bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Improves Cardiometabolic Risk and Renal Inflammation in Murine Lupus
Authors: Zhao Wenpu , Thacker Seth G. , Hodgin Jeffrey B. , Zhang Hongyu , Wang Jeffrey H. , Park James L. , Randolph Ann , Somers Emily C. , Pennathur Subramaniam , Kretzler Matthias , Brosius Frank C. , Kaplan Mariana J. 
Published: July 2009

AbstractIndividuals with systemic lupus erythematosus (SLE) have a striking increase in the risk of premature atherosclerosis, a complication preceded by significant subclinical vascular damage. A proposed mechanism leading to accelerated vascular disease in SLE is an imbalance between vascular damage and repair, as patients with this disease display significant abnormalities in phenotype and function of endothelial progenitor cells. In addition, individuals with SLE have a higher incidence of insulin resistance which may further contribute to the increased cardiovascular risk. This study examined the role of the peroxisome proliferator activated receptor γ agonist pioglitazone in improving endothelial function, endothelial progenitor cell numbers and functional capacity, metabolic parameters, and disease activity in the lupus-prone murine model New Zealand Black/New Zealand White (NZB × NZW)F1. Ten-week-old prenephritic female NZB/NZW F1 mice were exposed to 10 or 25 mg/kg/day of oral pioglitazone or vehicle for 15 or 24 wk. Mice exposed to pioglitazone exhibited pronounced enhancement in endothelial-dependent vasorelaxation of thoracic aortas and in endothelial progenitor cell function, as assessed by the capacity of bone marrow-derived endothelial progenitor cells to differentiate into mature endothelial cells. Pioglitazone-treated mice showed improvement in insulin resistance, adipokine, and lipid profile. Kidneys from pioglitazone-treated mice showed significant decreases in immune complex deposition, renal inflammation, T cell glomerular infiltration, and intrarenal synthesis of TNF-α, IL-1β, and VCAM-1. These results indicate that peroxisome proliferator-activated receptor γ agonists could serve as important tools in the prevention of premature cardiovascular disease and organ damage in SLE.
Perturbation of the CD4 T Cell Compartment and Expansion of Regulatory T Cells in Autoimmune-Prone Lyn-Deficient Mice
Authors: Tsantikos Evelyn , Quilici Cathy , Harder Kenneth W. , Wang Bo , Zhu Hong-Jian , Anderson Gary P. , Tarlinton David M. , Hibbs Margaret L. 
Published: July 2009

Abstract
Regulatory T cells (Tregs) are a subset of T lymphocytes that are responsible for suppressing the function of other immune cells, and preventing potentially harmful autoimmune responses. Studies in autoimmune-prone mice and human autoimmune diseases have shown reduced Treg number or function as a causative factor for the apparent loss of tolerance that contributes to disease. We have found that Lyn-deficient mice, which develop high titers of autoantibodies with age, have a perturbed Treg compartment. Contrary to what has been observed in some strains of autoimmune-prone mice, aged Lyn-deficient mice have increased numbers of Tregs. This expansion occurs in the presence of elevated serum IL-2 and diminished TGF-β. Despite expansion of the Treg compartment, Lyn-deficient mice succumb at ∼1 year of age due to immune complex-mediated glomerulonephritis. We have shown that Lyn is not expressed in Tregs or indeed in any T cell subset, suggesting that the expansion and apparent functional deficiency in Tregs in Lyn-deficient mice is due to extrinsic factors rather than an intrinsic Treg defect. Indeed, using an in vivo colitis model, we have shown that Lyn-deficient Tregs can suppress inflammation. These results suggest that Tregs are expanding in Lyn-deficient mice in an effort to control the autoimmune disease but are simply overwhelmed by the disease process. This study highlights the role of the inflammatory setting in autoimmune disease and its consideration when contemplating the use of Tregs as an autoimmune therapy.
Regulation of Inflammatory Monocyte/Macrophage Recruitment from the Bone Marrow during Murine Cytomegalovirus Infection: Role for Type I Interferons in Localized Induction of CCR2 Ligands
Authors: Crane Meredith J. , Hokeness-Antonelli Kirsten L. , Salazar-Mather Thais P. 
Published: July 2009

Abstract
Monocytes/macrophages are critical early innate immune responders during murine CMV (MCMV) infection. It has been established that inflammatory monocyte/macrophages are released from the bone marrow and into the peripheral blood before entry into infected tissue sites. We previously reported a role for IFN-α/β in promotion of CCR2-mediated recruitment of monocyte/macrophages into the liver in response to MCMV infection. However, the mechanisms that support the migration of monocyte/macrophages from the bone marrow and into the peripheral blood under conditions of MCMV infection have not been elucidated. Herein, we demonstrate an accumulation of monocyte/macrophages in the bone marrow of MCMV-infected CCR2-deficient mice, whereas circulating monocyte/macrophages are profoundly diminished. The CCR2 ligands MCP-1, MCP-3, and MCP-5 are detected in bone marrow and in serum from MCMV-infected mice. Furthermore, bone marrow leukocytes from naive mice produce high levels of MCP-1 and MCP-5, and moderate levels of MCP-3, when stimulated with recombinant IFN-α in culture. We identify bone marrow F4/80+ cells as major producers of MCP-1, MCP-3, and MCP-5. Moreover, induction of CCR2 ligands is dependent on IFN-α/β-mediated signals and MCMV infection. Taken together, the results reveal a critical role for inflammatory cytokines in stimulating production of CCR2-binding chemokines from F4/80+ cells in the bone marrow, and they suggest that local production of chemokines supports monocyte/macrophage egress from the bone marrow into the blood during a virus infection.
Human Neutrophils Kill Streptococcus pneumoniae via Serine Proteases
Authors: Standish Alistair J. , Weiser Jeffrey N. 
Published: July 2009

Abstract
Neutrophils, or polymorphonuclear leukocytes, comprise a crucial component of innate immunity, controlling bacterial and fungal infection through a combination of both oxidative and nonoxidative mechanisms. Indeed, neutrophils are believed to play an important role in controlling infection caused by the major human pathogen Streptococcus pneumoniae. However, the method by which neutrophils kill the pneumococcus as well as other Gram-positive bacteria, is not fully understood. We investigated human neutrophil killing of the pneumococcus in a complement-dependent opsonophagocytic assay. In contrast to other Gram-positive organisms, inhibition of the NADPH oxidase did not affect killing of S. pneumoniae. Supernatant from degranulated neutrophils killed the pneumococcus, suggesting a role for granular products. When neutrophil granule proteases were inhibited with either a protease mixture, or specific serine protease inhibitors 4-(2-Aminoethyl)benzenesulfonylfluoride and diisopropylfluorophosphate, killing by neutrophils was inhibited in a manner that correlated with increased intracellular survival. All three compounds inhibited intracellular activity of the three major neutrophil serine proteases: elastase, cathepsin G, and proteinase 3. Additionally, purified elastase and cathepsin G were sufficient to kill S. pneumoniae in a serine protease dependent-manner in in vitro assays. Inhibition studies using specific inhibitors of these serine proteases suggested that while each serine protease is sufficient to kill the pneumococcus, none is essential. Our findings show that Gram-positive pathogens are killed by human neutrophils via different mechanisms involving serine proteases.
Interactions between Innate Antiviral and Atopic Immunoinflammatory Pathways Precipitate and Sustain Asthma Exacerbations in Children
Authors: Subrata Lily S. , Bizzintino Joelene , Mamessier Emilie , Bosco Anthony , McKenna Katherine L. , Wikström Matthew E. , Goldblatt Jack , Sly Peter D. , Hales Belinda J. , Thomas Wayne R. , Laing Ingrid A. , LeSouëf Peter N. , Holt Patrick G. 
Published: July 2009

Abstract
Severe asthma exacerbations in children requiring hospitalization are typically associated with viral infection and occur almost exclusively among atopics, but the significance of these comorbidities is unknown. We hypothesized that underlying interactions between immunoinflammatory pathways related to responses to aeroallergen and virus are involved, and that evidence of these interactions is detectable in circulating cells during exacerbations. To address this hypothesis we used a genomics-based approach involving profiling of PBMC subpopulations collected during exacerbation vs convalescence by microarray and flow cytometry. We demonstrate that circulating T cells manifest the postactivated “exhausted” phenotype during exacerbations, whereas monocyte/dendritic cell populations display up-regulated CCR2 expression accompanied by phenotypic changes that have strong potential for enhancing local inflammation after their recruitment to the atopic lung. Notably, up-regulation of FcεR1, which is known to markedly amplify capacity for allergen uptake/presentation to Th2 effector cells via IgE-mediated allergen capture, and secondarily programming of IL-4/IL-13-dependent IL-13R+ alternatively activated macrophages that have been demonstrated in experimental settings to be a potent source of autocrine IL-13 production. We additionally show that this disease-associated activation profile can be reproduced in vitro by cytokine exposure of atopic monocytes, and furthermore that IFN-α can exert both positive and negative roles in the process. Our findings suggest that respiratory viral infection in atopic children may initiate an atopy-dependent cascade that amplifies and sustains airway inflammation initiated by innate antiviral immunity via harnessing underlying atopy-associated mechanisms. These interactions may account for the unique susceptibility of atopics to severe viral-induced asthma exacerbations.
Sphingosine 1-Phosphate Enhances Fcγ Receptor-Mediated Neutrophil Activation and Recruitment under Flow Conditions
Authors: Florey Oliver , Haskard Dorian O. 
Published: July 2009

Abstract
Sphingosine 1-phosphate (S1P) is a bioactive phospholipid that is released by platelets and endothelial cells and has been implicated in diverse biological functions. We hypothesized that S1P may influence immune complex-mediated polymorphonuclear neutrophil activation. Using flow cytometry and fluorescence spectrometry, we found that exogenous addition of S1P led to an enhanced polymorphonuclear neutrophil Fcγ receptor-mediated rise in intracellular Ca2+ and reactive oxygen species generation in a pertussis toxin-independent manner, while having only a small effect by itself. Thus, S1P amplifies a positive feedback loop where Fcγ receptor-mediated rises in Ca2+ and reactive oxygen species are interdependent, with reactive oxygen species acting to increase tyrosine phosphorylation and activity of upstream signaling intermediates. S1P augmentation of Fcγ receptor signaling translates to downstream functional consequences, including shape change and recruitment to endothelial surfaces coated with suboptimal levels of immune complexes. Taken together, S1P from activated platelets or endothelial cells may serve to amplify leukocyte recruitment and tissue injury at sites of immune complex deposition in vasculitis.
Helios Deficiency Has Minimal Impact on T Cell Development and Function
Authors: Cai Qi , Dierich Andrée , Oulad-Abdelghani Mustapha , Chan Susan , Kastner Philippe 
Published: July 2009

Abstract
Helios is a member of the Ikaros family of zinc finger transcription factors. It is expressed mainly in T cells, where it associates with Ikaros-containing complexes and has been proposed to act as a rate-limiting factor for Ikaros function. Overexpression of wild-type or dominant-negative Helios isoforms profoundly alters αβ T cell differentiation and activation, and endogenous Helios is expressed at strikingly high levels in regulatory T cells. Helios has also been implicated as a tumor suppressor in human T cell acute lymphoblastic leukemias. These studies suggest a central role for Helios in T cell development and homeostasis, but whether this protein is physiologically required in T cells is unclear. We report herein that inactivation of the Helios gene by homologous recombination does not impair the differentiation and effector cell function of αβ and γδ T cells, NKT cells, and regulatory T cells. These results suggest that Helios is not essential for T cells, and that its function can be compensated for by other members of the Ikaros family.
Promiscuous Zinc‐Dependent Acylase‐Mediated One‐Pot Synthesis of Monosaccharide‐Containing Pyrimidine Derivatives in Organic Medium
Authors: Wu Qi , Xu Jian‐Ming , Xia Li , Wang Jun‐Liang , Lin Xian‐Fu 
Published: July 2009

AbstractA facile one‐pot synthesis route to monosaccharide‐containing pyrimidine derivatives was developed by combining the two types of catalytic activities of one enzyme in an organic medium, i.e., the Michael addition/acylation activities of zinc‐dependent D‐aminoacylase (DA) from Escherichia coli. First, the stepwise approach was investigated. DA showed higher activity towards the Michael addition than acylation in this reaction system. The enzymatic Michael additions of pyrimidines to vinyl acrylate proceeded very rapidly and the initial reaction rates for the Michael addition of pyrimidines to vinyl acrylate were 7.2–16.5 mM min−1. The catalytic specificity of aminoacylases toward Michael addition was demonstrated by the combination of different control experiments. Then, the two steps could be performed in one pot and a single aminoacylase catalyzed one‐pot biotransformation was constructed. Using this strategy, a series of saccharide‐pyrimidine complexes with potentially biological and pharmacological applications was prepared efficiently. This high Michael addition activity of zinc‐dependent aminoacylases and the novel single aminoacylase‐catalyzed one‐pot synthesis combining two catalytic activities in vitro is of practical significance in expanding the application of enzymes and in the evolution of new biocatalysts.
Improved Chiral Olefin Metathesis Catalysts: Increasing the Thermal and Solution Stability via Modification of a C1‐Symmetrical N‐Heterocyclic Carbene Ligand
Authors: Savoie Jolaine , Stenne Brice , Collins Shawn K. 
Published: July 2009

AbstractFour new ruthenium‐based olefin metathesis catalysts that possess an N‐heterocyclic carbene (NHC) ligand with benzyl (Bn) or or n‐propyl (n‐Pr) N‐alkyl groups have been prepared. The synthetic routes developed for the synthesis of the required dihydroimidazolium salts are general. Catalysts bearing larger NHC ligands with larger N‐alkyl groups displayed improved thermal and solution state stability up to 80 °C. The reactivity of the new catalysts in ring‐closing metathesis is directly related to the increased steric bulk of the NHC ligand. The new catalysts have been evaluated in desymmetrization reactions and the nature of the N‐alkyl group of the NHC ligands has been shown to have an important effect on the observed enantioselectivities.
Quality in clinical genetics
Authors: Williams Marc S. 
Published: July 2009

AbstractApplication of quality improvement techniques to medical care has the potential to improve the quality of care, reduce variability in practice, and optimize medical and service outcomes and cost. While becoming more common in other specialties, clinical genetics is only beginning to address these issues. There are a number of challenges to the application of quality improvement to a specialty where rare and ultra‐rare disorders are the rule rather than the exception. This article briefly reviews some of these challenges while introducing the articles in this issue of Seminars. © 2009 Wiley‐Liss, Inc.
Improving service delivery by evaluation of the referral pattern and capacity in a clinical genetics setting
Authors: McCann Emma , Baines Elizabeth A. , Gray Jonathon R. , Procter Annie M. 
Published: July 2009

AbstractQuality improvement in specialist services such as clinical genetics is challenging largely due to the complexity of the service and the difficulty in obtaining accurate, reproducible, and measurable data. The objectives were to evaluate the pattern of referrals to the All Wales Medical Genetics Service (AWMGS) North Wales Genetics team based in three separate hospitals, define the capacity of the team and implement change to improve equity, timeliness and efficiency of care delivery to patients. The methodology required collating the monthly referral rates retrospectively for each center over a 2.5‐year period and plotting on statistical process control charts. Process mapping of the referral process in each center was undertaken, differences documented and a common pathway implemented. “Did not attend” and “time to first appointment” rates were also measured in one center. PDSA methodology was used to implement “patient focused booking.” The results show that the range for referral rates in any given month for each center was 3–33 referrals. The range for referral rate for the whole team was 18–64 per month. Since January 2004 the average number of monthly referrals to the North Wales service has increased by 50%. The potential range in monthly referrals varies between centers and the range of the variability has also increased also in two out of the three centers. Introduction of Patient Focused Booking reduced the “Failed to Attend” rate and 100% of patients were offered a choice of appointments. In addition 100% had a first face‐to‐face contact within 6 weeks if they chose. The measurement of improvement involved firstly introducing a series of continuous measures to provide a baseline for the process prior to the implementation of any changes and secondly to indicate the impact of the changes following implementation. The measures implemented included process (referrals numbers, percentage of patients offered a choice of appointments), outcome (percentage of patients seen within 6 weeks and the percentage failing to attend), and balancing measures (percentage declining the service or failing to respond). It was concluded that general tools of quality improvement can be used to good effect within specialist services. Good processes and accurate, reproducible and measurable data are essential. Small changes can have a major impact both on the quality of the service offered and the ability to deliver the service. © 2009 Wiley‐Liss, Inc.
Preparation and properties of wheat straw fiber‐polypropylene composites. I. Investigation of surface treatments on the wheat straw fiber
Authors: Pan Ming‐Zhu , Zhou Ding‐Guo , Deng James , Zhang S. Y. 
Published: July 2009

AbstractEffects of alkalization, acetylation, and maleic anhydride grafted polypropylene (MAPP) treatments on the thermal and chemical properties of the wheat straw fiber were investigated using thermogravimetric analysis, infrared spectrophotometer, X‐ray diffraction, and scanning electric microscopy techniques. It was found that the wheat straw fiber was not prone to weight loss at 170°C and the treated wheat straw fiber exhibited more thermal stability than the untreated wheat straw fiber. Alkalization increased relative cellulose content and exhibited more crystalline due to a rearrangement of the crystalline regions. It also prolonged the degradation of the wheat straw fiber at higher temperatures due to the increased crystallinity of cellulose. Compared with alkalization, acetylation had more effect on the thermal and chemical stability in the wheat straw fiber contributing to a formation of ester bonding. MAPP improved the thermal stability partly because of a lower grafted ratio of maleic anhydride. Acetylation and MAPP treatment both decreased the crystallinity of the wheat straw fiber. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Cell biology of molybdenum
Authors: Mendel Ralf R. 
Published: July 2009

AbstractThe transition element molybdenum (Mo) is an essential micronutrient that is needed as catalytically active metal during enzyme catalysis. In humans four enzymes depend on Mo: sulfite oxidase, xanthine oxidoreductase, aldehyde oxidase, and mitochondrial amidoxime reductase. In addition to these enzymes, plants harbor a fifth Mo‐enzyme namely nitrate reductase. To gain biological activity and fulfill its function in enzymes, Mo has to be complexed by a pterin compound thus forming the molybdenum cofactor. This article will review the way that Mo takes from uptake into the cell, via formation of the molybdenum cofactor and its storage, up to the final insertion of the molybdenum cofactor into apometalloenzymes. © 2009 International Union of Biochemistry and Molecular Biology, Inc.
A predictive high‐throughput scale‐down model of monoclonal antibody production in CHO cells
Authors: Legmann Rachel , Schreyer H. Brett , Combs Rodney G. , McCormick Ellen L. , Russo A. Peter , Rodgers Seth T. 
Published: July 2009

AbstractMulti‐factorial experimentation is essential in understanding the link between mammalian cell culture conditions and the glycoprotein product of any biomanufacturing process. This understanding is increasingly demanded as bioprocess development is influenced by the Quality by Design paradigm. We have developed a system that allows hundreds of micro‐bioreactors to be run in parallel under controlled conditions, enabling factorial experiments of much larger scope than is possible with traditional systems. A high‐throughput analytics workflow was also developed using commercially available instruments to obtain product quality information for each cell culture condition. The micro‐bioreactor system was tested by executing a factorial experiment varying four process parameters: pH, dissolved oxygen, feed supplement rate, and reduced glutathione level. A total of 180 micro‐bioreactors were run for 2 weeks during this DOE experiment to assess this scaled down micro‐bioreactor system as a high‐throughput tool for process development. Online measurements of pH, dissolved oxygen, and optical density were complemented by offline measurements of glucose, viability, titer, and product quality. Model accuracy was assessed by regressing the micro‐bioreactor results with those obtained in conventional 3 L bioreactors. Excellent agreement was observed between the micro‐bioreactor and the bench‐top bioreactor. The micro‐bioreactor results were further analyzed to link parameter manipulations to process outcomes via leverage plots, and to examine the interactions between process parameters. The results show that feed supplement rate has a significant effect (P < 0.05) on all performance metrics with higher feed rates resulting in greater cell mass and product titer. Culture pH impacted terminal integrated viable cell concentration, titer and intact immunoglobulin G titer, with better results obtained at the lower pH set point. The results demonstrate that a micro‐scale system can be an excellent model of larger scale systems, while providing data sets broader and deeper than are available by traditional methods. Biotechnol. Bioeng. 2009; 104: 1107–1120. © 2009 Wiley Periodicals, Inc.