bluuebunny/crossref_metadata_2025 huggingface dataset:
Cellular and immunological basis of the host-parasite relationship during infection withNeospora caninum
Authors: HEMPHILL A. , VONLAUFEN N. , NAGULESWARAN A.
Published: June 2006

Neospora caninumis an apicomplexan parasite that is closely related toToxoplasma gondii, the causative agent of toxoplasmosis in humans and domestic animals. However, in contrast toT. gondii, N. caninumrepresents a major cause of abortion in cattle, pointing towards distinct differences in the biology of these two species. There are 3 distinct key features that represent potential targets for prevention of infection or intervention against disease caused byN. caninum. Firstly, tachyzoites are capable of infecting a large variety of host cellsin vitroandin vivo. Secondly, the parasite exploits its ability to respond to alterations in living conditions by converting into another stage (tachyzoite-to-bradyzoite orvice versa). Thirdly, by analogy withT. gondii, this parasite has evolved mechanisms that modulate its host cells according to its own requirements, and these must, especially in the case of the bradyzoite stage, involve mechanisms that ensure long-term survival of not only the parasite but also of the host cell. In order to elucidate the molecular and cellular bases of these important features ofN. caninum, cell culture-based approaches and laboratory animal models are being exploited. In this review, we will summarize the current achievements related to host cell and parasite cell biology, and will discuss potential applications for prevention of infection and/or disease by reviewing corresponding work performed in murine laboratory infection models and in cattle.
The Book of Esther and the Enūma Elish
Authors: SILVERSTEIN ADAM
Published: June 2006

This article is concerned with the influence of Mesopotamian myths on the Old Testament Book of Esther, with particular reference to the role of the Enūma Elish. The Book of Esther has been the subject of numerous studies, some of which have asked the questions posed in this article. Although full account is taken of these important studies, the present article contends that previous scholars have misguidedly focused their attention on Ishtar-legends to the exclusion of the Marduk-legends that are at least as important in this context. The article is divided into two parts: first, it is argued that the central figure in the Book of Esther is Mordecai (=Marduk) and it is his triumph that is being commemorated in the story. Second, similarities between the Enūma Elish (being the foremost Marduk-legend of Mesopotamian culture) and the Book of Esther are drawn, with the evidence being arranged under three rubrics: ‘the plot’, ‘themes and motifs’ and ‘language’.
Negation patterns in Bengali
Authors: THOMPSON HANNE-RUTH
Published: June 2006

Bengali has some unusual negation patterns which have not yet been examined from a syntactic point of view. There are two negative verbs nei and noy, and a tensed negative ni, a past tense version of na. This article challenges some traditional misconceptions of these structures, it looks at the syntactic environments of each of these negators in the context of actual language use, examines the areas of overlap between them, and arrives at a new understanding of these patterns.
Predicting the emergence of human hantavirus disease using a combination of viral dynamics and rodent demographic patterns
Authors: SAUVAGE F. , LANGLAIS M. , PONTIER D.
Published: June 2006

The paper proposes a model explaining the spatial variation in incidence of nephropathia epidemica in Europe. We take into account the rodent dynamic features and the replicative dynamics of the virus in animals, high in the acute phase of newly infected animals and low in the subsequent chronic phase. The model revealed that only vole populations with multi-annual fluctuations allow for simultaneously high numbers of infected rodents and high proportions of those rodents in the acute excretion phase during the culminating phase of population build-up. This leads to a brief peak in exceptionally high concentrations of virus in the environment, and thereby, to human exposure. Such a mechanism suggests that a slight ecological disturbance in animal–parasite systems could result in the emergence of human diseases. Thus, the potential risk for public health due to several zoonotic diseases may be greater than previously believed, based solely on the distribution of human cases.
Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis
Authors: Basile John R. , Castilho Rogerio M. , Williams Vanessa P. , Gutkind J. Silvio
Published: June 2006

Tumor progression and metastasis depend on the ability of cancer cells to initiate angiogenesis and ensure delivery of oxygen, nutrients, and growth factors to rapidly dividing transformed cells and provide access to the systemic circulation. In addition to well established growth factors and inflammatory mediators that promote capillary sprouting and endothelial cell growth and migration, an emerging body of evidence supports a previously unrecognized function for axon guidance molecules in regulation of blood vessel development. Here we show that semaphorin 4D (Sema4D), a protein originally shown to regulate axonal growth cone guidance in the developing central nervous system through its receptor, plexin-B1, is highly expressed in cell lines derived from head and neck squamous cell carcinomas (HNSCCs) at both the protein and message level. Immunohistochemical analysis of a large collection of HNSCC specimens revealed high levels of Sema4D in a cell surface pattern in invading islands of transformed epithelial cells, but not in normal and noninvasive dysplastic epithelium. A similar pattern was observed in malignant cells from prostate, colon, breast, and lung cancer tissues. When shed from HNSCC cells, Sema4D stimulates endothelial cell migration, which can be prevented by Sema4D-blocking antibodies and by Sema4D knockdown. Furthermore, knocking down Sema4D by lentiviral expression of Sema4D shRNA reduces dramatically the size and vascularity of HNSCC tumor xenografts. These findings indicate that expression of Sema4D is a frequently used strategy by which a wide variety of carcinomas may promote angiogenesis, and therefore is a possible therapeutic target for the treatment of these malignancies.
microRNAs exhibit high frequency genomic alterations in human cancer
Authors: Zhang Lin , Huang Jia , Yang Nuo , Greshock Joel , Megraw Molly S. , Giannakakis Antonis , Liang Shun , Naylor Tara L. , Barchetti Andrea , Ward Michelle R. , Yao George , Medina Angelica , O’Brien-Jenkins Ann , Katsaros Dionyssios , Hatzigeorgiou Artemis , Gimotty Phyllis A. , Weber Barbara L. , Coukos George
Published: June 2006

MicroRNAs (miRNAs) are endogenous noncoding RNAs, which negatively regulate gene expression. To determine genomewide miRNA DNA copy number abnormalities in cancer, 283 known human miRNA genes were analyzed by high-resolution array-based comparative genomic hybridization in 227 human ovarian cancer, breast cancer, and melanoma specimens. A high proportion of genomic loci containing miRNA genes exhibited DNA copy number alterations in ovarian cancer (37.1%), breast cancer (72.8%), and melanoma (85.9%), where copy number alterations observed in >15% tumors were considered significant for each miRNA gene. We identified 41 miRNA genes with gene copy number changes that were shared among the three cancer types (26 with gains and 15 with losses) as well as miRNA genes with copy number changes that were unique to each tumor type. Importantly, we show that miRNA copy changes correlate with miRNA expression. Finally, we identified high frequency copy number abnormalities of
Dicer1
,
Argonaute2
, and other miRNA-associated genes in breast and ovarian cancer as well as melanoma. These findings support the notion that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types.
Activity of dual SRC-ABL inhibitors highlights the role of BCR/ABL kinase dynamics in drug resistance
Authors: Azam Mohammad , Nardi Valentina , Shakespeare William C. , Metcalf Chester A. , Bohacek Regine S. , Wang Yihan , Sundaramoorthi Raji , Sliz Piotr , Veach Darren R. , Bornmann William G. , Clarkson Bayard , Dalgarno David C. , Sawyer Tomi K. , Daley George Q.
Published: June 2006

Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance in patients with chronic myelogenous leukemia. Many mutations favor active kinase conformations that preclude imatinib binding. Because the active forms of ABL and SRC resemble one another, we tested two dual SRC-ABL kinase inhibitors, AP23464 and PD166326, against 58 imatinib-resistant (IM
R
) BCR/ABL kinase variants. Both compounds potently inhibit most IM
R
variants, and
in vitro
drug selection demonstrates that active (AP23464) and open (PD166326) conformation-specific compounds are less susceptible to resistance than imatinib. Combinations of inhibitors suppressed essentially all resistance mutations, with the notable exception of T315I. Guided by mutagenesis studies and molecular modeling, we designed a series of AP23464 analogues to target T315I. The analogue AP23846 inhibited both native and T315I variants of BCR/ABL with submicromolar potency but showed nonspecific cellular toxicity. Our data illustrate how conformational dynamics of the ABL kinase accounts for the activity of dual SRC-ABL inhibitors against IM
R
-mutants and provides a rationale for combining conformation specific inhibitors to suppress resistance.
Entamoeba histolytica
cysteine proteases cleave the MUC2 mucin in its C-terminal domain and dissolve the protective colonic mucus gel
Authors: Lidell Martin E. , Moncada Darcy M. , Chadee Kris , Hansson Gunnar C.
Published: June 2006

In order for the protozoan parasite
Entamoeba histolytica
(
E.h.
) to cause invasive intestinal and extraintestinal infection, which leads to significant morbidity and mortality, it must disrupt the protective mucus layer by a previously unknown mechanism. We hypothesized that cysteine proteases secreted from the amoeba disrupt the mucin polymeric network, thereby overcoming the protective mucus barrier. The MUC2 mucin is the major structural component of the colonic mucus gel. Heavily O-glycosylated and protease-resistant mucin domains characterize gel-forming mucins. Their N- and C-terminal cysteine-rich domains are involved in mucin polymerization, and these domains are likely to be targeted by proteases because they are less glycosylated, thereby exposing their peptide chains. By treating recombinant cysteine-rich domains of MUC2 with proteases from
E.h.
trophozoites, we showed that the C-terminal domain was specifically targeted at two sites by cysteine proteases, whereas the N-terminal domain was resistant to proteolysis. The major cleavage site is predicted to depolymerize the MUC2 polymers, thereby disrupting the protective mucus gel. The ability of the cysteine proteases to dissolve mucus gels was confirmed by treating mucins from a MUC2-producing cell line with amoeba proteases. These findings suggest a major role for
E.h.
cysteine proteases in overcoming the protective mucus barrier in the pathogenesis of invasive amoebiasis. In this report, we identify a specific cleavage mechanism used by an enteric pathogen to disrupt the polymeric nature of the mucin gel.
Ric-8B promotes functional expression of odorant receptors
Authors: Von Dannecker Luiz Eduardo C. , Mercadante Adriana F. , Malnic Bettina
Published: June 2006

Odorants are detected by a large family of odorant receptors (ORs) expressed in the nose. The information provided by the ORs is transmitted to specific regions of the brain, leading to odorant perception. The determination of the odorant specificities of the different ORs will contribute to the understanding of how odorants are discriminated by the olfactory system. However, to date only a few ORs have been linked to odorants they recognize, because ORs are poorly expressed on the cell surface of heterologous cells. Here we show that Ric-8B, a putative guanine nucleotide exchange factor for Gαolf, promotes efficient heterologous expression of ORs. Our results also show that Ric-8B enhances accumulation of Gαolf at the cell periphery, indicating that it promotes functional OR expression by improving the efficiency of OR coupling to Gαolf. Expression systems containing Gαolf and Ric-8B should contribute to the functional characterization of ORs.
Abolished cocaine reward in mice with a cocaine-insensitive dopamine transporter
Authors: Chen Rong , Tilley Michael R. , Wei Hua , Zhou Fuwen , Zhou Fu-Ming , Ching San , Quan Ning , Stephens Robert L. , Hill Erik R. , Nottoli Timothy , Han Dawn D. , Gu Howard H.
Published: June 2006

There are three known high-affinity targets for cocaine: the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). Decades of studies support the dopamine (DA) hypothesis that the blockade of DAT and the subsequent increase in extracellular DA primarily mediate cocaine reward and reinforcement. Contrary to expectations, DAT knockout (DAT-KO) mice and SERT or NET knockout mice still self-administer cocaine and/or display conditioned place preference (CPP) to cocaine, which led to the reevaluation of the DA hypothesis and the proposal of redundant reward pathways. To study the role of DAT in cocaine reward, we have generated a knockin mouse line carrying a functional DAT that is insensitive to cocaine. In these mice, cocaine suppressed locomotor activity, did not elevate extracellular DA in the nucleus accumbens, and did not produce reward as measured by CPP. This result suggests that blockade of DAT is necessary for cocaine reward in mice with a functional DAT. This mouse model is unique in that it is specifically designed to differentiate the role of DAT from the roles of NET and SERT in cocaine-induced biochemical and behavioral effects.
Cu-catalyzed cross-dehydrogenative coupling: A versatile strategy for C–C bond formations via the oxidative activation of sp
3
C–H bonds
Authors: Li Zhiping , Bohle D. Scott , Li Chao-Jun
Published: June 2006

Cu-catalyzed cross-dehydrogenative coupling (CDC) methodologies were developed based on the oxidative activation of sp
3
C–H bonds adjacent to a nitrogen atom. Various sp, sp
2
, and sp
3
C–H bonds of pronucleophiles were used in the Cu-catalyzed CDC reactions. Based on these results, the mechanisms of the CDC reactions also are discussed.
Centrosome-associated RNA in surf clam oocytes
Authors: Alliegro Mark C. , Alliegro Mary Anne , Palazzo Robert E.
Published: June 2006

Centrosomes are the major microtubule-organizing center in animal cells. They are composed of a pair of [9(3) + 0] centrioles surrounded by a relatively ill-defined pericentriolar matrix, provide the ciliary centriole–kinetosome (basal body) progenitor, and organize the assembly of microtubules into the mitotic spindle during cell division. Despite >100 years of microscopic observation and their obvious significance, our understanding of centrosome composition, dynamic organization, and mechanism of action is limited when compared with that of other cellular organelles. Centrosomes duplicate only once per cell cycle to ensure development of a normal bipolar spindle. The initial event in centrosome duplication is centriole replication, which is generative, semiconservative, and independent of the nucleus. Such observations led to the proposal that centrosomes contain their own complement of nucleic acids, possibly representative of an organellar genome comparable with those described for mitochondria and chloroplasts. The consensus in the field is that centrosomes lack DNA but may contain RNA. We isolated centrosomes from oocytes of the surf clam,
Spisula solidissima
, and purified from them a unique set of RNAs. We show here by biochemical means and subcellular
in situ
hybridization that the first transcript we analyzed is intimately associated with centrosomes. Sequence analysis reveals that this centrosome-associated RNA encodes a conserved RNA-directed polymerase domain. The hypothesis that centrosomes contain an intrinsic complement of specific RNAs suggests new opportunities to address the century-old problem of centrosome function, heredity, and evolution.
Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice
Authors: Le May Cedric , Chu Khoi , Hu Min , Ortega Christina S. , Simpson Evan R. , Korach Kenneth S. , Tsai Ming-Jer , Mauvais-Jarvis Franck
Published: June 2006

In diabetes, the death of insulin-producing β-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from β-cell injury. Consistent with this hypothesis, 17β-estradiol (estradiol) manifests antidiabetic actions in humans and rodents. In addition, estradiol has antiapoptotic actions in cells that are mediated by the estrogen receptor-a (ERα), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of β-cell apoptosis via ERα. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERα (αERKO) respectively. We show here that in both genders, ArKO
−/−
mice are vulnerable to β-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-induced β-cell apoptosis, helps sustain insulin production, and prevents diabetes.
In vitro
, in mouse pancreatic islets and β-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in β-cells and islets treated with an ERα antagonist and in αERKO islets. Accordingly, αERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating β-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ERα by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ERα, protects β-cells from oxidative injury and prevents diabetes in mice of both genders.
The complete genome sequence ofLactobacillus bulgaricusreveals extensive and ongoing reductive evolution
Authors: van de Guchte M. , Penaud S. , Grimaldi C. , Barbe V. , Bryson K. , Nicolas P. , Robert C. , Oztas S. , Mangenot S. , Couloux A. , Loux V. , Dervyn R. , Bossy R. , Bolotin A. , Batto J.-M. , Walunas T. , Gibrat J.-F. , Bessières P. , Weissenbach J. , Ehrlich S. D. , Maguin E.
Published: June 2006

Lactobacillus delbrueckiissp.bulgaricus(L. bulgaricus) is a representative of the group of lactic acid-producing bacteria, mainly known for its worldwide application in yogurt production. The genome sequence of this bacterium has been determined and shows the signs of ongoing specialization, with a substantial number of pseudogenes and incomplete metabolic pathways and relatively few regulatory functions. Several unique features of theL. bulgaricusgenome support the hypothesis that the genome is in a phase of rapid evolution. (i) Exceptionally high numbers of rRNA and tRNA genes with regard to genome size may indicate that theL. bulgaricusgenome has known a recent phase of important size reduction, in agreement with the observed high frequency of gene inactivation and elimination; (ii) a much higher GC content at codon position 3 than expected on the basis of the overall GC content suggests that the composition of the genome is evolving toward a higher GC content; and (iii) the presence of a 47.5-kbp inverted repeat in the replication termination region, an extremely rare feature in bacterial genomes, may be interpreted as a transient stage in genome evolution. The results indicate the adaptation ofL. bulgaricusfrom a plant-associated habitat to the stable protein and lactose-rich milk environment through the loss of superfluous functions and protocooperation withStreptococcus thermophilus.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims MHC class I-presented peptidesin vivoand plays an important role in immunodominance
Authors: York Ian A. , Brehm Michael A. , Zendzian Sophia , Towne Charles F. , Rock Kenneth L.
Published: June 2006

CD8+T cells respond to short peptides bound to MHC class I molecules. Although most antigenic proteins contain many sequences that could bind to MHC class I, few of these peptides actually stimulate CD8+T cell responses. Moreover, the T cell responses that are generated often follow a very reproducible hierarchy to different peptides for reasons that are poorly understood. We find that the loss of a single enzyme, endoplasmic reticulum aminopeptidase 1 (ERAP1), in the antigen-processing pathway results in a marked shift in the hierarchy of immunodominance in viral infections, even when the responding T cells have the same T cell receptor repertoire. In mice, ERAP1 is the major enzyme that trims precursor peptides in the endoplasmic reticulum and, in this process, can generate or destroy antigenic peptides. Consequently, when ERAP1 is lost, the immune response to some viral peptides is reduced, to others increased, and to yet others unchanged. Therefore, many epitopes must be initially generated as precursors that are normally trimmed by ERAP1 before binding to MHC class I, whereas others are normally degraded by ERAP1 to lengths that are too short to bind to MHC class I. Moreover, peptide trimming and the resulting abundance of peptide–MHC complexes are dominant factors in establishing immunodominance.
A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth
Authors: Holmgren Lars , Ambrosino Elena , Birot Olivier , Tullus Carl , Veitonmäki Niina , Levchenko Tetyana , Carlson Lena-Maria , Musiani Piero , Iezzi Manuela , Curcio Claudia , Forni Guido , Cavallo Federica , Kiessling Rolf
Published: June 2006

Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration.
In vivo
, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin.
A variant of estrogen receptor-α, hER-α36: Transduction of estrogen- and antiestrogen-dependent membrane-initiated mitogenic signaling
Authors: Wang ZhaoYi , Zhang XinTian , Shen Peng , Loggie Brian W. , Chang YunChao , Deuel Thomas F.
Published: June 2006

The status of the 66-kDa human estrogen receptor-α (hER-α66) is a critical determinant in the assessment of the prognosis and in the design of treatment strategies of human breast cancer. Recently, we cloned the cDNA of an alternatively spliced variant of hER-α66, termed hER-α36; the predicted protein lacks both transcriptional activation domains of hER-α66 but retains its DNA-binding domain, partial dimerization, and ligand-binding domains and three potential myristoylation sites located near the N terminus. These findings thus predict that hER-α36 functions very differently from hER-α66 in response to estrogen signaling. We now demonstrate that hER-α36 inhibits the estrogen-dependent and estrogen-independent transactivation activities of hER-α66 and hER-β. We further demonstrate that hER-α36 is predominantly associated with the plasma membrane where it transduces both estrogen- and antiestrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway and stimulates cell growth. We conclude that hER-α36 is a predominantly membrane-based, unique alternatively spliced variant of hER-α66 that acts as a dominant-negative effector of both estrogen-dependent and estrogen-independent transactivation functions signaled through hER-α66 and ER-β; it also transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase mitogenic signaling pathway. The estrogen and antiestrogen signaling pathways mediated by hER-α36 provide an alternative explanation for why some human breast cancers are resistant to and others are worsened by antiestrogen therapy; the data suggest that hER-α36 also may be an important marker to direct therapy in human breast cancers, and perhaps hER-α36 also may transduce estrogen-dependent signaling in other estrogen target tissues.
Therapy-induced antibodies to MHC class I chain-related protein A antagonize immune suppression and stimulate antitumor cytotoxicity
Authors: Jinushi Masahisa , Hodi F. Stephen , Dranoff Glenn
Published: June 2006

The activation of NKG2D on innate and adaptive cytotoxic lymphocytes contributes to immune-mediated tumor destruction. Nonetheless, tumor cell shedding of NKG2D ligands, such as MHC class I chain-related protein A (MICA), results in immune suppression through down-regulation of NKG2D surface expression. Here we show that some patients who respond to antibody-blockade of cytotoxic T lymphocyte-associated antigen 4 or vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte–macrophage colony-stimulating factor generate high titer antibodies against MICA. These humoral reactions are associated with a reduction of circulating soluble MICA (sMICA) and an augmentation of natural killer (NK) cell and CD8
+
T lymphocyte cytotoxicity. The immunotherapy-induced anti-MICA antibodies efficiently opsonize cancer cells for dendritic cell cross-presentation, which is correlated with a diversification of tumor antigen recognition. The anti-MICA antibodies also accomplish tumor cell lysis through complement fixation. Together, these findings establish a key role for the NKG2D pathway in the clinical activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade and granulocyte–macrophage colony-stimulating factor secreting tumor cell vaccines. Moreover, these results highlight the therapeutic potential of anti-MICA antibodies to overcome immune suppression and effectuate tumor destruction in patients.
The mouse
Clock
mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase–response curve amplitude
Authors: Vitaterna Martha Hotz , Ko Caroline H. , Chang Anne-Marie , Buhr Ethan D. , Fruechte Ethan M. , Schook Andrew , Antoch Marina P. , Turek Fred W. , Takahashi Joseph S.
Published: June 2006

The mouse
Clock
gene encodes a basic helix–loop–helix-PAS transcription factor, CLOCK, that acts in concert with BMAL1 to form the positive elements of the circadian clock mechanism in mammals. The original
Clock
mutant allele is a dominant negative (antimorphic) mutation that deletes exon 19 and causes an internal deletion of 51 aa in the C-terminal activation domain of the CLOCK protein. Here we report that heterozygous
Clock
/
+
mice exhibit high-amplitude phase-resetting responses to 6-h light pulses (Type 0 resetting) as compared with wild-type mice that have low amplitude (Type 1) phase resetting. The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes,
Per1
and
Per2
, are not affected by the
Clock
/+ mutation. However, the amplitude of the circadian rhythms of
Per
gene expression are significantly reduced in
Clock
homozygous and heterozygous mutants. Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in
Clock
heterozygotes. The phase–response curves to changes in culture medium are Type 0 in
Clock
heterozygotes, but Type 1 in wild types, similar to that seen for light
in vivo
. The increased efficacy of resetting stimuli and decreased PER expression amplitude can be explained in a unified manner by a model in which the
Clock
mutation reduces circadian pacemaker amplitude in the suprachiasmatic nuclei.
SAP regulates T cell–mediated help for humoral immunity by a mechanism distinct from cytokine regulation
Authors: Cannons Jennifer L. , Yu Li J. , Jankovic Dragana , Crotty Shane , Horai Reiko , Kirby Martha , Anderson Stacie , Cheever Allen W. , Sher Alan , Schwartzberg Pamela L.
Published: June 2006

X-linked lymphoproliferative disease is caused by mutations affecting SH2D1A/SAP, an adaptor that recruits Fyn to signal lymphocyte activation molecule (SLAM)-related receptors. After infection, SLAM-associated protein (SAP)−/− mice show increased T cell activation and impaired humoral responses. Although SAP−/− mice can respond to T-independent immunization, we find impaired primary and secondary T-dependent responses, with defective B cell proliferation, germinal center formation, and antibody production. Nonetheless, transfer of wild-type but not SAP-deficient CD4 cells rescued humoral responses in reconstituted recombination activating gene 2−/− and SAP−/− mice. To investigate these T cell defects, we examined CD4 cell function in vitro and in vivo. Although SAP-deficient CD4 cells have impaired T cell receptor–mediated T helper (Th)2 cytokine production in vitro, we demonstrate that the humoral defects can be uncoupled from cytokine expression defects in vivo. Instead, SAP-deficient T cells exhibit decreased and delayed inducible costimulator (ICOS) induction and heightened CD40L expression. Notably, in contrast to Th2 cytokine defects, humoral responses, ICOS expression, and CD40L down-regulation were rescued by retroviral reconstitution with SAP-R78A, a SAP mutant that impairs Fyn binding. We further demonstrate a role for SLAM/SAP signaling in the regulation of early surface CD40L expression. Thus, SAP affects expression of key molecules required for T–B cell collaboration by mechanisms that are distinct from its role in cytokine regulation.
Malaria infection changes the ability of splenic dendritic cell populations to stimulate antigen-specific T cells
Authors: Sponaas Anne-Marit , Cadman Emma Tamsin , Voisine Cecile , Harrison Vicky , Boonstra Andre , O'Garra Anne , Langhorne Jean
Published: June 2006

The capacity of splenic CD11c+ dendritic cell (DC) populations to present antigen (Ag) to T cells differs during malarial infection with Plasmodium chabaudi in mice. Both CD11c+CD8+ and CD8− DCs presented malarial peptides on their surface during infection. However, although both DC subsets expressing malaria peptides could induce interferon-γ production by CD4 T cells, only CD8− DCs isolated at the acute phase of infection stimulated Ag-specific T cell proliferation and interleukin (IL)-4 and -10 production from MSP1-specific T cell receptor for Ag transgenic T cells coincidental with our reported Th1 to Th2 switch at this stage in response to the pathogen. The timing of these distinct DC responses coincided with increased levels of apoptosis in the CD8+ population and an increase in the numbers of CD8− DCs in the spleen. Our data suggest that the switch in CD4 T cell responses observed in P. chabaudi–infected mice may be the result of the presentation by different DC populations modified by the malaria infection.
Collagens are functional, high affinity ligands for the inhibitory immune receptor LAIR-1
Authors: Lebbink Robert Jan , de Ruiter Talitha , Adelmeijer Jelle , Brenkman Arjan B. , van Helvoort Joop M. , Koch Manuel , Farndale Richard W. , Lisman Ton , Sonnenberg Arnoud , Lenting Peter J. , Meyaard Linde
Published: June 2006

Collagens are the most abundant proteins in the human body, important in maintenance of tissue structure and hemostasis. Here we report that collagens are high affinity ligands for the broadly expressed inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1). The interaction is dependent on the conserved Gly-Pro-Hyp collagen repeats. Antibody cross-linking of LAIR-1 is known to inhibit immune cell function in vitro. We now show that collagens are functional ligands for LAIR-1 and directly inhibit immune cell activation in vitro. Thus far, all documented ligands for immune inhibitory receptors are membrane molecules, implying a regulatory role in cell–cell interaction. Our data reveal a novel mechanism of peripheral immune regulation by inhibitory immune receptors binding to extracellular matrix collagens.
Dysregulated T cell expression of TIM3 in multiple sclerosis
Authors: Koguchi Ken , Anderson David E. , Yang Li , O'Connor Kevin C. , Kuchroo Vijay K. , Hafler David A.
Published: June 2006

T cell immunoglobulin- and mucin domain–containing molecule (TIM)3 is a T helper cell (Th)1–associated cell surface molecule that regulates Th1 responses and promotes tolerance in mice, but its expression and function in human T cells is unknown. We generated 104 T cell clones from the cerebrospinal fluid (CSF) of six patients with multiple sclerosis (MS) (n = 72) and four control subjects (n = 32) and assessed their cytokine profiles and expression levels of TIM3 and related molecules. MS CSF clones secreted higher amounts of interferon (IFN)-γ than did those from control subjects, but paradoxically expressed lower levels of TIM3 and T-bet. Interleukin 12–mediated polarization of CSF clones induced substantially higher amounts of IFN-γ secretion but lower levels of TIM3 in MS clones relative to control clones, demonstrating that TIM3 expression is dysregulated in MS CSF clones. Reduced levels of TIM3 on MS CSF clones correlated with resistance to tolerance induced by costimulatory blockade. Finally, reduction of TIM3 on ex vivo CD4+ T cells using small interfering (si)RNA enhanced proliferation and IFN-γ secretion, directly demonstrating that TIM3 expression on human T cells regulates proliferation and IFN-γ secretion. Failure to up-regulate T cell expression of TIM3 in inflammatory sites may represent a novel, intrinsic defect that contributes to the pathogenesis of MS and other human autoimmune diseases.
The Influence of Unobserved Factors on Position Timing and Content in the NAFTA Vote
Authors: Boehmke Frederick J.
Published: June 2006

A variety of factors have been shown to influence position timing and the content of positions taken by legislators on important issues. In addition to these observed factors, I argue that unobserved factors such as behind-the-scenes lobbying and party loyalty may also influence position timing and position content. Although hypotheses about observed factors can be tested using traditional methods, hypotheses about unobserved factors cannot. To test for systematic effects of unobserved factors on position timing and content, I develop a seemingly unrelated discrete-choice duration estimator and apply it to data from the vote for the North American Free Trade Agreement. The results indicate that even after controlling for observed factors, there is still evidence that unobserved factors such as Presidential lobbying and/or party loyalty influence both choices.
Sealworm (Pseudoterranova decipiens) transmission to fish trawled from Hvaler, Oslofjord, Norway
Authors: des Clers S. , Andersen K.
Published: June 2006

Demersal fish were sampled over 3 years to describe sealworm Pseudoterranova decipiens infection levels in relation to the size of a local colony of common seals Phoca vitulina in Hvaler, Oslofjord, Norway. More than 2000 fish were examined for worms, and five fish species were found to be infected, cod Gadus morhua, four‐bearded rockling Enchelyopus cimbrius, plaice Pleuronectes platessa, long rough dab Hippoglossoides platessoides and dab Limanda limanda. A detailed analysis of worm accumulation in cod, the only infected species present in large enough numbers, shows a net decrease in worm transmission following the phocine distemper virus epizootic which killed two‐thirds of the seals in Hvaler in 1988.
Comparative size and composition of yield from six Fijian reef fisheries
Authors: Jennings S. , Polunin N. V. C.
Published: June 2006

The size and composition of finfish yield from six Fijian reef fisheries was determined using catch records from a voluntary logbook scheme. A total of 172 logbooks were issued for 30‐day periods in October 1992 and February and June 1993 and they provided information on 1369 fishing trips. Catch records were weighted, using the results of contemporaneous fishing activity and fleet size surveys, to provide yield estimates for each fishing ground (qoliqoli). Yield from all qoliqoli was dominated by Serranidae and Lethrinidae which were favoured for consumption and sale. Yields were expressed on the basis of reef area for fish from different trophic groups. Macroinvertebrate‐feeders and piscivores accounted for more than half the yield in all qoliqoli and there were significant differences in area specific yield between qoliqoli. There was no evidence of fishers adopting more powerful fishing techniques or catching fish from lower trophic levels in order to maintain yield from any qoliqoli. This suggested that the fisheries examined were all capable of sustaining the reported yields of up to 3.4 tonne km−2qoliqoli year −1 or 10.2 tonne km−2 coral reef year −1 and that in sites where yields were less they might be increased sustainably.
Vertebral deformities in a school shark, Galeorhinus galeus: circumstantial evidence for endoskeletal resorption?
Authors: Officer R. A. , Clement J. G. , Rowler D. K.
Published: June 2006

The appearance of deformed vertebrae from a single mature female school shark, Galeorhinus galeus, are described. Two unusual, pronounced bumps were noticed in the caudal region of this shark. There were no scars in the skin over these protrusions, suggesting that the lesions had arisen internally. Radiographie and histologie investigation of these lesions showed that mineralized tissue had probably been lost following an injury to the tail. Histological observations provided circumstantial evidence that mineralized tissue had been removed by internal processes, but did not reveal the agency by which skeletal tissue had been resorbed. Since the capacity to resorb mineralized tissue is characteristic of animals possessing bone, the apparent loss of mineralized tissue seen in this shark provides circumstantial evidence for the existence of bone cell lineages in school sharks. This evidence is discussed in relation to the possible implications for evolutionary and fisheries biology.
Food and feeding habits of four species of juvenile mullet (Mugilidae) in a tidal lagoon in Ghana
Authors: Blay J.
Published: June 2006

Juvenile mugilid fishes, Liza falcipinnis, L. dumerilii, Mugil bananensis and M. curema, which enter the Elmina Lagoon in the Cape Coast District of Ghana, have a similar diet comprising mainly bacteria, diatoms, blue‐green/green algae, protozoans, detritus and particulate organic matter. No seasonal changes in the diet and feeding activity were observed. The relative gut length (intestine to standard length ratio) and diet showed no significant changes with size of fish in all the species. All four species were diurnal feeders, but their peak feeding times differed. Interspecific competition for food was possibly limited by species preferences for substrate particles of particular size range and differences in feeding chronology.
Schistocephalus infestation improves prey‐size selection by three‐spined sticklebacks, Gasterosteus aculeatus
Authors: Ranta E.
Published: June 2006

Schistocephalus‐infected sticklebacks ate slightly less but fed more selectively on larger prey than non‐infested fish. It follows that, in the short‐term, the net energy gain in foraging is larger for infested fish. This matches the expectation that infested sticklebacks compensate energy losses due to Schistocephalus.
Effects on growth of Arctic charr of handling, anaesthesia and repeated formalin bathing shortly after first exogenous feeding
Authors: Kristjansson B. A. , Hardarson Th. , Skulason S. , Sveinsson T.
Published: June 2006

An experiment was conducted to test whether handling, anaesthesia or repeated formalin bathing had any effect on the growth rate in first feeding Arctic charr held in separate containers. The results show that these treatments had no effect on the growth rate.
Relative abundance, sex ratio and population structure of the Japanese eel Anguilla japonica in the Tanshui River system of northern Taiwan
Authors: Tzeng W.‐N. , Cheng P.‐W. , Lin F.‐Y.
Published: June 2006

From the Gong‐Shy‐Tyan (GST) Stream and the Tanshui River, Taiwan, eels ranged from 5.53 cm t.l. (elvers) to 72.5 cm t.l. Anguilla japonica accounted for 93‐99%, A. marmorata 1‐7% and A. bicolor pacifica less than 1% of all eels caught. Mean eel lengths increased from 10 cm t.l. at the downstream sites to 50 cm t.l. at the upstream sites. Females made up 92.8% of the sex‐determined eels. Population density, averaged approximately 0.14 eel m−2 (2.42 g m−2) and 0.25 eel m−2 (0.92 g m−2) in downstream sites of the GST and Tanshui River, respectively, and decreased substantially with upstream distance. Eels were rarely found in the heavily polluted and dam constructed areas in the midstream site of the Tanshui River.
Morphometric analysis of orange roughy (Hoplostethus atlanticus) off the continental slope of southern Australia
Authors: Elliott N. G. , Haskard K. , Koslow J. A.
Published: June 2006

Morphometric variation was used to examine the stock structure, in southern Australian waters, of the deepwater marine teleost Hoplostethus atlanticus, orange roughy. Seven samples were collected from non‐spawning aggregations in 1989–1990. Three samples were also collected in the winter of 1992, two from the main spawning site off the eastern coast of Tasmania (St Helens), and the third from the other main fishing ground south of Tasmania. The 38 morphometric measurements taken from each of over 1300 fish were size‐standardized by an allometric formula and analysed by univariate and multivariate statistics. The results indicate significant variation in the morphology of orange roughy caught from geographically distinct aggregations. They further suggest that the main spawning aggregation may consist of fish from different groups at different times of the spawning period. There appear to be at least seven morphologically distinguishable stocks of orange roughy in southern Australian waters, despite genetic data indicating appreciable levels of gene flow between them.
Does RU486 modify hormonal responses to handling stressor and cortisol treatment in fed and fasted rainbow trout?
Authors: Reddy P. K. , Vijayan M. M. , Leatherland J. F. , Moon T. W.
Published: June 2006

This study examines the effect of the steroid analogue, RU486, on the physiological responses of fed and chronically fasted rainbow trout to an acute handling stressor. This potent ligand of the glucocorticoid receptor was administered as a slow‐release implant either alone, or in combination with cortisol. There were temporal changes in plasma cortisol concentrations following administration of cortisol implants in both fed and fasted trout. By day 14, plasma cortisol levels in fed fish were similar in all treatment groups, but in fasted fish, the effect of cortisol administration on plasma cortisol concentrations was still evident; RU486 administered with cortisol, did not affect this response. Cortisol administration also elicited a small, but significant increase in plasma GH concentrations in fed rainbow trout and in plasma glucose concentrations in fasted animals. RU486‐treatment prevented these responses. Conversely, whereas RU486 alone had no effect on hepatic 5′‐monodeiodinase activity, when administered with cortisol it enhanced the marked suppressive effect of cortisol evident in both fed and fasted groups, suggesting that it may exert an interactive effect with cortisol on this process. Stressor‐related changes in plasma cortisol, glucose, GH and thyroid hormone concentrations were evident in both fed and fasted groups; however, there was no evidence of a suppressive effect of RU486 treatment on any of the measured plasma parameters. Although RU486 did not prevent the stressor‐related changes, the post‐stressor cortisol profiles in RU‐treated trout were extremely erratic compared with the oil‐treated controls. This implies a disturbance of the normal interactions of the components of the hypothalamus‐pituitary‐interrenal tissue axis.
An experimental study of phytoplankton feeding in three tilapiine cichlids
Authors: Robinson R. L. , Turner G. F. , Grimm A. S. , Pitcher T. J.
Published: June 2006

Three species of tilapia (Oreochromis lidole, O. karongae and O. niloticus) were fed on four planktonic algal diets in the laboratory. The algal concentrations were measured over a 24‐h period and the ingestion rates calculated. In monocultures of large algae (average filament length=477 μm) O. niloticus had the highest ingestion rate, but on small algae (particle size <8 μm) O. lidole was the fastest, while O. karongae enhanced nanoplankton production. With algae of mixed sizes, O. niloticus was able to remove small algae quicker than the other fish species. Thus, the presence of larger algae can influence the impact of a planktivorous species on nanoplankton. O. lidole is likely to have the greatest impact on plankton communities heavily dominated by smaller algae.
Modelling the patterns of dispersion of length at age in teleost fishes
Authors: Bowker D. W.
Published: June 2006

The patterns of dispersion of length at age were analysed in 142 samples representing 115 stocks, 72 species and seven orders of teleost fishes. The coefficients of variation i.e. the ratios of the standard deviations to the mean lengths, declined with age in 85 samples, did not vary significantly with age in 50 samples and increased with age in seven samples. A rapid exponential decline in the coefficients of variation of length with age was a dominant characteristic of most short‐lived stocks. Conversely, in most long‐lived stocks, the coefficients of variation of length remained relatively constant, declined gradually, or increased slightly with age. It is proposed that the patterns of dispersion of length at age can be modelled empirically as a function of longevity. The probable sources of the observed patterns, including the intrinsic variability of life‐history parameters between individuals and the impact of social interactions, are discussed.
Effect of decreased environmental salinity on growth hormone cells in the gilthead sea bream (Sparus aurata)
Authors: Mancera J. M. , Fernandez‐Llebrez P. , Perez‐Figares J. M.
Published: June 2006

The effect of decreased environmental salinity on growth hormone producing cells (GH cells) of the adenohypophysial proximal pars distalis has been studied in the gilthead sea bream (Sparus aurata L.) adapted to sea water (SW, 980 mosmol kg −1) and brackish water (BW, 200 mosmol kg −1). A combined immunocytochemical, morphometric and electron microscopic study was carried out. GH cells offish adapted to BW occupied a greater hypophysial volume (about 21% of the total hypophysial volume in BW, 17% in SW) and had a larger nuclear area (mean 16 μm2 in BW, 13 μm2 in SW) than GH cells of SW‐adapted fish. The immunoreactivity against a salmon GH‐antiserum was lower in BW (mean optical density 142 in BW, 159 in SW). Ultrastructural characteristics of GH cells of BW‐adapted fish were distended rough endo‐plasmatic reticulum and large secretory granules (about 216 nm in diameter for BW, 209 nm in SW). Volumetric, densitometric and ultrastructural evidence suggested that the synthesis and release of GH were activated in S. aurata adapted to hypo‐osmotic environment.