bluuebunny/crossref_metadata_2025 huggingface dataset:
Essential Roles of IL-6 Trans-Signaling in Colonic Epithelial Cells, Induced by the IL-6/Soluble–IL-6 Receptor Derived from Lamina Propria Macrophages, on the Development of Colitis-Associated Premalignant Cancer in a Murine Model
Authors: Matsumoto Satoshi , Hara Taeko , Mitsuyama Keiichi , Yamamoto Mayuko , Tsuruta Osamu , Sata Michio , Scheller Jürgen , Rose-John Stefan , Kado Sho-ichi , Takada Toshihiko
Published: December 2009

Activation of the IL-6/Stat3 via IL-6 trans-signaling plays an important role in the pathogenesis of inflammatory bowel disease. Colitis-associated cancer (CAC) is a large bowel cancer and occurs with long-standing inflammatory bowel disease. The role of the IL-6/Stat3 in the development of CAC has not been fully understood. We investigate whether IL-6 trans-signaling contributes to the development of CAC using a mouse colitis-associated premalignant cancer (CApC) model. Chronic colitis (CC) was induced in BALB/c mice using dextran sodium sulfate. CApC was induced by dextran sodium sulfate treatment to CC-affected mice. IL-6 expression was determined by quantitative RT-PCR and immunofluorescence staining in colon. Phospho-Stat3 expression was examined by Western blotting and immunofluorescence analysis. The expression of IL-6 receptors (i.e., the IL-6R α-chain and gp130) and tumor necrosis factor-α converting enzyme in the colon was examined by laser-capture microdissection and immunofluorescence staining. Soluble IL-6Rα (sIL-6Rα) was examined by Western blotting of epithelial cell-depleted colonic tissues. We also investigated whether a soluble gp130-Fc fusion protein could prevent CApC. IL-6 expression was increased in the colon of CC- and CApC-affected mice and was restricted to lamina propria-macrophages. The expression of IL-6Rα and tumor necrosis factor-α converting enzyme was increased in the lamina propria CD11b-macrophages of CC-affected mice. sIL-6Rα expression was also increased in these tissues. Reduced levels of IL-6Rα generation were observed in the colonic epithelial cells of CC- and CApC-affected mice and were associated with the increased expression of gp130 and phospho-Stat3. Treatment with soluble gp130Fc significantly reduced the CApC. IL-6 trans-signaling in epithelial cells induced by macrophage-derived IL-6/sIL-6Rα plays a crucial role in the development of CAC.
IL-10 Induction by Bordetella parapertussis Limits a Protective IFN-γ Response
Authors: Wolfe Daniel N. , Karanikas Alexia T. , Hester Sara E. , Kennett Mary J. , Harvill Eric T.
Published: December 2009

Bordetella parapertussis causes the prolonged coughing illness known as pertussis or whooping cough, persisting for weeks within the respiratory tracts of infected hosts but inducing a very poor T cell response relative to that induced by Bordetella pertussis, the more common cause of pertussis. In this study, we examine the contributions of cytokines involved in the clearance of B. parapertussis and immunomodulation that delays effective clearance. The slow elimination of this pathogen from the respiratory tracts of mice coincides with the gradual accumulation of CD4+ T cells in the lungs and B. parapertussis-responsive IFN-γ–producing cells in the spleen. IFN-γ–deficient mice were defective in the accumulation of leukocytes in lungs and in clearance of B. parapertussis from the lungs. In vitro B. parapertussis-stimulated macrophages produced IL-10, which inhibited the generation of the IFN-γ response that is required for protection in vivo. As compared with wild-type mice, IL-10–deficient mice produced significantly higher levels of IFN-γ, had higher numbers of leukocytes accumulated in the lungs, and cleared B. parapertussis more rapidly. Together, these data indicate that B. parapertussis induces the production of IL-10, which facilitates its persistence within infected hosts by limiting a protective IFN-γ response.
Critical Protective Role for MCP-1 in Pneumonic Burkholderia mallei Infection
Authors: Goodyear Andrew , Jones Abby , Troyer Ryan , Bielefeldt-Ohmann Helle , Dow Steven
Published: December 2009

Burkholderia mallei is a Gram-negative bacterial pathogen of domestic equidae and humans that can cause severe, rapidly life-threatening pneumonic infections. Little is known regarding the role of chemokines and early cellular immune responses in protective immunity to pulmonary infection with B. mallei. Although the role of MCP-1 in Gram-positive bacterial infections has been previously investigated, the role of MCP-1 in immunity to acute pneumonia caused by Gram-negative bacteria, such as B. mallei, has not been assessed. In a mouse model of pneumonic B. mallei infection, we found that both MCP-1−/− mice and CCR2−/− mice were extremely susceptible to pulmonary infection with B. mallei, compared with wild-type (WT) C57Bl/6 mice. Bacterial burden and organ lesions were significantly increased in CCR2−/− mice, compared with WT animals, following B. mallei challenge. Monocyte and dendritic cell recruitment into the lungs of CCR2−/− mice was significantly reduced in comparison with that in WT mice following B. mallei infection, whereas neutrophil recruitment was actually increased. Depletion of monocytes and macrophages prior to infection also greatly raised the susceptibility of WT mice to infection. Production of IL-12 and IFN-γ in the lungs after B. mallei infection was significantly impaired in both MCP-1−/− and CCR2−/− mice, whereas treatment of CCR2−/− mice with rIFN-γ restored protection against lethal challenge with B. mallei. Thus, we conclude that MCP-1 plays a key role in regulating cellular immunity and IFN-γ production following pneumonic infection with B. mallei and therefore may also figure importantly in other Gram-negative pneumonias.
TCRβ Feedback Signals Inhibit the Coupling of Recombinationally Accessible Vβ14 Segments with DJβ Complexes
Authors: Yang-Iott Katherine S. , Carpenter Andrea C. , Rowh Marta A. W. , Steinel Natalie , Brady Brenna L. , Hochedlinger Konrad , Jaenisch Rudolf , Bassing Craig H.
Published: December 2009

Ag receptor allelic exclusion is thought to occur through monoallelic initiation and subsequent feedback inhibition of recombinational accessibility. However, our previous analysis of mice containing a V(D)J recombination reporter inserted into Vβ14 (Vβ14Rep) indicated that Vβ14 chromatin accessibility is biallelic. To determine whether Vβ14 recombinational accessibility is subject to feedback inhibition, we analyzed TCRβ rearrangements in Vβ14Rep mice containing a preassembled in-frame transgenic Vβ8.2Dβ1Jβ1.1 or an endogenous Vβ14Dβ1Jβ1.4 rearrangement on the homologous chromosome. Expression of either preassembled VβDJβC β-chain accelerated thymocyte development because of enhanced cellular selection, demonstrating that the rate-limiting step in early αβ T cell development is the assembly of an in-frame VβDJβ rearrangement. Expression of these preassembled VβDJβ rearrangements inhibited endogenous Vβ14-to-DJβ rearrangements as expected. However, in contrast to results predicted by the accepted model of TCRβ feedback inhibition, we found that expression of these preassembled TCR β-chains did not downregulate recombinational accessibility of Vβ14 chromatin. Our findings suggest that TCRβ-mediated feedback inhibition of Vβ14 rearrangements depends on inherent properties of Vβ14, Dβ, and Jβ recombination signal sequences.
Promoting Immune Responses by LIGHT in the Face of Abundant Regulatory T Cell Inhibition
Authors: Wang Yugang , Zhu Mingzhao , Yu Ping , Fu Yang-Xin
Published: December 2009

CD4+ regulatory T cell (Treg) populations are believed to play very important roles in the suppression of immune responses. Overriding Treg inhibition is necessary for initiating primary immune reaction upon inflammatory Ag stimulation. LIGHT, TNF superfamily member 14, has been shown to be a costimulatory molecule for effector T cells. Overexpression of lymphotoxin-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) on T cells induces strong T cell-mediated experimental intestinal inflammation. How this process is initiated by LIGHT in suppressive intestinal environments remains incompletely understood. In this study, we assessed the effect of LIGHT on Tregs. Our results indicate that LIGHT can support the expansion and function of Tregs. However, when LIGHT was highly expressed, these abundant Tregs failed to suppress the development of T cell-mediated experimental colitis and antitumor immunity. We showed that this might be, in part, due to an ability of LIGHT to promote effector T cell proliferation and differentiation even in a Treg-abundant environment. Our data collectively suggest that LIGHT might be a critical cytokine involved in the development of autoimmune inflammatory diseases and that LIGHT-targeted immunotherapy might be useful in the treatment of these diseases.
Inhibitory Role of Sphingosine 1-Phosphate Receptor 2 in Macrophage Recruitment during Inflammation
Authors: Michaud Jason , Im Dong-Soon , Hla Timothy
Published: December 2009

Macrophage recruitment to sites of inflammation is an essential step in host defense. However, the mechanisms preventing excessive accumulation of macrophages remain relatively unknown. The lysophospholipid sphingosine 1-phosphate (S1P) promotes T and B cell egress from lymphoid organs by acting on S1P receptor 1 (S1P1R). More recently, S1P5R was shown to regulate NK cell mobilization during inflammation, raising the possibility that S1P regulates the trafficking of other leukocyte lineages. In this study, we show that S1P2R inhibits macrophage migration in vitro and that S1P2R-deficient mice have enhanced macrophage recruitment during thioglycollate peritonitis. We identify the signaling mechanisms used by S1P2R in macrophages, involving the second messenger cAMP and inhibition of Akt phosphorylation. In addition, we show that the phosphoinositide phosphatase and tensin homolog deleted on chromosome 10, which has been suggested to mediate S1P2R effects in other cell types, does not mediate S1P2R inhibition in macrophages. Our results suggest that S1P serves as a negative regulator of macrophage recruitment by inhibiting migration in these cells and identify an additional facet to the regulation of leukocyte trafficking by S1P.
Regulation of FcεRI Expression during Murine Basophil Maturation: The Interplay between IgE, Cell Division, and FcεRI Synthetic Rate
Authors: Zaidi Asifa K. , MacGlashan Donald W.
Published: December 2009

Expression of FcεRI on basophils and mast cells is modulated by IgE Ab. Previous studies have noted in vivo receptor expression dynamics that are discordant with expectations derived from in vitro studies. The current study presents a formal hypothesis to explain the discordant observations and tests two assumptions that underlie a proposed model of receptor dynamics. After first showing that a murine model of receptor expression on basophils recapitulates observations made using human basophils, the effect of changes in IgE on basophil egress rates was examined. In the proposed model, egress rates from bone marrow (BM) were assumed to be unaffected by changes in IgE concentration. Egress was tested by examining the labeling of BM and peripheral blood (BL) basophils at various times after injection of BrdU with and without injection with IgE. The IgE Ab did not alter the appearance of BrdU label in peripheral BL basophils. In addition, BM and BL basophils were responsive to the elevations in IgE, with receptor expression increasing on BM basophils before BL basophils. It was also noted that BL basophils expressed ∼50% of the receptor density of BM basophils. There was a 3-fold greater synthetic rate of FcεRI on BM basophils that readily explained the difference. These results provide support for the proposed hypothesis of rapid changes in receptor expression being controlled by cell replacement. The studies also support a model whereby receptor expression is limited by cell division and that basophils, once mature, slow their rate of receptor synthesis.
Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6
Authors: Tsantikos Evelyn , Oracki Sarah A. , Quilici Cathy , Anderson Gary P. , Tarlinton David M. , Hibbs Margaret L.
Published: December 2009

Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn−/− mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn−/− leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn−/− dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn−/− mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn−/−IL-6−/− mice. Importantly, our studies show that although Lyn−/− B cells may be autoreactive, it is the IL-6–dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti–IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.
SHP-1 Deficient Mast Cells Are Hyperresponsive to Stimulation and Critical in Initiating Allergic Inflammation in the Lung
Authors: Zhang Li , Oh Sun Young , Wu Xinxing , Oh Min Hee , Wu Fan , Schroeder John T. , Takemoto Clifford M. , Zheng Tao , Zhu Zhou
Published: December 2009

Phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1)-deficient mice display an allergic asthma phenotype that is largely IL-13 and STAT6 dependent. The cell types responsible for the Th2 phenotype have not been identified. We hypothesized that SHP-1 deficiency leads to mast cell dysregulation and increased production and release of mediators and Th2 cytokines, leading to the allergic asthma phenotype. We examined SHP-1 regulation of mast cell differentiation, survival, and functional responses to stimulation using bone marrow-derived mast cells from viable motheaten (mev) mice. We assessed pulmonary phenotypical changes in mev mice on the mast cell-deficient KitW-Sh genetic background. The results showed that SHP-1 deficiency led to increased differentiation and survival, but reduced proliferation, of mast cells. SHP-1–deficient mast cells produced and released increased amounts of mediators and Th2 cytokines IL-4 and -13 spontaneously and in response to H2O2, LPS, and FcεI cross-linking, involving c-Kit–dependent and –independent processes. The FcεRI signaling led to binding of SHP-1 to linker for activation of T cells 2 and enhanced linker for activation of T cells 2 phosphorylation in mev bone marrow-derived mast cells. Furthermore, the number of mast cells in the lung tissue of mev mice was increased and mast cell production and release of Th2 cytokines were distinctly increased upon FcεRI stimulation. When backcrossed to the KitW-Sh background, mev mice had markedly reduced pulmonary inflammation and Th2 cytokine production. These findings demonstrate that SHP-1 is a critical regulator of mast cell development and function and that SHP-1–deficient mast cells are able to produce increased Th2 cytokines and initiate allergic inflammatory responses in the lung.
A Recombinant Bispecific Single-Chain Fragment Variable Specific for HLA Class II and FcαRI (CD89) Recruits Polymorphonuclear Neutrophils for Efficient Lysis of Malignant B Lymphoid Cells
Authors: Guettinger Yvonne , Barbin Karin , Peipp Matthias , Bruenke Joerg , Dechant Michael , Horner Heike , Thierschmidt Doreen , Valerius Thomas , Repp Roland , Fey Georg H. , Stockmeyer Bernhard
Published: December 2009

Bispecific Abs offer new perspectives for cancer immunotherapy. In this study, we describe a recombinant bispecific single-chain fragment variable (bsscFv) directed against FcαRI (CD89) on polymorphonuclear neutrophils (PMNs) or monocytes/macrophages and HLA class II on lymphoma target cells. FcαRI and HLA class II-directed single-chain fragment variable (scFv) fragments were isolated from phage display libraries, established from the hybridomas A77 and F3.3, respectively. The two scFv molecules were connected with a 20 aa flexible linker sequence. After expression in SF21 insect cells and chromatographic purification, the bispecific molecule showed specific binding to both Ags at KD values of 148 ± 42 nM and 113 ± 25 nM for the anti-FcαRI and anti-HLA class II scFv components in the bsscFv, respectively. In Ab-dependent cytotoxicity assays with PMNs as effectors and a series of lymphoma-derived cell lines (ARH-77, RAJI, REH, NALM-6, RS4;11), the bsscFv was significantly more cytotoxic than the parental murine IgG1 and its chimeric IgG1 derivative. When targeting primary tumor cell isolates from six patients with B cell malignancies, the killing capacity of the (FcαRI × HLA class II) bsscFv compared favorably to conventional HLA class II mAb. Importantly, the cell lines NALM-6 and RS411, as well as two primary tumor cell isolates, were exclusively lysed by the bsscFv. To our knowledge, this is the first report of an FcαRI-directed bsscFv effectively recruiting PMNs for redirected cytotoxicity against human B cell malignancies. Our data show that an (FcαRI × HLA class II) bsscFv is an interesting candidate for further engineering of small, modular immunopharmaceuticals.
A Single TCRα-Chain with Dominant Peptide Recognition in the Allorestricted HER2/neu-Specific T Cell Repertoire
Authors: Liang Xiaoling , Weigand Luise U. , Schuster Ingrid G. , Eppinger Elfriede , van der Griendt Judith C. , Schub Andrea , Leisegang Matthias , Sommermeyer Daniel , Anderl Florian , Han Yanyan , Ellwart Joachim , Moosmann Andreas , Busch Dirk H. , Uckert Wolfgang , Peschel Christian , Krackhardt Angela M.
Published: December 2009

T cells can recognize tumor cells specifically by their TCR and the transfer of TCR-engineered T cells is a promising novel tool in anticancer therapies. We isolated and characterized four allorestricted TCRs with specificity for the HER2/neu-derived peptide 369 (HER2369) demonstrating high peptide specificity. PBMCs transduced with especially one TCR, HER2-1, mediated specific tumor reactivity after TCR optimization suggesting that this TCR represents a potential candidate for targeting HER2 by TCR-transduced effector cells. Another TCR showed high-peptide specificity without tumor reactivity. However, the TCRα-chain of this TCR specifically recognized HER2369 not only in combination with the original β-chain but also with four other β-chains of the same variable family deriving from TCRs with diverse specificities. Pairing with one β-chain derived from another HER2369-specific TCR potentiated the chimeric TCRs in regard to functional avidity, CD8 independency, and tumor reactivity. Although the frequency of such TCR single chains with dominant peptide recognition is currently unknown, they may represent interesting tools for TCR optimization resulting in enhanced functionality when paired to novel partner chains. However, undirected mispairing with novel partner chains may also result in enhanced cross-reactivity and self-reactivity. These results may have an important impact on the further design of strategies for adoptive transfer using TCR-transduced T cells.
Cutting Edge: Nucleotide-Binding Oligomerization Domain 1-Dependent Responses Account for Murine Resistance against Trypanosoma cruzi Infection
Authors: Silva Grace K. , Gutierrez Fredy R. S. , Guedes Paulo M. M. , Horta Catarina V. , Cunha Larissa D. , Mineo Tiago W. P. , Santiago-Silva Juliana , Kobayashi Koichi S. , Flavell Richard A. , Silva João S. , Zamboni Dario S.
Published: December 2009

An effective innate immune recognition of the intracellular protozoan parasite Trypanosoma cruzi is critical for host resistance against Chagas disease, a severe and chronic illness that affects millions of people in Latin America. In this study, we evaluated the participation of nucleotide-binding oligomerization domain (Nod)-like receptor proteins in host response to T. cruzi infection and found that Nod1-dependent, but not Nod2-dependent, responses are required for host resistance against infection. Bone marrow-derived macrophages from Nod1−/− mice showed an impaired induction of NF-κB–dependent products in response to infection and failed to restrict T. cruzi infection in presence of IFN-γ. Despite normal cytokine production in the sera, Nod1−/− mice were highly susceptible to T. cruzi infection, in a similar manner to MyD88−/− and NO synthase 2−/− mice. These studies indicate that Nod1-dependent responses account for host resistance against T. cruzi infection by mechanisms independent of cytokine production.
T Cell–Dendritic Cell Interaction Dynamics during the Induction of Respiratory Tolerance and Immunity
Authors: Bakočević Nadja , Worbs Tim , Davalos-Misslitz Ana , Förster Reinhold
Published: December 2009

Dendritic cells (DCs) residing in the lung are known to acquire inhaled Ag and, after migration to the draining bronchial lymph node (brLN), to present it to naive T cells in an either tolerogenic or immunogenic context. To visualize endogenous lung-derived DCs, we applied fluorescent latex beads (LXs) intratracheally, thereby in vivo labeling the majority of phagocytic cells within the lung. Of note, LX-bearing cells subsequently arriving in the draining brLN were found to represent lung-derived migratory DCs. Imaging explanted brLN by two-photon laser-scanning microscopy, we quantitatively analyzed the migration and interaction behavior of naive CD4+ T cells and endogenous, lung-derived DC presenting airway-delivered Ag under inflammatory or noninflammatory conditions. Ag-specific naive CD4+ T cells engaged in stable as well as transient contacts with LX-bearing DCs in both situations and displayed similar overall motility kinetics, including a pronounced decrease in motility at 16–20 h after antigenic challenge. In contrast, the comparative analysis of T cell–DC cluster sizes as well as contact durations strongly suggests that lung-derived migratory DCs and naive CD4+ T cells form more stable, long-lasting contacts under inflammatory conditions favoring the induction of respiratory immunity.
Formation of a Mast Cell Synapse: FcεRI Membrane Dynamics upon Binding Mobile or Immobilized Ligands on Surfaces
Authors: Carroll-Portillo Amanda , Spendier Kathrin , Pfeiffer Janet , Griffiths Gary , Li Haitao , Lidke Keith A. , Oliver Janet M. , Lidke Diane S. , Thomas James L. , Wilson Bridget S. , Timlin Jerilyn A.
Published: December 2009

FcεRI on mast cells form a synapse when presented with mobile, bilayer-incorporated Ag. In this study, we show that receptor reorganization within the contacting mast cell membrane is markedly different upon binding of mobile and immobilized ligands. Rat basophilic leukemia mast cells primed with fluorescent anti-DNP IgE were engaged by surfaces presenting either bilayer-incorporated, monovalent DNP-lipid (mobile ligand), or chemically cross-linked, multivalent DNP (immobilized ligand). Total internal reflection fluorescence imaging and electron microscopy methods were used to visualize receptor reorganization at the contact site. The spatial relationships of FcεRI to other cellular components at the synapse, such as actin, cholesterol, and linker for activation of T cells, were also analyzed. Stimulation of mast cells with immobilized polyvalent ligand resulted in typical levels of degranulation. Remarkably, degranulation also followed interaction of mast cells, with bilayers presenting mobile, monovalent ligand. Receptors engaged with mobile ligand coalesce into large, cholesterol-rich clusters that occupy the central portion of the contacting membrane. These data indicate that FcεRI cross-linking is not an obligatory step in triggering mast cell signaling and suggest that dense populations of mobile receptors are capable of initiating low-level degranulation upon ligand recognition.
Mammalian Clock Gene Cryptochrome Regulates Arthritis via Proinflammatory Cytokine TNF-α
Authors: Hashiramoto Akira , Yamane Takashi , Tsumiyama Ken , Yoshida Kohsuke , Komai Koichiro , Yamada Hiroyuki , Yamazaki Fumiyoshi , Doi Masao , Okamura Hitoshi , Shiozawa Shunichi
Published: December 2009

The mammalian clock genes, Period and Cryptochrome (Cry), regulate circadian rhythm. We show that circadian rhythmicity and rhythmic expression of Period in the nuclei of inflammatory synovial cells and spleen cells are disturbed in mouse models of experimental arthritis. Expressions of other clock genes, Bmal1 and Dbp, are also disturbed in spleen cells by arthritis induction. Deletion of Cry1 and Cry2 results in an increase in the number of activated CD3+ CD69+ T cells and a higher production of TNF-α from spleen cells. When arthritis is induced, Cry1−/−Cry2−/− mice develop maximal exacerbation of joint swelling, and upregulation of essential mediators of arthritis, including TNF-α, IL-1β and IL-6, and matrix metalloproteinase-3. Wee-1 kinase is solely upregulated in Cry1−/−Cry2−/− mice, in line with upregulation of c-Fos and Wee-1 kinase in human rheumatoid arthritis. The treatment with anti–TNF-α Ab significantly reduced the severity and halted the progression of the arthritis of Cry1−/−Cry2−/− mice and vice versa, ectopic expression of Cry1 in the mouse embryonic fibroblast from Cry1−/−Cry2−/− mice significantly reduced the trans activation of TNF-α gene. Thus, the biological clock and arthritis influence each other, and this interplay can influence human health and disease.
Model-Independent 3D Descriptors of Vertebral Cancellous Bone Architecture
Authors: Parkinson Ian H. , Forbes Danielle , Sutton-Smith Peter , Fazzalari Nicola L.
Published: December 2009

High-resolution micro computed tomography has enabled measurement of bone architecture derived from 3D representations of cancellous bone. Twenty-eight vertebral bodies were obtained from four embalmed male cadavers. From 3D anaglyphs, trabecular rod thickness and length were measured and the trabecular rod Buckling index was calculated. From 3D voxel-based datasets, bone volume density, trabecular thickness, and trabecular separation were measured. Also, trabecular bone pattern factor, structural model index, connectivity density, and degree of anisotropy were calculated. Bone volume density alone explains 59% of the variability in trabecular rod Buckling index. The addition of connectivity density, trabecular separation, and structural model index, in a multiple regression statistical model, improves the explanatory power to 77%. The relationships between measures of cancellous bone architecture and a derived measure of trabecular rod strength were investigated. Morphological descriptors of cancellous bone provide a composite explanatory model of trabecular rod strength.
Quantum $\mathrm{SO}(3)$ groups and quantum group actions on $M_2$
Authors: Sołtan Piotr M.
Published: January 2010

Answering a question of Shuzhou Wang we give a description of quantum

\mathrm{SO}(3)

groups of Podleś as universal compact quantum groups acting on the

\mathrm{C}^*

-algebra

M_2

and preserving the Powers state. We use this result to give a complete classification of all continuous compact quantum group actions on

M_2

.
Topological graph polynomials and quantum field theory Part I: heat kernel theories
Authors: Krajewski Thomas , Rivasseau Vincent , Tanasă Adrian , Wang Zhituo
Published: January 2010

We investigate the relationship between the universal topological polynomials for graphs in mathematics and the parametric representation of Feynman amplitudes in quantum field theory. In this first article we consider translation invariant theories with the usual heat-kernel-based propagator. We show how the Symanzik polynomials of quantum field theory are particular multivariate versions of the Tutte polynomial, and how the new polynomials of noncommutative quantum field theory are special versions of the Bollobás–Riordan polynomials.
Relatively hyperbolic groups, rapid decay algebras, and a generalization of the Bass conjecture
Authors: Ji Ronghui , Ogle Crichton , Ramsey Bobby W.
Published: January 2010

By deploying dense subalgebras of

ℓ^1(G)

we generalize the Bass conjecture in terms of Connes’ cyclic homology theory. In particular, we propose a stronger version of the

ℓ^1

-Bass Conjecture. We prove that hyperbolic groups relative to finitely many subgroups, each of which posses the polynomial conjugacy bound property and nilpotent periodicity property, satisfy the

ℓ^1

-Stronger–Bass Conjecture. Moreover, we determine the conjugacy bound for relatively hyperbolic groups and compute the cyclic cohomology of the

ℓ^1

-algebra of any discrete group.
A Lefschetz fixed-point formula for certain orbifold $\mathrm C^*$-algebras
Authors: Echterhoff Siegfried , Emerson Heath , Kim Hyun Jeong
Published: January 2010

Using Poincaré duality in K-theory, we state and prove a Lefschetz fixed point formula for endomorphisms of crossed product

\mathrm C^*

-algebras

C_0(X) ⋊ G

coming from covariant pairs. Here

G

is assumed countable,

X

a manifold, and

X ⋊ G

cocompact and proper. The formula in question describes the graded trace of the map induced by the automorphism on K-theory of

C_0(X) ⋊ G

, i.e. the Lefschetz number, in terms of fixed orbits of the spatial map. Each fixed orbit contributes to the Lefschetz number by a formula involving twisted conjugacy classes of the corresponding isotropy group, and a secondary construction that associates, by way of index theory, a group character to any finite group action on a Euclidean space commuting with a given invertible matrix.
Long‐interval T2‐weighted subtraction magnetic resonance imaging: A powerful new outcome measure in multiple sclerosis trials
Authors: Moraal Bastiaan , van den Elskamp Ivo J. , Knol Dirk L. , Uitdehaag Bernard M. J. , Geurts Jeroen J. G. , Vrenken Hugo , Pouwels Petra J. W. , van Schijndel Ronald A. , Meier Dominik S. , Guttmann Charles R. G. , Barkhof Frederik
Published: December 2009

Objective

To compare long‐interval T2‐weighted subtraction (T2w‐Sub) imaging with monthly gadolinium‐enhanced T1‐weighted (Gd‐T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting.

Methods

Magnetic resonance imaging (MRI) data over 9 months from 120 patients (61 treatment, 59 placebo) from the oral temsirolimus trial were used. T2w‐Sub images were scored for active lesions, independent of the original reading of the monthly Gd‐T1w images. Treatment efficacy was evaluated using the nonparametric Mann‐Whitney U test, and parametric negative binomial (NB)‐regression and power calculations were conducted.

Results

Datasets from 116 patients (58 treatment, 58 placebo) were evaluated. The mean number of T2w‐Sub lesions in the treatment group was 3.0 (±4.6) versus 5.9 (±8.8) for placebo; the mean cumulative number of new Gd‐T1w lesions in the treatment group was 5.5(±9.1) versus 9.1(±17.2) for placebo. T2w‐Sub imaging showed increased power to assess treatment efficacy compared with Gd‐T1w imaging, when evaluated by Mann‐Whitney U test (p = 0.017 vs p = 0.177), or NB‐regression without (p = 0.011 vs p = 0.092) or with baseline adjustment (p < 0.001 vs p = 0.002). Depending on the magnitude of the simulated treatment effect, sample size calculations showed reductions of 22 to 34% in the number of patients (translating into reductions of 81–83% in the number of MRI scans) needed to detect a significant treatment effect in favor of T2w‐Sub imaging.

Interpretation

Compared with monthly Gd‐T1w imaging, long‐interval T2w‐Sub MRI exhibited increased power to assess treatment efficacy, and could greatly increase the cost‐effectiveness of phase 2 MS trials by limiting the number of patients, contrast injections, and MRI scans needed. ANN NEUROL 2010;67:667–675
Zwitterionische Verwandte kationischer Platinmetallkomplexe: Anwendungen in der stöchiometrischen und katalytischen σ‐Bindungsaktivierung
Authors: Stradiotto Mark , Hesp Kevin D. , Lundgren Rylan J.
Published: January 2010

Zwitterionische Komplexe von Platinmetallen, die sich durch eine formale Ladungstrennung zwischen einem kationischen Metallfragment und einem negativ geladenen Hilfsliganden auszeichnen, vereinigen das wünschenswerte Reaktivitätsprofil verwandter kationischer Komplexe mit der besseren Löslichkeit und Lösungsmitteltoleranz neutraler Spezies. Daher sind zwitterionische Komplexe dieser Art interessante Kandidaten für vielfältige Anwendungen, insbesondere für Reaktionen, in denen E‐H‐ und E‐C‐σ‐Bindungen zu Hauptgruppenelementen E gespalten und/oder gebildet werden. Hier werden Fortschritte bei der Entwicklung von Hilfsliganden vorgestellt, die die Synthese von Zwitterionen der Platinmetalle ermöglichten, und die Ergebnisse stöchiometrischer und katalytischer Untersuchungen werden zusammengefasst, wobei die Reaktivitäten der Zwitterionen und ihrer üblicherweise eingesetzten kationischen Verwandten bei der σ‐Bindungsaktivierung verglichen werden.
A longitudinal analysis of urinary biochemical markers and bone mineral density in STR/Ort mice as a model of spontaneous osteoarthritis
Authors: Sarukawa Junichiro , Takahashi Masaaki , Doi Mitsuhito , Suzuki Daisuke , Nagano Akira
Published: January 2010

Objective

To investigate the longitudinal changes both in the urinary concentrations of biochemical markers and in bone mineral density (BMD) during disease progression in the STR/Ort mouse model of osteoarthritis (OA).

Methods

Male STR/Ort mice were studied, with CBA mice used as nonarthritic controls. Radiographic evaluation and grading of the knee and measurements of urinary C‐terminal crosslinking telopeptide of type II collagen (CTX‐II), pyridinoline (Pyr), and deoxypyridinoline were performed between 8 weeks and 40 weeks of age. The BMD of the femoral shaft was measured from 20 weeks to 40 weeks of age and adjusted for body weight. Histologic evaluation and grading were performed at 40 weeks of age. STR/Ort mice were divided into 2 subgroups (STR OA and STR non‐OA) based on histologic grading.

Results

No significant differences between STR/Ort and CBA mice were observed for any biochemical marker or BMD at any time point. Urinary CTX‐II levels and BMD in the STR OA subgroup were higher than those in the STR non‐OA subgroup before radiographic changes of OA were apparent. Higher urinary Pyr levels in the STR OA subgroup were observed at the advanced stage of OA.

Conclusion

Urinary CTX‐II could be a useful marker in the early diagnosis and predicting the progression of OA, and urinary Pyr may be a potential marker to assess the severity of OA at an advanced stage. An increase in BMD prior to the establishment of radiographic OA may be related to the induction of OA.
Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model
Authors: Lin Philana Ling , Myers Amy , Smith Le'Kneitah , Bigbee Carolyn , Bigbee Matthew , Fuhrman Carl , Grieser Heather , Chiosea Ion , Voitenek Nikolai N. , Capuano Saverio V. , Klein Edwin , Flynn JoAnne L.
Published: January 2010

Objective

An increased risk of tuberculosis has been documented in humans treated with tumor necrosis factor α (TNFα)–neutralizing agents. In murine models, impaired signaling by TNF causes exacerbation of both acute and chronic infection associated with aberrant granuloma formation and maintenance. This study was undertaken to investigate immune modulation in the setting of TNF neutralization in primary and latent tuberculosis in a non‐human primate model.

Methods

Cynomolgus macaques 4 years of age or older were infected with Mycobacterium tuberculosis and subjected to clinical, microbiologic, immunologic, and radiographic examinations. Monkeys were classified as having active or latent disease 6–8 months after infection, based on clinical criteria. Monkeys used in acute infection studies were randomized to receive either adalimumab (prior to and during infection) or no treatment. Monkeys with latent infection that were randomized to receive TNF‐neutralizing agent were given either an inhibitor of soluble TNF, recombinant methionyl human soluble TNF receptor I (p55‐TNFRI), or adalimumab. Control monkeys with latent infection were given no treatment or saline. Data from previously studied monkeys with active or latent disease were also used for comparison.

Results

Administration of TNF‐neutralizing agents prior to M tuberculosis infection resulted in fulminant and disseminated disease by 8 weeks after infection. Neutralization of TNF in latently infected cynomolgus macaques caused reactivation in a majority of animals as determined by gross pathologic examination and bacterial burden. A spectrum of dissemination was noted, including extrapulmonary disease. Surprisingly, monkeys that developed primary and reactivation tuberculosis after TNF neutralization had similar granuloma structure and composition to that of control monkeys with active disease. TNF neutralization was associated with increased levels of interleukin‐12, decreased levels of CCL4, increased chemokine receptor expression, and reduced mycobacteria‐induced interferon‐γ production in blood but not in the affected mediastinal lymph nodes. Finally, the first signs of reactivation often occurred in thoracic lymph nodes.

Conclusion

These findings have important clinical implications for determining the mechanism of TNF neutralization–related tuberculosis.
Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll‐like receptors
Authors: Sacre Sandra , Medghalchi Mino , Gregory Bernard , Brennan Fionula , Williams Richard
Published: January 2010

Objective

Selective serotonin reuptake inhibitors (SSRIs), in addition to their antidepressant effects, have been reported to have antiinflammatory effects. The aim of this study was to assess the antiarthritic potential of 2 SSRIs, fluoxetine and citalopram, in murine collagen‐induced arthritis (CIA) and in a human ex vivo disease model of rheumatoid arthritis (RA).

Methods

Following therapeutic administration of SSRIs, paw swelling was assessed and clinical scores were determined daily in DBA/1 mice with CIA. Joint architecture was examined histologically at the end of the treatment period. Cultures of human RA synovial membranes were treated with SSRIs, and cytokine production was measured. Toll‐like receptor (TLR) function was examined in murine and human macrophages, human B cells, and human fibroblast‐like synovial cells treated with SSRIs.

Results

Both SSRIs significantly inhibited disease progression in mice with CIA, with fluoxetine showing the greatest degree of efficacy at the clinical and histologic levels. In addition, both drugs significantly inhibited the spontaneous production of tumor necrosis factor, interleukin‐6, and interferon‐γ–inducible protein 10 in human RA synovial membrane cultures. Fluoxetine and citalopram treatment also inhibited the signaling of TLRs 3, 7, 8, and 9, providing a potential mechanism for their antiinflammatory action.

Conclusion

Fluoxetine and citalopram treatment selectively inhibit endosomal TLR signaling, ameliorate disease in CIA, and suppress inflammatory cytokine production in human RA tissue. These data highlight the antiarthritic potential of the SSRI drug family and provide further evidence of the involvement of TLRs in the pathogenesis of RA. The SSRIs may provide a template for potential antiarthritic drug development.
Creating a new synergy on technical and vocational education via a general purpose computer interface unit
Authors: Ari Murat
Published: January 2010

This study is focused on improving and sustaining the analog experiment sets used in the laboratory applications of technical and vocational education (TVE) particularly in Electrical and Electronics by computerizing them to extend their usage period. The study is mainly about the improvement of the V‐LAB and D‐LAB interfaces. As the distance education has been increasingly and widely adopted in the recent years, it became apparent that some laboratory applications can also be adapted into the distance education via improvements including computerization, Internet connectivity, and remote monitoring technologies. This article describes the technical capabilities of the improved analog experiment laboratory systems and discusses the limitations and potential further improvements. The present work will also be a good reference to vocational education. © 2010 Wiley Periodicals, Inc. Comput Appl Eng Educ 20: 364–373, 2012
The tbx/bHLH transcription factor mga regulates gata4 and organogenesis
Authors: Rikin Amir , Evans Todd
Published: December 2009

The mga gene encodes a unique transcription factor containing both TBOX and bHLHzip DNA‐binding domains. Here we describe the structure, expression pattern, and loss‐of‐function phenotype for zebrafish mga. The mga gene is conserved with mammalian homologs for both DNA‐binding domains. It is expressed maternally, and subsequently in the developing brain, heart, and gut, and its depletion causes morphogenetic defects in each of these organ systems. The heart and gut phenotypes are similar to those described previously for loss of gata4, and the mga morphant shows increased levels of gata4 transcripts in lateral mesoderm. Knockdown of gata4 rescues the early heart‐looping defect (but not the gut defect), indicating that mga restricts the normal levels of Gata4 required for heart tube looping, while both genes are important for gut development. Transcript profiling experiments show that mga functions early to influence key regulators of mesendoderm, including tbx6, cas, and sox17. Developmental Dynamics 239:535–547, 2010. © 2009 Wiley‐Liss, Inc.
Agonist‐selective signaling of G protein‐coupled receptor: Mechanisms and implications
Authors: Zheng Hui , Loh Horace H. , Law Ping‐Yee
Published: January 2010

Agonist‐selective signaling or ligand‐biased signaling of G protein‐coupled receptor (GPCR) has become the focus of an increasing number of laboratories. The principle of this concept is that agonist possesses different abilities to activate different signaling pathways. Current review summarizes the observations of agonist‐selective signaling of various GPCRs, indicating the significance of agonist‐selective signaling in biological processes. In addition, current review also provides an overview on how agonist‐selective signaling is initiated. Especially, the relationship between GPCR‐G protein interaction and GPCR‐β‐arrestin interaction is discussed in depth. © 2010 IUBMB IUBMB Life, 62(2): 112–119, 2010
Ab initio periodic study of the conformational behavior of glycine helical homopeptides
Authors: Ferrari Anna Maria , Civalleri Bartolomeo , Dovesi Roberto
Published: January 2010

Representative helicoidal conformations of polyglycine infinite chains have been investigated by using periodic boundary conditions, the B3LYP hybrid functional, and large basis sets, by means of the CRYSTAL code. The exploitation of the helix roto‐translational symmetry permits to optimize at a relatively low cost the structure of systems whose unit cell contains more than 300 atoms, much larger than the one investigated till now. In the present calculations, the helix symmetry is exploited at three levels. First, for the automatic generation of the structure. Second, for the calculation of the one‐ and two‐electron integrals that enter into the Fock matrix definition. Only the irreducible wedge of the Fock matrix is computed. Finally, for the diagonalization of the Fock matrix, where each irreducible representation is separately treated. The efficiency and accuracy of the computational scheme are documented, by considering cells containing up to 47 glycine residues. Results are compared with previous calculations and available experimental data. The role of hydrogen bonding in stabilizing polyglycine conformers is also addressed. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010
Factors associated with developing cholesteatoma: A study of 45,980 children with middle ear disease
Authors: Spilsbury Katrina , Miller Ian , Semmens James B. , Lannigan Francis J.
Published: January 2010

Objectives/Hypothesis:

To identify factors associated with the rate of developing cholesteatoma following ventilation tube insertion (VTI).

Study Design:

A population‐based retrospective cohort study.

Methods:

Administrative health data from all private and public hospitals in Western Australia for children who had at least one VTI from 1980 to 2004 was used to identify subsequent hospital admissions for cholesteatoma. Main outcome measures were time to cholesteatoma (survival) outcomes, including hazard ratios, log‐rank tests, and Kaplan‐Meier failure functions.

Results:

There were 45,980 children who underwent at least one VTI from 1980 to 2004 with 460 subsequently developing cholesteatoma. The cumulative percentage of children who developed cholesteatoma within 15 years after one VTI procedure was 0.9% (95% confidence interval [CI], 0.8–1.0), after two VTIs 2.1% (95% CI, 1.6–2.3), after three VTIs 3.8% (95% CI, 2.9–4.8), and after four or more VTIs 5.2% (95% CI, 4.0–6.7). The rate of developing cholesteatoma increased 10% (95% CI, 6–14) for each additional year in age before first VTI. For children who underwent two or more VTIs, the rate of cholesteatoma increased 21% (95% CI, 12–32) with each additional year between VTIs. Adenoid removal was associated with a 27% (95% CI, 11–40) reduction in the rate of developing cholesteatoma.

Conclusions:

Children with persistent or refractory middle ear disease who required multiple VTIs were at increased risk of cholesteatoma. First ventilation tubes inserted at an early age, subsequent ventilation tubes inserted without delay, and adenoid removal were associated with a reduced rate of cholesteatoma development. Laryngoscope, 2010
Synthesis and Characterisation of Poly[oligo(ε‐caprolactone)L‐malate‐graft‐poly(L‐lactide)]
Authors: Hahn Christian , Keul Helmut , Möller Martin
Published: January 2010

Graft copolyesters with a PCL backbone and PLLA side chains were successfully prepared in three steps avoiding transesterification. First ε‐caprolactone was polymerised with 1,6‐hexane diol as initiator to obtain hydroxytelechelic oligo(ε‐caprolactone)s. These diols were then subjected—in the second step—to polycondensation with L‐malic acid yielding in linear poly[oligo(ε‐caprolactone)L‐malate] having secondary hydroxyl functions in the side chain. For both reactions scandium triflate Sc(OTf)3 was used as a catalyst. In the third step various amounts of L‐lactide were grafted from the polymer backbone using Zn(oct)2 as catalyst. The successful reaction was confirmed by NMR and SEC (size exclusion chromatography) analysis. Further the thermal properties of the graft copolymers with different graft lengths were determined via differential scanning calorimetry.

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