Biomedical subjects

D Liu

Publications and source records attributed to D Liu.

At least 217 records · Page 12Linked to original sources

PubMed2000

Effects of Cu2+ on root growth, cell division, and nucleolus of Helianthus annuus L.

The effects of different concentrations (10-5 - 10-2 M) of copper sulfate on root growth, cell division and nucleoli in root-tip cells of Helianthus annuus L. were investigated. Cu had an inhibitory effect on the root growth at 10-4 - 10-2 M during the entire treatment. Cu has toxic effects on chromosomal morphology including anaphase bridges and chromosome stickiness and on nucleoli, causing some similar silver-stained particulate material scattered in the nuclei. Once the nucleolus is poisoned, showing some silver-stained particles scattered in the nucleus, the root growth of H. annuus is obviously inhibited. And once more silver-stained particles appear in the nucleus, the root growth is almost or completely stopped. The possible mechanism of the Cu poisoning of root-tip cells of H. annuus is also briefly discussed.

Cell Division↗

PubMed2000

Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells.

Bcl-2 and related proteins are key regulators of apoptosis or programmed cell death implicated in human disease including cancer. We recently showed that cell-permeable Bcl-2 binding peptides could induce apoptosis of human myeloid leukemia in vitro and suppress its growth in severe combined immunodeficient mice. Here we report the discovery of HA14-1, a small molecule (molecular weight = 409) and nonpeptidic ligand of a Bcl-2 surface pocket, by using a computer screening strategy based on the predicted structure of Bcl-2 protein. In vitro binding studies demonstrated the interaction of HA14-1 with this Bcl-2 surface pocket that is essential for Bcl-2 biological function. HA14-1 effectively induced apoptosis of human acute myeloid leukemia (HL-60) cells overexpressing Bcl-2 protein that was associated with the decrease in mitochondrial membrane potential and activation of caspase-9 followed by caspase-3. Cytokine response modifier A, a potent inhibitor of Fas-mediated apoptosis, did not block apoptosis induced by HA14-1. Whereas HA14-1 strongly induced the death of NIH 3T3 (Apaf-1(+/+)) cells, it had little apoptotic effect on Apaf-1-deficient (Apaf-1(-/-)) mouse embryonic fibroblast cells. These data are consistent with a mechanism by which HA14-1 induces the activation of Apaf-1 and caspases, possibly by binding to Bcl-2 protein and inhibiting its function. The discovery of this cell-permeable molecule provides a chemical probe to study Bcl-2-regulated apoptotic pathways in vivo and could lead to the development of new therapeutic agents.

Animals↗

PubMed2000

Peptide-directed suppression of a pro-inflammatory cytokine response.

Signal-dependent nuclear translocation of transcription factor nuclear factor kappaB (NF-kappaB) is required for the activation of downstream target genes encoding the mediators of immune and inflammatory responses. To inhibit this inducible signaling to the nucleus, we designed a cyclic peptide (cSN50) containing a cell-permeable motif and a cyclized form of the nuclear localization sequence for the p50-NF-kappaB1 subunit of NF-kappaB. When delivered into cultured macrophages treated with the pro-inflammatory agonist lipopolysaccharide, cSN50 was a more efficient inhibitor of NF-kappaB nuclear import than its linear analog. When delivered into mice challenged with lipopolysaccharide, cSN50 potently blocked the production of proinflammatory cytokines (tumor necrosis factor alpha and interferon gamma) and significantly reduced the lethality associated with ensuing endotoxic shock. Based on specificity studies conducted with a mutated form of cSN50, a functional nuclear localization motif is required for this protective effect. Taken together, our findings demonstrate effective targeting of a cell-permeable peptide that attenuates cytokine signaling in vivo. This new class of biological response modifiers may be applicable to the control of systemic inflammatory reactions.

Amino Acid Sequence↗

PubMed2000

A zebrafish ftz-F1 (Fushi tarazu factor 1) homologue requires multiple subdomains in the D and E regions for its transcriptional activity.

A zebrafish Ftz-F1 homologue, zFF1A (zebrafish Ff1a or Nr5a2, a member of nuclear receptor superfamily) and its C-terminally truncated variant (zFF1B) were previously identified. Due to lack of the identity box (I-box) and activation function 2 (AF-2) domain, zFF1B lacks transactivation function and fails to synergize with estrogen receptor (ER) in regulating promoters. It was speculated that the I-box might be involved in the zFF1A/ER interaction. In the present study, the function of the I-box was examined. In the absence of the I-box or with an altered heptad 9, the AF-2 of zFF1A was not functional, either in the presence or absence of ER. The GST pull-down assay showed that zFF1A and its mutants exerted similar physical contacts with ER-LBD, suggesting that the "dimerization" domain (I-box) is essential for the transcriptional activity of zFF1A. Moreover, nuclear receptor coactivator selectively activated zFF1 with the I-box but exerted no effect on zFF1B, indicating that the I-box is able to interact with the coactivators. By deletion study and analysis of the identified domains in GAL4-DNA binding domain, other regions of zFF1A critical for its AF were also delineated. Consistent with the mutation analysis, AF-2 was active only in the presence of the I-box. We also identified a novel AF domain (AF-3) located in the hinge region (amino acids 155-267), although the activity of AF-3 was inhibited by its flanking region. We suggest that the D and E regions of zFF1A possess both positive and negative transactivation functions, and interdomain "cross-talk" may confer the full transcriptional activity of the protein.

Amino Acid Sequence↗

PubMed2000

Zebrafish ftz-f1 gene has two promoters, is alternatively spliced, and is expressed in digestive organs.

Fushi-tarazu Factor-1 (FTZ-F1) is a family of nuclear receptors involved in various developmental processes. We have cloned a zebrafish FTZ-F1 gene, termed ff1, which belongs to the fetoprotein transcription factor/liver receptor homologue-1 (FTF/LRH-1) subgroup of the FTZ-F1 family. Four transcripts arise as a result of differential promoter usage and alternative splicing at the 3'-most exons. The longer transcript, form A, encodes a transcriptional activator. The shorter transcript, form B, lacks the activation domain, and hence could not activate transcription. The difference in promoter usage generates FF1 proteins with different N-terminal sequences. All four transcripts appear to be expressed in most of the adult tissues, whereas, during embryo development, the IIA form is the predominant transcript. Reverse transcriptase-PCR and in situ hybridization experiments showed that the ff1 transcript is expressed in the hypothalamus, spinal cord, mandibular arch and digestive organs, including pancreas, liver, and intestine. The expression of ff1 in the digestive organs implies its function in gut development.

Alternative Splicing↗

PubMed2000

LEA.135 expression: an independent and favorable prognostic biomarker for patients with primary invasive breast cancer.

The prognostic significance of LEA.135 expression, detected by immunohistochemistry in formalin-fixed and paraffin-embedded tissue sections, was evaluated and compared with the widely utilized clinicopathological parameters for patients with primary invasive breast carcinomas. Pathological parameters such as tumor size, histological tumor type, histological grade, nuclear grade, lymph node (LN) status, bone marrow (BM) status, as well as age of patient at initial diagnosis together with follow-up in years were available for this group of patients (n = 178). Among these parameters, tumor size, histological tumor type, histological grade, LN status, and BM status were individually and significantly associated with increased probability of recurrence by univariate analysis. By multivariate analysis, however, only tumor size, LN status, and BM status remained statistically significant. LEA.135-positive patients showed a statistically significant probability of not recurring (77 +/- 5% at 5 years after surgery) compared with patients who were LEA. 135-negative (49 +/- 6% at 5 years after surgery) (log-rank p < 0. 001). Furthermore, the association remained statistically significant by multivariate analysis (log-rank p = 0.019), demonstrating that LEA.135 expression independently and significantly identified breast cancer patients with favorable clinical outcome. In addition, there was a statistically significant association between loss of LEA.135 expression and poor prognosis when patients were stratified by pathological parameters. Furthermore, a subgroup of patients who were LEA. 135-positive/LN-negative experienced a decreased rate of recurrence compared with those who were LEA.135-negative/LN-negative (16% vs. 27%, respectively). A similar result was also obtained when BM-negative patients were stratified on the basis of LEA. 135-positive or LEA.135-negative subgroups for recurrence (18% vs. 43%, respectively). Most interestingly, the patients whose cancer cells were LEA.135-positive/LN-positive experienced a much lower rate of recurrence than those whose cells were LEA. 135-negative/LN-positive (29% vs. 57%, respectively). The results clearly demonstrate that LEA.135 expression was a significantly independent and favorable prognostic marker for patients with primary invasive breast carcinoma by both univariate and multivariate analyses.

Adult↗

PubMed2000

The RIP-like kinase, RIP3, induces apoptosis and NF-kappaB nuclear translocation and localizes to mitochondria.

A RIP-like protein, RIP3, has recently been reported that contains an N-terminal kinase domain and a novel C-terminal domain that promotes apoptosis. These experiments further characterize RIP3-mediated apoptosis and NF-kappaB activation. Northern blots indicate that rip3 mRNA displays a restricted pattern of expression including regions of the adult central nervous system. The rip3 gene was localized by fluorescent in situ hybridization to human chromosome 14q11.2, a region frequently altered in several types of neoplasia. RIP3-mediated apoptosis was inhibited by Bcl-2, Bcl-x(L), dominant-negative FADD, as well as the general caspase inhibitor Z-VAD. Further dissection of caspase involvement in RIP3-induced apoptosis indicated inhibition by the more specific inhibitors Z-DEVD (caspase-3, -6, -7, -8, and -10) and Z-VDVAD (caspase-2). However, caspase-1, -6, -8 and -9 inhibitors had little or no effect on RIP3-mediated apoptosis. Mutational analysis of RIP3 revealed that the C-terminus of RIP3 contributed to its apoptotic activity. This region is similar, but distinct, to the death domain found in many pro-apoptotic receptors and adapter proteins, including FAS, FADD, TNFR1, and RIP. Furthermore, point mutations of RIP3 at amino acids conserved among death domains, abrogated its apoptotic activity. RIP3 was localized by immunofluorescence to the mitochondrion and may play a key role in the mitochondrial disruptions often associated with apoptosis.

Amino Acid Sequence↗

PubMed2000

Mouse mammary tumor virus-Ki-rasB transgenic mice develop mammary carcinomas that can be growth-inhibited by a farnesyl:protein transferase inhibitor.

For Ras oncoproteins to transform mammalian cells, they must be posttranslationally modified with a farnesyl group in a reaction catalyzed by the enzyme farnesyl:protein transferase (FPTase). Inhibitors of FPTase have therefore been developed as potential anticancer agents. These compounds reverse many of the malignant phenotypes of Ras-transformed cells in culture and inhibit the growth of tumor xenografts in nude mice. Furthermore, the FPTase inhibitor (FTI) L-744,832 causes tumor regression in mouse mammary tumor virus (MMTV)-v-Ha-ras transgenic mice and tumor stasis in MMTV-N-ras mice. Although these data support the further development of FTIs, it should be noted that Ki-ras is the ras gene most frequently mutated in human cancers. Moreover, Ki-RasB binds more tightly to FPTase than either Ha- or N-Ras, and thus higher concentrations of FTIs that are competitive with the protein substrate may be required to inhibit Ki-Ras processing. Given the unique biochemical and biological features of Ki-RasB, it is important to evaluate the efficacy of FTIs or any other modulator of oncogenic Ras function in model systems expressing this Ras oncoprotein. We have developed strains of transgenic mice carrying the human Ki-rasB cDNA with an activating mutation (G12V) under the control of the MMTV enhancer/promoter. The predominant pathological feature that develops in these mice is the stochastic appearance of mammary adenocarcinomas. High levels of the Ki-rasB transgene RNA are detected in these tumors. Treatment of MMTV-Ki-rasB mice with L-744,832 caused inhibition of tumor growth in the absence of systemic toxicity. Although FPTase activity was inhibited in tumors from the treated mice, unprocessed Ki-RasB was not detected. These results demonstrate the utility of the MMTV-Ki-rasB transgenic mice for testing potential anticancer agents. Additionally, the data suggest that although the FTI L-744,832 can inhibit tumor growth in this model, Ki-Ras may not be the sole mediator of the biological effects of the FTI.

Alkyl and Aryl Transferases↗

PubMed2000

Synthesis and evaluation of vitamin D-based cationic lipids for gene delivery in vitro.

A new panel of steroidal cationic lipids has been synthesized for gene delivery. Using commercially available vitamin D2 (calciferol) or vitamin D3 (cholecalciferol) as hydrophobic motifs and a variety of cationic head groups as binding sites for negatively charged phosphate groups in DNA, we demonstrated that the transfection activity of the synthetic vitamin D-based cationic lipids 1d, 2d formulated with dioleoylphosphatidylethanolamine (DOPE) as a co-lipid is comparable to that of 3-(-[N-N',N'-dimethylaminoethane)carbamoyl]cholesterol (DC-Chol). These synthetic lipids are effective in transfecting a variety of cell lines. These results suggest that vitamin D-based cationic lipids are useful transfection reagents for in vitro gene transfer studies.

3T3 Cells↗

PubMed2000

Caspase-8-mediated intracellular acidification precedes mitochondrial dysfunction in somatostatin-induced apoptosis.

Activation of initiator and effector caspases, mitochondrial changes involving a reduction in its membrane potential and release of cytochrome c (cyt c) into the cytosol, are characteristic features of apoptosis. These changes are associated with cell acidification in some models of apoptosis. The hierarchical relationship between these events has, however, not been deciphered. We have shown that somatostatin (SST), acting via the Src homology 2 bearing tyrosine phosphatase SHP-1, exerts cytotoxic action in MCF-7 cells, and triggers cell acidification and apoptosis. We investigated the temporal sequence of apoptotic events linking caspase activation, acidification, and mitochondrial dysfunction in this system and report here that (i) SHP-1-mediated caspase-8 activation is required for SST-induced decrease in pH(i). (ii) Effector caspases are induced only when there is concomitant acidification. (iii) Decrease in pH(i) is necessary to induce reduction in mitochondrial membrane potential, cyt c release and caspase-9 activation and (iv) depletion of ATP ablates SST-induced cyt c release and caspase-9 activation, but not its ability to induce effector caspases and apoptosis. These data reveal that SHP-1-/caspase-8-mediated acidification occurs at a site other than the mitochondrion and that SST-induced apoptosis is not dependent on disruption of mitochondrial function and caspase-9 activation.

Acids↗

PubMed2000

DNA damage-induced activation of p53 by the checkpoint kinase Chk2.

Chk2 is a protein kinase that is activated in response to DNA damage and may regulate cell cycle arrest. We generated Chk2-deficient mouse cells by gene targeting. Chk2-/- embryonic stem cells failed to maintain gamma-irradiation-induced arrest in the G2 phase of the cell cycle. Chk2-/- thymocytes were resistant to DNA damage-induced apoptosis. Chk2-/- cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to gamma irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. This provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage.

Animals↗

PubMed2000

Blocking of CD44-hyaluronic acid interaction prolongs rat allograft survival.

BACKGROUND: Lymphocyte activation and infiltration into a transplanted organ is an integral component of the rejection process. Graft infiltration of lymphocytes requires adhesion of leukocytes to the endothelium, diapedesis, and transmigration. One of several proteins involved in this process is CD44, which is known to interact with endothelial hyaluronan (HA). Blockade of cell-matrix and cell-cell interactions have been used extensively for modulation of immune responses and graft rejection. Based on these observations, we evaluated the effects of blocking CD44-HA interactions in a transplantation model. METHODS: We used a low molecular weight hyaluronic acid formulation (LMWHA) for the treatment of rat renal and cardiac allograft recipients. LMWHA was administered intraperitoneally at 0.5-5 mg/kg for 5-10 days after transplantation with or without a subtherapeutic dose of cyclosporine. RESULTS: LMWHA monotherapy prolonged allograft survival significantly, but only for a few days. In combination with low-dose cyclosporine, long-term survival of allografts was observed in some of recipients. CONCLUSION: Further definition of the underlying mechanism of LMWHA therapy may provide a rationale for the development of novel, nontoxic, nonimmunogenic immunotherapies.

Animals↗

PubMed2000

TFIIA-TAF regulatory interplay: NMR evidence for overlapping binding sites on TBP.

TATA box binding protein (TBP)-promoter interaction nucleates assembly of the RNA polymerase II transcription initiation complex. Transcription factor IIA (TFIIA) stabilizes the TBP-promoter complex whereas the N-terminal domain of the largest TAF(II) inhibits TBP-promoter interaction. We have mapped the interaction sites on TBP of Drosophila TAF(II)230 and yeast TFIIA (comprising two subunits, TOA1 and TOA2), using nuclear magnetic resonance (NMR), and also report structural evidence that subdomain II of the TAF(II)230 N-terminal inhibitory domain and TFIIA have overlapping binding sites on the convex surface of TBP. Together with previous mutational and biochemical data, our NMR results indicate that subdomain II augments subdomain I-mediated inhibition of TBP function by blocking TBP-TFIIA interaction.

Amino Acid Sequence↗

PubMed2000

Backbone dynamics and refined solution structure of the N-terminal domain of DNA polymerase beta. Correlation with DNA binding and dRP lyase activity.

Mammalian DNA polymerase beta functions in the base excision DNA repair pathway filling in short patches (1-5 nt) in damaged DNA and removing deoxyribose 5'-phosphate from the 5'-side of damaged DNA. The backbone dynamics and the refined solution structure of the N-terminal domain of beta-Pol have been characterized in order to establish the potential contribution(s) of backbone motion to the DNA binding and deoxyribose 5'-phosphate lyase function of this domain. The N-terminal domain is formed from four helices packed as two antiparallel pairs with a 60 degrees crossing between the pairs. The RMSD of the NMR conformers (residues 13-80) is 0.37 A for the backbone heavy atoms and 0.78 A for all heavy atoms. NMR characterization of the binding site(s) for a ssDNA-5mer, ssDNA-8mer, ssDNA-9mer, and dsDNA-12mer shows a consensus surface for the binding of these various DNA oligomers, that surrounds and includes the deoxyribose 5'-phosphate lyase active site region. Connection segments between helices 1 and 2 and between helices 3 and 4 each contribute to DNA binding. Helix-3-turn-helix-4 forms a helix-hairpin-helix motif. The highly conserved hairpin sequence (LPGVG) displays a significant degree of picosecond time-scale motion within the backbone, that is possibly important for DNA binding at the phosphodiester backbone. An Omega-loop connecting helices 1 and 2 and helix-2 itself display significant exchange contributions (R(ex)) at the backbone amides due to apparent conformational type motion on a millisecond time-scale. This motion is likely important in allowing the Omega-loop and helix-2 to shift toward, and productively interact with, gapped DNA. The deoxyribose 5'-phosphate lyase catalytic residues that include K72 which forms the Schiff's base, Y39 which is postulated to promote proton transfer to the aldehyde, and K35 which assists in phosphate elimination, show highly restricted backbone motion. H34, which apparently participates in detection of the abasic site hole and assists in the opening of the hemiacetal, shows conformational exchange.

Amino Acid Sequence↗

PubMed2000

[Effect of fish oil supplementation on fatty acid composition and neurotransmitters of growing rats].

In order to observe the change of brain fatty acid composition and neurotransmitter by DHA supplementation during the development stage of young rats, pregnant rats were randomly divided into four groups: normal control group (O), low (L), medium (M) and high (H) dose-DHA supplemented groups. The fatty acids composition, the levels of 5-hydroxy-tryptamine (5-HT), dopamine (DA), norepinephrine (NE) and somatostatin (SS) in ceretral cortex and hippocampus of offsprings were measured. The body weight of pregnant rats and offsprings were also observed. The results showed that DHA content of brain homogenate and the levels of 5-HT, DA and SS in hippocampus of experimental young rats were significantly higher than those of the control group. And the body weight of young rats in the three DHA-supplemented groups were retarded in different degree. It was concluded that DHA supplementation changed the fatty acid composition and increased the levels of 5-HT, DA and SS in hippocampus. Proper ratio of n-3 and n-6 fatty acids in dietary supplementation should be considered.

Animals↗

PubMed2000

Siglec-8. A novel eosinophil-specific member of the immunoglobulin superfamily.

We describe the characterization of siglec-8, a novel sialic acid-binding immunoglobulin-like lectin that is expressed specifically by eosinophils. A full-length cDNA encoding siglec-8 was isolated from a human eosinophil cDNA library. Siglec-8 is predicted to contain three extracellular immunoglobulin-like domains, a transmembrane region, and a cytoplasmic tail of 47 amino acids. The siglec-8 gene mapped on chromosome 19q13.33-41, closely linked to genes encoding CD33 (siglec-3), siglec-5, siglec-6, and siglec-7. When siglec-8 was expressed on COS cells or as a recombinant protein fused to the Fc region of human IgG(1), it was able to mediate sialic acid-dependent binding to human erythrocytes and to soluble sialoglycoconjugates. Using specific monoclonal antibodies, siglec-8 could be detected only on eosinophils and hence appears to be the first example of an eosinophil-specific transmembrane receptor.

Amino Acid Sequence↗

PubMed2000

Experimental infection of nonenveloped DNA virus (TTV) in rhesus monkey.

Virus fragments homologous to TTV were detected previously from an enterically transmitted outbreak of non-A-E hepatitis [Luo et al., 1999]. To test the susceptibility of the Rhesus monkey to this virus and to establish its transmission routes, 6 Rhesus monkeys were inoculated, 3 orally and another 3 intravenously. The inoculum was prepared by extracting and filtering feces collected from a patient during the incubation period identified in the described outbreak. A second group of 3 monkeys was used for the passage study. The feces and blood samples were collected for detection of the virus by polymerase chain reaction (PCR). Four animals were subjected to liver biopsies and bile aspiration by open surgery for in situ virus detection. Viremia occurred in 4-7 days after intravenous and 7-10 days after oral inoculation. The virus was excreted in feces a few days after oral infection and simultaneously with viremia after intravenous inoculation. The virus was also detected in bile during the viremic phase. There was a prolonged carrier state with persistent viremia and virus excretion in feces for more than 6 months. Serum transaminase levels were not raised during the infection. The virus was present in both the cytoplasm and nuclei of hepatocytes, but no significant pathology was found. Therefore, the Rhesus monkey is susceptible to TT virus infection, but the virus seems nonpathogenic. Infection of the liver may be established either by oral or parenteral inoculation. The virus may be released from liver into the blood or via bile into feces, so it may be transmitted by both blood and fecal routes.

Alanine Transaminase↗

PubMed2000

Gene therapy that inhibits nuclear translocation of nuclear factor kappaB results in tumor necrosis factor alpha-induced apoptosis of human synovial fibroblasts.

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) increases the survival and proliferation of human rheumatoid arthritis (RA) cell lines. These experiments were designed to determine if inhibition of nuclear factor kappaB (NF-kappaB) nuclear translocation leads to increased apoptosis of TNFalpha-treated human RA cell lines. METHODS: We constructed an inhibitor of nuclear factor kappaB(IkappaB) dominant-negative adenovirus (AdCMVIkappaB-DN) and an X-linked inhibitor of apoptosis (XIAP) antisense adenovirus (AdCMVXIAP-AS). Primary RA synovial fibroblast (RASF) cell lines were transfected in vitro, and SV40-transformed RA synovial cell lines in SCID mice were transfected in vivo. Cells were treated with TNFalpha and analyzed for apoptosis. RESULTS: There was no apoptosis of primary RASF transfected in vitro with AdCMVIkappaB-DN alone. In contrast, there was apoptosis of >85% of cells treated with AdCMVIkappaB-DN plus TNFalpha. Primary RASF in SCID mice also exhibited high levels of apoptosis after in vivo transfection with AdCMVIkappaB-DN followed by treatment with TNFalpha. There was no apoptosis after treatment with AdCMVIkappaB-DN in the absence of TNFalpha. XIAP is an inhibitor of apoptosis which was up-regulated by TNFalpha, and this up-regulation was inhibited by AdCMVIkappaB-DN plus TNFalpha. Transfection of an AdCMVXIAP-AS gene therapy resulted in increased TNFa-induced apoptosis. CONCLUSION: AdCMVIkappaB-DN gene therapy greatly enhances apoptosis due to inhibition of an NF-kappaB-mediated antiapoptosis signaling pathway, and XIAP is a TNFalpha-inducible specific inhibitor of apoptosis in RA synovial cell lines. This and other modulators of TNF receptor or the Fas apoptosis pathway may be therapeutically beneficial in facilitating apoptosis of synovial tissue in patients with RA.

Animals↗