bluuebunny/crossref_metadata_2025_split huggingface dataset:
LPS resistance in monocytic cells caused by reverse signaling through transmembrane TNF (mTNF) is mediated by the MAPK/ERK pathway
Authors: Kirchner Silvia , Boldt Simone , Kolch Walter , Haffner Silvia , Kazak Seran , Janosch Petra , Holler Ernst , Andreesen Reinhard , Eissner Günther 
Published: November 2003

AbstractThe transmembrane form of tumor necrosis factor (mTNF), expressed on activated monocytes (MO) and macrophages (MΦ), is able to induce apoptosis in human endothelial cells (EC). Apoptosis is mediated by two distinct mechanisms: direct cell contact and a yet-unidentified soluble protein, death factor X. In addition, mTNF acts as a receptor that transduces a “reverse signal” into MO/MΦ when bound to the TNF receptor on EC. Reverse signaling by mTNF confers resistance to bacterial lipopolysaccharide (LPS). Stimulation of reverse signaling by mTNF blocks the ability of MO/MΦ to produce death factor X and proinflammatory cytokines. We have investigated which signaling pathways are used by mTNF acting as receptor. Reverse signaling triggers two independent pathways that can be distinguished by protein kinase C (PKC) inhibitors. The suppression of LPS-induced death factor X is dependent on PKC, whereas the suppression of LPS-mediated cytokine release is not. LPS and reverse signaling stimulate the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. It is interesting that the activation of reverse signaling by mTNF renders MO/MΦ refractory to a subsequent activation of the MAPK/ERK pathway by LPS. Thus, reverse signaling achieves LPS resistance in monocytic cells through interference with key signal-transduction pathways.
Cyclin D2controls B cell progenitor numbers
Authors: Mohamedali Azim , Soeiro Inês , Lea Nicholas C , Glassford Janet , Banerji Lolita , Mufti Ghulam J , Lam Eric W-F , Thomas N Shaun B 
Published: November 2003

AbstractCyclin D2 affects B cell proliferation and differentiation in vivo. It is rate-limiting for B cell receptor (BCR)-dependent proliferation of B cells, and cyclin D2−/− mice lack CD5+(B1) B lymphocytes. We show here that the bone marrow (BM) of cyclin D2−/− mice contains half the numbers of Sca1+B220+ B cell progenitors but normal levels of Sca1+ progenitor cells of other lineages. In addition, clonal analysis of BM from the cyclin D2−/− and cyclin D2+/+ mice confirmed that there were fewer B cell progenitors (B220+) in the cyclin D2−/− mice. In addition, the colonies from cyclin D2−/− mice were less mature (CD19lo) than those from cyclin D2+/+ mice (CD19Hi). The number of mature B2 B cells in vivo is the same in cyclin D2−/− and cyclin D2+/+ animals. Lack of cyclin D2 protein may be compensated by cyclin D3, as cyclin-dependent kinase (cdk)6 coimmunoprecipitates with cyclin D3 but not cyclin D1 from BM mononuclear cells of cyclin D2−/− mice. It is active, as endogenous retinoblastoma protein is phosphorylated at the cdk6/4-cyclin D-specific sites, S807/811. We conclude that cyclin D2 is rate-limiting for the production of B lymphoid progenitor cells whose proliferation does not depend on BCR signaling.
Transgenic Expression of 11β-Hydroxysteroid Dehydrogenase Type 2 in Osteoblasts Reveals an Anabolic Role for Endogenous Glucocorticoids in Bone
Authors: Sher Lorin B. , Woitge Henning W. , Adams Douglas J. , Gronowicz Gloria A. , Krozowski Zygmunt , Harrison John R. , Kream Barbara E. 
Published: November 2003

AbstractGlucocorticoid excess leads to bone loss, primarily by decreasing bone formation. However, a variety of in vitro models show that glucocorticoids can promote osteogenesis. To elucidate the role of endogenous glucocorticoids in bone metabolism, we developed transgenic (TG) mice in which a 2.3-kb Col1a1 promoter fragment drives 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression in mature osteoblasts. 11β-HSD2 should metabolically inactivate endogenous glucocorticoids in the targeted cells, thereby reducing glucocorticoid signaling. The inhibitory effect of 300 nm hydrocortisone on percent collagen synthesis was blunted in TG calvariae, demonstrating that the transgene was active. Collagen synthesis rates were lower in TG calvarial organ cultures compared with wild-type. Trabecular bone parameters measured by microcomputed tomography were reduced in L3 vertebrae, but not femurs, of 7- and 24-wk-old TG females. These changes were also not seen in males. In addition, histomorphometry showed that osteoid surface was increased in TG female vertebrae, suggesting that mineralization may be impaired. Our data demonstrate that endogenous glucocorticoid signaling is required for normal vertebral trabecular bone volume and architecture in female mice.
Distribution of the VPAC2 Receptor in Peripheral Tissues of the Mouse
Authors: Harmar Anthony J. , Sheward W. John , Morrison Christine F. , Waser Beatrice , Gugger Mathias , Reubi Jean Claude 
Published: November 2003

Abstract
The neuropeptide vasoactive intestinal peptide (VIP) exerts its actions through two structurally related G protein-coupled receptors (VPAC1 and VPAC2). Pituitary adenylate cyclase-activating polypeptide (PACAP) is also a potent agonist of VPAC1 and VPAC2 receptors as well as of a third, PACAP-specific receptor (PAC1). We report here the distribution of the VPAC2 receptor in peripheral tissues of the mouse, determined by receptor autoradiography using [125I]VIP and the selective VPAC2 receptor agonist [125I]Ro25-1553 in wild-type and VPAC2 receptor-null mice. In addition, displacement experiments with the VPAC2-selective agonist Ro25-1553 and the VPAC1-selective agonist [K15,R16,L27]VIP(1–7)/GRF(8–27) were performed using the universal radioligand [125I]VIP. The VPAC2 receptor is found predominantly in smooth muscle (in blood vessels and in the smooth muscle layers of the gastrointestinal and reproductive systems), the basal part of the mucosal epithelium in the colon, lung, the vasculature of the kidney, adrenal medulla, and retina. Unexpectedly, the receptor was also present in thyroid follicular cells and acinar cells of the pancreas, tissues that have not been found to express the receptor in other species, and in very large amounts in the lung. Our data suggest novel functions of the VPAC2 receptor and additional potential therapeutic uses of drugs acting at the receptor (including the treatment of erectile dysfunction), but our results also indicate that caution should be exercised in using the mouse as an animal model for the evaluation of VIP analogs intended for diagnostic or therapeutic use in man.
Negative Regulation of Insulin-Stimulated Mitogen-Activated Protein Kinase Signaling By Grb10
Authors: Langlais Paul , Dong Lily Q. , Ramos Fresnida J. , Hu Derong , Li Yunhua , Quon Michael J. , Liu Feng 
Published: November 2003

AbstractGrb10 is a Pleckstrin homology and Src homology 2 (SH2) domain-containing protein that binds to the tyrosine-phosphorylated insulin receptor in response to insulin stimulation. Loss of Grb10 function in mice results in fetal and placental overgrowth; however, the molecular mechanism remains unknown. In the present study, we show that overexpression of Grb10 in Chinese hamster ovary cells expressing the insulin receptor or in 3T3-L1 adipocytes reduced insulin-stimulated phosphorylation of MAPK. Overexpression of Grb10 in rat primary adipocytes also inhibited insulin-stimulated phosphorylation of the MAPK downstream substrate Elk1. To determine the mechanism by which Grb10 inhibited insulin-stimulated MAPK signaling, we examined whether Grb10 affects the phosphorylation of MAPK upstream signaling components. We found that overexpression of Grb10 inhibited the insulin-stimulated phosphorylation of Shc, a positive regulator of the MAPK signaling pathway. The inhibitory effect was diminished when the SH2 domain of Grb10 was deleted. The negative role of Grb10 in insulin signaling was established by suppression of endogenous Grb10 by RNA interference in HeLa cells overexpressing the insulin receptor, which enhanced insulin-stimulated phosphorylation of MAPK, Shc, and Akt. Taken together, our findings suggest that Grb10 functions as a negative regulator in the insulin-stimulated MAPK signaling pathway. In addition, the inhibitory effect of Grb10 on the MAPK pathway is most likely due to a direct block of insulin-stimulated Shc tyrosine phosphorylation.
First observation of homozygous hemoglobin hamadan (B 56 (D7) GLY‐ARG) and beta thalassemia (‐29 G>A)‐ hemoglobin Hamadan combination in a Turkish family
Authors: Akar Ece , Özdemir Sibel , Hakki Timur Ismail , Akar Nejat 
Published: November 2003

AbstractDuring screening surveys for beta thalassemia and abnormal hemoglobins in Mugla, a city located in the Aegean Region of Turkey, a hemoglobin variant was detected in two large families residing in two neigboring cities (i.e., Muğla and Aydin) without any clinical signs. Further analysis of the variant revealed it as Hb Hamadan (B 56 (D7) GLY‐ARG). Family screening revealed the father of the propositus as homozygote Hb Hamadan. The grandfather of the index case was detected as combination of Hb Hamadan with beta thalassemia. The beta thalassemia carrier had a promotor mutation at −29 G>A, which is also a novel mutation. Furthermore, we described a simple and rapid restriction enzyme digestion protocol (Hha I) for the verification of Hb Hamadan. The clinical and hematologic data of the index case and his father showed that neither homozygous Hb Hamadan nor combination with beta thalassemia has clinical importance. This is also important especially from the prenatal diagnosis point of view. Am. J. Hematol. 74:280–282, 2003. © 2003 Wiley‐Liss, Inc.
Successful treatment of acquired pure red cell aplasia (PRCA) by allogeneic peripheral blood stem cell transplantation
Authors: Tseng Shih‐Bin , Lin Sheng‐Fung , Chang Chao‐Sung , Liu Ta‐Chih , Hsiao Hui‐Hua , Liu Yi‐Chang , Tsai Hui‐Jen , Chen Tyen‐Po 
Published: November 2003

AbstractA 37‐year‐old male was treated successfully by peripheral blood stem cell transplantation (PBSCT) from his HLA‐identical sister for refractory acquired pure red cell aplasia (PRCA). The conditioning regimen was cyclophosphamide 50 mg/kg/day for 4 days plus TBI 300 cGy in a single fraction. Absolute neutrophil count (ANC) >500/μl and platelet counts >20,000/μl were achieved 8 days after PBSCT without transfusion. Chimerism study on day 218 revealed full donor chimerism. The hemoglobin level was stable around 12–13 g/dl with normal leukocyte and platelet counts after PBSCT during a long follow‐up period. From this case, PBSCT should be considered for patients with refractory acquired PRCA with an HLA‐identical donor. Am. J. Hematol. 74:273–275, 2003. © 2003 Wiley‐Liss, Inc.
Identification of hemochromatosis gene polymorphisms in chronically transfused patients with sickle cell disease
Authors: Jeng Michael R. , Adams‐Graves Patricia , Howard Thad A. , Whorton Matthew R. , Li Chin‐Shang , Ware Russell E. 
Published: November 2003

AbstractThree polymorphic gene mutations in the human hemochromatosis (HFE) gene (C282Y, H63D, S65C) are associated with non‐transfusion–related iron overload in Caucasians. More recently, these mutations have also been identified in African‐Americans. However, the prevalence of HFE gene mutations in African‐Americans with sickle cell disease (SCD) has not been described. The presence of these mutations in this population is particularly important, because patients with SCD may be placed on chronic red cell transfusion therapy and are thus at further risk for iron overload. Thus, we attempted to establish the gene mutation prevalence in African‐Americans with SCD, to compare this frequency with published gene frequencies in African‐Americans, and to evaluate their significance with regard to transfusion‐related iron overload. Eighty‐nine African‐American patients with SCD, all of whom were receiving chronic red cell transfusion therapy, were screened by DNA analysis for the three HFE gene mutations. Two patients were heterozygous for the C282Y HFE mutation (2.3%), six were heterozygous for the H63D mutation (6.8%), none carried the S65C mutation (0.0%), and no homozygous or compound heterozygous subjects were identified. The prevalence of C282Y and H63D in the SCD population was similar to that observed in the general African‐American population. In addition, there was no increased mutation prevalence when comparing those SCD patients on chronic transfusion therapy who had ferritin levels greater than 2,500 ng/mL and those less than 2,500 ng/mL. This study represents the first identification of the known HFE gene mutations by DNA analysis in the SCD population. We conclude that the presence of recognized HFE coding region mutations do not seem to have an impact on the degree of iron overload in patients with SCD receiving chronic transfusion therapy. Am J. Hematol. 74:243–248, 2003. © 2003 Wiley‐Liss, Inc.
Non‐Hodgkin's lymphoma, leukemia, and exposures in agriculture: Results from the Italian multicenter case‐control study
Authors: Miligi Lucia , Costantini Adele Seniori , Bolejack Vanessa , Veraldi Angela , Benvenuti Alessandra , Nanni Oriana , Ramazzotti Valerio , Tumino Rosario , Stagnaro Emanuele , Rodella Stefania , Fontana Arabella , Vindigni Carla , Vineis Paolo 
Published: November 2003

AbstractBackgroundThe etiology of non‐Hodgkin's lymphoma (NHL) and leukemia is still largely unknown, but exposure to chemicals, in particular pesticides, has been suggested to be a risk factor.MethodsA large population‐based case‐control study was conducted in Italy with the aim of investigating the associations between pesticide exposure and NHL, and solvents and leukemia. Data presented in this article refer to 1,575 interviewed cases and 1,232 controls in the nine agricultural study areas.ResultsExposure to nitro‐derivatives and phenylimides among fungicides, hydrocarbon derivatives and insecticide oils among insecticides, and the herbicide amides are the chemical classes observed to be associated with the pathologies under investigation.ConclusionsThe results of the case‐control study suggest an increased risk for NHL and leukemia, and some chemical classes of pesticides, although few are statistically significant and some are based on few exposed cases. The results also show that men and women experience both similar and different risks for the same environmental agricultural exposures. Am. J. Ind. Med. 44:627–636, 2003. © 2003 Wiley‐Liss, Inc.
The incidence of respiratory symptoms in female Swedish hairdressers
Authors: Brisman Jonas , Albin Maria , Rylander Lars , Mikoczy Zoli , Lillienberg Linnéa , Höglund Anna Dahlman , Torén Kjell , Meding Birgitta , Diab Kerstin Kronholm , Nielsen Jørn 
Published: November 2003

AbstractBackgroundAirway diseases in hairdressers are a concern. The objective of this investigation is to evaluate the risk for three respiratory symptoms, wheeze, dry cough, and nasal blockage, in hairdressers.MethodsA questionnaire on respiratory symptoms, atopy, smoking, and work history was answered by 3,957 female hairdressers and 4,905 women from the general population as referents. Incidence rates (IR) and incidence rate ratios (IRRs) for the three symptoms were estimated.ResultsThe IRs of all three studied symptoms were higher in the hairdressers compared with the referents. Smoking modified the effects of cohort affiliation for all three symptoms; the combined effect from hairdressing work and smoking was less than expected. In addition, the effect of cohort affiliation for wheeze was also modified by atopy, and the effect of cohort affiliation for nasal blockage was also modified by calendar year.ConclusionsHairdressing work was associated with increased incidences of respiratory symptoms. Smoking had a negative modifying effect. Am. J. Ind. Med. 44:673–678, 2003. © 2003 Wiley‐Liss, Inc.
Cancer incidence among laboratory workers in biomedical research and routine laboratories in Israel: Part II–nested case‐control study
Authors: Shaham Judith , Gurvich Rachel , Kneshet Yael 
Published: November 2003

AbstractBackgroundA case‐control study nested within a cohort study of biomedical laboratory workers was conducted to examine whether the excess cancer morbidity that we found can be explained by exposure to a particular group of substances, taking into consideration potential confounders.MethodsThe study population included 163 cases and two matched control groups: laboratory workers (311) and general population (448) workers.ResultsMultiple conditional regression analysis showed that working in research laboratories involved an increased risk of cancer generally among women [risk ratio 2.2 (1.2–4.3)], and of breast cancer particularly [risk ratio 2.3 (1.1–4.7). Seventy‐six percent (76%) of breast, 87% of thyroid, 60% of ovary and prostate, 94% of melanoma, and 50% of leukemia cases were ever exposed to at least one known human carcinogen.ConclusionOur results exclude the possibility that the excess cancer morbidity was related to personal risk factors but they may be explained by exposure factors. Am. J. Ind. Med. 44:611–626, 2003. © 2003 Wiley‐Liss, Inc.
Synapse signalling complexes and networks: machines underlying cognition
Authors: Grant Seth G.N. 
Published: November 2003

AbstractAll thoughts and actions are encoded in patterns of neuronal electrical activity. Circuits of nerve cells connected by synapses are dedicated to processing information in these patterns. Information is not only transmitted across the synapse but also monitored by postsynaptic molecular machines. These machines are macromolecular complexes of ∼100 proteins organised into a network of protein interactions. The network can be mathematically described as a scale‐free network. Components of the complexes are necessary for decoding the neural code and converting electrical information into biochemical changes. The network properties of these complexes may explain many of the features of neuronal plasticity and cognitive function in rodents. Importantly, these multiprotein complexes and their network properties shed new light on the basis of human cognitive diseases including schizophrenia, autism, Huntington's disease and mental retardation. Supplementary material for this article can be found on the BioEssays website http://www.interscience.wiley.com/jpages/0265‐9247/suppmat/index.html. BioEssays 25:1229–1235, 2003. ©2003, Wiley Periodicals Inc.
The Dirichlet problem for the minimal surface system in arbitrary dimensions and codimensions
Authors: Wang Mu‐Tao 
Published: November 2003

AbstractLet Ω be a bounded C2 domain in ℝn and ϕ ∂Ω → ℝm be a continuous map. The Dirichlet problem for the minimal surface system asks whether there exists a Lipschitz map f : Ω → ℝm with f|∂Ω = ϕ and with the graph of f a minimal submanifold in ℝn+m. For m = 1, the Dirichlet problem was solved more than 30 years ago by Jenkins and Serrin [12] for any mean convex domains and the solutions are all smooth. This paper considers the Dirichlet problem for convex domains in arbitrary codimension m. We prove that if ψ : ¯Ω → ℝm satisfies 8nδ supΩ |D2ψ| + √2 sup∂Ω |Dψ| < 1, then the Dirichlet problem for ψ|∂Ω is solvable in smooth maps. Here δ is the diameter of Ω. Such a condition is necessary in view of an example of Lawson and Osserman [13]. In order to prove this result, we study the associated parabolic system and solve the Cauchy‐Dirichlet problem with ψ as initial data. © 2003 Wiley Periodicals, Inc.
Runx2/Cbfa1 stimulation by retinoic acid is potentiated by BMP2 signaling through interaction with Smad1 on the collagen X promoter in chondrocytes
Authors: Drissi M. Hicham , Li Xufeng , Sheu Tzong J. , Zuscik Michael J. , Schwarz Edward M. , Puzas J. Edward , Rosier Randy N. , O'Keefe Regis J. 
Published: November 2003

AbstractChondrocyte differentiation is a fundamental process during endochondral ossification. Several factors regulate maturation via the activity of downstream signaling pathways that target specific transcription factors and regulate chondrocyte‐specific genes. In this study, we investigated the mechanisms involved in the regulation of chick lower sternal chondrocyte maturation upon stimulation by retinoic acid (RA) and the bone morphogenetic protein BMP2. RA‐induced Runx2 in lower sternal chondrocyte cultures and over‐expression of wild‐type (WT) Runx2 enhanced colX and alkaline phosphatase activity, while over‐expression of dominant negative Runx2 was inhibitory. Furthermore, WT Runx2 enhanced the effects of both BMP2 and RA on colX expression, while the effects of both growth factors were completely blocked in cultures over‐expressing dominant negative Runx2. Similarly, WT Runx2 enhanced the induction of colX by Smad1. Smad1 and Runx2 were found to act cooperatively at the chicken type X collagen promoter and elimination of either the putative Smad binding site or Runx2 binding site eliminated responsiveness to BMP2, RA, or either of the transcription factors. Altogether the results show cross talk between the BMP‐associated Smads and Runx2 during chondrocyte differentiation and dependence upon both signals for induction of the type X collagen promoter. Factors or signals that alter either of these transcription factors regulate the rate of chondrocyte differentiation. © 2003 Wiley‐Liss, Inc.
BMP treatment of C3H10T1/2 mesenchymal stem cells induces both chondrogenesis and osteogenesis
Authors: Shea Colleen M. , Edgar Cory M. , Einhorn Thomas A. , Gerstenfeld Louis C. 
Published: November 2003

AbstractThe molecular mechanisms by which bone morphogenetic proteins (BMPs) promote skeletal cell differentiation were investigated in the murine mesenchymal stem cell line C3H10T1/2. Both BMP‐7 and BMP‐2 induced C3H10T1/2 cells to undergo a sequential pattern of chondrogenic followed by osteogenic differentiation that was dependent on both the concentration and the continuous presence of BMP in the growth media. Differentiation was determined by the expression of chondrogenesis and osteogenesis associated matrix genes. Subsequent experiments using BMP‐7 demonstrated that withdrawal of BMP from the growth media led to a complete loss of skeletal cell differentiation accompanied by adipogenic differentiation of these cells. Continuous treatment with BMP‐7 increased the expression of Sox9, Msx 2, and c‐fos during the periods of chondrogenic differentiation after which point their expression decreased. In contrast, Dlx 5 expression was induced by BMP‐7 treatment and remained elevated throughout the time‐course of skeletal cell differentiation. Runx2/Cbfa1 was not detected by ribonuclease protection assay (RPA) and did not appear to be induced by BMP‐7. The sequential nature of differentiation of chondrocytic and osteoblastic cells and the necessity for continuous BMP treatment to maintain skeletal cell differentiation suggests that the maintenance of selective differentiation of the two skeletal cell lineages might be dependent on BMP‐7‐regulated expression of other morphogenetic factors. An examination of the expression of Wnt, transforming growth factor‐β (TGF‐β), and the hedgehog family of morphogens showed that Wnt 5b, Wnt 11, BMP‐4, growth and differentiation factor‐1 (GDF‐1), Sonic hedgehog (Shh), and Indian hedgehog (Ihh) were endogenously expressed by C3H10T1/2 cells. Wnt 11, BMP‐4, and GDF‐1 expression were inhibited by BMP‐7 treatment in a dose‐dependent manner while Wnt 5b and Shh were selectively induced by BMP‐7 during the period of chondrogenic differentiation. Ihh expression also showed induction by BMP‐7 treatment, however, the period of maximal expression was during the later time‐points, corresponding to osteogenic differentiation. An interesting phenomenon was that BMP‐7 activity could be further enhanced twofold by growing the cells in a more nutrient‐rich media. In summary, the murine mesenchymal stem cell line C3H10T1/2 was induced to follow an endochondral sequence of chondrogenic and osteogenic differentiation dependent on both dose and continual presence of BMP‐7 and enhanced by a nutrient‐rich media. Our preliminary results suggest that the induction of osteogenesis is dependent on the secondary regulation of factors that control osteogenesis through an autocrine mechanism. © 2003 Wiley‐Liss, Inc.