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PubMed1957

The nucleolus and parachromatin of the ascites tumor cell.

1. A method is described for distinguishing the ribonucleoproteins of the nucleolus and parachromatin of ascitic tumor cells of the mouse. 2. In these cells the transfer of ribonucleoprotein from the nucleus to the cytoplasm can occur in two ways. (a) At the end of prophase the nucleolus separates from the chromosomes and nucleolar fragments are released into the cytoplasm. (b) During prophase the parachromatin is aggregated to form parachromatin bodies which are discharged into the cytoplasm, where they can be detected during metaphase, anaphase, and telophase. 3. A metachromatic form of RNA is demonstrable, and may be synthesized, in close relation to the chromosomes during prophase, metaphase, and anaphase. During telophase the distribution of metachromatic RNA changes, the chromatin loses its metachromasia, and intranuclear metachromatic parachromatin becomes evident.

Anaphase↗
PubMed2025

PLSKO: a robust knockoff generator to control false discovery rate in omics variable selection.

MOTIVATION: Integrating the knockoff framework with any variable-selection method delivers stringent false discovery rate (FDR) control without recourse to p-values, offering a powerful alternative for differential expression analysis of high-throughput omics datasets. However, existing knockoff generators rely on restrictive modelling assumptions or coarse approximations that often inflate the FDR when applied to real-world data. RESULTS: We introduce Partial Least Squares Knockoff (PLSKO), an efficient, assumption-free generator that remains robust across diverse omics platforms. Our extensive simulations show that PLSKO is the only method to maintain FDR control with sufficient power in complex non-linear settings. Our semi-simulation studies drawn from RNA-seq, proteomics, metabolomics, and microbiome experiments confirm PLSKO generates valid knockoff variables. In pre-eclampsia multi-omics case studies, we combine PLSKO with Aggregation Knockoff to address the randomness of knockoffs and improve power, and demonstrate the method's ability to recover biologically meaningful features. AVAILABILITY AND IMPLEMENTATION: Our proposed algorithm is available on Github (https://github.com/guannan-yang/PLSKO) and Zenodo (https://doi.org/10.5281/zenodo.16879594).

Algorithms↗
PubMed2005

Proteinase-activated receptor-1 is an anti-inflammatory signal for colitis mediated by a type 2 immune response.

BACKGROUND: Activation of colonic proteinase activated receptor-1 (PAR1) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is not neurogenic like in the paw of rats but depends on PAR1-mediated activation monocytic cells. PAR1 activation in the colon increases the release of lymphocyte T helper-1 (TH1) cytokines. Moreover, PAR1 expression is increased in biopsies from patients with inflammatory bowel disease, and its activation during TH1-mediated colitis in mice increases all of the hallmarks of inflammation. METHODS: This study aimed to characterize the effects of PAR1 activation in oxazolone-mediated colitis, involving a TH2 cytokine profile. RESULTS: Intracolonic administration of oxazolone increased myeloperoxidase activity, damage score, and interleukin (IL)-4, IL-10, tumor necrosis factor alpha, and IL-1beta mRNA expression but lowered interferon-gamma mRNA expression, indicating colonic inflammation of a TH2 profile. The concurrent intracolonic administration of a PAR1 agonist in oxazolone-treated mice inhibited colitis, resulting in a reduction of myeloperoxidase activity, damage score, and inflammatory cytokine mRNA expression. Using PAR1-deficient mice, we confirmed that the anti-inflammatory effects of PAR1 agonists were mediated by PAR1. Moreover, in PAR1-deficient mice or in mice treated with a PAR1 antagonist, oxazolone-induced colitis was exacerbated, showing an endogenous modulatory role for PAR1 in this TH2 cytokine profile of colitis. CONCLUSIONS: Thus, as opposed to a previously shown proinflammatory role for PAR1 in a TH1 cytokine-mediated colitis, our new data show anti-inflammatory role for PAR1 activation in the setting of TH2 cytokine colitis model.

Animals↗
PubMed1992

Ligand-independent reduction of cAMP receptors in Dictyostelium discoideum cells over-expressing a mutated ras gene.

Drug-resistance selection in Dictyostelium discoideum transformants resulted in up to eight-times-higher ras protein levels. Over-production of the wild-type ras protein did not lead to an aberrant phenotype. Increased levels of the mutated [G12T]ras protein, however, were correlated with severe deficiencies in aggregation and development. This aberrant phenotype is associated with reduced cAMP binding, due to a lower number of cell-surface receptors. We show that both RNA and cAMP-receptor-protein levels are reduced. These results indicate that ras in Dictyostelium discoideum seems to be involved in regulating cAMP-receptor-gene expression.

Animals↗
PubMed2006

Mammary gland tissue targeted overexpression of human protease-activated receptor 1 reveals a novel link to beta-catenin stabilization.

Protease-activated receptor 1 (PAR1) is emerging with distinct assignments in tumor biology. We show that tissue targeted overexpression of hPar1 in mice mammary glands results in precocious hyperplasia, characterized by a dense network of ductal side branching and accelerated proliferation. These glands exhibit increased levels of wnt-4 and wnt-7b and a striking beta-catenin stabilization. Nuclear localization of beta-catenin is observed in hPar1 transgenic mouse tissue sections but not in the wild-type, age-matched counterparts. PAR1 induces beta-catenin nuclear localization also in established epithelial tumor cell lines of intact beta-catenin system (transformed on the background of mismatch repair system; RKO cells). We propose hereby that PAR1-mediated beta-catenin stabilization is taking place primarily via the increase of Wnt expression. Enforced expression of a specific Wnt antagonist family member, secreted frizzled receptor protein 5 (SFRP5), efficiently inhibited PAR1-induced beta-catenin stabilization. Likewise, application of either SFRP2 or SFRP5 on epithelial tumor cells completely abrogated PAR1-induced beta-catenin nuclear accumulation. This takes place most likely via inhibition of Wnt signaling at the level of cell surface (forming a neutralizing complex of "Receptors-SFRP-Wnt"). Furthermore, depletion of hPar1 by small interfering RNA (siRNA) vectors markedly inhibited PAR1-induced Wnt-4. The striking stabilization of beta-catenin, inhibited by SFRPs on one hand and Wnt-4 silencing by hPar1 siRNA on the other hand, points to a novel role of hPar1 in Wnt-mediated beta-catenin stabilization. This link between PAR1 and beta-catenin may bear substantial implications both in developmental and tumor progression processes.

Adaptor Proteins, Signal Transducing↗
PubMed2006

In vivo and in vitro evidence for transforming growth factor-beta1-mediated epithelial to mesenchymal transition in esophageal adenocarcinoma.

There is increasing evidence that epithelial to mesenchymal transition (EMT) is involved in cancer progression. Because local invasion and metastasis occurs early in the pathogenesis of esophageal adenocarcinoma, we hypothesized that EMT may be important in this disease. Using immunohistochemistry in a well-characterized set of adenocarcinoma tissues, we showed down-regulation of epithelial markers (E-cadherin and cytokeratin 18) and up-regulation of mesenchymal markers (vimentin and alpha-smooth muscle actin) with concomitant transforming growth factor-beta1 (TGF-beta1) expression at the invasive margin compared with the central tumor. A panel of esophageal cell lines was examined for the ability of TGF-beta1 to induce EMT in vitro. TE7 cells were selected as a model because TGF-beta1 (0-5 ng/mL) treatment induced morphologic and molecular expression changes suggestive of EMT. In TE7 cells, these TGF-beta1-induced changes were reversed by 100 ng/mL of bone morphogenetic protein 7 (BMP7), another member of the TGF-beta1 superfamily. EMT was mediated via canonical TGF-beta1 signaling with concomitant up-regulation of SMAD-interacting protein 1. Alterations in functional variables (aggregation, wounding, motility, and invasion) following TGF-beta1 treatment were consistent with a more invasive phenotype. These functional changes were reversed by BMP7 and SMAD4 RNA interference in vitro. These data suggest that TGF-beta1-mediated EMT may be relevant in esophageal carcinogenesis.

Adenocarcinoma↗
PubMedDate not supplied

[An informational approach to recognizing the similarity of tRNA genes and their global classification].

Based on informational approach to the comparative analysis of DNA sequences and the conception of fuzzy relations, new classification schemes were suggested for two aggregates of tRNA genes from the EMBL-8 data bank connecting amino acids TRP and ASP. These classification schemes are presented as a dendrogram and reflect possible evolutionary interrelation between tRNA genes in both aggregates. Evolutionary interrelations between tRNA genes were analyzed from two standpoints: 1) taking into consideration the interrelation between DNA sequences by all four nucleotides; 2) taking into account possible evolutionary pressure to the divergence of DNA sequences towards transitions. The similarity and difference of dendrograms for each gene aggregate were considered in both instances. It was shown that the analysis of all possible directions of the evolutionary pressure to the divergence of DNA and RNA sequences provides a new approach to the construction of a global tRNA phylogeny.

Amino Acid Sequence↗
PubMed1990

The production of transforming growth factor-beta in acute megakaryoblastic leukemia and its possible implications in myelofibrosis.

Acute myelofibrosis is often associated with acute megakaryoblastic leukemia (AMKBL). Although the exact mechanism for the progression of myelofibrosis in AMKBL is unclear, certain humoral factors from megakaryoblastic cells, the precursors of platelets, may be involved in the enhancement of collagen synthesis by bone marrow fibroblasts. The present study, therefore, is an investigation of the possible pathogenic role of transforming growth factor-beta (TGF-beta), known to be a very potent collagen-stimulating factor found in platelets in the myelofibrosis of AMKBL. The results obtained were as follows: (1) Conditioned media from peripheral megakaryoblasts taken from an AMKBL patient and from established megakaryoblast cell lines (MEG-01) had much greater stimulatory effects on collagen synthesis in bone marrow fibroblasts than conditioned media from other leukemic cell types. (2) Based on an assessment of soft agar colony formation, there was greater TGF-beta activity in media that had been conditioned from megakaryoblasts than in media from other leukemic cell types. (3) When compared with other leukemic-cell types, megakaryoblasts showed substantially greater expression of TGF-beta mRNA that was hybridized at 2.5 kb with a TGF-beta cDNA probe, and TGF-beta polypeptides were detected at 13 Kd with anti-TGF-beta antibodies. (4) The addition of the anti-TGF-beta antibody inhibited the stimulatory effects of the megakaryoblast conditioned medium on collagen synthesis in bone marrow fibroblasts. These results clearly suggest that megakaryoblasts produce and secrete an active form of TGF-beta and stimulate collagen synthesis in bone marrow fibroblasts in a paracrine manner.

Animals↗
PubMed1975

Mechanisms of variability of vertebrate virus populations.

A number of factors favouring the persistence and accumulation of mutant virus particles are active in virus populations with a complicated genetic structure. The latter circumstance permits to apply the concept of genetic load to these virus populations. Complication of the genetic structure permits a virus population to make a qualitative leap in the struggle for existence.

Arboviruses↗
PubMed1986

Immune electron microscopy of hepatitis delta-antigen in hepatocytes.

Immune electron microscopic examination of hepatitis delta delta-antigen (HDAg) was carried out on liver biopsies from seven patients with chronic type B hepatitis and delta-infection. HDAg was mainly found in the nucleus, but in some scattered hepatocytes it was found in the cytoplasm also, either in association with ribosomes or in the hyaloplasm. The association of HDAg with ribosomes may be the result of translation from delta-messenger RNA on the same ribosomes. In the nucleus, delta-antigen was present in the chromatin area as irregular granular structures, and there was staining of aggregates of 20 to 30-nm particulate structures, similar to those first described in non-A, non-B hepatitis. However, similar particulate structures were also present in HDAg negative nuclei. The delta-particles which have been described in blood could not be identified in hepatocytes.

Cell Nucleus↗
PubMed1998

Regulation of E-cadherin-mediated adhesion in Langerhans cell-like dendritic cells by inflammatory mediators that mobilize Langerhans cells in vivo.

Adhesion of Langerhans cells (LC) to keratinocytes is mediated by E-cadherin. IL-1, TNF-alpha, and LPS mobilize LC from epidermis and presumably attenuate LC-keratinocyte adhesion. To determine whether these mediators modulated LC E-cadherin-dependent adhesion directly, we characterized their effects on LC-like dendritic cells expanded from murine fetal skin (FSDDC). FSDDC were propagated from day 16 C57BL/6 fetal skin and isolated as aggregates (FSDDC-A) in which homophilic adhesion was mediated by E-cadherin. IL-1, TNF-alpha, and LPS induced dissociation of FSDDC-A that began within 4 to 8 h and was complete within 20 h. Anti-IL-1RI mAb inhibited disaggregation caused by IL-1alpha and IL-1beta, but not that induced by TNF-alpha or LPS. Anti-TNF-alpha mAb inhibited the effect of TNF-alpha and LPS, but not that caused by IL-1alpha or IL-1beta. Flow cytometry of FSDDC-A revealed that IL-1, TNF-alpha, and LPS induced increased expression of MHC class II, CD40, and CD86 and decreased E-cadherin expression that was temporally related to dissociation of aggregates. IL-1 and TNF-alpha caused a rapid reduction in FSDDC E-cadherin mRNA levels that preceded the decrease in E-cadherin surface expression. These results demonstrate that cytokines that induce LC emigration in vivo act directly on LC-like cells in vitro, reduce E-cadherin mRNA levels, down-regulate E-cadherin surface expression, and induce a loss of E-cadherin-mediated adhesion.

Animals↗
PubMed2026

CTCF aligns single-cell TAD-like domain boundaries and stabilizes long-range active chromatin clusters.

CCCTC-binding factor (CTCF) is a key architectural protein in the three-dimensional (3D) genome, yet how its loss reshapes chromatin structure and transcription at single-cell resolution remains unclear. Using HiRES, which jointly profiles chromatin contacts and RNA from the same nucleus, we examined genome-wide effects of CTCF depletion. Topologically associating domain (TAD)-like domains (TLDs) across single cells remained largely unchanged in number and size after CTCF loss, but their boundaries became more variably positioned, and pseudobulk analyses revealed reduced interactions within A compartments. We also developed SALTAFinder to identify Spatially Aggregated Long-distance TLD Assemblies (SALTAs), clusters of TLDs occupying shared 3D space within single cells. A subset of SALTAs is enriched for highly expressed genes and super-enhancers and declines upon CTCF depletion. This structural reorganization coincided with a global reduction in per-cell RNA output, as indicated by HiRES and orthogonal measurements. Together, these findings suggest that CTCF contributes to the coordinated regulation of chromatin organization and transcriptional capacity and is associated with stabilization of long-range active chromatin clusters.

CCCTC-Binding Factor↗
PubMed1995

Targeting pyrimidine single strands by triplex formation: structural optimization of binding.

Recent reports describe a new strategy for the binding of single-stranded pyrimidine sequences by triple helix formation. In this approach, a double-length purine-rich oligonucleotide binds a target strand, folding back to form an antiparallel pur.pur.pyr triple helix. We now describe a series of studies in which sequence and structural variations are made in such purine-rich ligands, in an effort to optimize binding properties. Comparison is made between the use of two separate strands and the use of single two-domain ligands; the latter are found to bind more tightly and to aggregate less in media containing Na+ or K+. Placement of mismatched bases in the target shows that sequence selectivity of binding is as high as that for Watson-Crick duplex formation. Variation of the lengths and sequences of loops bridging the binding domains demonstrates that dinucleotide loops composed of pyrimidines give the highest stability. Oligoethylene glycol-derived loop replacements are shown to give good binding affinity as well. The binding of an RNA target is shown to occur with the same affinity as the binding of DNA. In general, it is found that circular variants bind more tightly than do either separate strands or singly-linked ligands and unlike linear oligomers, the circular compounds do not aggregate to a large extent even in buffers containing 100 mM K+. Such structurally optimized ligands are useful in expanding the number of possible naturally-occurring sequences which can be targeted by triplex formation.

Base Sequence↗
PubMed2000

[Pathological features of liver biopsy from 66 cases of long term blood donors with chronic hepatitis C].

OBJECTIVE: To study the pathological features of liver biopsy from long-term blood donors with chronic hepatitis C. METHODS: From 250 long-term blood donors with positive serum anti-HCV antibody for more than five years, 66 donors with abnormal ALT level were selected and enrolled in this study. Liver biopsy was performed on these cases and the specimens stained with HE, and reticulin. Modified Schemer's classification for grading and staging was used during pathological observation. Twenty biopsies with serum HCV-RNA levels higher than 5.0 Meq/ml (bDNA) were studied immunohistochemically (SABC) for NS5. RESULTS: All cases displayed mild pathological changes. Grade 1 (G(1)) inflammation was 4.8% (3/63), G(2) 63.5% (40/63), G(3) 28.6%(18/63), G(4) two case. Stage 1 (S(1)) fibrosis was 60.3% (38/63), S(2) 34.9% (22/63), S(3) 3.2% (2/63), S(4) only one case. The main lesion was periportal inflammation, such as bile duct damage (100.0%), dense lymphoid aggregates (82.5%) and piecemeal necrosis (89.5%). Intralobular injury of hepatocytes was rather mild. Bridging necrosis and steatosis were not common and observed in only 12.3% (8/66) and 9.2% (6/66) respectively. As for fibrosis, proliferation and deposition of collagen were mainly distributed in the portal and perisinusoidal areas. Among 20 specimens with serum HCV-RNA levels higher than 5.0 Meq/ml (bDNA), all bile duct epithelial cells were positive for HCV-NS5 antigen, while hepatocytes in 4 cases were negative. CONCLUSION: (1) The pathological changes in this series show overall similarity with that of patients with posttransfusion hepatitis C. The main damages are portal and periportal inflammation, such as lymphoid aggregates, bile duct damage, piecemeal necrosis, and extensive periportal and perisinusoidal fibrosis. Intralobular damage was mild with occasional steatosis, which may be related to malnutrition, low level of serum iron due to long term donation. (2) Epithelial cells of the bile duct may be of another site for virus replication, thus it is related with bile duct damage and periportal inflammation.

Adult↗
PubMed2007

TLR3-mediated synthesis and release of eotaxin-1/CCL11 from human bronchial smooth muscle cells stimulated with double-stranded RNA.

Respiratory infections with RNA viruses, such as rhinovirus or respiratory syncytial virus, are a major cause of asthma exacerbation, accompanied by enhanced neutrophilic and/or eosinophilic inflammation of the airways. We studied the effects of dsRNA synthesized during RNA virus replication, and of its receptor, TLR3, on the synthesis of eosinophilic chemokines in bronchial smooth muscle cells (BSMC). Synthetic dsRNA, polyinosinic-cystidic acid (poly(I:C)), induced the synthesis of eosinophilic chemokines, eotaxin-1/CCL11 and RANTES/CCL5, from primary cultures of human BSMC, and IL-4 increased synergistically the synthesis of poly(I:C)-induced CCL11. A robust eosinophil chemotactic activity was released from BSMC stimulated with poly(I:C) and IL-4, which was mostly inhibited by preincubation with an anti-CCL11, but not with an anti-CCL5 Ab. Although the immunoreactivity of TLR3 was detectable on the cellular surface of BSMC by flow cytometric analysis, pretreatment with an anti-TLR3-neutralizing Ab failed to block the poly(I:C)-induced synthesis of CCL11. We have determined by confocal laser-scanning microscopy that the immunoreactivity of TLR3 was aggregated intracellularly in poly(I:C)-stimulated BSMC, colocalizing with fluorescein-labeled poly(I:C). The synthesis of CCL11 was prominently inhibited by the transfection of TLR3-specific small interfering RNA or by bafilomycin A1, an endosomal acidification inhibitor, further supporting the essential role played by intracellular TLR3 in the synthesis of poly(I:C)-induced CCL11 in BSMC. In conclusion, these observations suggest that, by activating intracellular TLR3 in BSMC, respiratory RNA virus infections stimulate the production of CCL11 and enhance eosinophilic inflammation of the airways in the Th2-dominant microenvironment.

Bronchi↗
PubMed1995

Berenil [1,3-bis(4'-amidinophenyl)triazene] binding to DNA duplexes and to a RNA duplex: evidence for both intercalative and minor groove binding properties.

Berenil is an antitrypanosomal agent that binds to nucleic acid duplexes. The generally accepted mode of berenil binding is via complexation into the minor groove of AT-rich domains of DNA double helices. We find that berenil can bind to RNA as well as DNA duplexes, while exhibiting properties characteristic of both intercalation as well as minor groove binding. More specifically, we use spectroscopic, calorimetric, and hydrodynamic techniques to characterize berenil binding to four DNA duplexes and to one RNA duplex. Our results reveal the following features: (i) Berenil binding to the poly[d(A-T)]2, poly(dA).poly(dT), poly[d(I-C)]2, poly[d(G-C)]2, and poly(rA).poly(rU) duplexes exhibits intercalative as well as minor groove binding characteristics. (ii) The apparent "site sizes" associated with berenil binding to these five duplexes range from 1 to 13 base pairs per bound berenil and depend, in part, on the host duplex. One of the site sizes common to all five duplexes is consistent with berenil binding to the minor groove. (iii) The apparent berenil binding affinity follows the hierarchy: poly(dA).poly(dT) > poly-[d(A-T)]2 approximately poly[d(I-C)]2 >> poly(rA).poly(rU) > poly[d(G-C)]2. (iv) Viscometric data reveal properties characteristic of a significant contribution from an intercalative mode of binding when berenil interacts with the poly[d(A-T)]2, poly[d(I-C)]2, poly[d(G-C)]2, and poly(rA).poly(rU) duplexes, while revealing an apparent nonintercalative mode when the drug binds to the poly(dA).poly(dT) duplex. (v) Berenil binding unwinds negative supercoils in the pBR322 plasmid, an observation consistent with an intercalative mode of binding to duplex DNA. (vi) Salt-dependent melting data suggest that both positively charged amidino groups of berenil participate in the complexation of the drug to the poly[d(I-C)]2, poly[d(A-T)]2, poly(dA).poly(dT), and poly(rA).poly(rU) duplexes, while also suggesting that the binding event is site-specific. In the aggregate, our results suggest that, in contrast to the conventional wisdom, berenil can exhibit intercalative as well as minor groove binding properties when it binds to both DNA and RNA duplexes, while also exhibiting a preference for DNA duplexes with unobstructed minor grooves. We comment on the potential correlation between drugs, such as berenil, that exhibit "mixed" binding motifs and those that express anticancer activity via inhibition of topoisomerase I activity.

Binding Sites↗
PubMed1976

The involvement of RNA in the initiation of DNA synthesis in mammalian cells. Artifacts arising during caesium-salt density-gradient centrifugation which simulate a covalent attachment of RNA to newly synthesized DNA.

Artifacts were encountered during caesium salt density gradient centrifugation which simulated results expected if newly synthesized DNA is covalently attached to RNA. Newly synthesized DNA (in baby hamster kidney cells, BHK-21/C13), pulse-labelled with [3H]thymidine for 10 min at temperatures below 25 degrees C, banded at a greater buoyant density than mature [14C]DNA (heat-denatured nucleic acids) when centrifuged to equilibrium in caesium chloride gradients. Some of the newly synthesized RNA, labelled with [3H]uridine, banded at a buoyant density slightly greater than DNA in caesium sulphate gradients. These results were not obtained when nucleic acids were pulse-labelled at 37 degrees C, nor when samples were heat-denatured in the presence of formaldehyde. This suggests that nucleic acids can aggregate during centrifugation; this is discussed in relation to the molecular size of the DNA.

Cell Line↗