in women. Plasma leptin showed a significant positive correlation with BMI (r = 0.604, P < 0.0001 in men; r = 0.763, P < 0.0001 in women) and HOMA‐IR (r = 0.618, P < 0.0001 in men; r = 0.679, P < 0.0001 in women). The mean plasma leptin in the obesity group was significantly higher than that in the non‐obesity group (P < 0.01 in men; P < 0.01 in women). In contrast to plasma leptin, plasma adiponectin showed gender difference in relation to BMI and HOMA‐IR.
Regional cerebral blood flow deficits in mild Alzheimer's disease using high resolution single photon emission computerized tomography
Authors: TROLLOR JULIAN N. , SACHDEV PERMINDER S. , HAINDL WALTER , BRODATY HENRY , WEN WEI , WALKER BRENDA M.
Published: May 2005

Abstract  In spite of its wide availability, single photon emission computerized tomography (SPECT) scanning is uncommonly used in the assessment of Alzheimer's disease (AD) and related dementias. In light of recent advances in scanning protocols and image analysis, SPECT needs to be re‐examined as a tool in the diagnosis of dementia. A total of 18 subjects with early AD and 10 healthy elderly control subjects were examined with high resolution SPECT during the performance of a simple word discrimination task. SPECT images were coregistered with individual magnetic resonance imaging scans, allowing delineation of predetermined neuroanatomical Regions of Interest (ROI). There was a gradation of regional cerebral blood flow (rCBF) values in both groups, with the lowest values being in the hippocampus and the highest in the striatum, thalamus and cerebellum. Compared to healthy controls, AD subjects demonstrated lower relative rCBF in parietal and prefrontal cortices. Analysis of individual ROI demonstrated bilateral reduction of rCBF in prefrontal poles, posterior temporal and anterior parietal cortex, and unilateral reduction of rCBF in left dorsolateral prefrontal cortex, right posterior parietal cortex and the left cingulate body. There were no significant differences for hippocampal, occipital or basal ganglia rCBF. Discriminant function analysis indicated that rCBF in the prefrontal polar regions achieved the best classification of cases. SPECT has utility in the diagnostic assessment of AD if standardized and semiquantitative techniques are used.
Lack of an association between 5‐HT6 receptor gene polymorphisms and suicide victims
Authors: OKAMURA KENJI , SHIRAKAWA OSAMU , NISHIGUCHI NAOKI , ONO HISAE , NUSHIDA HIDEYUKI , UENO YASUHIRO , MAEDA KIYOSHI
Published: May 2005

Abstract  An association between serotonergic dysfunction in the brain and suicidal behavior has previously been suggested. The high affinity of some antipsychotic and antidepressant drugs to serotonin 6 (5‐HT6) receptors, and the predominant localization of 5‐HT6 receptors in some limbic regions, suggest that 5‐HT6 receptors play a role in the pathogenesis of suicide. The objective of the present study was to examine the association between suicide victims and two polymorphisms of the 5‐HT6 receptor gene: a biallelic polymorphism (267C/T) in exon 1 and a trinucleotide repeat polymorphism ([GCC]2/3) in the 5′‐upstream region of the gene. The two polymorphisms were genotyped in 163 suicide victims and 166 controls, and the distribution of genotype and allele frequencies between the two groups were compared. Haplotype frequencies of these two polymorphisms were estimated from genotypic data by the maximum‐likelihood method. In both polymorphisms, there were no significant differences in genotype or allele frequencies between the suicide victims and the controls. Moreover, there were no significant differences in the haplotype distributions of these polymorphisms between the two groups. These findings suggest that it is unlikely that the 5‐HT6 receptor gene is involved in the susceptibility to suicide.