bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic Transcriptional Changes of TIEG1 and TIEG2 During Mouse Tissue Development
Authors: Jiang Lei , Chen Yangchao , Chan Chu‐Yan , Lu Gang , Wang Hua , Li Ji‐Cheng , Kung Hsiang‐Fu 
Published: March 2010

AbstractTGF‐β‐inducible early‐response gene (TIEG) is a family of primary response genes induced by TGF‐β, which are well recognized in regulating cellular proliferation and apoptosis. However, their expression profile has never been investigated during embryogenesis in different organs. In this study, we aimed to investigate the transcriptional level of both TIEG1 and TIEG2 during development in various mice organs, including the brain cortex, cerebellum and stem, brain striatum, muscle, heart, liver, kidney, and lung. Quantitative real‐time PCR was used to profile the change of transcriptional level of the two TIEG members in the mice tissues at six developmental stages. Taken together, the expression of TIEG1 and TIEG2 was specific in different organs yet varied with different developmental time points. Their dynamic changes were moderately consistent in most organs including the brain cortex, striatum, liver, kidney, and lung. However, their mRNA expression in both the heart and muscle was significantly different at all developmental stages, which might propose a compensation of functions in the TIEG family. Nevertheless, our data indicate that both the TIEG genes are essential in regulating the normal organ development and functioning in murine model, as their expressions were ubiquitous and tissue specific at various developmental stages. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.
Genetic deficiency of Syk protects mice from autoantibody‐induced arthritis
Authors: Jakus Zoltán , Simon Edina , Balázs Bálint , Mócsai Attila 
Published: March 2010

AbstractObjectiveThe Syk tyrosine kinase plays an important role in diverse functions in hematopoietic lineage cells. Although previous in vitro and pharmacologic analyses suggested Syk to be a possible player in the development of autoimmune arthritis, no in vivo genetic studies addressing that issue have yet been reported. The aim of the present study was to test whether genetic deficiency of Syk affects autoantibody‐induced experimental arthritis in the K/BxN serum–transfer model.MethodsSyk−/− bone marrow chimeras carrying a Syk‐deficient hematopoietic system were generated by transplanting Syk−/− fetal liver cells into lethally irradiated wild‐type recipients. After complete repopulation of the hematopoietic compartment, autoantibody‐mediated arthritis was induced by injection of arthritogenic K/BxN serum. Arthritis development was monitored by macroscopic and microscopic observation of the ankle joints, micro–computed tomography of bone morphology, as well as a joint function assay.ResultsGenetic deficiency of Syk in the hematopoietic compartment completely blocked the development of all macroscopic and microscopic signs of arthritis. The Syk−/− mutation also prevented the appearance of periarticular bone erosions. Finally, Syk−/− bone marrow chimeras were completely protected from arthritis‐induced loss of articular function.ConclusionOur results indicate that Syk is critically involved in the development of all clinically relevant aspects of autoantibody‐mediated K/BxN serum–transfer arthritis in experimental mice. These results provide the first in vivo genetic evidence of the role of Syk in the development of autoimmune arthritis.
META060 inhibits osteoclastogenesis and matrix metalloproteinases in vitro and reduces bone and cartilage degradation in a mouse model of rheumatoid arthritis
Authors: Konda Veera Reddy , Desai Anuradha , Darland Gary , Bland Jeffrey S. , Tripp Matthew L. 
Published: March 2010

AbstractObjectiveThe multikinase inhibitor META060 has been shown to inhibit NF‐κB activation and expression of markers of inflammation. This study was undertaken to investigate the effect of META060 on biomarkers associated with bone and cartilage degradation in vitro and its antiinflammatory efficacy in vivo in both acute and chronic inflammation models.MethodsGlycogen synthase kinase 3β (GSK3β)–dependent β‐catenin phosphorylation was evaluated in RAW 264.7 macrophages to assess kinase inhibition. The inhibition of osteoclastogenesis and tartrate‐resistant acid phosphatase (TRAP) activity was evaluated in RANKL‐treated RAW 264.7 cells. The inhibition of interleukin‐1β (IL‐1β)–mediated markers of inflammation was analyzed in human rheumatoid arthritis synovial fibroblasts (RASFs). Mice with carrageenan‐induced acute inflammation and collagen‐induced arthritis (CIA) were used to assess efficacy.ResultsMETA060 inhibited the activity of kinases (spleen tyrosine kinase [Syk], Bruton's tyrosine kinase [Btk], phosphatidylinositol 3‐kinase [PI 3‐kinase], and GSK3) associated with RA and inhibited β‐catenin phosphorylation. META060 inhibited osteoclastogenesis, as indicated by decreased transformation of RAW 264.7 cells to osteoclasts and reduced TRAP activity, and inhibited IL‐1β–activated prostaglandin E2, matrix metalloproteinase 3, IL‐6, IL‐8, and monocyte chemotactic protein 1 in RASFs. In mice with acute inflammation, oral administration of META060 reduced paw swelling similar to the effect of aspirin. In mice with CIA, META060 significantly reduced the arthritis index and decreased bone, joint, and cartilage degradation. Serum IL‐6 concentrations in these mice were inhibited in a dose‐dependent manner.ConclusionOur findings indicate that META060 reduces swelling in a model of acute inflammation and inhibits bone and cartilage destruction in a model of chronic inflammation. Its efficacy is associated with the inhibition of multiple protein kinases, including Syk, Btk, PI 3‐kinase, and GSK3. These results warrant further clinical testing of META060 for its therapeutic potential in the treatment of inflammatory diseases.
Markers of oxidative and nitrosative stress in systemic lupus erythematosus: Correlation with disease activity
Authors: Wang Gangduo , Pierangeli Silvia S. , Papalardo Elizabeth , Ansari G. A. S. , Khan M. Firoze 
Published: March 2010

AbstractObjectiveFree radical–mediated reactions have been implicated as contributors in a number of autoimmune diseases, including systemic lupus erythematosus (SLE). However, the potential for oxidative/nitrosative stress to elicit an autoimmune response or to contribute to disease pathogenesis, and thus be useful when determining a prognosis, remains largely unexplored in humans. This study was undertaken to investigate the status and contribution of oxidative/nitrosative stress in patients with SLE.MethodsSera from 72 SLE patients with varying levels of disease activity according to the SLE Disease Activity Index (SLEDAI) and 36 age‐ and sex‐matched healthy controls were evaluated for serum levels of oxidative/nitrosative stress markers, including antibodies to malondialdehyde (anti‐MDA) protein adducts and to 4‐hydroxynonenal (anti‐HNE) protein adducts, MDA/HNE protein adducts, superoxide dismutase (SOD), nitrotyrosine (NT), and inducible nitric oxide synthase (iNOS).ResultsSerum analysis showed significantly higher levels of both anti–MDA/anti–HNE protein adduct antibodies and MDA/HNE protein adducts in SLE patients compared with healthy controls. Interestingly, not only was there an increased number of subjects positive for anti‐MDA or anti‐HNE antibodies, but also the levels of both of these antibodies were statistically significantly higher among SLE patients whose SLEDAI scores were ≥6 as compared with SLE patients with lower SLEDAI scores (SLEDAI score <6). In addition, a significant correlation was observed between the levels of anti‐MDA or anti‐HNE antibodies and the SLEDAI score (r = 0.734 and r = 0.647, respectively), suggesting a possible causal relationship between these antibodies and SLE. Furthermore, sera from SLE patients had lower levels of SOD and higher levels of iNOS and NT compared with healthy control sera.ConclusionThese findings support an association between oxidative/nitrosative stress and SLE. The stronger response observed in serum samples from patients with higher SLEDAI scores suggests that markers of oxidative/nitrosative stress may be useful in evaluating the progression of SLE and in elucidating the mechanisms of disease pathogenesis.
MicroRNA‐29, a key regulator of collagen expression in systemic sclerosis
Authors: Maurer Britta , Stanczyk Joanna , Jüngel Astrid , Akhmetshina Alfiya , Trenkmann Michelle , Brock Matthias , Kowal‐Bielecka Otylia , Gay Renate E. , Michel Beat A. , Distler Jörg H. W. , Gay Steffen , Distler Oliver 
Published: March 2010

AbstractObjectiveTo investigate the role of microRNA (miRNA) as posttranscriptional regulators of profibrotic genes in systemic sclerosis (SSc).MethodsMicroRNA, which target collagens, were identified by in silico analysis. Expression of miRNA‐29 (miR‐29) was determined by TaqMan real‐time polymerase chain reaction analysis of skin biopsy and fibroblast samples from SSc patients and healthy controls as well as in the mouse model of bleomycin‐induced skin fibrosis. Cells were transfected with precursor miRNA (pre‐miRNA)/anti‐miRNA of miR‐29 using Lipofectamine. Collagen gene expression was also studied in luciferase reporter gene assays. For stimulation, recombinant transforming growth factor β (TGFβ), platelet‐derived growth factor B (PDGF‐B), or interleukin‐4 (IL‐4) was used. The effects of inhibiting PDGF‐B and TGFβ signaling on the levels of miR‐29 were studied in vitro and in the bleomycin model.ResultsWe found that miR‐29a was strongly down‐regulated in SSc fibroblasts and skin sections as compared with the healthy controls. Overexpression in SSc fibroblasts significantly decreased, and accordingly, knockdown in normal fibroblasts increased, the levels of messenger RNA and protein for type I and type III collagen. In the reporter gene assay, cotransfection with pre‐miR‐29a significantly decreased the relative luciferase activity, which suggests a direct regulation of collagen by miR‐29a. TGFβ, PDGF‐B, or IL‐4 reduced the levels of miR‐29a in normal fibroblasts to those seen in SSc fibroblasts. Similar to human SSc, the expression of miR‐29a was reduced in the bleomycin model of skin fibrosis. Inhibition of PDGF‐B and TGFβ pathways by treatment with imatinib restored the levels of miR‐29a in vitro and in the bleomycin model in vivo.ConclusionThese data add the posttranscriptional regulation of collagens by miR‐29a as a novel aspect to the fibrogenesis of SSc and suggest miR‐29a as a potential therapeutic target.
Modulation of antigen expression in B‐cell precursor acute lymphoblastic leukemia during induction therapy is partly transient: Evidence for a drug‐induced regulatory phenomenon. Results of the AIEOP‐BFM‐ALL‐FLOW‐MRD‐Study Group
Authors: Dworzak Michael N. , Gaipa Giuseppe , Schumich Angela , Maglia Oscar , Ratei Richard , Veltroni Marinella , Husak Zvenyslava , Basso Giuseppe , Karawajew Leonid , Gadner Helmut , Biondi Andrea 
Published: March 2010

AbstractBackground: Changes of antigen expression on residual blast cells of acute lymphoblastic leukemia (ALL) occur during induction treatment. Many markers used for phenotyping and minimal residual disease (MRD) monitoring are affected. Glucocorticoid (GC)‐induced expression modulation has been causally suspected, however, subclone selection may also cause the phenomenon.Methods: We investigated this by following the phenotypic evolution of leukemic cells with flow cytometry from diagnosis to four time points during and after GC containing chemotherapy in the 20 (of 360 consecutive) B‐cell precursor patients with ALL who had persistent MRD throughout.Results: The early expression changes of CD10 and CD34 were reversible after stop of GC containing chemotherapy. Modulation of CD20 and CD45 occurred mostly during the GC phase, whereas CD11a also changed later on. Blast cells at diagnosis falling into gates designed according to “shifted” phenotypes from follow‐up did not form clusters and were frequently less numerous than later on.Conclusions: Our data support the idea that drug‐induced modulation rather than selection causes the phenomenon. The good message for MRD assessment is that modulation is transient in at least two (CD10 and CD34) of the five prominent antigens investigated and reverts to initial aberrant patterns after stop of GC therapy, whereas CD20 expression gains new aberrations exploitable for MRD detection. © 2010 Clinical Cytometry Society
Identification of a distantcis‐regulatory element controlling pharyngeal arch‐specific expression of zebrafishgdf6a/radar
Authors: Reed Nykolaus P. , Mortlock Douglas P. 
Published: March 2010

AbstractSkeletal formation is an essential and intricately regulated part of vertebrate development. Humans and mice deficient in growth and differentiation factor 6 (Gdf6) have numerous skeletal abnormalities, including joint fusions and cartilage reductions. The expression ofGdf6is dynamic and in part regulated by distant evolutionarily conservedcis‐regulatory elements.radar/gdf6ais a zebrafish ortholog ofGdf6and has an essential role in embryonic patterning. Here, we show thatradaris transcribed in the cells surrounding and between the developing cartilages of the ventral pharyngeal arches, similar to mouseGdf6. A 312 bp evolutionarily conserved region (ECR5), 122 kilobases downstream, drives expression in a pharyngeal arch‐specific manner similar to endogenousradar/gdf6a. Deletion analysis identified a 78 bp region within ECR5 that is essential for transgene activity. This work illustrates thatradaris regulated in the pharyngeal arches by a distant conserved element and suggestsradarhas similar functions in skeletal development in fish and mammals. Developmental Dynamics 239:1047–1060, 2010. © 2010 Wiley‐Liss, Inc.
Differential time course of FSH/FSH receptor complex endocytosis within sertoli and germ cells during rat testis development
Authors: Segretain Dominique , Gilleron Jérome , Carette Diane , Denizot Jean‐Pierre , Pointis Georges 
Published: March 2010

AbstractFollicle‐stimulating hormone (FSH) is required for initiation and maintenance of spermatogenesis, a dynamic process of cell proliferation and maturation. By using FSH‐gold particles and pulse‐chase experiments, we analyzed the kinetics of FSH endocytosis in Sertoli and germ cells during development. Ultrastructural time‐dependent analysis demonstrates that FSH was first located on plasma membrane, before being accumulated within the endosomal compartment, in the early endosomes, identified by morphological criteria and Rab‐5 colocalization. Thereafter, FSH‐gold was routed to the degradation pathway. The FSH endocytosis kinetic was similar in Sertoli cells, spermatogonia and spermatocytes. However, quantitative analysis of gold particles revealed differences in the dynamic of FSH accumulation in the endosomes between immature and mature rats. This age‐dependent kinetic of FSH endocytosis, mostly detectable by ultrastructural analysis associated with quantitative data, argues for a potential new regulatory mechanism of the FSH signalling pathway that could occur during maturation of testicular cells. Developmental Dynamics 239:1113–1123, 2010. © 2010 Wiley‐Liss, Inc.
NTPDase1 governs P2X7‐dependent functions in murine macrophages
Authors: Lévesque Sébastien A. , Kukulski Filip , Enjyoji Keiichi , Robson Simon C. , Sévigny Jean 
Published: March 2010

AbstractP2X7 receptor is an adenosine triphosphate (ATP)‐gated ion channel within the multiprotein inflammasome complex. Until now, little is known about regulation of P2X7 effector functions in macrophages. In this study, we show that nucleoside triphosphate diphosphohydrolase 1 (NTPDase1)/CD39 is the dominant ectonucleotidase expressed by murine peritoneal macrophages and that it regulates P2X7‐dependent responses in these cells. Macrophages isolated from NTPDase1‐null mice (Entpd1−/−) were devoid of all ADPase and most ATPase activities when compared with WT macrophages (Entpd1+/+). Entpd1−/− macrophages exposed to millimolar concentrations of ATP were more susceptible to cell death, released more IL‐1β and IL‐18 after TLR2 or TLR4 priming, and incorporated the fluorescent dye Yo‐Pro‐1 more efficiently (suggestive of increased pore formation) than Entpd1+/+ cells. Consistent with these observations, NTPDase1 regulated P2X7‐associated IL‐1β release after synthesis, and this process occurred independently of, and prior to, cytokine maturation by caspase‐1. NTPDase1 also inhibited IL‐1β release in vivo in the air pouch inflammatory model. Exudates of LPS‐injected Entpd1−/− mice had significantly higher IL‐1β levels when compared with Entpd1+/+ mice. Altogether, our studies suggest that NTPDase1/CD39 plays a key role in the control of P2X7‐dependent macrophage responses.
Influence of human cytomegalovirus infection on the NK cell receptor repertoire in children
Authors: Monsiváis‐Urenda Adriana , Noyola‐Cherpitel Daniel , Hernández‐Salinas Alba , García‐Sepúlveda Christian , Romo Neus , Baranda Lourdes , López‐Botet Miguel , González‐Amaro Roberto 
Published: March 2010

AbstractHuman cytomegalovirus (hCMV) infection is usually asymptomatic but may cause disease in immunocompromised hosts. It has been reported that hCMV infection may shape the NK cell receptor (NKR) repertoire in adult individuals, promoting a variable expansion of the CD94/NKG2C+ NK cell subset. We explored the possible relationship between this viral infection and the expression pattern of different NKR including CD94/NKG2C, CD94/NKG2A, immunoglobulin‐like transcript 2 (ILT2, CD85j), KIR2DL1/2DS1, KIR3DL1, and CD161 in peripheral blood lymphocytes from healthy children, seropositive (n=21) and seronegative (n=20) for hCMV. Consistent with previous observations in adults, a positive serology for hCMV was associated with increased numbers of NKG2C+ NK and T cells as well as with ILT2+ T lymphocytes. Moreover, the proportions of CD161+ and NKG2C+CD56−CD3− NK cells also tended to be increased in hCMV+ individuals. Excretion of the virus was associated with higher proportions of NKG2C+ NK cells. Altogether, these data reveal that hCMV may have a profound influence on the NKR repertoire in early childhood.
Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells
Authors: Crawley Angela M. , Vranjkovic Agatha , Young Charlene , Angel Jonathan B. 
Published: March 2010

AbstractSignaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8+ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL‐4 is a potential contributor to impaired CD8+ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated.
The NLRP3 inflammasome, a target for therapy in diverse disease states
Authors: Cook Graham P. , Savic Sinisa , Wittmann Miriam , McDermott Michael F. 
Published: March 2010

AbstractA role for NLRP3 inflammasome in recurrent and chronic inflammation was initially described in a group of rare autoinflammatory conditions, termed cryopyrin‐associated periodic syndrome. Subsequently, inflammasomes have been implicated in the pathology of many common diseases, including cancer, gout and diabetes. Despite diverse pathologies, the central role of the inflammasome in innate defences and tumour elimination suggests common therapeutic approaches to reduce inflammation where appropriate.
The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll‐pathway activation function
Authors: Matskevich Alexey A. , Quintin Jessica , Ferrandon Dominique 
Published: March 2010

AbstractThe Drosophila Toll‐signaling pathway controls the systemic antifungal host response. Gram‐negative binding protein 3 (GNBP3), a member of the β‐glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3hades mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll‐independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles “attack complexes”, which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms.
New insights into the nature of autoinflammatory diseases from mice with Nlrp3 mutations
Authors: Meng Guangxun , Strober Warren 
Published: March 2010

AbstractMutations in the Nlrp3 (CIAS1, cryopyrin) gene are associated with cryopyrin‐associated periodic syndrome, autoinflammatory diseases characterized by excessive IL‐1 production and neutrophilia in blood and tissues. Recent studies with gene‐targeted mice expressing mutations homologous to those found in cryopyrin‐associated periodic syndrome patients have advanced the understanding of NLRP3‐associated autoinflammation. In this Viewpoint, we will discuss the mechanisms of NLRP3 inflammasome activation and its induction of Th17‐cell‐dominant immunologic responses.
Genetics of inflammasome‐associated disorders: A lesson in the guiding principals of inflammasome function
Authors: Rodrigue‐Gervais Ian Gaël , Saleh Maya 
Published: March 2010

AbstractHuman genetics research has had a great impact on the genesis of the inflammasome field and the treatment of certain inflammasomopathies. The identification of mutations causing rare autoinflammatory syndromes, reproductive wastage disorders and of single nucleotide polymorphisms influencing susceptibility to complex diseases such as vitiligo, sepsis, and Crohn's disease has not only led to the characterization of novel proteins involved in NOD‐like receptor‐coupled inflammatory signaling pathways but also to greater insights into pathogenic mechanisms.