bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conservation implications of a long‐term decline in body condition of the Brothers Island tuatara (Sphenodon guntheri)
Authors: Hoare J. M. , Pledger S. , Keall S. N. , Nelson N. J. , Mitchell N. J. , Daugherty C. H. 
Published: August 2006

AbstractUnderstanding the factors that drive the dynamics of remnant populations of long‐lived species presents a unique challenge for conservation management. The long‐lived Brothers Island tuatara Sphenodon guntheri is represented by one natural, self‐sustaining population on 4‐ha North Brother Island, New Zealand, and two small, translocated populations. The North Brother Island population was almost driven to extinction by extreme habitat modification and collecting in the late 19th century. Analysis of a long‐term (1957–2001) dataset, following the population's recovery, reveals a significant decline in tuatara body condition over time, which is more pronounced in females. Declining body condition, coupled with very low reproductive output, may be symptomatic of a density‐dependent response to elevated population size exacerbated by resource limitation. Sex‐specific effects that disadvantage females could compromise this small population, particularly as it exhibits a male‐biased sex ratio. We recommend removal of infrequently used structures and habitat restoration to alleviate intense resource competition. Population‐level manipulation should be considered if future monitoring indicates an increasingly male‐biased sex ratio and continued decline of female body condition.
Angiotensin II Type 1 Receptor–Mediated Inflammation Is Required for Choroidal Neovascularization
Authors: Nagai Norihiro , Oike Yuichi , Izumi-Nagai Kanako , Urano Takashi , Kubota Yoshiaki , Noda Kousuke , Ozawa Yoko , Inoue Makoto , Tsubota Kazuo , Suda Toshio , Ishida Susumu 
Published: August 2006

Background—Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration, the most common cause of blindness in the developed countries. The aim of the current study was to determine the involvement of the renin-angiotensin system (RAS) with the development of CNV, using human surgical samples and the murine model of laser-induced CNV.Methods and Results—In the human and murine CNV tissues, the vascular endothelium expressed angiotensin II type 1 receptor (AT1-R), AT2-R, and angiotensin II. The CNV volume was significantly suppressed by treatment with an AT1-R blocker telmisartan, but not with an AT2-R blocker. AT1-R signaling blockade with telmisartan inhibited various inflammatory mechanisms including macrophage infiltration and upregulation of VEGF, intercellular adhesion molecule-1 (ICAM-1), MCP-1, and IL-6 in the retinal pigment epithelium-choroid complex. A PPAR-γ antagonist partially but significantly reversed the suppressive effect of telmisartan on in vivo induction of CNV and in vitro upregulation of ICAM-1 and MCP-1 in endothelial cells and IL-6 in macrophages, showing the dual contribution of PPAR-γ-agonistic and AT1-R-antagonistic actions in the telmisartan treatment.Conclusions—AT1-R–mediated inflammation plays a pivotal role in the development of CNV, indicating the possibility of AT1-R blockade as a novel therapeutic strategy to inhibit CNV.
Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes
Authors: Marteijn Jurgen A. F. , van der Meer Laurens T. , Van Emst Liesbeth , de Witte Theo , Jansen Joop H. , van der Reijden Bert A. 
Published: August 2006

Abstract
Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1−/− mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1−/− mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPα, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.
Overlapping functions of human CD3δ and mouse CD3γ in αβ T-cell development revealed in a humanized CD3γ-deficient mouse
Authors: Fernández-Malavé Edgar , Wang Ninghai , Pulgar Manuel , Schamel Wolfgang W. A. , Alarcón Balbino , Terhorst Cox 
Published: August 2006

AbstractHumans lacking the CD3γ subunit of the pre-TCR and TCR complexes exhibit a mild αβ T lymphopenia, but have normal T cells. By contrast, CD3γ-deficient mice are almost devoid of mature αβ T cells due to an early block of intrathymic development at the CD4–CD8– double-negative (DN) stage. This suggests that in humans but not in mice, the highly related CD3δ chain replaces CD3γ during αβ T-cell development. To determine whether human CD3δ (hCD3δ) functions in a similar manner in the mouse in the absence of CD3γ, we introduced an hCD3δ transgene in mice that were deficient for both CD3δ and CD3γ, in which thymocyte development is completely arrested at the DN stage. Expression of hCD3δ efficiently supported pre-TCR–mediated progression from the DN to the CD4+CD8+ double-positive (DP) stage. However, αβTCR-mediated positive and negative thymocyte selection was less efficient than in wild-type mice, which correlated with a marked attenuation of TCR-mediated signaling. Of note, murine CD3γ-deficient TCR complexes that had incorporated hCD3δ displayed abnormalities in structural stability resembling those of T cells from CD3γ-deficient humans. Taken together, these data demonstrate that CD3δ and CD3γ play a different role in humans and mice in pre-TCR and TCR function during αβ T-cell development.
Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP
Authors: Vendetti Silvia , Patrizio Mario , Riccomi Antonella , De Magistris Maria Teresa 
Published: August 2006

Abstract
We have previously shown that cholera toxin (CT) and other cAMP-elevating agents induce up-regulation of the inhibitory molecule CTLA-4 on human resting T lymphocytes. In this study, we evaluated the function of these cells. We found that purified human CD4+ T lymphocytes pretreated with CT were able to inhibit proliferation of autologous PBMC in a dose-dependent manner. It is interesting that this phenomenon was not mediated by inhibitory cytokines such as IL-10, IL-4, or TGF-β but was in part caused by the release of extracellular cAMP by the CD4+ T lymphocytes. Purified CD4+ T cells pretreated with forskolin, a transient cAMP inducer, or with dibutyryl cAMP, an analog of cAMP, did not exert suppressive functions, suggesting that a sustained production of cAMP, such as that induced by CT, was required to identify a novel regulatory function mediated by CD4+ T cells. Our results show that CD4+ T lymphocytes can exert regulatory functions through the release of extracellular cAMP and that the cyclic nucleotide acts as a primary messenger, which could play a biological role in the modulation of immune responses.
Suppression of experimental colitis by intestinal mononuclear phagocytes
Authors: Qualls Joseph E , Kaplan Alan M , Van Rooijen Nico , Cohen Donald A 
Published: August 2006

Abstract
The contribution of innate immunity to inflammatory bowel disease (IBD) remains an area of intense interest. Macrophages (MØ) and dendritic cells (DC) are considered important factors in regulating the onset of IBD. The goal of this study was to determine if intestinal mononuclear phagocytes (iMNP) serve a pathological or protective role in dextran sulfate sodium (DSS)-induced colitis in mice. Using a conditional MØ/DC depletion transgenic mouse line—MØ Fas-induced apoptosis—to systemically deplete iMNP, DSS colitis histopathology was shown to be more severe in MØ/DC-depleted compared with MØ/DC-intact mice. Similarly, localized iMNP depletion by clodronate-encapsulated liposomes into C57BL/6, BALB/c, and CB.17/SCID mice also increased DSS colitis severity, as indicated by increased histopathology, weight loss, rectal bleeding, decreased stool consistency, and colon length compared with MØ/DC-intact, DSS-treated mice. Histology revealed that iMNP depletion during DSS treatment led to increased neutrophilic inflammation, increased epithelial injury, and enhanced mucin depletion from Goblet cells. iMNP depletion did not further elevate DSS-induced expression of TNF-α and IFN-γ mRNA but significantly increased expression of CXCL1 chemokine mRNA. Myeloperoxidase activity was increased in colons of MØ/DC-depleted, DSS-treated mice, compared with DSS alone, coincident with increased neutrophil infiltration in diseased colons. Neutrophil depletion combined with MØ/DC depletion prevented the increase in DSS colitis severity compared with MØ/DC depletion alone. This study demonstrates that iMNP can serve a protective role during development of acute colitis and that protection is associated with MØ/DC-mediated down-regulation of neutrophil infiltration.
A Novel Pathway Involving Progesterone Receptor, Endothelin-2, and Endothelin Receptor B Controls Ovulation in Mice
Authors: Palanisamy Gopinath S. , Cheon Yong-Pil , Kim Jaeyeon , Kannan Athilakshmi , Li Quanxi , Sato Marcey , Mantena Srinivasa R. , Sitruk-Ware Regine L. , Bagchi Milan K. , Bagchi Indrani C. 
Published: August 2006

AbstractThe steroid hormone progesterone (P) plays a pivotal role during ovulation. Mice lacking P receptor (Pgr) gene fail to ovulate due to a defect in follicular rupture. The P receptor (PGR)-regulated pathways that modulate ovulation, however, remain poorly understood. To identify these pathways, we performed gene expression profiling using ovaries from mice subjected to gonadotropin-induced superovulation in the presence and in the absence of CDB-2914, a synthetic PGR antagonist. Prominent among the genes that were down-regulated in response to CDB-2914 was endothelin (ET)-2, a potent vasoactive molecule. ET-2 mRNA was transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. This induction was absent in the ovaries of PGR null mice, indicating a critical role of this receptor in ET-2 expression. To investigate the functional role of ET-2 during ovulation, we employed selective antagonists of endothelin receptors, ETR-A and ETR-B. Mice treated with an ETR-B antagonist exhibited a dramatic (&gt;85%) decline in the number of released oocytes. Strong expression of ETR-B was observed in the mural and cumulus granulosa cells of the preovulatory follicles as well as in the capillaries lining the inner border of the theca interna. We also identified cGMP-dependent protein kinase II, a previously reported PGR-regulated gene, as a downstream target of ET-2 during ovulation. Collectively, our studies uncovered a unique pathway in which ET-2, produced by PGR in mural granulosa cells, acts in a paracrine or autocrine manner on multiple cell types within the preovulatory follicle to control the final events leading to its rupture.
Peroxisome Proliferator-Activated Receptor-γ Activates p53 Gene Promoter Binding to the Nuclear Factor-κB Sequence in Human MCF7 Breast Cancer Cells
Authors: Bonofiglio Daniela , Aquila Saveria , Catalano Stefania , Gabriele Sabrina , Belmonte Maria , Middea Emilia , Qi Hongyan , Morelli Catia , Gentile Mariaelena , Maggiolini Marcello , Andò Sebastiano 
Published: August 2006

AbstractThe aim of the present study was to provide new mechanistic insight into the growth arrest and apoptosis elicited by peroxisome proliferator-activated receptor (PPAR)γ in breast cancer cells. We ascertained that PPARγ mediates the inhibition of cycle progression in MCF7 cells exerted by the specific PPARγ agonist rosiglitazone [BRL4653 (BRL)], because this response was no longer notable in the presence of the receptor antagonist GW9662. We also provided evidence that BRL is able to up-regulate mRNA and protein levels of the tumor suppressor gene p53 and its effector p21WAF1/Cip1 in a time- and dose-dependent manner. Moreover, in transfection experiments with deletion mutants of the p53 gene promoter, we documented that the nuclear factor-κB sequence is required for the transcriptional response to BRL. Interestingly, EMSA showed that PPARγ binds directly to the nuclear factor-κB site located in the promoter region of p53, and chromatin immunoprecipitation experiments demonstrated that BRL increases the recruitment of PPARγ on the p53 promoter sequence. Next, both PPARγ and p53 were involved in the cleavage of caspases-9 and DNA fragmentation induced by BRL, given that GW9662 and an expression vector for p53 antisense blunted these effects. Our findings provide evidence that the PPARγ agonist BRL promotes the growth arrest and apoptosis in MCF7 cells, at least in part, through a cross talk between p53 and PPARγ, which may be considered an additional target for novel therapeutic interventions in breast cancer patients.
Proteomic Analysis of Cerebrospinal Fluid Changes Related to Postmortem Interval
Authors: Finehout Erin J , Franck Zsofia , Relkin Norman , Lee Kelvin H 
Published: August 2006

Abstract
Background: The study of proteins with altered production in postmortem cerebrospinal fluid (CSF) compared with antemortem CSF may improve the understanding of biochemical changes that occur immediately after death.
Methods: Two CSF samples (1 antemortem and 1 postmortem) were collected from 7 patients and analyzed by 2-dimensional gel electrophoresis. An analysis was also performed to identify proteins that showed a correlation between concentration change and postmortem interval. Tandem mass spectrometry was used to identify the proteins.
Results: Fifty-four protein spots were identified that showed a consistent and significant change in concentration in the postmortem CSF of all 7 patients (&gt;3.5-fold, P &lt;0.01). The proteins in these spots derive from a variety of functional groups, including cytoskeletal proteins, enzymes involved in glycolysis, and proteins that prevent oxidative stress. Fourteen protein spots were found to have an increase in production that correlated with postmortem interval.
Conclusions: Changes in protein production of postmortem vs antemortem CSF were studied. The proteins observed to change production in the postmortem CSF include several proteins previously observed as potential stroke biomarkers.
Population Genetics Models of Competition Between Transposable Element Subfamilies
Authors: Rouzic Arnaud Le , Capy Pierre 
Published: August 2006

Abstract
Transposable elements are one of the major components of genomes. Some copies are fully efficient; i.e., they are able to produce the proteins needed for their own transposition, and they can move and duplicate into the genome. Other copies are mutated. They may have lost their moving ability, their coding capacity, or both, thus becoming pseudogenes slowly eliminated from the genome through deletions and natural selection. Little is known about the dynamics of such mutant elements, particularly concerning their interactions with autonomous copies. To get a better understanding of the transposable elements' evolution after their initial invasion, we have designed a population genetics model of transposable elements dynamics including mutants or nonfunctional sequences. We have particularly focused on the case where these sequences are nonautonomous elements, known to be able to use the transposition machinery produced by the autonomous ones. The results show that such copies generally prevent the system from achieving a stable transposition–selection equilibrium and that nonautonomous elements can invade the system at the expense of autonomous ones. The resulting dynamics are mainly cyclic, which highlights the similarities existing between genomic selfish DNA sequences and host–parasite systems.
Genetic Analysis of Slipper/Mixed Lineage Kinase Reveals Requirements in Multiple Jun-N-Terminal Kinase-Dependent Morphogenetic Events During Drosophila Development
Authors: Polaski Stephanie , Whitney Lisa , Barker Barbara White , Stronach Beth 
Published: August 2006

Abstract
Mixed lineage kinases (MLKs) function as Jun-N-terminal kinase (JNK) kinase kinases to transduce extracellular signals during development and homeostasis in adults. slipper (slpr), which encodes the Drosophila homolog of mammalian MLKs, has previously been implicated in activation of the JNK pathway during embryonic dorsal epidermal closure. To further define the specific functions of SLPR, we analyzed the phenotypic consequences of slpr loss and gain of function throughout development, using a semiviable maternal-effect allele and wild-type or dominant-negative transgenes. From these analyses we confirm that failure of dorsal closure is the null phenotype in slpr germline clones. In addition, there is a functional maternal contribution, which can suffice for embryogenesis in the zygotic null mutant, but rarely suffices for pupal metamorphosis, revealing later functions for slpr as the maternal contribution is depleted. Zygotic null mutants that eclose as adults display an array of morphological defects, many of which are shared by hep mutant animals, deficient in the JNK kinase (JNKK/MKK7) substrate for SLPR, suggesting that the defects observed in slpr mutants primarily reflect loss of hep-dependent JNK activation. Consistent with this, the maternal slpr contribution is sensitive to the dosage of positive and negative JNK pathway regulators, which attenuate or potentiate SLPR-dependent signaling in development. Although SLPR and TAK1, another JNKKK family member, are differentially used in dorsal closure and TNF/Eiger-stimulated apoptosis, respectively, a Tak1 mutant shows dominant genetic interactions with slpr, suggesting potential redundant or combinatorial functions. Finally, we demonstrate that SLPR overexpression can induce ectopic JNK signaling and that the SLPR protein is enriched at the epithelial cell cortex.
Design of Microarray Experiments for Genetical Genomics Studies
Authors: Filho Júlio S S Bueno , Gilmour Steven G , Rosa Guilherme J M 
Published: August 2006

Abstract
Microarray experiments have been used recently in genetical genomics studies, as an additional tool to understand the genetic mechanisms governing variation in complex traits, such as for estimating heritabilities of mRNA transcript abundances, for mapping expression quantitative trait loci, and for inferring regulatory networks controlling gene expression. Several articles on the design of microarray experiments discuss situations in which treatment effects are assumed fixed and without any structure. In the case of two-color microarray platforms, several authors have studied reference and circular designs. Here, we discuss the optimal design of microarray experiments whose goals refer to specific genetic questions. Some examples are used to illustrate the choice of a design for comparing fixed, structured treatments, such as genotypic groups. Experiments targeting single genes or chromosomic regions (such as with transgene research) or multiple epistatic loci (such as within a selective phenotyping context) are discussed. In addition, microarray experiments in which treatments refer to families or to subjects (within family structures or complex pedigrees) are presented. In these cases treatments are more appropriately considered to be random effects, with specific covariance structures, in which the genetic goals relate to the estimation of genetic variances and the heritability of transcriptional abundances.
The Genetic Architecture of Life Span and Mortality Rates: Gender and Species Differences in Inbreeding Load of Two Seed-Feeding Beetles
Authors: Fox Charles W , Scheibly Kristy L , Wallin William G , Hitchcock Lisa J , Stillwell R Craig , Smith Benjamin P 
Published: August 2006

AbstractWe examine the inbreeding load for adult life span and mortality rates of two seed beetle species, Callosobruchus maculatus and Stator limbatus. Inbreeding load differs substantially between males and females in both study populations of C. maculatus—life span of inbred females was 9–13% shorter than the life span of outbred females, whereas the life span of inbred males did not differ from the life span of outbred males. The effect of inbreeding on female life span was largely due to an increase in the slope of the mortality curve. In contrast, inbreeding had only a small effect on the life span of S. limbatus—life spans of inbred beetles were ∼5% shorter than those of outbred beetles, and there was no difference in inbreeding load between the sexes. The inbreeding load for mean life span was ∼0.4–0.6 lethal equivalents per haploid gamete for female C. maculatus and ∼0.2–0.3 for both males and females of S. limbatus, all within the range of estimates commonly obtained for Drosophila. However, contrary to the predictions of mutation-accumulation models, inbreeding load for loci affecting mortality rates did not increase with age in either species, despite an effect of inbreeding on the initial rate of increase in mortality. This was because mortality rates decelerated with age and converged to a mortality plateau for both outbred and inbred beetles.
The Fate of Transposable Elements in Asexual Populations
Authors: Dolgin Elie S , Charlesworth Brian 
Published: August 2006

Abstract
Sexual reproduction and recombination are important for maintaining a stable copy number of transposable elements (TEs). In sexual populations, elements can be contained by purifying selection against host carriers with higher element copy numbers; however, in the absence of sex and recombination, asexual populations could be driven to extinction by an unchecked proliferation of TEs. Here we provide a theoretical framework for analyzing TE dynamics under asexual reproduction. Analytic results show that, in an infinite asexual population, an equilibrium in copy number is achieved if no element excision is possible, but that all TEs are eliminated if there is some excision. In a finite population, computer simulations demonstrate that small populations are driven to extinction by a Muller's ratchet-like process of element accumulation, but that large populations can be cured of vertically transmitted TEs, even with excision rates well below transposition rates. These results may have important consequences for newly arisen asexual lineages and may account for the lack of deleterious retrotransposons in the putatively ancient asexual bdelloid rotifers.