bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expansion of CD4+CD28− T cells producing high levels of interferon-γ in peripheral blood of patients with multiple sclerosis
Authors: Miyazaki Y , Iwabuchi K , Kikuchi S , Fukazawa T , Niino M , Hirotani M , Sasaki H , Onoé K 
Published: June 2008

CD4+ T cells that lack surface expression of the CD28 co-stimulatory molecule (CD4+CD28− T cells) were expanded in peripheral blood of patients with multiple sclerosis (MS) [5.20 ± 1.67% vs 13.00 ± 2.68% (healthy controls (HC) versus patients with MS)]. Both the CD4+CD28+ and CD4+CD28− T-cell populations of patients with MS produced higher levels of interferon (IFN)-γ compared with those in HC. In particular, the proportion of IFN-γ+ cells among CD4+CD28− T cells from patients with MS was considerably high. However, expression of co-stimulatory molecules including inducible costimulator (ICOS), activating natural killer receptors, or members of tumor necrosis factor receptor family that replace CD28 in CD4+CD28− T cells of patients with MS could not be identified. A unique subpopulation bearing the CD45RAhighCCR7− phenotype was identified among the CD4+CD28− T cells of some patients with MS. Because only MS samples contained this CD45RAhighCCR7− population attributed to terminally differentiated effector memory cells and lacked naive CD45RAhighCCR7+ cells, we suggest that CD4+CD28− T cells of patients with MS represent a cell population which is in more differentiated state than healthy subjects. In patients treated with IFN-β-1b, IFN-γ production from CD4+CD28+ T cells was suppressed compared with that in untreated patients. On the contrary, in the CD4+CD28− population, production of IFN-γ in IFN-β-1b-treated patients was not significantly suppressed compared with that in untreated patients with MS. Thus, an additional treatment strategy that specifically targets this cell population may enhance the beneficial effect of IFN-β on MS.
Education for sustainable development in the UK: Making the connections between the environment and development agendas
Authors: Bourn Douglas 
Published: June 2008

Education for Sustainable Development (ESD) is an initiative that dates back to the early 1990s. Whilst policy statements at this time referred to ESD as a bringing together of environmental and development education, in the UK, as in most other industrialized countries, it has been the environmental agenda that has tended to dominate. In the UK, policy-makers have since 1997 played an increasingly leading role in promoting ESD, particularly within schools. However, the drive behind these initiatives poses wider questions about their ultimate purpose: a learning agenda or one based on seeking behavioural change? Development education has always been the junior partner in the ESD debates in the UK, in part because of its low academic profile but also because of the policy separation by governments.This has, however, begun to change through the merging of policy initiatives around ESD and global citizenship which, by their very nature, are again posing the wider questions about the purpose and goal of these agendas.
Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway
Authors: Haspot Fabienne , Fehr Thomas , Gibbons Carrie , Zhao Guiling , Hogan Timothy , Honjo Tasuku , Freeman Gordon J. , Sykes Megan 
Published: June 2008

Abstract
Although interaction between programmed death-1 (PD-1) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires CD4 cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T-cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells up-regulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism.
Transient blockade of the inducible costimulator pathway generates long-term tolerance to factor VIII after nonviral gene transfer into hemophilia A mice
Authors: Peng Baowei , Ye Peiqing , Blazar Bruce R. , Freeman Gordon J. , Rawlings David J. , Ochs Hans D. , Miao Carol H. 
Published: June 2008

Abstract
Formation of inhibitory antibodies is a common problem encountered in clinical treatment for hemophilia. Human factor VIII (hFVIII) plasmid gene therapy in hemophilia A mice also leads to strong humoral responses. We demonstrate that short-term therapy with an anti-ICOS monoclonal antibody to transiently block the inducible costimulator/inducible costimulator ligand (ICOS/ICOSL) signaling pathway led to sustained tolerance to hFVIII in hFVIII plasmid–treated hemophilia A mice and allowed persistent, high-level FVIII functional activity (100%-300% of normal). Anti-ICOS treatment resulted in depletion of ICOS+CD4+ T cells and activation of CD25+Foxp3+ Tregs in the peripheral blood, spleen, and lymph nodes. CD4+ T cells from anti-ICOS–treated mice did not proliferate in response to hFVIII stimulation and produced high levels of regulatory cytokines, including interleukin-10 and transforming growth factor-β. Moreover, CD4+CD25+ Tregs from tolerized mice adoptively transferred dominant tolerance in syngeneic hFVIII plasmid-treated hemophilia A mice and reduced the production of antibodies against FVIII. Anti-ICOS–treated mice tolerized to hFVIII generated normal primary and secondary antibody responses after immunization with the T-dependent antigen, bacteriophage Φx 174, indicating maintenance of immune competency. Our data indicate that transient anti-ICOS monoclonal antibody treatment represents a novel single-agent immunomodulatory strategy to overcome the immune responses against transgene product after gene therapy.
Analysis of clonotypic switch junctions reveals multiple myeloma originates from a single class switch event with ongoing mutation in the isotype-switched progeny
Authors: Taylor Brian J. , Kriangkum Jitra , Pittman Julie A. , Mant Michael J. , Reiman Tony , Belch Andrew R. , Pilarski Linda M. 
Published: June 2008

AbstractMultiple myeloma (MM) is a cancer of plasma cells (PCs) expressing immunoglobulin heavy chain (IgH) postswitch isotypes. The discovery of earlier stage cells related to postswitch PCs, called preswitch clonotypic IgM (cIgM) cells led to the hypothesis that cIgM cells may be MM progenitors, replenishing the tumor throughout malignancy. cIgM cells may do this by undergoing class switch recombination (CSR), a process detectable in postswitch PCs as multiple IgH switch junctions associated with a single clonotypic IgH V/D/J. We addressed this with a specific clonotypic-switch polymerase chain reaction (PCR), informative for 32 of 41 cases. Here we made 2 significant discoveries: (1) in all cases, we detected only a single clonotypic switch fragment that persists over time (1-7.6 years), and (2) we detected ongoing mutation upstream of the switch junction in 5 of 6 patients, often targeting the intronic enhancer, a key control region in IgH expression. The presence of a single, unchanging clonotypic switch junction suggests that cIgM cells are not MM-PC progenitors; rather, postswitch PCs arise from a single cIgM cell, and MM-PC progenitors reside in the postswitch population. Furthermore, mutations revealed here provide a new marker to identify MM-PC progenitors and aggressive clones that evolve throughout malignancy.
Effective elimination of fludarabine-resistant CLL cells by PEITC through a redox-mediated mechanism
Authors: Trachootham Dunyaporn , Zhang Hui , Zhang Wan , Feng Li , Du Min , Zhou Yan , Chen Zhao , Pelicano Helene , Plunkett William , Wierda William G. , Keating Michael J. , Huang Peng 
Published: June 2008

Abstract
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia, and resistance to fludarabine-based therapies is a major challenge in CLL treatment. Because CLL cells are known to have elevated levels of reactive oxygen species (ROS), we aimed to test a novel ROS-mediated strategy to eliminate fludarabine-resistant CLL cells based on this redox alteration. Using primary CLL cells and normal lymphocytes from patients (n = 58) and healthy subjects (n = 12), we showed that both fludarabine-resistant and -sensitive CLL cells were highly sensitive to β-phenylethyl isothiocyanate (PEITC) with mean IC50 values of 5.4 μM and 5.1 μM, respectively. Normal lymphocytes were significantly less sensitive to PEITC (IC50 = 27 μM, P < .001). CLL cells exhibited intrinsically higher ROS level and lower cellular glutathione, which were shown to be the critical determinants of CLL sensitivity to PEITC. Exposure of CLL cells to PEITC induced severe glutathione depletion, ROS accumulation, and oxidation of mitochondrial cardiolipin leading to massive cell death. Such ROS stress also caused deglutathionylation of MCL1, followed by a rapid degradation of this cell survival molecule. Our study demonstrated that the natural compound PEITC is effective in eliminating fludarabine-resistant CLL cells through a redox-mediated mechanism with low toxicity to normal lymphocytes, and warrants further clinical evaluation.
Literature-aided meta-analysis of microarray data: a compendium study on muscle development and disease
Authors: Jelier Rob , 't Hoen Peter AC , Sterrenburg Ellen , den Dunnen Johan T , van Ommen Gert-Jan B , Kors Jan A , Mons Barend 
Published: June 2008

Abstract

Background
Comparative analysis of expression microarray studies is difficult due to the large influence of technical factors on experimental outcome. Still, the identified differentially expressed genes may hint at the same biological processes. However, manually curated assignment of genes to biological processes, such as pursued by the Gene Ontology (GO) consortium, is incomplete and limited. We hypothesised that automatic association of genes with biological processes through thesaurus-controlled mining of Medline abstracts would be more effective. Therefore, we developed a novel algorithm (LAMA: Literature-Aided Meta-Analysis) to quantify the similarity between transcriptomics studies. We evaluated our algorithm on a large compendium of 102 microarray studies published in the field of muscle development and disease, and compared it to similarity measures based on gene overlap and over-representation of biological processes assigned by GO.

Results
While the overlap in both genes and overrepresented GO-terms was poor, LAMA retrieved many more biologically meaningful links between studies, with substantially lower influence of technical factors. LAMA correctly grouped muscular dystrophy, regeneration and myositis studies, and linked patient and corresponding mouse model studies. LAMA also retrieves the connecting biological concepts. Among other new discoveries, we associated cullin proteins, a class of ubiquitinylation proteins, with genes down-regulated during muscle regeneration, whereas ubiquitinylation was previously reported to be activated during the inverse process: muscle atrophy.

Conclusion
Our literature-based association analysis is capable of finding hidden common biological denominators in microarray studies, and circumvents the need for raw data analysis or curated gene annotation databases.
Identification of genes associated with regenerative success of Xenopus laevishindlimbs
Authors: Pearl Esther J , Barker Donna , Day Robert C , Beck Caroline W 
Published: June 2008

Abstract

Background
Epimorphic regeneration is the process by which complete regeneration of a complex structure such as a limb occurs through production of a proliferating blastema. This type of regeneration is rare among vertebrates but does occur in the African clawed frog Xenopus laevis, traditionally a model organism for the study of early development. Xenopus tadpoles can regenerate their tails, limb buds and the lens of the eye, although the ability of the latter two organs to regenerate diminishes with advancing developmental stage. Using a heat shock inducible transgene that remains silent unless activated, we have established a stable line of transgenic Xenopus (strain N1) in which the BMP inhibitor Noggin can be over-expressed at any time during development. Activation of this transgene blocks regeneration of the tail and limb of Xenopus tadpoles.

Results
In the current study, we have taken advantage of the N1 transgenic line to directly compare morphology and gene expression in same stage regenerating vs. BMP signalling deficient non-regenerating hindlimb buds. The wound epithelium of N1 transgenic hindlimb buds, which forms over the cut surface of the limb bud after amputation, does not transition normally into the distal thickened apical epithelial cap. Instead, a basement membrane and dermis form, indicative of mature skin. Furthermore, the underlying mesenchyme remains rounded and does not expand to form a cone shaped blastema, a normal feature of successful regeneration.
Using Affymetrix Gene Chip analysis, we have identified genes linked to regenerative success downstream of BMP signalling, including the BMP inhibitor Gremlin and the stress protein Hsp60 (no blastema in zebrafish). Gene Ontology analysis showed that genes involved in embryonic development and growth are significantly over-represented in regenerating early hindlimb buds and that successful regeneration in the Xenopus hindlimb correlates with the induction of stress response pathways.

Conclusion

N1 transgenic hindlimbs, which do not regenerate, do not form an apical epithelial cap or cone shaped blastema following amputation. Comparison of gene expression in stage matched N1 vs. wild type hindlimb buds has revealed several new targets for regeneration research.
Identification of geographically distributed sub-populations of Leishmania (Leishmania) majorby microsatellite analysis
Authors: Al-Jawabreh Amer , Diezmann Stephanie , Müller Michaela , Wirth Thierry , Schnur Lionel F , Strelkova Margarita V , Kovalenko Dmitri A , Razakov Shavkat A , Schwenkenbecher Jan , Kuhls Katrin , Schönian Gabriele 
Published: June 2008

Abstract

Background

Leishmania (Leishmania) major, one of the agents causing cutaneous leishmaniasis (CL) in humans, is widely distributed in the Old World where different species of wild rodent and phlebotomine sand fly serve as animal reservoir hosts and vectors, respectively. Despite this, strains of L. (L.) major isolated from many different sources over many years have proved to be relatively uniform. To investigate the population structure of the species highly polymorphic microsatellite markers were employed for greater discrimination among it's otherwise closely related strains, an approach applied successfully to other species of Leishmania.

Results
Multilocus Microsatellite Typing (MLMT) based on 10 different microsatellite markers was applied to 106 strains of L. (L.) major from different regions where it is endemic. On applying a Bayesian model-based approach, three main populations were identified, corresponding to three separate geographical regions: Central Asia (CA); the Middle East (ME); and Africa (AF). This was congruent with phylogenetic reconstructions based on genetic distances. Re-analysis separated each of the populations into two sub-populations. The two African sub-populations did not correlate well with strains' geographical origin. Strains falling into the sub-populations CA and ME did mostly group according to their place of isolation although some anomalies were seen, probably, owing to human migration.

Conclusion
The model- and distance-based analyses of the microsatellite data exposed three main populations of L. (L.) major, Central Asia, the Middle East and Africa, each of which separated into two sub-populations. This probably correlates with the different species of rodent host.
Transcriptome profiling of developmental and xenobiotic responses in a keystone soil animal, the oligochaete annelid Lumbricus rubellus
Authors: Owen Jennifer , Hedley B Ann , Svendsen Claus , Wren Jodie , Jonker Martijs J , Hankard Peter K , Lister Linsey J , Stürzenbaum Stephen R , Morgan A John , Spurgeon David J , Blaxter Mark L , Kille Peter 
Published: June 2008

AbstractBackgroundNatural contamination and anthropogenic pollution of soils are likely to be major determinants of functioning and survival of keystone invertebrate taxa. Soil animals will have both evolutionary adaptation and genetically programmed responses to these toxic chemicals, but mechanistic understanding of such is sparse. The clitellate annelidLumbricus rubellusis a model organism for soil health testing, but genetic data have been lacking.ResultsWe generated a 17,000 sequence expressed sequence tag dataset, defining ~8,100 different putative genes, and built an 8,000-element transcriptome microarray forL. rubellus. Strikingly, less than half the putative genes (43%) were assigned annotations from the gene ontology (GO) system; this reflects the phylogenetic uniqueness of earthworms compared to the well-annotated model animals. The microarray was used to identify adult- and juvenile-specific transcript profiles in untreated animals and to determine dose-response transcription profiles following exposure to three xenobiotics from different chemical classes: inorganic (the metal cadmium), organic (the polycyclic aromatic hydrocarbon fluoranthene), and agrochemical (the herbicide atrazine). Analysis of these profiles revealed compound-specific fingerprints which identify the molecular responses of this annelid to each contaminant. The data and analyses are available in an integrated database, LumbriBASE.ConclusionL. rubellushas a complex response to contaminant exposure, but this can be efficiently analysed using molecular methods, revealing unique response profiles for different classes of effector. These profiles may assist in the development of novel monitoring or bioremediation protocols, as well as in understanding the ecosystem effects of exposure.
Apoptosis of supraoptic AVP neurons is involved in the development of central diabetes insipidus after hypophysectomy in rats
Authors: Wang Yihua , Zhao Cuiping , Wang Zhigang , Wang Chengwei , Feng Wenfeng , Huang Lijin , Zhang Jialin , Qi Songtao 
Published: June 2008

AbstractBackgroundIt has been reported that various types of axonal injury of hypothalamo-neurohypophyseal tract can result in degeneration of the magnocellular neurons (MCNs) in hypothalamus and development of central diabetes insipidus (CDI). However, the mechanism of the degeneration and death of MCNs after hypophysectomy in vivo is still unclear. This present study was aimed to disclose it and to figure out the dynamic change of central diabetes insipidus after hypophysectomy.ResultsThe analysis on the dynamic change of daily water consumption (DWC), daily urine volume(DUV), specific gravity of urine(USG) and plasma vasopressin concentration showed that the change pattern of them was triphasic and neuron counting showed that the degeneration of vasopressin neurons began at 10 d, aggravated at 20 d and then stabilized at 30 d after hypophysectomy. There was marked upregulation of cleaved Caspase-3 expression of vasopressin neurons in hypophysectomy rats. A "ladder" pattern of migration of DNA internucleosomal fragments was detected and apoptotic ultrastructure was found in these neurons. There was time correlation among the occurrence of diabetes insipidus, the changes of plasma vasopressin concentration and the degeneration of vasopressin neurons after hypophysectomy.ConclusionThis study firstly demonstrated that apoptosis was involved in degeneration of supraoptic vasopressin neurons after hypophysectomy in vivo and development of CDI. Our study on time course and correlations among water metabolism, degeneration and apoptosis of vasopressin neurons suggested that there should be an efficient therapeutic window in which irreversible CDI might be prevented by anti-apoptosis.
Age-specific seroprevalence of hepatitis A in Antananarivo (Madagascar)
Authors: Raharimanga Vaomalala , Carod Jean-François , Ramarokoto Charles-Emile , Chrétien Jean-Baptiste , Rakotomanana Fanjasoa , Talarmin Antoine , Richard Vincent 
Published: June 2008

Abstract

Background
Hepatitis A virus (HAV) is an enteric, viral, infectious disease endemic in many developing countries such as Madagascar. Infection is often subclinical or asymptomatic in children; however, symptomatic acute infections become more common with increasing age. In some developing countries, improvements in living conditions have led to changes in the epidemiological pattern of HAV infection. There are very few reports on the prevalence of HAV in Madagascar.
This study was to determine the seroprevalence of hepatitis A virus antibodies in relation to age in the city of Antananarivo, Madagascar.

Methods
Serum samples collected in 2004 during a cross-sectional survey of individuals aged between two and 24 years from Antananarivo were tested for anti-HAV antibody using a commercial enzyme immunoassay kit. Subjects were investigated using a standardized social and medical history questionnaire.

Results
926 subjects were enrolled including 406 males and 520 females. There were 251 children under 10 years old and 675 subjects between 10 and 24 years old. Of the 926 serum samples tested, 854 (92.2%) were positive for anti-HAV antibodies. The number of seropositive samples was similar for males and females. The overall seroprevalence was 83.7% (210/251) for children under 10 years old and 95.5% (644/675) for subjects aged between 10 and 24 years (p < 0.001).

Conclusion
Despite improvements in sanitary conditions and hygiene over the last few years, the prevalence of HAV in Antananarivo is high. Only children under five years old remain susceptible to HAV infection. Immunization against HAV is not needed at the present time in the Madagascan population, but should be recommended for travellers.