bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Regulation of ARHI in Breast and Ovarian Cancer Cells
Authors: YU YINHUA , FUJII SATOSHI , YUAN JIUHONG , LUO ROBERT Z. , WANG LIN , BAO JIAJU , KADOTA MITSUTAKA , OSHIMURA MITSUO , DENT SHARON R. , ISSA JEAN‐PIERRE , BAST ROBERT C.
Published: July 2009

Abstract: ARHI (Ras homologue member I) encodes a 26‐kDa GTPase with 50–60% amino acid homology to Ras and Rap. ARHI and Ras share similar GTP/GDP binding domains, but exert opposite functions. ARHI is one of the first reported tumor suppressors in the ras superfamily. ARHI is expressed consistently in normal breast and ovarian epithelial cells, but not in breast or ovarian cancers. The loss of ARHI can be related to tumor progression. Reexpression of ARHI induces apoptosis of breast and ovarian cancer cells by a caspase‐independent, calpain‐dependent pathway. ARHI is consistently expressed in normal breast and ovarian epithelial cells but is dramatically downregulated in more then 70% of breast and ovarian cancers. ARHI is maternally imprinted with methylation of the three CpG islands in the maternal allele of normal cells. ARHI is expressed only from the paternal allele whose three CpG islands are not methylated. Loss of ARHI expression can occur through a genetic event, with loss of heterozygosity observed in 40% of breast, ovarian, and pancreatic cancers; but it can also occur through epigenetic mechanisms, including DNA methylation, histone deacetylation, histone methylation, and transcriptional regulation. Our data suggest that acetylation and methylation of chromatin associated with the ARHI promoter leads to loss of both ARHI expression and the ability to suppress tumor growth. Changes in chromatin that silence ARHI may be driven by methylation‐dependent and ‐independent pathways. Reactivation of both the silenced paternal and imprinted maternal alleles can be achieved by demethylation and inhibition of histone deacetylation.
Epigenetic Changes: Potential Therapeutic Targets
Authors: KALEBIC THEA
Published: July 2009

Abstract: Recent advances in human genome research have resulted in novel approaches for the identification of epigenetic modifications associated with cancer. Modulators of DNA methylation and chromatin structure have a dramatic effect on gene expression, cellular proliferation, differentiation, and apoptosis. Molecular pathways regulating epigenetic events that occur during tumorigenesis have been exploited as new targets for therapeutic intervention. Clinical studies exploring the effectiveness of therapeutic agents targeting DNA methylation and acetylation of histones have yielded promising results. Molecular profiles of epigenetic alterations in cancer cells could allow better stratification of patients who may show responsiveness to specific treatments.
Membrane Technologies Applied to Textile Wastewater Treatment
Authors: MARCUCCI MANUELE , CIABATTI INGRID , MATTEUCCI ALESSANDRO , VERNAGLIONE GUIDO
Published: July 2009

Abstract: This paper describes the experimental results of a pilot‐scale application of membrane technologies to textile wastewater advanced treatment, downstream of a biological activated sludge process, aimed at water reuse in textile technology processes. The chosen approach consisted of sand filtration as a pretreatment, a microfiltration (MF) or ultrafiltration (UF) membrane process, and a final separation treatment performed by means of a nanofiltration (NF) or a reverse osmosis (RO) membrane. An experimental study to compare spiral wound membranes, operating under pressure, to flat membranes, operating under vacuum was conducted. The technical results and a preliminary economic analysis indicate the possibility of technological transfer of the membrane technologies to an industrial scale for textile wastewater reclamation.
Water Quality Monitoring in Membrane Filtration Systems
Authors: ABOGREAN ELHADI M. , BOERLAGE SIOBHAN F.E. , KENNEDY MARIA D. , EL‐AZIZI IBRAHIM M. , GALJAARD GILBERT , SCHIPPERS JAN S.
Published: July 2009

Abstract: We report on an experimental study of UF membrane fouling by colloidal particles. Deposition colloidal particles during membrane filtration causes a decline in permeate flux. Membrane flux is monitored on a laboratory scale, crossflow employing UF membranes. The existing modified fouling index (MFI) uses a microfilter membrane as a quick test of feed water quality. The MFI is based on cake filtration, and thus, a model can be developed for flux decline predication. However, this MFI is not sensitive to the presence of smaller particles. Therefore, more recently MFI using ultrafiltration membranes (MFI‐UF) was developed. This research investigates various critical aspects of the MFI‐UF test for use as a water quality indicator; stability of the MFI‐UF over time, linearity of the index with particulate concentration, and reproducibility (1) of the test (reusability of a UF module) and (2) module manufacture. Pressure dependence of the MFI‐UF was also examined. The aforementioned criteria were examined using a polyacrylonitrile module with 13,000 molecular weight cutoff for low fouling (tap and process water). The MFI‐UF was stable over time and directly related to colloidal concentration. The MFI‐UF test was reproducible for one module with repeated testing; reproducible module manufacture was found for 80% of the test modules.
Removal and Recovery of Metals and Other Materials by Supported Liquid Membranes with Strip Dispersion
Authors: HO W.S. WINSTON
Published: July 2009

Abstract: This paper reviews recent advances in supported liquid membranes (SLMs) with strip dispersion for removal and recovery of metals including chromium, copper, zinc, and strontium; it also discusses potential applications of SLMs for removal and recovery of other materials, including cobalt and penicillin G. The technology for chromium that we developed, not only removes the Cr(VI) from about 100–1,000 ppm to less than 0.05 ppm in the treated effluent allowable for discharge or recycle, but also recovers the chromium product at a high concentration of about 20% Cr(VI) (62.3% Na2CrO4) suitable for resale or reuse. In other words, we have achieved the goals of zero discharge and no sludge. The stability of the SLM is ensured by a modified SLM with strip dispersion, where the aqueous strip solution is dispersed in the organic membrane solution in a mixer. The strip dispersion formed is circulated from the mixer to the membrane module to provide a constant supply of the organic solution to the membrane pores. The copper SLM system that we have identified, not only removed the copper from 150 ppm in the inlet feed to less than 0.15 ppm in the treated feed, but also recovered the copper at a high concentration of greater than 10,000 ppm in the strip solution. For the zinc SLM system identified, zinc at an inlet feed concentration of 550 ppm was removed to less than 0.3 ppm in the treated feed, whereas a high zinc concentration of more than 17,000 ppm was recovered in the strip solution. For strontium removal, we synthesized a family of new extractants, alkyl phenylphosphonic acids. The SLM removed radioactive 90Sr to the target of 8 pCi/L or lower from feed solutions of 300–1,000 pCi/L. The SLM removed cobalt from about 525 ppm to 0.7 ppm in the treated feed solution, concentrating it to at least 30,000 ppm in the aqueous strip solution. Concerning penicillin G recovery, the SLM removed penicillin G from a feed of 8,840 ppm and concentrated it to a high concentration of 41,011 ppm in the aqueous strip solution with a high recovery of about 93%.
Membrane Separation in Green Chemical Processing
Authors: LIVINGSTON ANDREW , PEEVA LUDMILA , HAN SHEJIAO , NAIR DINESH , LUTHRA SATINDER SINGH , WHITE LLOYD S. , FREITAS DOS SANTOS LUISA M.
Published: July 2009

Abstract: This paper describes ideas together with preliminary experimental results for applying solvent nanofiltration to liquid phase organic synthesis reactions. Membranes for organic solvent nanofiltration have only recently (during the 1990s) become available and, to date, have been applied primarily to food processing (vegetable oil processing, in particular) and refinery processes. Applications to organic synthesis, even at a laboratory feasibility level, are few. However, these membranes have great potential to improve the environmental performance of many liquid phase synthesis reactions by reducing the need for complex solvent handling operations. Examples that are shown to be feasible are solvent exchanges, where it is desired to swap a high molecular weight molecule from one solvent to another between separate stages in a complex synthesis, and recycle and reuse of homogeneous catalysts. In solvent exchanges, nanofiltration is shown to provide a fast and effective means of swapping from a high boiling point solvent to a solvent with a lower boiling point—this is a difficult operation by means of distillation. Solvent nanofiltration is shown to be able to separate two distinct types of homogeneous catalysts, phase transfer catalysts and organometallic catalysts, from their respective reaction products. In both cases the application of organic solvent nanofiltration allows several reuses of the same catalyst. Catalyst stability is shown to be an essential requirement for this technique to be effective. Finally, we present a discussion of scale‐up aspects including membrane flux and process economics.
The Use of Conducting Polymers in Membrane‐Based Separations
Authors: PELLEGRINO JOHN
Published: July 2009

Abstract: As a material family, π‐conjugated polymers (also known as intrinsically conductive polymers) elicit the possibility of both exploiting the chemical and physical attributes of the polymer for membrane‐based separations and incorporating its electronic and electrochemical properties to enhance the separation figures‐of‐merit. This review article, although by no means comprehensive, provides a current snapshot of the investigations from many research laboratories in the use of conducting polymers for membrane‐based separations. The review focuses primarily on polyaniline, polypyrrole, and substituted‐polythiophene and includes applications in gas separations, liquid (and/or vapor) separations, and ion separations. Additionally, we discuss the broad challenges and accomplishments in membrane formation from conducting polymers.
Thin Composite Palladium and Palladium/Alloy Membranes for Hydrogen Separation
Authors: MA YI HUA , MARDILOVICH IVAN P. , ENGWALL ERIK E.
Published: July 2009

Abstract:Dense composite Pd and Pd/alloy membranes are currently being extensively investigated. The synthesis and characterization of these membranes, with a special emphasis on Pd/alloy membranes, are reviewed in this paper. Experimental results on Pd/Cu membranes supported on porous stainless steel exhibited good thermal stability and reasonable hydrogen flux. Furthermore, optical micrographs showed the formation of the dense palladium layer was unaffected by the topological features of the porous stainless steel, although the surface of the support directs the topology of the final Pd layer.
Mixed Matrix Membrane Development
Authors: KULPRATHIPANJA SANTI
Published: July 2009

Abstract: Two types of mixed matrix membranes were developed by UOP in the late 1980s. The first type includes adsorbent polymers, such as silicalite‐cellulose acetate (CA), NaX‐CA, and AgX‐CA mixed matrix membranes. The silicalite‐CA has a CO2/H2 selectivity of 5.15 ± 2.2. In contrast, the CA membrane has a CO2/H2 selectivity of 0.77 ± 0.06. The second type of mixed matrix membrane is PEG‐silicone rubber. The PEG‐silicone rubber mixed matrix membrane has high selectivity for polar gases, such as SO2, NH3, and H2S.
Membrane Bioreactors for Treating Waste Streams
Authors: HOWELL J. A. , ARNOT T. C. , LIU W.
Published: July 2009

Abstract: Membrane bioreactors (MBRs) have a number of advantages for treating wastewater containing large quantities of BOD. This paper reviews the inherent advantages of an MBR, which include high potential biomass loadings, lower sludge yields, and retention of specialized organisms that may not settle well in clarifiers. A major problem in effluent treatment occurs when mixed inorganic and organic wastes occur with high concentrations of pollutants. Inorganics that might cause extremes of pH and/or salinity will inhibit microbial growth and only specialized organisms can survive under these conditions. Refractory organics are only biodegraded with difficulty by specialized organisms, which usually do not resist the extreme inorganic environments. The use of membrane bioreactors to help separate the micro‐organisms from the inorganic compounds, yet permit the organics to permeate, has been developed in two different designs that are outlined in this paper. The use of membrane contactors in a multimembrane stripping system to treat acidic chlorinated wastes is proposed and discussed.
Why and How Membrane Bioreactors with Unsteady Filtration Conditions Can Improve the Efficiency of Biological Processes
Authors: DAUBERT ISABELLE , MERCIER‐BONIN MURIEL , MARANGES CLAUDE , GOMA GÉRARD , FONADE CHRISTIAN , LAFFORGUE CHRISTINE
Published: July 2009

Abstract: A membrane bioreactor (MBR), an association of a bioreactor with a crossflow filtration unit, enables continuous processes with total cell retention within the reactor to be realized. Provided that high dilution rates can be applied and that inhibition processes are avoided, very high biomass concentrations can be reached, thereby improving the volumetric productivities. These membrane bioreactors have been successfully applied to various microbial bioconversion, such as alcoholic fermentation, solvents, organic acid production, starters, and wastewater treatment. On the basis of the biological reaction characteristics and bibliographic results, the potentialities and bottlenecks of this methodology are discussed. Depending on the application, it is shown how the performance of the membrane bioreactor can be enhanced by acting either on the biological reaction achievement, by controlling the balance between cell growth and death, or on the dilution rate, by increasing the permeate flux through the filtration unit. This discussion is based on results obtained in specific biological treatments applied to polluted liquid and gas.
Effect of Immobilization Site and Membrane Materials on Multiphasic Enantiocatalytic Enzyme Membrane Reactors
Authors: LI N.A. , GIORNO LIDIETTA , DRIOLI ENRICO
Published: July 2009

Abstract: In the experimental work reported here the optical resolution of racemic naproxen methyl ester with crude lipase immobilized in a membrane reactor was studied. The multiphasic enantiocatalytic enzyme membrane reactor consisted of an organic phase that dissolved the naproxen methyl ester, a lipase‐loaded membrane, and an aqueous phase that extracted the reaction product. Lipase preferentially converted the (S)‐naproxen methyl ester to (S)‐naproxen acid that was simultaneously separated by a membrane. The effect of the immobilization site and membrane type on the performance of the enzyme membrane reactor was studied. Capillary polyamide membrane with 10kDa nominal molecular weight cutoff (NMWCO) and polysulfone membrane with 30kDa NMWCO were applied, with lipase loaded in the sponge layer or on a membrane thin layer. With various immobilization sites and membrane types, the enzyme membrane reactors showed different productivity and enantioselectivity resulting from the varying amounts of immobilized enzyme and varying microenvironment of the hydrolysis reaction. Higher amounts of immobilized enzyme led to increased productivity and generally higher enantioslectivity of the membrane reactor. It seems that the location of organic/aqueous interface on membrane, which plays an important role in a multiphasic enzyme membrane reactor, was influenced by the immobilization site and membrane type and this affected the productivity and enantioselectivity. As much as 90% enantioexcess was obtained with a polyamide membrane, and lower values with a polysulfone membrane. A sponge layer of polyamide membrane is the preferred immobilization site for its higher productivity than a thin membrane layer, and for its higher enantioselectivity than a polysulfone membrane. In comparison with the unstable hydrolysis activity of free lipase in stirred tank reactor, a stable lipase activity can be obtained with the lipase‐immobilized membrane reactor, irrespective of whether a polyamide or polysulfone membrane is used.
Designing Blood Oxygenators
Authors: WICKRAMASINGHE S. R. , GOERKE A. R. , GARCIA J. D. , HAN BINBING
Published: July 2009

Abstract: Extracorporeal blood oxygenators are used to provide cardiopulmonary support during open heart surgery. In the study reported here, mass transfer correlations were determined for commercially available blood oxygenators. Two configurations used commercially, flow outside and across bundles of hollow fibers and flow in thin channels between parallel flat sheet membranes, were investigated. Water and glycerol/water mixtures were used as a substitute for blood. Diffusion of oxygen into and out of these solutions was studied. For flow across bundles of hollow fibers, the mass transfer correlations derived here are in agreement with analogous correlations for crossflow heat exchangers. However, for flow in thin channels, the rate of mass transfer is often less than predicted from theory. This compromised mass transfer can be explained by considering slight variations in the thickness of the blood flow channels. The mass transfer correlations developed here could be used to design better blood oxygenators.
Membrane Evaporative Cooling to 30°C or Less
Authors: LOEB SIDNEY
Published: July 2009

Abstract: Microporous hydrophobic membranes have been examined for possible use as containers in the evaporative cooling of water, particularly in desert climates. An experimental determination was made of the overall heat and mass transfer coefficients of these membranes while surmounting contained water and with air flowing over the surface of the membranes. Similar tests were made with water alone, that is, without a membrane. The coefficients were then used to compare the performance of existing (canvas water) coolers and membrane evaporative coolers under desert conditions. The performance of the membrane coolers was close enough to that of the canvas coolers that extensive investigation of various aspects of membrane evaporative cooling appears to be justified, particularly in view of the potential advantages of the latter over the existing evaporative cooling methods. For example, for cool storage of perishable goods in a desert climate, the membrane container might be uniquely qualified because of its low rate of water consumption compared to that of a canvas cooler.
Activation‐Induced Cytidine Deaminase Links Class Switch Recombination and Somatic Hypermutation
Authors: OKAZAKI ILMI , YOSHIKAWA KIYOTSUGU , KINOSHITA KAZUO , MURAMATSU MASAMICHI , NAGAOKA HITOSHI , HONJO TASUKU
Published: July 2009

Abstract: Activation‐induced cytidine deaminase (AID), a putative RNA‐editing cytidine deaiminase that is expressed strictly in activated B cells, is indispensable in three apparently distinct genetic alterations of immunoglobulin genes—namely, class switch recombination, somatic hypermutation, and gene conversion. Recent findings led us to propose a common DNA cleaving mechanism, in which the transient secondary structure of the S and V region DNA is recognized by a nicking enzyme regulated by the putative RNA‐editing activity of AID.
Molecular Mechanisms of B Cell Antigen Receptor Trafficking
Authors: CLARK MARCUS R. , MASSENBURG DON , ZHANG MIAO , SIEMASKO KARYN
Published: July 2009

Abstract: B lymphocytes are among the most efficient cells of the immune system in capturing, processing, and presenting MHC class II restricted peptides to T cells. Antigen capture is essentially restricted by the specificity of the clonotypic antigen receptor expressed on each B lymphocyte. However, receptor recognition is only one factor determining whether an antigen is processed and presented. The context of antigen encounter is crucial. In particular, polyvalent arrays of repetitive epitopes, indicative of infection, accelerate the delivery of antigen to specialized processing compartments, and up‐regulate the surface expression of MHC class II and co‐stimulatory molecules such as B7. Recent studies have demonstrated that receptor‐mediated signaling and receptor‐facilitated peptide presentation to T cells are intimately related. For example, rapid sorting of endocytosed receptor complexes through early endosomes requires the activation of the tyrosine Syk. This proximal kinase initiates all BCR‐dependent signaling pathways. Subsequent entry into the antigen‐processing compartment requires the tyrosine phosphorylation of the BCR constituent Igα and direct recruitment of the linker protein BLNK. Signals from the BCR also regulate the biophysical and biochemical properties of the targeted antigen‐processing compartments. These observations indicate that the activation and recruitment of signaling molecules by the BCR orchestrate a complex series of cellular responses that favor the presentation of even rare or low‐affinity antigens if encountered in contexts indicative of infection. The requirement for BCR signaling provides possible mechanisms by which cognate B:T cell interactions can be controlled by the milieu in which antigen engagement occurs.
Activation of Rheumatoid Factor (RF) B Cells and Somatic Hypermutation Outside of Germinal Centers in Autoimmune‐Prone MRL/lpr Mice
Authors: SHLOMCHIK MARK J. , EULER CHAD W. , CHRISTENSEN SEAN C. , WILLIAM JACQUELINE
Published: July 2009

Abstract: Two critical questions need to be answered concerning the origins of autoreactive B cells in autoimmunity. First, how are autoreactive B cells regulated in normal situations? Second, how do such B cells escape tolerance mechanisms during autoimmunity? To address these questions, an Ig transgenic (Tg) mouse system based on the rheumatoid factor (RF) specificity has been developed. Tg mice express either the H or both H and L chains from AM14, an MRL/lpr‐derived RF. Using this system, it was first shown that RF B cells are neither tolerized nor activated in a normal mouse. New insights into the timing and sites of initial RF B cell activation in MRL/lpr mice have been gained recently. RF B cells are activated. It was found, unexpectedly, that RF B cell activation, somatic hypermutation, and selection take place outside of the germinal center. We discuss the implications of this for the regulation of autoreactive B cells as well as for the regulation of hypermutation.
Mechanisms of Autoantibody Diversification to SLE‐Related Autoantigens
Authors: DESHMUKH UMESH S. , GASKIN FELICIA , LEWIS JANET E. , KANNAPELL CAROL C. , FU SHU MAN
Published: July 2009

Abstract: Systemic lupus erythematosus is a prototype of systemic autoimmunity with autoantibodies (autoAbs) to ribonucleoproteins such as Ro/La, snRNP, dsDNA, and other cellular constituents. A/J mice were used to explore the mechanism of autoAb diversification with recombinant proteins and synthetic peptides. Previous studies showed that Ro60316–335 induced Abs to Ro60, La, and snRNP proteins. Specific Abs to determinants outside Ro60316‐335 were detected. Absorption experiments showed that Abs to La and snRNP proteins were due to the induction of anti‐Ro60 Abs cross‐reactive with these peptides. With snRNP proteins, SmD, SmB, and A‐RNP as immunogens, specific patterns of intermolecular spreading were obtained in addition to Abs to the immunogens. With SmD‐immunized mice, specific Abs to A‐RNP and SmB were detected. With SmB as the immunogen, specific Abs to A‐RNP were detected in the majority of the mice. Only in a rare incident, specific Abs to SmD were induced. In A‐RNP‐immunized mice, only Abs to the 70‐kD U1‐RNP were seen. In all cases, Abs capable of precipitating snRNP particles were detected. Thus, the intermolecular epitope spreading is immunogen‐dependent. Evidence for the presence of cross‐reactive T cells to more than one autoAg was obtained. The Ag‐dependent unique patterns of Ab diversification will facilitate analyses of patients' sera. These results have implications regarding the nature of the Ag‐driven autoimmune process.
Role of Homeostatic Chemokine and Sphingosine‐1‐Phosphate Receptors in the Organization of Lymphoid Tissue
Authors: MÜLLER GERD , REITERER PHILLIP , HÖPKEN UTA E. , GOLFIER SVEN , LIPP MARTIN
Published: July 2009

Abstract: Chemokines regulate both homeostatic leukocyte recirculation and trafficking to sites of infection and inflammation. Apart from the well‐established physiological functions, chemokines receive growing interest for their role in pathophysiological processes such as autoimmune diseases, cancer, and allograft rejection. The chemokine receptor CCR7, which is responsible for directing T cells, B cells, and dendritic cells (DCs) into secondary lymphoid organs and their precise positioning therein, has already been implicated in lymphoid organ infiltration by neoplastic cells and the localization of metastasis formation. We have shown that the differential expression of CCR7 by neoplastic cells in two entities of Hodgkin's disease (HD), classic HD (cHD) and the nodular lymphocyte predominant HD (NLPHD), may account for the differences observed in tumor cell dissemination within the affected lymph nodes. Because of the prominent role of the chemokine receptors CCR7 and CXCR5 in lymphocyte homing to secondary lymphoid organs, we hypothesized that they may also be involved in the action of FTY720, a synthetic immunosuppressant inducing lymphopenia. By using CXCR5 and CCR7 knockout mice, we have tested for a possible function of these receptors in the FTY720‐induced migration of lymphocytes into Peyer's patches (PPs) and peripheral lymph nodes (PLNs). Lymphopenia is noticeably delayed in mice lacking CCR7, whereas CXCR5 knockout mice show a significant reduction of lymphocyte accumulation in secondary lymphoid organs that are infrequently present in these mice. However, FTY720‐induced lymphocyte sequestration appears to be essentially independent of CCR7 and CXCR5.
The Human Marginal Zone B Cell
Authors: DONO MARIELLA , ZUPO SIMONA , COLOMBO MONICA , MASSARA ROSANNA , GAIDANO GIANLUCA , TABORELLI GIUSEPPE , CEPPA PAOLA , BURGIO VITO L. , CHIORAZZI NICHOLAS , FERRARINI MANLIO
Published: July 2009

Abstract: This study describes the features of the marginal zone (MZ) B cells of human tonsils and spleens and compares them with those of the follicular mantle (FM) B cells from the same tissues. The two B cell subpopulations displayed marked differences in phenotype, in response capacity to T cell‐independent antigens and polyclonal B cell activators, and in presentation of antigens to T cells. FM B cells expressed surface CD5, and hence should be considered as B1 cells by current nomenclature. Fractionation of MZ B cells according to the presence or absence of surface IgD revealed the presence of two subsets. These subsets were characterized by different properties, including the presence of Ig VH gene mutations and the response capacity to TI‐2 antigens, this latter property being associated with IgD‐positive cells. Comparison of the data with those reported for mice revealed that human MZ B cells had strong analogies with both the murine MZ and B1 cells. In contrast, human B1 cells (that is, CD5‐positive FM cells) were considerably different, an observation that should prompt further studies. Indeed, B cells with characteristics analogous to those of murine B1 cells were detected in small but definite proportions in the peripheral blood and tonsils. If the current distinction into B1 and B2 cells has to be maintained also for humans, it is likely that only these CD5‐positive cells rather than the FM B cells should be called B1 cells.
Ectopic Germinal Center Formation in Rheumatoid Synovitis
Authors: WEYAND CORNELIA M. , GORONZY JÖRG J.
Published: July 2009

Abstract: Synovial inflammation in rheumatoid arthritis is closely related to the formation of ectopic lymphoid microstructures. In synovial tissue from some patients, one finds seemingly diffuse infiltrates; in others, T cells and B cells cluster in aggregates with interdigitating dendritic cells (DCs) but no follicular DCs (FDCs). In a third group, T cell/B cell follicles with germinal center (GC) reactions are generated. Within a given patient, aggregates and GCs are mutually exclusive and stable over time. Because antigen storage capacity, lymphoid density, and three‐dimensional topography of GCs optimize immune responses, synovial GCs should play a crucial role in the breakdown of self‐tolerance. We have identified factors critical for ectopic GCs, thereby transforming the synovial inflammatory process. Tissues with GCs produced 10‐ to 20‐fold higher amounts of the chemokines CXCL13 and CCL21. CXCL13 derived from three sources, endothelial cells, synovial fibroblasts, and FDC networks. The level of CXCL13 transcripts strongly predicted GCs; however, some tissues had high levels of CXCL13 but lacked GCs. Tissue expression of LT‐β emerged as a second key factor. LT‐β protein was detected on follicular center and mantle zone B cells. Multivariate regression analysis identified CXCL13 and LT‐β as the only cytokines predicting GCs. Remarkably, LT‐α did not contribute independently. The contribution of B cells to ectopic lymphoid organogenesis was not limited to LT‐β production. Rather, synovial tissue B cells were critical in regulating T cell activation. In adoptive transfer experiments in human synovium‐SCID mouse chimeras, activation of synovium‐derived CD4 T cells was strictly dependent on T cell/B cell follicles. Depletion of synovial tissue B cells abrogated T cell function, and non‐B cell antigen‐presenting cells could not maintain T cell stimulation. Unexpectedly, GC function in the rheumatoid lesion was also dependent on CD8 T cells. The majority of T cell receptors derived from CD8 T cells were shared between distinct GCs. Depletion of CD8 T cells disrupted synovial GCs, FDC networks disappeared, and transcription of LT‐β, IgG, and Igκ declined. Follicle‐sustaining CD8 T cells were located at the edge of or within the mantle zone. Cell‐cell communication in the mantle zone, including CD8 T cells, appears to be critical for ectopic GC formation in rheumatoid synovitis.
Gene Expression Dynamics during Germinal Center Transit in B Cells
Authors: KLEIN ULF , TU YUHAI , STOLOVITZKY GUSTAVO A. , KELLER JEFFREY L. , HADDAD JOSEPH , MILJKOVIC VLADAN , CATTORETTI GIORGIO , CALIFANO ANDREA , DALLA‐FAVERA RICCARDO
Published: July 2009

Abstract: The germinal center (GC) reaction in T cell dependent antibody responses is crucial for the generation of B cell memory and plays a critical role in B cell lymphomagenesis. To gain insight into the physiology of this reaction, we identified the transcriptional changes that occur in B cells during the GC‐transit (naïve B cells → CD77+ centroblasts (CBs) → CD77− centrocytes (CCs) → memory B cells) by DNA microarray experiments and the subsequent data analysis employing unsupervised and supervised hierarchical clustering. The naïve B cell is characterized by a nonproliferative, anti‐apoptotic phenotype and the expression of various chemokine and cytokine receptors. The transition from naïve B cells to CBs is associated with (1) the up‐regulation of genes associated with cellular proliferation, DNA‐repair, and chromatin remodeling; (2) the acquisition of a pro‐apoptotic phenotype; (3) the down‐regulation of cytokine, chemokine, and adhesion receptors expressed in the naïve cells; and (4) the expression of a distinct adhesion repertoire. The CB and the CC revealed surprisingly few gene expression differences, suggesting that the CC is heterogeneous in its cellular composition. The CB/CC to memory B cell transition shows a general reversion to the profile characteristic for the naïve B cells, with the exception of the up‐regulation of several surface receptors, including CD27, CD80, and IL‐2Rβ, and the simultaneous expression of both anti‐ and pro‐apoptotic genes. These gene expression profiles of the normal B cell subpopulations are being used to identify the signals occurring during GC development, the cellular derivation of various types of B cell malignancies, and the genes deregulated in GC‐derived tumors.
Dendritic Cells
Authors: BANCHEREAU JACQUES , PACZESNY SOPHIE , BLANCO PATRICK , BENNETT LYNDA , PASCUAL VIRGINIA , FAY JOSEPH , PALUCKA A. KAROLINA
Published: July 2009

Abstract: The immune system is controlled by dendritic cells (DCs). Just as lymphocytes comprise different subsets, DCs comprise several subsets that differentially control lymphocyte function. In humans, the myeloid pathway includes Langerhans cells (LCs) and interstitial DCs (intDCs). While both subsets produce IL‐12, only intDCs make IL‐10 and induce B cell differentiation. Another pathway includes plasmacytoid DCs, which promptly secrete large amounts of IFN‐α/β viral encounter. Thus, insights into in vivo DC functions are important to understand the launching and modulation of immunity.
Co‐Stimulatory Blockade in the Treatment of Murine Systemic Lupus Erythematosus (SLE)
Authors: DAVIDSON ANNE , WANG XIAOBO , MIHARA MASAHIKO , RAMANUJAM MEERA , HUANG WEIQING , SCHIFFER LENA , SINHA JAYASHREE
Published: July 2009

Abstract: Although the life span of patients with systemic lupus erythematosus (SLE) has improved considerably over the last several decades, the toxicities of chronic immunosuppressive therapy are major causes of morbidity and mortality. Safer and more effective therapies for SLE are clearly needed. SLE is characterized by excessive activation of both B and T lymphocytes. Activation of these cells requires both antigen engagement and co‐stimulatory signals from interacting lymphocytes (Carreno, B.M. & M. Collins, 2002, Annu. Rev. Immunol. 20: 29–53; Grewal, I.S. & R.A. Flavell, 1998, Annu. Rev. Immunol. 16: 111–135). Thus, blockade of co‐stimulatory signals offers a new therapeutic approach to SLE. Our short‐term goal has been to understand the effect of co‐stimulatory blocking reagents on the development, selection, and activation of pathogenic anti‐dsDNA antibody producing B cells in mice genetically pre‐determined to develop SLE and showing signs of either early or advanced disease activity. Our long‐term goal is to use the knowledge we gain to design therapeutic regimens for humans that avoid the complications of long‐term immunosuppression. As new co‐stimulatory molecules are discovered, studying their mechanism of action in animal models and their clinical utility in human autoimmune disease should lead both to a new understanding of disease pathogenesis and also to safer and more effective therapies.
The Transfer of Immunity from Mother to Child
Authors: HANSON LARS Å. , KOROTKOVA MARINA , LUNDIN SAMUEL , HÅVERSEN LILJANA , SILFVERDAL SVEN‐ARNE , MATTSBY‐BALTZER INGER , STRANDVIK BIRGITTA , TELEMO ESBJÖRN
Published: July 2009

Abstract: The newborn's immune system grows fast from a small size at birth by exposure primarily to the intestinal microflora normally obtained from the mother at and after birth. While building up its immune system, the infant is supported by the transplacental IgG antibodies, which also contain anti‐idiotypic antibodies, possibly also actively priming the offspring. The second mode of transfer of immunity occurs via the milk. Numerous major protective components, including secretory IgA (SIgA) antibodies and lactoferrin, are present.

The breastfed infant is better protected against numerous common infections than the non‐breastfed. Breastfeeding also seems to actively stimulate the infant's immune system by anti‐idiotypes, uptake of milk lymphocytes, cytokines, etc. Therefore, the breastfed child continues to be better protected against various infections for some years. Vaccine responses are also often enhanced in breastfed infants. Long‐lasting protection against certain immunological diseases such as allergies and celiac disease is also noted.
Peptide Mimics of a Major Lupus Epitope of SmB/B′
Authors: KAUFMAN KENNETH M. , KIRBY MONICA Y. , HARLEY JOHN B. , JAMES JUDITH A.
Published: July 2009

Abstract: One of the most distinguishing features of systemic lupus erythematosus is the presence of high concentrations of autoantibodies that recognize a limited number of self‐antigens. Even though many lupus autoantigens have been identified, the inciting triggers of these abnormal immune responses are not fully understood. One mechanism that could generate these autoantibodies is a normal immune response toward a foreign epitope that mimics a common antigenic target of an autoantigen. Antibody generated toward the foreign epitope could also bind the autoantigen. This ‘cross‐reactivity’ would result in the presentation of the autoantigen to the immune system. Under autoimmune‐prone conditions, tolerance toward the native protein is broken and an autoimmune response is initiated. Previously, it was suggested that Epstein‐Barr virus might use such a mechanism to initiate an autoimmune response. Cross‐reactive epitopes may have a similar amino acid sequence or a similar tertiary structure that is independent of amino acid sequence. A major, and likely initial, target of the lupus anti‐SmB′ response is a repeated, proline‐rich sequence, PPPGMRPP. To identify potential cross‐reactive targets, we used affinity‐purified autoantibodies specific for PPPGMRPP to screen a random heptapeptide phage display library. Eighty‐five clones were isolated and sequenced with eleven distinct sequence motifs being identified. Two of these motifs were homologous to the SmB′ epitope, while the other nine were not. Interestingly, one of the peptide motifs that mimicked the SmB′ epitope is identical to a peptide sequence found in the Epstein‐Barr virus major DNA binding protein.
A Genome‐Wide Analysis of the Acute‐Phase Response and Its Regulation by Stat3β
Authors: DESIDERIO STEPHEN , YOO JOO‐YEON
Published: July 2009

Abstract: The acute‐phase response (APR) is the systemic inflammatory component of innate immunity. A global assessment of hepatic gene expression during an APR has been undertaken. In response to endotoxin, an inducer of the APR, about 7% of mouse genes exhibited significant changes in expression. Genes for cholesterol, fatty acid, and phospholipid synthesis were suppressed, while genes participating in innate defense and antigen presentation were induced. Upon challenge with endotoxin, mice deficient in Stat3β, a dominant‐negative variant of Stat3, exhibited impaired recovery and susceptibility to protracted shock. These findings are accompanied by overexpression and hyperresponsiveness of a subset of lipopolysaccharide (LPS)‐inducible genes in liver, suggesting a critical role for Stat3β in the control of systemic inflammation.
Structural Explanation in Chemistry and Its Evolving Forms
Authors: HARRÉ ROM
Published: July 2009

Abstract: Historically, there has been a close relationship between the concepts of structure and of shape. Is the relationship a matter of fact or is it conceptual? Exploring this question with examples enables us to distinguish several senses of structure. Clearly, spatial shape is not conceptually related to constitutive structure, since a molecule may consist only of an ordered set of potentialities. The concept of structure in chemistry developed in the nineteenth century from an ambiguous but essentially taxonomic use in type theory to a realist hypothesis as to the spatial distribution of atoms in the molecule. This development required a defense of the Daltonian view of elements as constituted by minute corpuscularian atoms. Once a realist concept of structure had been established, the issue of the nature of structural explanation could then be addressed. Template explanation formats as well as jigsaw formats can be found in chemistry. The problem of halting a regress of structural explanations leads to a sketch of a way in which physics can serve as a heterogeneous foundation for chemistry without reductionist implications.
The Ignis Fatuusa of Reduction and Unification
Authors: VAN BRAKEL J.
Published: July 2009

Abstract: Given the enormous variety of possible intertheoretical relations, the proliferation of definitions of reduction, supervenience, emergence, unification, and so on, as well as the fact that empirical studies have provided support for almost any metaphysical option or, alternatively, have shown rather conclusively that empirically the case is inconclusive, I suggest a moratorium on the use of words such as ‘reduction,’‘supervenience,’ and ‘unification’ and to go back to the rough ground and give perspicuous renderings of the practice of chemistry. What is needed are very detailed case studies and further discussions about them, instead of bickering about whether chemistry can be reduced to physics, supervenes on it, can be unified with it, and similar ‘metaphysical’ concerns.
Natural Kinds, Explanation, and Essentialism in Chemistry
Authors: VIHALEMM REIN
Published: July 2009

Abstract: The problem of natural kinds in chemistry is analyzed, proceeding mainly from Rom Harré's and Jaap van Brakel's writings. The problem of natural kinds proves to be different in general philosophy and in philosophy of science. This problem, which originally emerged at the borderline of science and philosophy, belongs to the domain of philosophy of science. Philosophy in general cannot hope that scientific knowledge will help to explain philosophical issues. Chemistry has to be taken very seriously in philosophy of science. Not only do empirical arguments indicate that chemistry should be regarded as a typical science, but it is also relevant for elaborating a theoretical model of science. Chemistry as the science of substances is well suited for the philosophical analysis of the role of the concept of natural kinds in science. The viability of the concept of a natural kind in philosophy of chemistry derives from the explanatory role of chemical natural kinds. The problem of explanation in its turn relates natural kinds to the laws of nature and scientific theories, that is, to classical issues in philosophy of science and to discussions on their (supposed) specificity in chemistry. In philosophy of science, one can demonstrate that there exists a third option between metaphysical realism and internal realism (to use Putnam's terminology). According to this third type of realism our ‘world versions’ (including natural kinds identified by us), but not the world itself, are relative to us.
The Primary Properties?
Authors: VOLLMER S. H.
Published: July 2009

Abstract: Science is concerned not just with objects but also with their various aspects, such as their colors, temperatures, sizes, and shapes. These aspects, or properties, are generally thought to be of at least two kinds: primary properties, such as shape, size, and motion and secondary ones, such as temperature and color. However, there is little agreement on just what the difference is between these two kinds of properties. An argument has recently been put forth that assumes the two kinds of properties differ only in that the secondary ones are dependent on the conditions under which they are observed. This paper suggests, however, that since the primary properties depend on conditions, too, any argument based on this assumption is flawed. There are two main traditional accounts of the distinction. The first account of the distinction—the ideas of primary qualities resemble the properties that cause these ideas, whereas those of the secondary ones do not resemble them—relies on what to many is an implausible assumption, that some of our ideas resemble features of the world and we can speak intelligibly about such resemblances. This paper suggests that we cannot, and hence we have no more reason to believe that the ideas of the primary qualities resemble aspects of the world than we do that those of the secondary qualities do so. The second traditional account—primary properties are those a body has, however small it might be, whereas secondary properties are a consequence just of relations between bodies—fares better than the other two accounts. However, the notion of force posed a serious problem for this second basis for the distinction, one that has, astonishingly, hardly found its way into the philosophical literature.
Chemical Kinetics and Dynamics
Authors: PRIGOGINE ILYA
Published: July 2009

Abstract: Chemical reactions correspond to irreversible processes creating entropy. Chemistry belongs to the class of nonintegrable Poincare systems. In general, chemistry is associated with resonances—transitions of quantum states. We have studied some very simple examples of such processes, like decay of an unstable state, in detail. (In such cases, there are always multiple time scales.) We obtain a nonunitary (‘star unitary’), invertible, nondistributive operator Λ (which reduces to the unitary transformation operator U for integrable systems). The explicit form of Λ depends on the interaction of each species with all other types of molecules in the system including the solvent. The basic property that results from Λ is that the fundamental description of nonintegrable systems is no longer in terms of Hamiltonian equations, but in terms of kinetic equations with broken time symmetry. Once we have the kinetic equations, it is easy to show that we have irreversible processes and entropy production.
Physical Explanation of the Periodic Table
Authors: OSTROVSKY V. N.
Published: July 2009

Abstract: The Periodic Table of the elements, the most important generalization in chemistry, is often considered as a representative special case in the study of the relation between chemistry and physics. Its quantum interpretation was initiated, but not completed, by Niels Bohr. In this paper, post‐Bohr conceptual developments are discussed from historical and epistemological points of view. The difference between high‐precision numerical calculations for individual atoms and the theory of the periodic system as a whole is emphasized. Periodic laws met in Nature are not restricted to the chemical Periodic Table. A comparative study of these laws makes it possible to single out essential features that define the particular pattern of periodicity. It is shown that the periodic system of neutral ground state atoms now has a firm nonempirical quantum‐theoretical basis. Alternative approaches, based on group theory and other mathematical schemes, are briefly discussed. It is argued that, while quantum theory is capable of fully accurate calculations for relatively simple atoms or molecular objects, the complexity of polyatomic molecules and chemical reactions guarantees the flourishing of chemistry as a separate scientific discipline.
Negotiated Identities of Chemical Instrumentation
Authors: ROBERTS JODY A.
Published: July 2009

Abstract: What is an NMR spectrometer? Beginning with this seemingly simple question, I will explore the development of nuclear magnetic resonance spectroscopy between the years 1956 and 1969 from two vantage points: the organic chemists who used the new instrument, and Varian Associates—the makers of the first NMR spectrometers—. Through an examination of the articles and advertisements published in the Journal of Organic Chemistry, I will draw two conclusions. First, organic chemists and Varian Associates (along with other actors) are co‐responsible for the development of nuclear magnetic resonance spectroscopy (i.e., NMR spectroscopy was not created by a single actor). Second, by changing the way NMR spectrometers are used, organic chemists attempted to change to the identity of the instrument. Similarly, when Varian Associates advertised their NMR spectrometers in a different way, they, too, attempted to change the identity of the instrument.