BCL11B is up-regulated by EWS/FLI and contributes to the transformed phenotype in Ewing sarcoma.

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Elizabeth T Wiles

Full Text Available The EWS/FLI translocation product is the causative oncogene in Ewing sarcoma and acts as an aberrant transcription factor. EWS/FLI dysregulates gene expression during tumorigenesis by abnormally activating or repressing genes. The expression levels of thousands of genes are affected in Ewing sarcoma, however, it is unknown which of these genes contribute to the transformed phenotype. Here we characterize BCL11B as an up-regulated EWS/FLI target that is necessary for the maintenance of transformation in patient derived Ewing sarcoma cells lines. BCL11B, a zinc finger transcription factor, acts as a transcriptional repressor in Ewing's sarcoma and contributes to the EWS/FLI repressed gene signature. BCL11B repressive activity is mediated by the NuRD co-repressor complex. We further demonstrate that re-expression of SPRY1, a repressed target of BCL11B, limits the transformation capacity of Ewing sarcoma cells. These data define a new pathway downstream of EWS/FLI required for oncogenic maintenance in Ewing sarcoma.

Involvement of p53 and Bcl-2 in sensory cell degeneration in aging rat cochleae.

Science.gov (United States)

Xu, Yang; Yang, Wei Ping; Hu, Bo Hua; Yang, Shiming; Henderson, Donald

2017-06-01

p53 and Bcl-2 (B-cell lymphoma 2) are involved in the process of sensory cell degeneration in aging cochleae. To determine molecular players in age-related hair cell degeneration, this study examined the changes in p53 and Bcl-2 expression at different stages of apoptotic and necrotic death of hair cells in aging rat cochleae. Young (3-4 months) and aging (23-24 months) Fisher 344/NHsd rats were used. The thresholds of the auditory brainstem response (ABR) were measured to determine the auditory function. Immunolabeling was performed to determine the expression of p53 and Bcl-2 proteins in the sensory epithelium. Propidium iodide staining was performed to determine the morphologic changes in hair cell nuclei. Aging rats exhibited a significant elevation in ABR thresholds at all tested frequencies (p aging hair cells showing the early signs of apoptotic changes in their nuclei. The Bcl-2 expression increase was also observed in hair cells displaying early signs of necrosis. As the hair cell degenerative process advanced, p53 and Bcl-2 immunoreactivity became reduced or absent. In the areas where no detectable nuclear staining was present, p53 and Bcl-2 immunoreactivity was absent.

MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas.

Science.gov (United States)

Huang, Wenting; Medeiros, L Jeffrey; Lin, Pei; Wang, Wei; Tang, Guilin; Khoury, Joseph; Konoplev, Sergej; Yin, C Cameron; Xu, Jie; Oki, Yasuhiro; Li, Shaoying

2018-05-21

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34-85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p hit lymphoma and double hit lymphoma and overall survival in triple hit lymphoma patients was 17.6 months, similar to the overall survival of patients with double hit lymphoma (p = 0.67). Patients with triple hit lymphoma showing P53 overexpression had significantly worse overall survival compared with those without P53 overexpression (p = 0.04). On the other hand, double expressor status and prior history of B-cell lymphoma did not correlate with overall survival. In conclusion, most patients with triple hit lymphoma have an aggressive clinical course and poor prognosis and these tumors have a germinal center B-cell immunophenotype, similar to patients with double hit lymphomas. P53 expression is a poor prognostic factor in patients with triple hit lymphoma.

Illegitimate V(D)J recombination-mediated deletions in Notch1 and Bcl11b are not sufficient for extensive clonal expansion and show minimal age or sex bias in frequency or junctional processing

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Champagne, Devin P., E-mail: devin.champagne@uvm.edu; Shockett, Penny E., E-mail: pshockett@selu.edu

2014-03-15

Highlights: • Examines illegitimate V(D)J deletion junctions in Notch1 and Bcl11b. • Suggests little influence of deletions alone on clonal outgrowth in wild-type mice. • No age or sex biases in frequency, clonality, or junctional processing observed. • Contrasts with previous results at TCRβ and HPRT1 loci. • Deletions in Bcl11b may be tolerated more easily than those in Notch1. - Abstract: Illegitimate V(D)J recombination at oncogenes and tumor suppressor genes is implicated in formation of several T cell malignancies. Notch1 and Bcl11b, genes involved in developing T cell specification, selection, proliferation, and survival, were previously shown to contain hotspots for deletional illegitimate V(D)J recombination associated with radiation-induced thymic lymphoma. Interestingly, these deletions were also observed in wild-type animals. In this study, we conducted frequency, clonality, and junctional processing analyses of Notch1 and Bcl11b deletions during mouse development and compared results to published analyses of authentic V(D)J rearrangements at the T cell receptor beta (TCRβ) locus and illegitimate V(D)J deletions observed at the human, nonimmune HPRT1 locus not involved in T cell malignancies. We detect deletions in Notch1 and Bcl11b in thymic and splenic T cell populations, consistent with cells bearing deletions in the circulating lymphocyte pool. Deletions in thymus can occur in utero, increase in frequency between fetal and postnatal stages, are detected at all ages examined between fetal and 7 months, exhibit only limited clonality (contrasting with previous results in radiation-sensitive mouse strains), and consistent with previous reports are more frequent in Bcl11b, partially explained by relatively high Recombination Signal Information Content (RIC) scores. Deletion junctions in Bcl11b exhibit greater germline nucleotide loss, while in Notch1 palindromic (P) nucleotides are more abundant, although average P nucleotide length is

The Tumor Suppressor BCL7B Functions in the Wnt Signaling Pathway.

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Tomoko Uehara

2015-01-01

Full Text Available Human BCL7 gene family consists of BCL7A, BCL7B, and BCL7C. A number of clinical studies have reported that BCL7 family is involved in cancer incidence, progression, and development. Among them, BCL7B, located on chromosome 7q11.23, is one of the deleted genes in patients with Williams-Beuren syndrome. Although several studies have suggested that malignant diseases occurring in patients with Williams-Beuren syndrome are associated with aberrations in BCL7B, little is known regarding the function of this gene at the cellular level. In this study, we focused on bcl-7, which is the only homolog of BCL7 gene family in Caenorhabditis elegans, and analyzed bcl-7 deletion mutants. As a result, we found that bcl-7 is required for the asymmetric differentiation of epithelial seam cells, which have self-renewal properties as stem cells and divide asymmetrically through the WNT pathway. Distal tip cell development, which is regulated by the WNT pathway in Caenorhabditis elegans, was also affected in bcl-7-knockout mutants. Interestingly, bcl-7 mutants exhibited nuclear enlargement, reminiscent of the anaplastic features of malignant cells. Furthermore, in KATOIII human gastric cancer cells, BCL7B knockdown induced nuclear enlargement, promoted the multinuclei phenotype and suppressed cell death. In addition, this study showed that BCL7B negatively regulates the Wnt-signaling pathway and positively regulates the apoptotic pathway. Taken together, our data indicate that BCL7B/BCL-7 has some roles in maintaining the structure of nuclei and is involved in the modulation of multiple pathways, including Wnt and apoptosis. This study may implicate a risk of malignancies with BCL7B-deficiency, such as Williams-Beuren syndrome.

DNA rearrangement in human follicular lymphoma can involve the 5' or the 3' region of the bcl-2 gene

International Nuclear Information System (INIS)

Tsujimoto, Y.; Bashir, M.M.; Givol, I.; Cossman, J.; Jaffe, E.; Croce, C.M.

1987-01-01

In most human lymphomas, the chromosome translocation t(14;18) occurs within two breakpoint clustering regions on chromosome 18, the major one at the 3' untranslated region of the bcl-2 gene and the minor one at 3' of the gene. Analysis of a panel of follicular lymphoma DNAs using probes for the first exon of the bcl-2 gene indicates that DNA rearrangements may also occur 5' to the involved bcl-2 gene. In this case the IgH locus and the bcl-2 gene are found in an order suggesting that an inversion also occurred during the translocation process. The coding region of the bcl-2 gene, however, are left intact in all cases of follicular lymphoma studied to date

Xanthorrhizol induced DNA fragmentation in HepG2 cells involving Bcl-2 family proteins

International Nuclear Information System (INIS)

Tee, Thiam-Tsui; Cheah, Yew-Hoong; Meenakshii, Nallappan; Mohd Sharom, Mohd Yusof; Azimahtol Hawariah, Lope Pihie

2012-01-01

Highlights: ► We isolated xanthorrhizol, a sesquiterpenoid compound from Curcuma xanthorrhiza. ► Xanthorrhizol induced apoptosis in HepG2 cells as observed using SEM. ► Apoptosis in xanthorrhizol-treated HepG2 cells involved Bcl-2 family proteins. ► DNA fragmentation was observed in xanthorrhizol-treated HepG2 cells. ► DNA fragmentation maybe due to cleavage of PARP and DFF45/ICAD proteins. -- Abstract: Xanthorrhizol is a plant-derived pharmacologically active sesquiterpenoid compound isolated from Curcuma xanthorrhiza. Previously, we have reported that xanthorrhizol inhibited the proliferation of HepG2 human hepatoma cells by inducing apoptotic cell death via caspase activation. Here, we attempt to further elucidate the mode of action of xanthorrhizol. Apoptosis in xanthorrhizol-treated HepG2 cells as observed by scanning electron microscopy was accompanied by truncation of BID; reduction of both anti-apoptotic Bcl-2 and Bcl-X L expression; cleavage of PARP and DFF45/ICAD proteins and DNA fragmentation. Taken together, these results suggest xanthorrhizol as a potent antiproliferative agent on HepG2 cells by inducing apoptosis via Bcl-2 family members. Hence we proposed that xanthorrhizol could be used as an anti-liver cancer drug for future studies.

Xanthorrhizol induced DNA fragmentation in HepG2 cells involving Bcl-2 family proteins

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Tee, Thiam-Tsui, E-mail: thiamtsu@yahoo.com [School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor (Malaysia); Cheah, Yew-Hoong [School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor (Malaysia); Bioassay Unit, Herbal Medicine Research Center, Institute for Medical Research, Jalan Pahang, Kuala Lumpur (Malaysia); Meenakshii, Nallappan [Biology Department, Faculty of Science, Universiti Putra Malaysia, 43400 Serdang, Selangor (Malaysia); Mohd Sharom, Mohd Yusof; Azimahtol Hawariah, Lope Pihie [School of Biosciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 Bangi, Selangor (Malaysia)

2012-04-20

Highlights: Black-Right-Pointing-Pointer We isolated xanthorrhizol, a sesquiterpenoid compound from Curcuma xanthorrhiza. Black-Right-Pointing-Pointer Xanthorrhizol induced apoptosis in HepG2 cells as observed using SEM. Black-Right-Pointing-Pointer Apoptosis in xanthorrhizol-treated HepG2 cells involved Bcl-2 family proteins. Black-Right-Pointing-Pointer DNA fragmentation was observed in xanthorrhizol-treated HepG2 cells. Black-Right-Pointing-Pointer DNA fragmentation maybe due to cleavage of PARP and DFF45/ICAD proteins. -- Abstract: Xanthorrhizol is a plant-derived pharmacologically active sesquiterpenoid compound isolated from Curcuma xanthorrhiza. Previously, we have reported that xanthorrhizol inhibited the proliferation of HepG2 human hepatoma cells by inducing apoptotic cell death via caspase activation. Here, we attempt to further elucidate the mode of action of xanthorrhizol. Apoptosis in xanthorrhizol-treated HepG2 cells as observed by scanning electron microscopy was accompanied by truncation of BID; reduction of both anti-apoptotic Bcl-2 and Bcl-X{sub L} expression; cleavage of PARP and DFF45/ICAD proteins and DNA fragmentation. Taken together, these results suggest xanthorrhizol as a potent antiproliferative agent on HepG2 cells by inducing apoptosis via Bcl-2 family members. Hence we proposed that xanthorrhizol could be used as an anti-liver cancer drug for future studies.

Involvement of Bcl-xL degradation and mitochondrial-mediated apoptotic pathway in pyrrolizidine alkaloids-induced apoptosis in hepatocytes

International Nuclear Information System (INIS)

Ji Lili; Chen Ying; Liu Tianyu; Wang Zhengtao

2008-01-01

Pyrrolizidine alkaloids (PAs) are natural hepatotoxins with worldwide distribution in more than 6000 high plants including medicinal herbs or teas. The aim of this study is to investigate the signal pathway involved in PAs-induced hepatotoxicity. Our results showed that clivorine, isolated from Ligularia hodgsonii Hook, decreased cell viability and induced apoptosis in L-02 cells and mouse hepatocytes. Western-blot results showed that clivorine induced caspase-3/-9 activation, mitochondrial release of cytochrome c and decreased anti-apoptotic Bcl-xL in a time (8-48 h)- and concentration (1-100 μM)-dependent manner. Furthermore, inhibitors of pan-caspase, caspase-3 and caspase-9 significantly inhibited clivorine-induced apoptosis and rescued clivorine-decreased cell viability. Polyubiquitination of Bcl-xL was detected after incubation with 100 μM clivorine for 40 h in the presence of proteasome specific inhibitor MG132, indicating possible degradation of Bcl-xL protein. Furthermore, pretreatment with MG132 or calpain inhibitor I for 2 h significantly enhanced clivorine-decreased Bcl-xL level and cell viability. All the other tested PAs such as senecionine, isoline and monocrotaline decreased mouse hepatocytes viability in a concentration-dependent manner. Clivorine (10 μM) induced caspase-3 activation and decreased Bcl-xL was also confirmed in mouse hepatocytes. Meanwhile, another PA senecionine isolated from Senecio vulgaris L also induced apoptosis, caspase-3 activation and decreased Bcl-xL in mouse hepatocytes. In conclusion, our results suggest that PAs may share the same hepatotoxic signal pathway, which involves degradation of Bcl-xL protein and thus leading to the activation of mitochondrial-mediated apoptotic pathway

Novel ZEB2-BCL11B Fusion Gene Identified by RNA-Sequencing in Acute Myeloid Leukemia with t(2;14(q22;q32.

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Synne Torkildsen

Full Text Available RNA-sequencing of a case of acute myeloid leukemia with the bone marrow karyotype 46,XY,t(2;14(q22;q32[5]/47,XY,idem,+?4,del(6(q13q21[cp6]/46,XY[4] showed that the t(2;14 generated a ZEB2-BCL11B chimera in which exon 2 of ZEB2 (nucleotide 595 in the sequence with accession number NM_014795.3 was fused to exon 2 of BCL11B (nucleotide 554 in the sequence with accession number NM_022898.2. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. All functional domains of BCL11B are retained in the chimeric protein. Abnormal expression of BCL11B coding regions subjected to control by the ZEB2 promoter seems to be the leukemogenic mechanism behind the translocation.

Bcl-2 protein expression in mucoepidermoid carcinoma of salivary glands: a single institution experience.

Science.gov (United States)

Janjua, Omer Sefvan; Qureshi, Sana Mehmood; Khan, Tariq Sarfraz; Alamgir, Wajiha

2012-01-01

Mucoepidermoid carcinoma is the most common salivary gland tumor with varying behavior among different histopathological grades. The objective of this study was to determine the expression of Bcl-2 protein in mucoepidermoid carcinoma (MEC) and to correlate with histological grades. The records of 40 cases of MEC were collected from the histopathology department. Fresh slides were prepared and fresh diagnoses were made using the grading criteria for MEC. Immunohistochemical markers for Bcl-2 were applied and the results analyzed using the chi-square test. Of 40 cases, 20 were males and 20 were females. The range in age of the patients was 6 to 67 years mean (SD) was 42.6 (1.85) years. Twenty-two were low grade (55%), 11 high grade (27.5%) and 7 (17.5%) were intermediate grade MEC. Among these 40 cases, Bcl-2 expression was positive in 24 cases and negative in 16 cases. In 22 cases of low-grade MEC, 19 were positive while only 3 were negative. In high-grade tumors, all 11 cases were found to have a negative expression of Bcl-2 protein. In intermediate-grade MEC, 5 cases showed positive expression while only 2 cases showed negative expression. Bcl-2 protein expression showed positive expression in low-grade and negative expression in high-grade MEC. Intermediate grade showed more than 50% positive results for Bcl-2. Correlation between grades of MEC and expression of Bcl-2 is statistically significant and can be used for the depicting the prognosis of MEC along with other prognostic and clinico-pathological parameters.

Borax-induced apoptosis in HepG2 cells involves p53, Bcl-2, and Bax.

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Wei, Y; Yuan, F J; Zhou, W B; Wu, L; Chen, L; Wang, J J; Zhang, Y S

2016-06-21

Borax, a boron compound and a salt of boric acid, is known to inhibit the growth of tumor cells. HepG2 cells have been shown to be clearly susceptible to the anti-proliferative effects of borax. However, the specific mechanisms regulating this effect are poorly understood. This study aimed to investigate the pathways underlying the growth inhibition induced by borax in HepG2 cells. The effects of borax on HepG2 cell viability were characterized using MTT. Apoptosis was also verified by annexin V/propidium iodide staining. JC-1 dye and western blotting techniques were used to measure mitochondrial membrane potential and p53, Bax, and Bcl-2 protein expression, respectively. Relevant mRNA levels were measured by qRT-PCR. Borax inhibited the proliferation of HepG2 cells in a time- and dose-dependent manner in vitro. The apoptotic process triggered by borax involved the upregulation of p53 and Bax and the downregulation of Bcl-2, which was confirmed by a change in the mitochondrial membrane potential. These results elucidate a borax-induced apoptotic pathway in HepG2 cells that involves the upregulation of p53 and Bax and the downregulation of Bcl-2.

Interaction between Na-K-ATPase and Bcl-2 proteins BclXL and Bak.

Science.gov (United States)

Lauf, Peter K; Alqahtani, Tariq; Flues, Karin; Meller, Jaroslaw; Adragna, Norma C

2015-01-01

In silico analysis predicts interaction between Na-K-ATPase (NKA) and Bcl-2 protein canonical BH3- and BH1-like motifs, consistent with NKA inhibition by the benzo-phenanthridine alkaloid chelerythrine, a BH3 mimetic, in fetal human lens epithelial cells (FHLCs) (Lauf PK, Heiny J, Meller J, Lepera MA, Koikov L, Alter GM, Brown TL, Adragna NC. Cell Physiol Biochem 31: 257-276, 2013). This report establishes proof of concept: coimmunoprecipitation and immunocolocalization showed unequivocal and direct physical interaction between NKA and Bcl-2 proteins. Specifically, NKA antibodies (ABs) coimmunoprecipitated BclXL (B-cell lymphoma extra large) and BAK (Bcl-2 antagonist killer) proteins in FHLCs and A549 lung cancer cells. In contrast, both anti-Bcl-2 ABs failed to pull down NKA. Notably, the molecular mass of BAK1 proteins pulled down by NKA and BclXL ABs appeared to be some 4-kDa larger than found in input monomers. In silico analysis predicts these higher molecular mass BAK1 proteins as alternative splicing variants, encoding 42 amino acid (aa) larger proteins than the known 211-aa long canonical BAK1 protein. These BAK1 variants may constitute a pool separate from that forming mitochondrial pores by specifically interacting with NKA and BclXL proteins. We propose a NKA-Bcl-2 protein ternary complex supporting our hypothesis for a special sensor role of NKA in Bcl-2 protein control of cell survival and apoptosis. Copyright © 2015 the American Physiological Society.

Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements.

Science.gov (United States)

Miyaoka, Masashi; Kikuti, Yara Y; Carreras, Joaquim; Ikoma, Haruka; Hiraiwa, Shinichiro; Ichiki, Akifumi; Kojima, Minoru; Ando, Kiyoshi; Yokose, Tomoyuki; Sakai, Rika; Hoshikawa, Masahiro; Tomita, Naoto; Miura, Ikuo; Takata, Katsuyoshi; Yoshino, Tadashi; Takizawa, Jun; Bea, Silvia; Campo, Elias; Nakamura, Naoya

2018-02-01

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (Phit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular

Expression of Bcl-2 in canine osteosarcoma

Science.gov (United States)

Piro, F.; Leonardi, L.

2015-01-01

Osteosarcoma (OS) is the most common primary malignancy of bone. It is responsible for 80-85% of the primary bone tumors affecting dogs and it is characterized by aggressive and invasive behavior, with a high metastatic potential. Several studies on cancer and related tumorigenesis, show an involvement of the mechanisms of programmed cell death and cell survival. Many signals seem to be involved in the related mechanism of autophagy and in particular, our interest is focused on the expression of a family of Bcl-2 that seems to be involved either in the control of biomolecular mechanisms like autophagy and apoptosis. In this study we investigated the expression of Bcl-2 in different cases of spontaneous canine osteosarcoma and the related preliminary results are described. We found Bcl-2 activity was increased in OS tissue compared to normal bone tissue. These results suggested that Bcl-2 activity may play an important role in the formation of OS and as a diagnostic for neoplastic activity. However, further research is needed to confirm the role of Bcl-2 activity in OS in canines. PMID:26623359

Behavior of solvent-exposed hydrophobic groove in the anti-apoptotic Bcl-XL protein: clues for its ability to bind diverse BH3 ligands from MD simulations.

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Dilraj Lama

Full Text Available Bcl-XL is a member of Bcl-2 family of proteins involved in the regulation of intrinsic pathway of apoptosis. Its overexpression in many human cancers makes it an important target for anti-cancer drugs. Bcl-XL interacts with the BH3 domain of several pro-apoptotic Bcl-2 partners. This helical bundle protein has a pronounced hydrophobic groove which acts as a binding region for the BH3 domains. Eight independent molecular dynamics simulations of the apo/holo forms of Bcl-XL were carried out to investigate the behavior of solvent-exposed hydrophobic groove. The simulations used either a twin-range cut-off or particle mesh Ewald (PME scheme to treat long-range interactions. Destabilization of the BH3 domain-containing helix H2 was observed in all four twin-range cut-off simulations. Most of the other major helices remained stable. The unwinding of H2 can be related to the ability of Bcl-XL to bind diverse BH3 ligands. The loss of helical character can also be linked to the formation of homo- or hetero-dimers in Bcl-2 proteins. Several experimental studies have suggested that exposure of BH3 domain is a crucial event before they form dimers. Thus unwinding of H2 seems to be functionally very important. The four PME simulations, however, revealed a stable helix H2. It is possible that the H2 unfolding might occur in PME simulations at longer time scales. Hydrophobic residues in the hydrophobic groove are involved in stable interactions among themselves. The solvent accessible surface areas of bulky hydrophobic residues in the groove are significantly buried by the loop LB connecting the helix H2 and subsequent helix. These observations help to understand how the hydrophobic patch in Bcl-XL remains stable in the solvent-exposed state. We suggest that both the destabilization of helix H2 and the conformational heterogeneity of loop LB are important factors for binding of diverse ligands in the hydrophobic groove of Bcl-XL.

Outdoor Long-Range WLANs : A Lesson for IEEE 802.11ah

NARCIS (Netherlands)

Aust, Stefan; Venkatesha Prasad, R.; Niemegeers, Ignas G M M

2015-01-01

Several service applications have been reported by many who proposed the use of wireless LANs (WLANs) over a wide variety of outdoor deployments. In particular, the upcoming IEEE 802.11ah WLAN protocol will enable a longer transmission range between WLAN access points (APs) and stations (STAs) up to

Long Noncoding RNA HOTAIR Modulates MiR-206-mediated Bcl-w Signaling to Facilitate Cell Proliferation in Breast Cancer.

Science.gov (United States)

Ding, Wei; Ren, Jin; Ren, Hui; Wang, Dan

2017-12-08

LncRNA HOX transcript antisense RNA (HOTAIR) is involved in lots of cancers. The pro-survival protein Bcl-w is frequently found in cancer development. However, the effect of HOTAIR on Bcl-w in breast cancer is not well documented. In this study, we first evaluated the correlation between HOTAIR level and Bcl-w expression in clinical breast cancer tissues. We observed that the expression levels of Bcl-w were much higher in the breast cancer samples than that in their paired noncancerous tissues. Moreover, the levels of HOTAIR were positively associated with those of Bcl-w in clinical breast cancer samples. As expected, we observed that HOTAIR was able to up-regulate the expression of Bcl-w in breast cancer cells. Mechanistically, we found that miR-206 was capable of inhibiting the expression of Bcl-w by directly binding to the 3'UTR of Bcl-w mRNA. Interestingly, HOTAIR could increase the expression of Bcl-w through sequestering miR-206 at post-transcriptional level. Functionally, our data showed that HOTAIR-induced Bcl-w by miR-206 facilitated the proliferation of breast cancer cells. Thus, we conclude that HOTAIR up-regulates Bcl-w to enhance cell proliferation through sequestering miR-206 in breast cancer. Our finding provides new insights into the mechanism of breast cancer mediated by HOTAIR.

Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1.

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Amanda J Grieco

Full Text Available The molecular mechanisms governing γ-globin expression in a subset of fetal hemoglobin (α2γ2: HbF expressing red blood cells (F-cells and the mechanisms underlying the variability of response to hydroxyurea induced γ-globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F-cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of γ-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate γ-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea.

Expression of Bcl-2 in canine osteosarcoma

Directory of Open Access Journals (Sweden)

F. Piro

2015-03-01

Full Text Available Osteosarcoma (OS is the most common primary malignancy of bone. It is responsible for 80-85% of the primary bone tumors affecting dogs and it is characterized by aggressive and invasive behavior, with a high metastatic potential. Several studies on cancer and related tumorigenesis, show an involvement of the mechanisms of programmed cell death and cell survival. Many signals seem to be involved in the related mechanism of autophagy and in particular, our interest is focused on the expression of a family of Bcl-2 that seems to be involved either in the control of biomolecular mechanisms like autophagy and apoptosis. In this study we investigated the expression of Bcl-2 in different cases of spontaneous canine osteosarcoma and the related preliminary results are described. We found Bcl-2 activity was increased in OS tissue compared to normal bone tissue. These results suggested that Bcl-2 activity may play an important role in the formation of OS and as a diagnostic for neoplastic activity. However, further research is needed to confirm the role of Bcl-2 activity in OS in canines.

A Model for Long Range Planning for Seminole Community College.

Science.gov (United States)

Miner, Norris

A model for long-range planning designed to maximize involvement of college personnel, to improve communication among various areas of the college, to provide a process for evaluation of long-range plans and the planning process, to adjust to changing conditions, to utilize data developed at a level useful for actual operations, and to have…

Akt regulates drug-induced cell death through Bcl-w downregulation.

Science.gov (United States)

Garofalo, Michela; Quintavalle, Cristina; Zanca, Ciro; De Rienzo, Assunta; Romano, Giulia; Acunzo, Mario; Puca, Loredana; Incoronato, Mariarosaria; Croce, Carlo M; Condorelli, Gerolama

2008-01-01

Akt is a serine threonine kinase with a major role in transducing survival signals and regulating proteins involved in apoptosis. To find new interactors of Akt involved in cell survival, we performed a two-hybrid screening in yeast using human full-length Akt c-DNA as bait and a murine c-DNA library as prey. Among the 80 clones obtained, two were identified as Bcl-w. Bcl-w is a member of the Bcl-2 family that is essential for the regulation of cellular survival, and that is up-regulated in different human tumors, such as gastric and colorectal carcinomas. Direct interaction of Bcl-w with Akt was confirmed by immunoprecipitation assays. Subsequently, we addressed the function of this interaction: by interfering with the activity or amount of Akt, we have demonstrated that Akt modulates the amount of Bcl-w protein. We have found that inhibition of Akt activity may promote apoptosis through the downregulation of Bcl-w protein and the consequential reduction in interaction of Bcl-w with pro-apoptotic members of the Bcl-2 family. Our data provide evidence that Bcl-w is a new member of the Akt pathway and that Akt may induce anti-apoptotic signals at least in part through the regulation of the amount and activity of Bcl-w.

Multiplex PCR for the detection of BCL-1/IGH and BCL-2/IGH gene rearrangements--clinical validation in a prospective study of blood and bone marrow in 258 patients with or suspected of non-Hodgkin's lymphoma

DEFF Research Database (Denmark)

Nyvold, Charlotte G; Bendix, Knud; Brandsborg, Margrethe

2007-01-01

prospectively been evaluated. Eleven patients (4%) were found t(11;14)+ and 37 patients (14%) t(14;18)+. Comparing these results to standard diagnostic methods of PB and/or BM identified PCR+ samples that were normal by morphology (BCL-1/IGH: 1/11; BCL-2/IGH: 17/37). Equally important, patients who were......We have designed a multiplex PCR, which allows for fast and high throughput demonstration of the BCL-1/IGH and BCL-2/IGH fusion DNA observed primarily in mantle cell- and follicular non-Hodgkin's lymphoma (NHL). Blood (PB) and/or bone marrow (BM) from 258 patients suspected of NHL have...... not clonal in PB and/or BM by flow cytometry were identified as PCR+ (BCL-1/IGH: 3/11; BCL-2/IGH: 23/37). We conclude that this multiplex approach allows for easy and sensitive molecular determination of molecular lesions in NHL, which have diagnostic and prognostic importance. Udgivelsesdato: 2007-null...

Williamsport Area Community College Long Range Planning: The Long Range Plan, Update 1987.

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Williamsport Area Community Coll., PA.

This update to Williamsport Area Community College's (WACC's) 1984-89 long-range plan offers a status report on each of the plan's 78 objectives, reassigns responsibility for specific objectives to make the plan responsive to the current organizational structure of the college, and offers 11 new objectives for the 1986-87 academic year. After…

Akt regulates drug-induced cell death through Bcl-w downregulation.

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Michela Garofalo

Full Text Available Akt is a serine threonine kinase with a major role in transducing survival signals and regulating proteins involved in apoptosis. To find new interactors of Akt involved in cell survival, we performed a two-hybrid screening in yeast using human full-length Akt c-DNA as bait and a murine c-DNA library as prey. Among the 80 clones obtained, two were identified as Bcl-w. Bcl-w is a member of the Bcl-2 family that is essential for the regulation of cellular survival, and that is up-regulated in different human tumors, such as gastric and colorectal carcinomas. Direct interaction of Bcl-w with Akt was confirmed by immunoprecipitation assays. Subsequently, we addressed the function of this interaction: by interfering with the activity or amount of Akt, we have demonstrated that Akt modulates the amount of Bcl-w protein. We have found that inhibition of Akt activity may promote apoptosis through the downregulation of Bcl-w protein and the consequential reduction in interaction of Bcl-w with pro-apoptotic members of the Bcl-2 family. Our data provide evidence that Bcl-w is a new member of the Akt pathway and that Akt may induce anti-apoptotic signals at least in part through the regulation of the amount and activity of Bcl-w.

Involvement of ERK, Bcl-2 family and caspase 3 in recombinant human activin A-induced apoptosis in A549

International Nuclear Information System (INIS)

Wang Baiding; Feng Yuling; Song Xingbo; Liu Qingqing; Ning Yunye; Ou Xuemei; Yang Jie; Zhang Xiaohong; Wen, Fuqiang

2009-01-01

Background: Activins are members of the transforming growth factor-β (TGF-β) superfamily. Previous studies have shown that activin A may have a central role in regulating both apoptosis and proliferation. However, direct studies of recombination human activin A on human NSCLC A549 cells have not yet been reported. The purpose of this study was to investigate whether activin A could induce apoptosis in A549 cells and the possible mechanisms via which it worked. Methods: Cellular apoptosis induced by activin A was detected by TUNEL assay and the levels of protein expression were detected by western blot. Results: Recombination human activin A induced apoptosis in human NSCLC A549 cells in a concentrate-dependent manner. Activin A-induced A549 apoptosis was accompanied by the up-regulation of Bax, Bad and Bcl-Xs and down-regulation of Bcl-2. Moreover, activin A treatment increased the expression of its typeII receptors, activated ERK and caspase 3 in A549. These results clearly demonstrate that the induction of apoptosis by activin-A involves multiple cellular/molecular pathways and strongly suggest that pro- and anti-apoptotic Bcl-2 family proteins and caspase 3 participate in activin A-induced apoptotic process in A549 cells. On the other hand, activin A treatment had little effect on primary human small airway epithelial cells (SAECs). Conclusion: Recombination human activin A induced apoptosis in A549 cells, at least partially, through ERK and mitochondrial pathway. The result that activin A did not affect the normal SAEC revealed activin A might be considered as a potential anticancer agent and worthy of further studies

Long-range correlated percolation

International Nuclear Information System (INIS)

Weinrib, A.

1984-01-01

This paper is a study of the percolation problem with long-range correlations in the site or bond occupations. An extension of the Harris criterion for the relevance of the correlations is derived for the case that the correlations decay as x/sup -a/ for large distances x. For a d the correlations are relevant if dν-2<0. Applying this criterion to the behavior that results when the correlations are relevant, we argue that the new behavior will have ν/sub long/ = 2/a. It is shown that the correlated bond percolation problem is equivalent to a q-state Potts model with quenched disorder in the limit q→1. With the use of this result, a renormalization-group study of the problem is presented, expanding in epsilon = 6-d and in delta = 4-a. In addition to the normal percolation fixed point, we find a new long-range fixed point. The crossover to this new fixed point follows the extended Harris criterion, and the fixed point has exponents ν/sub long/ = 2/a (as predicted) and eta/sub long/ = (1/11)(delta-epsilon). Finally, several results on the percolation properties of the Ising model at its critical point are shown to be in agreement with the predictions of this paper

NF-κB activation fails to protect cells to TNFα-induced apoptosis in the absence of Bcl-xL, but not Mcl-1, Bcl-2 or Bcl-w.

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Casanelles, Elisenda; Gozzelino, Raffaella; Marqués-Fernández, Fernando; Iglesias-Guimarais, Victoria; Garcia-Belinchón, Mercè; Sánchez-Osuna, María; Solé, Carme; Moubarak, Rana S; Comella, Joan X; Yuste, Victor J

2013-05-01

TNFα can promote either cell survival or cell death. The activation of NF-κB plays a central role in cell survival while its inhibition makes TNFα-triggered cytotoxicity possible. Here, we report that the overexpression of a non-degradable mutant of the inhibitor of NF-κB (super-repressor (SR)-IκBα) sensitizes HeLa cells towards TNFα-induced apoptosis, involving caspases activation and cytocrome C release from the mitochondria. Interestingly, we describe that the specific knockdown of Bcl-xL, but not that of Bcl-2, Bcl-w or Mcl-1, renders cells sensitive to TNFα-induced apoptosis. This cytotoxic effect occurs without altering the activation of NF-κB. Then, the activation of the NF-κB pathway is not sufficient to protect Bcl-xL-downregulated cells from TNFα-induced cell death, meaning that TNFα is not able to promote cell survival in the absence of Bcl-xL. In addition, Bcl-xL silencing does not potentiate the cytotoxicity afforded by the cytokine in SR-IκBα-overexpressing cells. This indicates that TNFα-induced apoptosis in SR-IκBα-overexpressing cells relies on the protein levels of Bcl-xL. We have corroborated these findings using RD and DU-145 cells, which also become sensitive to TNFα-induced apoptosis after Bcl-xL knockdown despite that NF-κB remains activated. Altogether, our results point out that the impairment of the anti-apoptotic function of Bcl-xL should make cells sensitive towards external insults circumventing the TNFα-triggered NF-κB-mediated cytoprotective effect. Hence, the specific inhibition of Bcl-xL could be envisaged as a promising alternative strategy against NF-κB-dependent highly chemoresistant proliferative malignancies. Copyright © 2013 Elsevier B.V. All rights reserved.

Expression of Bcl-2 in canine osteosarcoma | Piro | Open Veterinary ...

African Journals Online (AJOL)

Many signals seem to be involved in the related mechanism of autophagy and in particular, our interest is focused on the expression of a family of Bcl-2 that seems to be involved either in the control of biomolecular mechanisms like autophagy and apoptosis. In this study we investigated the expression of Bcl-2 in different ...

Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization.

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Shah, O Jameel; Lin, Xiaoyu; Li, Leiming; Huang, Xiaoli; Li, Junling; Anderson, Mark G; Tang, Hua; Rodriguez, Luis E; Warder, Scott E; McLoughlin, Shaun; Chen, Jun; Palma, Joann; Glaser, Keith B; Donawho, Cherrie K; Fesik, Stephen W; Shen, Yu

2010-07-13

Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.

Withaferin A Suppresses Anti-apoptotic BCL2, Bcl-xL, XIAP and ...

African Journals Online (AJOL)

apoptotic genes, BCL2, Bcl-xL, XIAP and Survivin), in cervical carcinoma cells. Methods: Annexin V-FITC/propidium iodide (PI) staining was used for the investigation of cell apoptosis. RNA RNeasy Kits was used to isolate RNA and Omniscript ...

The Impact of XmnI-HBG2, BCL11A and HBS1L-MYB Single Nucleotide Polymorphisms on Hb F Variation of Hematologically Normal Iranian Individuals.

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Keyhani, Elaheh; Jafari Vesiehsari, Mahjoobeh; Talebi Kakroodi, Setareh; Darabi, Elham; Zamani, Fahimeh; Karimlou, Masoud; Kamali, Koorosh; Neishabury, Maryam

2016-06-01

The impact of Hb F on severity of sickle cell disease and β-thalassemia (β-thal) is well documented. The XmnI-HBG2, BCL11A and HBS1L-MYB single nucleotide polymorphisms (SNPs) have been introduced as the most important factors causing variation in fetal hemoglobin (Hb F) levels in different population studies. However, the extent of their effect could be population-specific. In this study, multivariate linear regression analysis was used to evaluate the association of Hb F with age, sex, and eight SNPs, including XmnI-HBG2, four BCL11A, two HBS1L-MYB SNPs and the polymorphic palindromic 5' hypersensitive 4-locus control region (5'HS4-LCR). One hundred and twenty-two hematologically normal individuals, from a previous study cohort, constituted our study population. In multivariate regression analyses, no association of Hb F was observed with age or sex of the individuals and SNPs in this study. We conducted a univariate regression analysis to further investigate the results, which among all the factors only detected XmnI-HBG2 and 5'HS4 SNPs as significant modifiers of Hb F. The significance of these two factors disappeared in a bivariate analysis. These results suggest that either XmnI-HBG2 or 5'HS4-LCR have a stronger contribution in Hb F variations of the Iranian population than BCL11A and HBS1L-MYB SNPs. Furthermore, the effect of low population size and technical limitations on obtained results could not be ruled out.

CASP10-BCL::Fold efficiently samples topologies of large proteins.

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Heinze, Sten; Putnam, Daniel K; Fischer, Axel W; Kohlmann, Tim; Weiner, Brian E; Meiler, Jens

2015-03-01

During CASP10 in summer 2012, we tested BCL::Fold for prediction of free modeling (FM) and template-based modeling (TBM) targets. BCL::Fold assembles the tertiary structure of a protein from predicted secondary structure elements (SSEs) omitting more flexible loop regions early on. This approach enables the sampling of conformational space for larger proteins with more complex topologies. In preparation of CASP11, we analyzed the quality of CASP10 models throughout the prediction pipeline to understand BCL::Fold's ability to sample the native topology, identify native-like models by scoring and/or clustering approaches, and our ability to add loop regions and side chains to initial SSE-only models. The standout observation is that BCL::Fold sampled topologies with a GDT_TS score > 33% for 12 of 18 and with a topology score > 0.8 for 11 of 18 test cases de novo. Despite the sampling success of BCL::Fold, significant challenges still exist in clustering and loop generation stages of the pipeline. The clustering approach employed for model selection often failed to identify the most native-like assembly of SSEs for further refinement and submission. It was also observed that for some β-strand proteins model refinement failed as β-strands were not properly aligned to form hydrogen bonds removing otherwise accurate models from the pool. Further, BCL::Fold samples frequently non-natural topologies that require loop regions to pass through the center of the protein. © 2015 Wiley Periodicals, Inc.

LncRNA TUG1 sponges microRNA-9 to promote neurons apoptosis by up-regulated Bcl2l11 under ischemia.

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Chen, Shengcai; Wang, Mengdie; Yang, Hang; Mao, Ling; He, Quanwei; Jin, Huijuan; Ye, Zi-Ming; Luo, Xue-Ying; Xia, Yuan-Peng; Hu, Bo

2017-03-25

Emerging studies have illustrated that LncRNAs TUG1 play critical roles in multiple biologic processes. However, the LncRNA TUG1 expression and function in ischemic stroke have not been reported yet. In this study, we found that LncRNA TUG1 expression was significantly up-regulated in brain ischemic penumbra from rat middle carotid artery occlusion (MCAO) model, while similar results were also observed in cultured neurons under oxygen-glucose deprivation (OGD) insult. Knockdown of TUG1 decreased the ratio of apoptotic cells and promoted cells survival in vitro, which may be regulated by the elevated miRNA-9 expression and decreased Bcl2l11 protein. Furthermore, TUG1 could directly interact with miR-9 and down-regulating miR-9 could efficiently reverse the function of TUG1 on the Bcl2l11 expression. In summary, our result sheds light on the role of LncRNA TUG1 as a miRNA sponge for ischemic stroke, possibly providing a new therapeutic target in stroke. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of a human chromosome 11 radiation hybrid panel to map markers at 11q13

International Nuclear Information System (INIS)

Withers, D.; Richard, C. III; Meeker, T.C.; Maurer, S.; Evans, G.; Myers, R.M.; Cox, D.R.

1990-01-01

A human/hamster hybrid cell line containing human chromosome 11 was X-irradiated and 102-independent derivative lines were recovered. These 'radiation hybrids' contain random fragments of human chromosome 11. This radiation hybrid panel was used to score the retention of markers at band 11q13. Statistical analysis of marker co-retention patterns in the radiation hybrid panel permits a preliminary ordering and mapping of the markers used. The best order for six scored markers is: proximal - CD5 - CD20 - PGA - HST - BCL1 - SEA - distal. Additional markers are currently being scored. The six 11q13 markers above are spread over approximately 10-12 mB of DNA. The mapping data has implications for the identification of the bcl-1 gene. bcl-1 is the site of chromosome breakage in translocations associated with B lymphocytic malignancy. bcl-1 markers map at least 4 Mb away from any of four genes previously hypothesized to be activated by such translocations, thereby making them unlikely candidates for activation

Bcl-w, a Radio-resistant Protein, Promotes the Gastric Cancer Cell Migration by inducing the phosphorylation of Focal Adhesion Kinase

International Nuclear Information System (INIS)

Bae, In Hwa; Yoon, Sung Hwan; Um, Hong Duck

2008-01-01

Gastric cancer is one of the leading malignancies in many countries and lethal for the high incidence of recurrence even after drastic surgical resection. Because local invasion and subsequent metastasis contributes to the failure of anticancer treatments of gastric cancer, a better understanding of the mechanisms involved in tumor invasiveness within the stomach seems to be essential for the control of this disease. Bcl-w is a prosurvival member of the Bcl-2 protein family, and thus protects cells from γ-irradiation. Recent reports suggest that Bcl-w can be upregulated in gastric cancer cells in a manner associated with the infiltrative (diffuse) types of the tumor. An analysis of Bcl-w function consistently revealed that Bcl-w can also promote the migratory and invasive potentials of gastric cancer cells. While it was shown that Bcl-w increases the invasiveness of cancer cells by sequentially inducing PI3K, Akt, SP1, and MMP-2, cellular components involved in Bcl-w-induced cell migration remain to be determined. This was the reason why we undertook the present study, which shows that FAK is a critical mediator of the cell migration induced by Bcl-w

The roles of Bcl-xL in modulating apoptosis during development of Xenopus laevis

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Calderon-Segura Maria

2005-09-01

Full Text Available Abstract Background Apoptosis is a common and essential aspect of development. It is particularly prevalent in the central nervous system and during remodelling processes such as formation of the digits and in amphibian metamorphosis. Apoptosis, which is dependent upon a balance between pro- and anti-apoptotic factors, also enables the embryo to rid itself of cells damaged by gamma irradiation. In this study, the roles of the anti-apoptotic factor Bcl-xL in protecting cells from apoptosis were examined in Xenopus laevis embryos using transgenesis to overexpress the XR11 gene, which encodes Bcl-xL. The effects on developmental, thyroid hormone-induced and γ-radiation-induced apoptosis in embryos were examined in these transgenic animals. Results Apoptosis was abrogated in XR11 transgenic embryos. However, the transgene did not prevent the apoptotic response of tadpoles to thyroid hormone during metamorphosis. Post-metamorphic XR11 frogs were reared to sexual maturity, thus allowing us to produce second-generation embryos and enabling us to distinguish between the maternal and zygotic contributions of Bcl-xL to the γ-radiation apoptotic response. Wild-type embryos irradiated before the mid-blastula transition (MBT underwent normal cell division until reaching the MBT, after which they underwent massive, catastrophic apoptosis. Over-expression of Bcl-xL derived from XR11 females, but not males, provided partial protection from apoptosis. Maternal expression of XR11 was also sufficient to abrogate apoptosis triggered by post-MBT γ-radiation. Tolerance to post-MBT γ-radiation from zygotically-derived XR11 was acquired gradually after the MBT in spite of abundant XR11 protein synthesis. Conclusion Our data suggest that Bcl-xL is an effective counterbalance to proapoptotic factors during embryonic development but has no apparent effect on the thyroid hormone-induced apoptosis that occurs during metamorphosis. Furthermore, post-MBT apoptosis

Bcl-2 inhibitors potentiate the cytotoxic effects of radiation in Bcl-2 overexpressing radioresistant tumor cells

International Nuclear Information System (INIS)

Hara, Takamitsu; Omura-Minamisawa, Motoko; Chao Cheng; Nakagami, Yoshihiro; Ito, Megumi; Inoue, Tomio

2005-01-01

Purpose: Bcl-2, an inhibitor of apoptosis frequently shows elevated expression in human tumors, thus resulting in resistance to radiation therapy. Therefore, inhibiting Bcl-2 function may enhance the radiosensitivity of tumor cells. Tetrocarcin A (TC-A) and bcl-2 antisense oligonucleotides exhibit antitumor activity by inhibiting Bcl-2 function and transcription, respectively. We investigated whether these antitumor agents would enhance the cytotoxic effects of radiation in tumor cells overexpressing Bcl-2. Methods and materials: We used HeLa/bcl-2 cells, a stable Bcl-2-expressing cell line derived from wild-type HeLa (HeLa/wt) cells. Cells were incubated with TC-A and bcl-2 antisense oligonucleotides for 24 h after irradiation, and cell viability was then determined. Apoptotic cells were quantified by flow cytometric assay. Results: The HeLa/bcl-2 cells were more resistant to radiation than HeLa/wt cells. At concentrations that are not inherently cytotoxic, both TC-A and bcl-2 antisense oligonucleotides increased the cytotoxic effects of radiation in HeLa/bcl-2 cells, but not in HeLa/wt cells. However, in HeLa/bcl-2 cells, additional treatment with TC-A in combination with radiation did not significantly increase apoptosis. Conclusions: The present results suggest that TC-A and bcl-2 antisense oligonucleotides reduce radioresistance of tumor cells overexpressing Bcl-2. Therefore, a combination of radiotherapy and Bcl-2 inhibitors may prove to be a useful therapeutic approach for treating tumors that overexpress Bcl-2

Sheeppox virus SPPV14 encodes a Bcl-2-like cell death inhibitor that counters a distinct set of mammalian proapoptotic proteins.

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Okamoto, Toru; Campbell, Stephanie; Mehta, Ninad; Thibault, John; Colman, Peter M; Barry, Michele; Huang, David C S; Kvansakul, Marc

2012-11-01

Many viruses express inhibitors of programmed cell death (apoptosis), thereby countering host defenses that would otherwise rapidly clear infected cells. To counter this, viruses such as adenoviruses and herpesviruses express recognizable homologs of the mammalian prosurvival protein Bcl-2. In contrast, the majority of poxviruses lack viral Bcl-2 (vBcl-2) homologs that are readily identified by sequence similarities. One such virus, myxoma virus, which is the causative agent of myxomatosis, expresses a virulence factor that is a potent inhibitor of apoptosis. In spite of the scant sequence similarity to Bcl-2, myxoma virus M11L adopts an almost identical 3-dimensional fold. We used M11L as bait in a sequence similarity search for other Bcl-2-like proteins and identified six putative vBcl-2 proteins from poxviruses. Some are potent inhibitors of apoptosis, in particular sheeppox virus SPPV14, which inhibited cell death induced by multiple agents. Importantly, SPPV14 compensated for the loss of antiapoptotic F1L in vaccinia virus and acts to directly counter the cell death mediators Bax and Bak. SPPV14 also engages a unique subset of the death-promoting BH3-only ligands, including Bim, Puma, Bmf, and Hrk. This suggests that SPPV14 may have been selected for specific biological roles as a virulence factor for sheeppox virus.

MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

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Liu, Xiaoyou [Department of Organ Transplantation, Zhujiang Hospital, Guangzhou 510282 (China); Dong, Changgui [Institute of Molecular Ecology and Evolution, East China Normal University, Shanghai 200062 (China); Jiang, Zhengyao [Department of Organ Transplantation, Zhujiang Hospital, Guangzhou 510282 (China); Wu, William K.K. [Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Chan, Matthew T.V. [Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Shatin, NT, Hong Kong (China); Zhang, Jie [Department of Organ Transplantation, Zhujiang Hospital, Guangzhou 510282 (China); Li, Haibin; Qin, Ke [Guangxi Key Laboratory for Transplantation Medicine Department of Organ Transplantation in Guangzhou Military Region, Institute of Transplant Medicine, 303 Hospital of People' s Liberation Army, Nanning, Guangxi 530021 (China); Sun, Xuyong, E-mail: sunxuyong0528@163.com [Guangxi Key Laboratory for Transplantation Medicine Department of Organ Transplantation in Guangzhou Military Region, Institute of Transplant Medicine, 303 Hospital of People' s Liberation Army, Nanning, Guangxi 530021 (China)

2015-04-10

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.

MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

International Nuclear Information System (INIS)

Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao; Wu, William K.K.; Chan, Matthew T.V.; Zhang, Jie; Li, Haibin; Qin, Ke; Sun, Xuyong

2015-01-01

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, and chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11

Early diagnostic value of Bcl-3 localization in colorectal cancer

International Nuclear Information System (INIS)

Saamarthy, Karunakar; Björner, Sofie; Johansson, Martin; Landberg, Göran; Massoumi, Ramin; Jirström, Karin; Masoumi, Katarzyna Chmielarska

2015-01-01

B-cell leukemia 3 (Bcl-3) is a member of the inhibitor of κB family, which regulates a wide range of biological processes by functioning as a transcriptional activator or as a repressor of target genes. Elevated expression, sustained nuclear accumulation, and uncontrolled activation of Bcl-3 causes increased cellular proliferation or survival, dependent on the tissue and type of stimuli. We retrospectively reviewed patients who were diagnosed with colorectal cancer at Skåne University Hospital in Malmö between 1st of January 1990 and 31st of December 1991. Bcl-3 localization in colorectal cancer was assessed by immunohistochemistry on tissue microarray and freshly isolated colon from patients. Correlation between Bcl-3 localization and clinicopathological parameters of the cohort were evaluated using the Spearman rank-order correlation coefficient. In addition, Bcl-3 expression and localization in colon adenocarcinoma cells were analysed by western blot, immunohistochemistry and subcellular fractionation separately. We found that Bcl-3 was mainly localized in the cytoplasm in the tumour tissue isolated from colon cancer patients. Normal colon samples from the same patients showed Bcl-3 localization in the nucleus. In three out of six colon cancer cell lines, we detected elevated levels of Bcl-3. In these cell lines Bcl-3 was accumulated in the cytosol. We confirmed these findings by analysing Bcl-3 localization in a colon tissue micro array consisting of 270 cases. In these samples Bcl-3 localization correlated with the proliferation marker Ki-67, but not with the apoptotic marker Caspase 3. These findings indicate that analysis of the subcellular localization of Bcl-3 could be a potential-early diagnostic marker in colon cancer

Prognostic Importance of Bcl-2 Expression in Colon Cancer

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Arsenal Alikanoðlu

2012-09-01

Full Text Available Aim: TNM classification, that had been established according to pathologic and anatomic characteristics of the lesion , is the most important factor in decision of adjuvant therapy in colon cancer. Despite curative resection, recurrence can ocur with a rate of 20-30% in early stage disease. Therefore efficieny of TNM classification is controversial. In recent years ,significance of molecular characteristics of the tumors besides their anatomic and pathologic characteristics in determining the biological behaviour and response to treatment have been discussed. In our study, relation between expression of Bcl-2 and the other known prognostic factors in colon cancer had been searched. Material and Method: Patients who had been followed up in our clinic were enrolled in this study. Expression of Bcl-2 was searched by immunohistochemical method. Results: A total of 52, 19 (%36.5 female and 33 (%63.5 male patients were enrolled in this study. Bcl-2 expression was found positive in 7 (%13.5 and negative in 45 (%86.5 patients. Statistically no significant relationship was found between Bcl-2 expression and sex, stage, regional lymph node involvement, presence of distant metastasis and histologic grade. Discussion: In our study, although not in a statistical significance, we found that Bcl-2 expression is related to early stage disease. Bcl-2 is a low-priced and easily accessible prognostic marker. We think that establishing expression of Bcl-2 by immunohistohemistry may play a role in determining prognosis of patients with colon cancer.

Probing the role of long-range interactions in the dynamics of a long-range Kitaev chain

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Dutta, Anirban; Dutta, Amit

2017-09-01

We study the role of long-range interactions (more precisely, the long-range superconducting gap term) on the nonequilibrium dynamics considering a long-range p -wave superconducting chain in which the superconducting term decays with distance between two sites in a power-law fashion characterized by an exponent α . We show that the Kibble-Zurek scaling exponent, dictating the power-law decay of the defect density in the final state reached following a slow (in comparison to the time scale associated with the minimum gap in the spectrum of the Hamiltonian) quenching of the chemical potential μ across a quantum critical point, depends nontrivially on the exponent α as long as α 2 , we find that the exponent saturates to the corresponding well-known value of 1 /2 expected for the short-range model. Furthermore, studying the dynamical quantum phase transitions manifested in the nonanalyticities in the rate function of the return possibility I (t ) in subsequent temporal evolution following a sudden change in μ , we show the existence of a new region; in this region, we find three instants of cusp singularities in I (t ) associated with a single sector of Fisher zeros. Notably, the width of this region shrinks as α increases and vanishes in the limit α →2 , indicating that this special region is an artifact of the long-range nature of the Hamiltonian.

Degeneracy and long-range correlation: A simulation study

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Marmelat Vivien

2011-12-01

Full Text Available We present in this paper a simulation study that aimed at evidencing a causal relationship between degeneracy and long-range correlations. Long-range correlations represent a very specific form of fluctuations that have been evidenced in the outcomes time series produced by a number of natural systems. Long-range correlations are supposed to sign the complexity, adaptability and flexibility of the system. Degeneracy is defined as the ability of elements that are structurally different to perform the same function, and is presented as a key feature for explaining the robustness of complex systems. We propose a model able to generate long-range correlated series, and including a parameter that account for degeneracy. Results show that a decrease in degeneracy tends to reduce the strength of long-range correlation in the series produced by the model.

Fluorescence immunophenotyping and interphase cytogenetics (FICTION) detects BCL6 abnormalities, including gene amplification, in most cases of nodular lymphocyte-predominant Hodgkin lymphoma.

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Bakhirev, Alexei G; Vasef, Mohammad A; Zhang, Qian-Yun; Reichard, Kaaren K; Czuchlewski, David R

2014-04-01

BCL6 translocations are a frequent finding in B-cell lymphomas of diverse subtypes, including some cases of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). However, reliable analysis of BCL6 rearrangements using fluorescence in situ hybridization is difficult in NLPHL because of the relative paucity of neoplastic cells. Combined immunofluorescence microscopy and fluorescence in situ hybridization, or fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms (FICTION), permits targeted analysis of neoplastic cells. To better define the spectrum of BCL6 abnormalities in NLPHL using FICTION analysis. We performed an optimized FICTION analysis of 24 lymph nodes, including 11 NLPHL, 5 follicular hyperplasia with prominent progressive transformation of germinal centers, and 8 follicular hyperplasia without progressive transformation of germinal centers. BCL6 rearrangement was identified in 5 of 11 cases of NLPHL (46%). In addition, BCL6 gene amplification, with large clusters of BCL6 signals in the absence of chromosome 3 aneuploidy, was detected in 3 of 11 cases of NLPHL (27%). One NLPHL showed extra copies of BCL6 present in conjunction with multiple copies of chromosome 3. Altogether, we detected BCL6 abnormalities in 9 of 11 cases of NLPHL (82%). None of the progressive transformation of germinal centers or follicular hyperplasia cases showed BCL6 abnormalities by FICTION. To our knowledge, this is the first report of BCL6 gene amplification in NLPHL. Our optimized protocol for FICTION permits detection of cytogenetic abnormalities in most NLPHL cases and may represent a useful ancillary diagnostic technique.

Involvement of Bax and Bcl2 in Neuroprotective Effect of Curcumin in Kainic Acid-Induced Model of Temporal Lobe Epilepsy in Male Rat

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zahra Kiasalari

2016-04-01

Full Text Available Background & objectives: Temporal lobe epilepsy is associated with neuronal apoptosis. Curcumin has antioxidant and anticonvulsant activities, therefore this study was conducted to assess involvement of Bax and Bcl2 in protective effect of curcumin in epileptic rats. Methods: 28 rats were divided into sham, curcumin-pretreated sham, epileptic (kainate, and curcumin-pretreated epileptic groups. Experimental model of epilepsy was induced by intrahippocampal administration of kainic acid. Rats received curcumin at a dose of 100 mg/kg. Finally, Nissl staining and Bax and Bcl2 immunohistochemistry were conducted on hippocampal sections and data were analyzed using one-way ANOVA and unpaired t-test. The p-value less than 0.05was considered statistically significant. Results: Induction of epilepsy was followed by a significant seizure and curcumin pretreatment significantly reduced seizure intensity (p<0.01. In addition, there were no significant differences between the groups in Nissl staining of CA3 area neurons. In addition, Bax positive neurons were observed in CA3 area in kainate group and significantly decreased in curcumin pretreated rats (p<0.05. Meanwhile, Bcl2 positive neurons were also moderately observed in kainate group and curcumin pretreatment significantly increased it (p<0.05. Conclusion: Curcumin pretreatment exhibits anticonvulsant activity in epileptic rats. It also decreases the expression of pro-apoptotic protein Bax and significantly enhances the expression of anti-apoptotic protein Bcl2 and hence could reduce neuronal apoptosis.

Genetic Variants at BCL11A and HBS1L-MYB loci Influence Hb F Levels in Chinese Zhuang β-Thalassemia Intermedia Patients.

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Lai, Yunli; Chen, Yun; Chen, Biyan; Zheng, Haiyang; Yi, Sheng; Li, Guojian; Wei, Hongwei; He, Sheng; Zheng, Chenguang

2016-11-01

Increased Hb F levels can ameliorate the symptoms of β-thalassemia (β-thal). Due to the genetic heterogenicity of β-thal, the relationship between genetic variants in modifier genes and Hb F level has been studied in different populations. The Chinese Zhuang has the second largest population in China and has 6.78% prevalence of β-thal. However, the effects of these single nucleotide polymorphism (SNP) variants on the Hb F levels of β-thal intermedia (β-TI) patients in this population have not been reported. To explore the association between modifier loci (β-globin gene cluster, HBS1L-MYB intergenic region and BCL11A) and Hb F levels in Chinese Zhuang β-TI patients, 96 unrelated β-TI patients (50 males and 46 females) with different Hb F levels were recruited and genotyped by mass spectrometry. A total of 13 SNPs were confirmed to be in a significant relationship with Hb F levels in this population. Of these, high-risk genotypes of six Hb F-associated SNPs, rs9376090, rs7776054, rs9399137, rs9389268, rs9402685 in the HBS1L-MYB intergenic region and rs189984760 in the BCL11A locus, showed association with high Hb F levels, especially for SNPs in linkage disequilibrium. One novel Hb F-associated SNP, rs189984760, was identified in our study. Our findings will be of valuable reference for correlation between modifier genes and Hb F in Chinese Zhuang populations and may lead to better understand the modifying mechanisms for β-thal.

MicroRNAs expression in ox-LDL treated HUVECs: MiR-365 modulates apoptosis and Bcl-2 expression

Energy Technology Data Exchange (ETDEWEB)

Qin, Bing; Xiao, Bo [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Liang, Desheng [State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan 410078 (China); Xia, Jian; Li, Ye [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China); Yang, Huan, E-mail: yangh69@yahoo.cn [Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008 (China)

2011-06-24

Highlights: {yields} We evaluated the role of miRNAs in ox-LDL induced apoptosis in ECs. {yields} We found 4 up-regulated and 11 down-regulated miRNAs in apoptotic ECs. {yields} Target genes of the dysregulated miRNAs regulate ECs apoptosis and atherosclerosis. {yields} MiR-365 promotes ECs apoptosis via suppressing Bcl-2 expression. {yields} MiR-365 inhibitor alleviates ECs apoptosis induced by ox-LDL. -- Abstract: Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play a critical role in atherosclerosis. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. However, whether miRNAs are associated with ox-LDL induced apoptosis and their effect on ECs is still unknown. Therefore, this study evaluated potential miRNAs and their involvement in ECs apoptosis in response to ox-LDL stimulation. Microarray and qRT-PCR analysis performed on human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL identified 15 differentially expressed (4 up- and 11 down-regulated) miRNAs. Web-based query tools were utilized to predict the target genes of the differentially expressed miRNAs, and the potential target genes were classified into different function categories with the gene ontology (GO) term and KEGG pathway annotation. In particular, bioinformatics analysis suggested that anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) is a target gene of miR-365, an apoptomir up-regulated by ox-LDL stimulation in HUVECs. We further showed that transfection of miR-365 inhibitor partly restored Bcl-2 expression at both mRNA and protein levels, leading to a reduction of ox-LDL-mediated apoptosis in HUVECs. Taken together, our findings indicate that miRNAs participate in ox-LDL-mediated apoptosis in HUVECs. MiR-365 potentiates ox-LDL-induced ECs apoptosis by regulating the

Boundary Associated Long Noncoding RNA Mediates Long-Range Chromosomal Interactions.

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Ifeoma Jane Nwigwe

Full Text Available CCCTC binding factor (CTCF is involved in organizing chromosomes into mega base-sized, topologically associated domains (TADs along with other factors that define sub-TAD organization. CTCF-Cohesin interactions have been shown to be critical for transcription insulation activity as it stabilizes long-range interactions to promote proper gene expression. Previous studies suggest that heterochromatin boundary activity of CTCF may be independent of Cohesin, and there may be additional mechanisms for defining topological domains. Here, we show that a boundary site we previously identified known as CTCF binding site 5 (CBS5 from the homeotic gene cluster A (HOXA locus exhibits robust promoter activity. This promoter activity from the CBS5 boundary element generates a long noncoding RNA that we designate as boundary associated long noncoding RNA-1 (blncRNA1. Functional characterization of this RNA suggests that the transcript stabilizes long-range interactions at the HOXA locus and promotes proper expression of HOXA genes. Additionally, our functional analysis also shows that this RNA is not needed in the stabilization of CTCF-Cohesin interactions however CTCF-Cohesin interactions are critical in the transcription of blncRNA1. Thus, the CTCF-associated boundary element, CBS5, employs both Cohesin and noncoding RNA to establish and maintain topologically associated domains at the HOXA locus.

Is upregulation of BCL2 a determinant of tumor development driven by inactivation of CDH1/E-cadherin?

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Inga Karch

Full Text Available Inactivation of CDH1, encoding E-cadherin, promotes cancer initiation and progression. According to a newly proposed molecular mechanism, loss of E-cadherin triggers an upregulation of the anti-apoptotic oncoprotein BCL2. Conversely, reconstitution of E-cadherin counteracts overexpression of BCL2. This reciprocal regulation is thought to be critical for early tumor development. We determined the relevance of this new concept in human infiltrating lobular breast cancer (ILBC, the prime tumor entity associated with CDH1 inactivation. BCL2 expression was examined in human ILBC cell lines (IPH-926, MDA-MB-134, SUM-44 harboring deleterious CDH1 mutations. To test for an intact regulatory axis between E-cadherin and BCL2, wild-type E-cadherin was reconstituted in ILBC cells by ectopic expression. Moreover, BCL2 and E-cadherin were evaluated in primary invasive breast cancers and in synchronous lobular carcinomas in situ (LCIS. MDA-MB-134 and IPH-926 showed little or no BCL2 expression, while SUM-44 ILBC cells were BCL2-positive. Reconstitution of E-cadherin failed to impact on BCL2 expression in all cell lines tested. Primary ILBCs were almost uniformly E-cadherin-negative (97% and were frequently BCL2-negative (46%. When compared with an appropriate control group, ILBCs showed a trend towards an increased frequency of BCL2-negative cases (P = 0.064. In terminal duct-lobular units affected by LCIS, the E-cadherin-negative neoplastic component showed a similar or a reduced BCL2-immunoreactivity, when compared with the adjacent epithelium. In conclusion, upregulation of BCL2 is not involved in lobular breast carcinogenesis and is unlikely to represent an important determinant of tumor development driven by CDH1 inactivation.

Long-range eye tracking: A feasibility study

Energy Technology Data Exchange (ETDEWEB)

Jayaweera, S.K.; Lu, Shin-yee

1994-08-24

The design considerations for a long-range Purkinje effects based video tracking system using current technology is presented. Past work, current experiments, and future directions are thoroughly discussed, with an emphasis on digital signal processing techniques and obstacles. It has been determined that while a robust, efficient, long-range, and non-invasive eye tracking system will be difficult to develop, such as a project is indeed feasible.

A leukemic double-hit follicular lymphoma associated with a complex variant translocation, t(8;14;18)(q24;q32;q21), involving BCL2, MYC, and IGH.

Science.gov (United States)

Minakata, Daisuke; Sato, Kazuya; Ikeda, Takashi; Toda, Yumiko; Ito, Shoko; Mashima, Kiyomi; Umino, Kento; Nakano, Hirofumi; Yamasaki, Ryoko; Morita, Kaoru; Kawasaki, Yasufumi; Sugimoto, Miyuki; Yamamoto, Chihiro; Ashizawa, Masahiro; Hatano, Kaoru; Oh, Iekuni; Fujiwara, Shin-Ichiro; Ohmine, Ken; Kawata, Hirotoshi; Muroi, Kazuo; Miura, Ikuo; Kanda, Yoshinobu

2018-01-01

Double-hit lymphoma (DHL) is defined as lymphoma with concurrent BCL2 and MYC translocations. While the most common histological subtype of DHL is diffuse large B-cell lymphoma, the present patient had leukemic follicular lymphoma (FL). A 52-year-old man was admitted to our hospital due to general fatigue and cervical and inguinal lymph node swelling. The patient was leukemic and the pathological diagnosis of the inguinal lymph node was FL grade 1. Chromosomal analysis revealed a complex karyotype including a rare three-way translocation t(8;14;18)(q24;q32;q21) involving the BCL2, MYC, and IGH genes. Based on a combination of fluorescence in situ hybridization (FISH), using BCL2, MYC and IGH, and spectral karyotyping (SKY), the karyotype was interpreted as being the result of a multistep mechanism in which the precursor B-cell gained t(14;18) in the bone marrow and acquired a translocation between der(14)t(14;18) and chromosome 8 in the germinal center, resulting in t(8;14;18). The pathological diagnosis was consistently FL, not only at presentation but even after a second relapse. The patient responded well to standard chemotherapies but relapsed after a short remission. This patient is a unique case of leukemic DH-FL with t(8;14;18) that remained in FL even at a second relapse. Copyright © 2017 Elsevier Inc. All rights reserved.

Mito-priming as a method to engineer Bcl-2 addiction.

Science.gov (United States)

Lopez, Jonathan; Bessou, Margaux; Riley, Joel S; Giampazolias, Evangelos; Todt, Franziska; Rochegüe, Tony; Oberst, Andrew; Green, Douglas R; Edlich, Frank; Ichim, Gabriel; Tait, Stephen W G

2016-02-02

Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject to tight control by Bcl-2 family proteins. We have developed a powerful new technique to investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression of pro- and anti-apoptotic Bcl-2 proteins to engineer Bcl-2 addiction. On addition of Bcl-2 targeting BH3 mimetics, mito-primed cells undergo apoptosis in a rapid and synchronous manner. Using this method we have comprehensively surveyed the efficacy of BH3 mimetic compounds, identifying potent and specific MCL-1 inhibitors. Furthermore, by combining different pro- and anti-apoptotic Bcl-2 pairings together with CRISPR/Cas9-based genome editing, we find that tBID and PUMA can preferentially kill in a BAK-dependent manner. In summary, mito-priming represents a facile and robust means to trigger mitochondrial apoptosis.

Double-hit lymphoma demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-hit translocations, MYC/BCL-2 and IRF4/BCL-2.

Science.gov (United States)

Tabata, Rie; Yasumizu, Ryoji; Tabata, Chiharu; Kojima, Masaru

2013-01-01

Here, we report a rare case of double-hit lymphoma, demonstrating t(6;14;18)(p25;q32;q21), suggesting two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2. The present case had a rare abnormal chromosome, t(6;14;18)(p25;q32;q21), independently, in addition to known dual-hit chromosomal abnormalities, t(14;18)(q32;q21) and t(8;22)(q24;q11.2). Lymph node was characterized by a follicular and diffuse growth pattern with variously sized neoplastic follicles. The intrafollicular area was composed of centrocytes with a few centroblasts and the interfollicular area was occupied by uniformly spread medium- to large-sized lymphocytes. CD23 immunostaining demonstrated a disrupted follicular dendritic cell meshwork. The intrafollicular tumor cells had a germinal center phenotype with the expression of surface IgM, CD10, Bcl-2, Bcl-6, and MUM1/IRF4. However, the interfollicular larger cells showed plasmacytic differentiation with diminished CD20, Bcl-2, Bcl-6, and positive intracytoplasmic IgM, and co-expression of MUM1/IRF4 and CD138 with increased Ki-67-positive cells (> 90%). MUM1/IRF4 has been found to induce c-MYC expression, and in turn, MYC transactivates MUM1/IRF4, creating a positive autoregulatory feedback loop. On the other hand, MUM1/IRF4 functions as a tumor suppressor in c-MYC-induced B-cell leukemia. The present rare case arouses interest in view of the possible "dual" activation of both c-MYC and MUM1/IRF4 through two independent dual-translocations, c-MYC/BCL-2 and IRF4/BCL-2.

Empirical mode decomposition and long-range correlation analysis of sunspot time series

International Nuclear Information System (INIS)

Zhou, Yu; Leung, Yee

2010-01-01

Sunspots, which are the best known and most variable features of the solar surface, affect our planet in many ways. The number of sunspots during a period of time is highly variable and arouses strong research interest. When multifractal detrended fluctuation analysis (MF-DFA) is employed to study the fractal properties and long-range correlation of the sunspot series, some spurious crossover points might appear because of the periodic and quasi-periodic trends in the series. However many cycles of solar activities can be reflected by the sunspot time series. The 11-year cycle is perhaps the most famous cycle of the sunspot activity. These cycles pose problems for the investigation of the scaling behavior of sunspot time series. Using different methods to handle the 11-year cycle generally creates totally different results. Using MF-DFA, Movahed and co-workers employed Fourier truncation to deal with the 11-year cycle and found that the series is long-range anti-correlated with a Hurst exponent, H, of about 0.12. However, Hu and co-workers proposed an adaptive detrending method for the MF-DFA and discovered long-range correlation characterized by H≈0.74. In an attempt to get to the bottom of the problem in the present paper, empirical mode decomposition (EMD), a data-driven adaptive method, is applied to first extract the components with different dominant frequencies. MF-DFA is then employed to study the long-range correlation of the sunspot time series under the influence of these components. On removing the effects of these periods, the natural long-range correlation of the sunspot time series can be revealed. With the removal of the 11-year cycle, a crossover point located at around 60 months is discovered to be a reasonable point separating two different time scale ranges, H≈0.72 and H≈1.49. And on removing all cycles longer than 11 years, we have H≈0.69 and H≈0.28. The three cycle-removing methods—Fourier truncation, adaptive detrending and the

Investigation of scattering processes in quantum few-body systems involving long-range interaction by the complex-rotation method

International Nuclear Information System (INIS)

Volkov, M. V.; Elander, N.; Yakovlev, S. L.; Yarevsky, E. A.

2013-01-01

The complex-rotation method adapted to solving the multichannel scattering problem in the two-body system where the interaction potential contains the long-range Coulomb components is described. The scattering problem is reformulated as the problem of solving a nonhomogeneous Schrödinger equation in which the nonhomogeneous term involves a Coulomb potential cut off at large distances. The incident wave appearing in the nonhomogeneous term is a solution of the Schrödinger equation with longrange Coulomb interaction. This formulation is free from approximations associated with a direct cutoff of Coulomb interaction at large distances. The efficiency of this formalism is demonstrated by considering the example of solving scattering problems in the α-α and p-p systems.

Long-Range WindScanner System

DEFF Research Database (Denmark)

Vasiljevic, Nikola; Lea, Guillaume; Courtney, Michael

2016-01-01

The technical aspects of a multi-Doppler LiDAR instrument, the long-range WindScanner system, are presented accompanied by an overview of the results from several field campaigns. The long-range WindScanner system consists of three spatially-separated, scanning coherent Doppler LiDARs and a remote......-rangeWindScanner system measures the wind field by emitting and directing three laser beams to intersect, and then scanning the beam intersection over a region of interest. The long-range WindScanner system was developed to tackle the need for high-quality observations of wind fields on scales of modern wind turbine...

Genetic ablation of Bcl-x attenuates invasiveness without affecting apoptosis or tumor growth in a mouse model of pancreatic neuroendocrine cancer.

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Jeffrey H Hager

Full Text Available Tumor cell death is modulated by an intrinsic cell death pathway controlled by the pro- and anti-apoptotic members of the Bcl-2 family. Up-regulation of anti-apoptotic Bcl-2 family members has been shown to suppress cell death in pre-clinical models of human cancer and is implicated in human tumor progression. Previous gain-of-function studies in the RIP1-Tag2 model of pancreatic islet carcinogenesis, involving uniform or focal/temporal over-expression of Bcl-x(L, demonstrated accelerated tumor formation and growth. To specifically assess the role of endogenous Bcl-x in regulating apoptosis and tumor progression in this model, we engineered a pancreatic beta-cell-specific knockout of both alleles of Bcl-x using the Cre-LoxP system of homologous recombination. Surprisingly, there was no appreciable effect on tumor cell apoptosis rates or on tumor growth in the Bcl-x knockout mice. Other anti-apoptotic Bcl-2 family members were expressed but not substantively altered at the mRNA level in the Bcl-x-null tumors, suggestive of redundancy without compensatory transcriptional up-regulation. Interestingly, the incidence of invasive carcinomas was reduced, and tumor cells lacking Bcl-x were impaired in invasion in a two-chamber trans-well assay under conditions mimicking hypoxia. Thus, while the function of Bcl-x in suppressing apoptosis and thereby promoting tumor growth is evidently redundant, genetic ablation implicates Bcl-x in selectively facilitating invasion, consistent with a recent report documenting a pro-invasive capability of Bcl-x(L upon exogenous over-expression.

Expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia

Science.gov (United States)

Li, Sheng-Mian; Yao, Shu-Kun; Yamamura, Nobuyoshi; Nakamura, Toshitsugu

2003-01-01

AIM: To compare the difference of expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia, and to analyze the role of Bcl-2 and Bax proteins in the progression from dysplasia to carcinoma and to evaluate the correlation of Bcl-2/Bax protein expression with the biological behaviors. METHODS: Expressions of Bcl-2 and Bax were examined immunohistochemically in 27 cases of extrahepatic biliary tract carcinomas (bile duct carcinoma: n = 21, carcinoma of ampulla of Vater: n = 6), and 10 cases of atypical dysplasia. Five cases of normal biliary epithelial tissues were used as controls. A semiquantitative scoring system was used to assess the Bcl-2 and Bax reactivity. RESULTS: The expression of Bcl-2 was observed in 10 out of 27 (37.0%) invasive carcinomas, 1 out of 10 dysplasias, none out of 5 normal epithelial tissues. Bax expression rate was 74.1% (20/27) in invasive carcinoma, 30% (3/10) in dysplasia, and 40% (2/5) in normal biliary epithelium. Bcl-2 and Bax activities were more intense in carcinoma than in dysplasia, with no significant difference in Bcl-2 expression (P = 0.110), and significant difference in Bax expression (P = 0.038). Level of Bax expression was higher in invasive carcinoma than in dysplasia and normal tissue (P = 0.012). Bcl-2 expression was correlated to Bax expression (P = 0.0059). However, Bcl-2/Bax expression had no correlation with histological subtype, grade of differentiation, or level of invasion. CONCLUSION: Increased Bcl-2/Bax expression from dysplasia to invasive tumors supports the view that this is the usual route for the development of extrahepatic biliary tract carcinoma. Bcl-2/Bax may be involved, at least in part, in the apoptotic activity in extrahepatic biliary carcinoma. PMID:14606101

Analysis list: Bcl6 [Chip-atlas[Archive

Lifescience Database Archive (English)

Full Text Available Bcl6 Blood,Liver,Pancreas + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Bcl6.1.tsv http:...//dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Bcl6.5.tsv http://dbarchive.biosciencedb...c.jp/kyushu-u/mm9/target/Bcl6.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Bcl6.Blood.tsv,http:...//dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Bcl6.Liver.tsv,http://dbarchive.b...iosciencedbc.jp/kyushu-u/mm9/colo/Bcl6.Pancreas.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Blood.gml,http:

Withaferin A Suppresses Anti-apoptotic BCL2, Bcl-xL, XIAP and ...

African Journals Online (AJOL)

apoptotic ... Quantitative real-time polymerase chain reaction (qPCR) was performed using Taq PCR Master ... Keywords: Anti-apoptotic genes, Cervical cancer, Apoptosis, Cell viability, BCL2, .... polyclonal anti-rabbit immunoglobulin HRP-linked.

Targeting BCL2 Family in Human Myeloid Dendritic Cells: A Challenge to Cure Diseases with Chronic Inflammations Associated with Bone Loss

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Selma Olsson Åkefeldt

2013-01-01

Full Text Available Rheumatoid arthritis (RA and Langerhans cell histiocytosis (LCH are common and rare diseases, respectively. They associate myeloid cell recruitment and survival in inflammatory conditions with tissue destruction and bone resorption. Manipulating dendritic cell (DC, and, especially, regulating their half-life and fusion, is a challenge. Indeed, these myeloid cells display pathogenic roles in both diseases and may be an important source of precursors for differentiation of osteoclasts, the bone-resorbing multinucleated giant cells. We have recently documented that the proinflammatory cytokine IL-17A regulates long-term survival of DC by inducing BCL2A1 expression, in addition to the constitutive MCL1 expression. We summarize bibliography of the BCL2 family members and their therapeutic targeting, with a special emphasis on MCL1 and BCL2A1, discussing their potential impact on RA and LCH. Our recent knowledge in the survival pathway, which is activated to perform DC fusion in the presence of IL-17A, suggests that targeting MCL1 and BCL2A1 in infiltrating DC may affect the clinical outcomes in RA and LCH. The development of new therapies, interfering with MCL1 and BCL2A1 expression, to target long-term surviving inflammatory DC should be translated into preclinical studies with the aim to increase the well-being of patients with RA and LCH.

Sensory Neuropathy Due to Loss of Bcl-w

Science.gov (United States)

Courchesne, Stephanie L.; Karch, Christoph; Pazyra-Murphy, Maria F.; Segal, Rosalind A.

2010-01-01

Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w −/− mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w −/− sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w −/− mice as an animal model of small fiber sensory neuropathy, and provide new insight regarding the role of bcl-w and of mitochondria in preventing axonal degeneration. PMID:21289171

Bcl6 promotes osteoblastogenesis through Stat1 inhibition

Energy Technology Data Exchange (ETDEWEB)

Fujie, Atsuhiro; Funayama, Atsushi; Miyauchi, Yoshiteru [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Sato, Yuiko [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kobayashi, Tami [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kanagawa, Hiroya; Katsuyama, Eri; Hao, Wu; Tando, Toshimi; Watanabe, Ryuichi [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Morita, Mayu [Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Kana; Kanaji, Arihiko; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Takeshi, E-mail: miyamoto@z5.keio.jp [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan)

2015-02-13

Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition. - Highlights: • Bcl6 is required for osteoblast differentiation. • Bcl6{sup −/−} mice exhibited altered osteoblastogenesis and reduced bone mass in vivo and in vitro. • We identified Stat1 as a direct target of Bcl6 in osteoblasts. • Bcl6 and Stat1 doubly deficient mice exhibited rescued bone phenotypes compared with Bcl6{sup −/−} mice.

Immunogenicity of Bcl-2 in patients with cancer

DEFF Research Database (Denmark)

Andersen, Mads Hald; Svane, Inge Marie; Kvistborg, Pia

2005-01-01

patients suffering from unrelated tumor types (ie, pancreatic cancer, breast cancer, acute myeloid leukemia [AML], and chronic lymphocytic leukemia [CLL]). Additionally, we show that these Bcl-2-reactive T cells are indeed peptide-specific, cytotoxic effector cells. Thus, Bcl-2 may serve as an important......B-cell lymphoma 2 (Bcl-2) is a pivotal regulator of apoptotic cell death and it is overexpressed in many cancers. Consequently, the Bcl-2 protein is an attractive target for drug design, and Bcl-2-specific antisense oligonucleotides or small-molecule Bcl-2 inhibitors have shown broad anticancer......-2 in cancer and the fact that immune escape by down-regulation or loss of expression of this protein would impair sustained tumor growth makes Bcl-2 a very attractive target for anticancer immunotherapy. Herein, we describe spontaneous T-cell reactivity against Bcl-2 in peripheral blood from...

Long range planning of radiotherapy facilities in the Netherlands

NARCIS (Netherlands)

Postma, T.J.B.M.; Terpstra, S.

2000-01-01

The subject of this paper is long range planning or policy development for healthcare in the Netherlands. Especially the co-ordinating function of planning will be discussed. In healthcare different actors or stakeholders are involved. Each of these actors may have their own interests, expectations,

Political Mechanisms for Long-Range Survival and Development

Science.gov (United States)

Marshall, W.

As the first species aware of extinction and capable of proactively ensuring our long-term survival and development, it is striking that we do not do so with the rigor, formality, and foresight it requires. Only from a reactive posture have we responded to the challenges of global warfare, human rights, environmental concerns, and sustainable development. Despite our awareness of the possibility for extinction and apocalyptic set-backs to our evolution, and despite the existence of long-range studies-which must still be dramatically increased-proactive global policy implementation regarding our long-term survival and development is arguably non-existent. This lack of long-term policy making can be attributed in part to the lack of formal political mechanisms to facilitate longer-range policy making that extends 30 years or more into the future. Political mechanisms for infusing long-range thinking, research, and strategic planning into the policy-making process can help correct this shortcoming and provide the motivation needed to adequately address long-term challenges with the political rigor required to effectively establish and implement long-term policies. There are some efforts that attempt to address longer-range issues, but those efforts often do not connect to the political process, do not extend 30 or more years into the future, are not well-funded, and are not sufficiently systemic. Political mechanisms for long-range survival and prosperity could correct these inadequacies by raising awareness, providing funding, and most importantly, leveraging political rigor to establish and enforce long-range strategic planning and policies. The feasibility of such mechanisms should first be rigorously studied and assessed in a feasibility study, which could then inform implementation. This paper will present the case for such a study and suggest some possible political mechanisms that should be investigated further in the proposed study. This work is being further

Immunogenicity of Bcl-2 in patients with cancer

DEFF Research Database (Denmark)

Andersen, Mads Hald; Svane, Inge Marie; Kvistborg, Pia

2005-01-01

activities in preclinical models and are currently in several clinical trials. The clinical application of immunotherapy against cancer is rapidly moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The overexpression of Bcl......-2 in cancer and the fact that immune escape by down-regulation or loss of expression of this protein would impair sustained tumor growth makes Bcl-2 a very attractive target for anticancer immunotherapy. Herein, we describe spontaneous T-cell reactivity against Bcl-2 in peripheral blood from......B-cell lymphoma 2 (Bcl-2) is a pivotal regulator of apoptotic cell death and it is overexpressed in many cancers. Consequently, the Bcl-2 protein is an attractive target for drug design, and Bcl-2-specific antisense oligonucleotides or small-molecule Bcl-2 inhibitors have shown broad anticancer...

Targeting MUC1-C suppresses BCL2A1 in triple-negative breast cancer.

Science.gov (United States)

Hiraki, Masayuki; Maeda, Takahiro; Mehrotra, Neha; Jin, Caining; Alam, Maroof; Bouillez, Audrey; Hata, Tsuyoshi; Tagde, Ashujit; Keating, Amy; Kharbanda, Surender; Singh, Harpal; Kufe, Donald

2018-01-01

B-cell lymphoma 2-related protein A1 (BCL2A1) is a member of the BCL-2 family of anti-apoptotic proteins that confers resistance to treatment with anti-cancer drugs; however, there are presently no agents that target BCL2A1. The MUC1-C oncoprotein is aberrantly expressed in triple-negative breast cancer (TNBC) cells, induces the epithelial-mesenchymal transition (EMT) and promotes anti-cancer drug resistance. The present study demonstrates that targeting MUC1-C genetically and pharmacologically in TNBC cells results in the downregulation of BCL2A1 expression. The results show that MUC1-C activates the BCL2A1 gene by an NF-κB p65-mediated mechanism, linking this pathway with the induction of EMT. The MCL-1 anti-apoptotic protein is also of importance for the survival of TNBC cells and is an attractive target for drug development. We found that inhibiting MCL-1 with the highly specific MS1 peptide results in the activation of the MUC1-C→NF-κB→BCL2A1 pathway. In addition, selection of TNBC cells for resistance to ABT-737, which inhibits BCL-2, BCL-xL and BCL-W but not MCL-1 or BCL2A1, is associated with the upregulation of MUC1-C and BCL2A1 expression. Targeting MUC1-C in ABT-737-resistant TNBC cells suppresses BCL2A1 and induces death, which is of potential therapeutic importance. These findings indicate that MUC1-C is a target for the treatment of TNBCs unresponsive to agents that inhibit anti-apoptotic members of the BCL-2 family.

Expanding the Cancer Arsenal with Targeted Therapies: Disarmament of the Antiapoptotic Bcl-2 Proteins by Small Molecules.

Science.gov (United States)

Yap, Jeremy L; Chen, Lijia; Lanning, Maryanna E; Fletcher, Steven

2017-02-09

A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.

25 CFR 170.413 - What is the public role in developing the long-range transportation plan?

Science.gov (United States)

2010-04-01

... Roads Program Facilities Long-Range Transportation Planning § 170.413 What is the public role in developing the long-range transportation plan? BIA or the tribe must solicit public involvement. If there are... newspapers when the draft long-range transportation plan is complete. In the absence of local public...

Long-range airplane study: The consumer looks at SST travel

Science.gov (United States)

Landes, K. H.; Matter, J. A.

1980-01-01

The attitudes of long-range air travelers toward several basic air travel decisions, were surveyed. Of interest were tradeoffs involving time versus comfort and time versus cost as they pertain to supersonic versus conventional wide-body aircraft on overseas routes. The market focused upon was the segment of air travelers most likely to make that type of tradeoff decision: those having flown overseas routes for business or personal reasons in the recent past. The information generated is intended to provide quantifiable insight into consumer demand for supersonic as compared to wide-body aircraft alternatives for long-range overseas air travel.

Evaluation of Bcl-2, Bcl-x and Cleaved Caspase-3 in Malignant Peripheral Nerve Sheath Tumors and Neurofibromas

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KARIN S. CUNHA

2013-11-01

Full Text Available AIMS: To study the expression of Bcl-2, Bcl-x, as well the presence of cleaved caspase-3 in neurofibromas and malignant peripheral nerve sheath tumors. The expression of Bcl-2 and Bcl-x and the presence of cleaved caspase 3 were compared to clinicopathological features of malignant peripheral nerve sheath tumors and their impact on survival rates were also investigated. MATERIALS AND METHODS: The evaluation of Bcl-2, Bcl-x and cleaved caspase-3 was performed by immunohistochemistry using tissue microarrays in 28 malignant peripheral nerve sheath tumors and 38 neurofibromas. Immunoquantification was performed by computerized digital image analysis. CONCLUSIONS: Apoptosis is altered in neurofibromas and mainly in malignant peripheral nerve sheath tumors. High levels of cleaved caspase-3 are more common in tumors with more aggressive histological features and it is associated with lower disease free survival of patients with malignant peripheral nerve sheath tumors.

Increased expression of Bcl-2 during mucous cell metaplasia induced by endotoxin and ozone

Energy Technology Data Exchange (ETDEWEB)

Tesfaigzi, J.; Ray, L.M.; Hotchkiss, J.A. [Michigan State Univ., East Lansing, MI (United States)] [and others

1995-12-01

Apoptosis or programmed cell death is accompanied by characteristic morphological changes that distinguish apoptosis from other forms of cell death. These changes include DNA fragmentation, chromatin condensation, cell shrinkage, cell surface pseudopodia, and finally the cellular collapse into membrane-enclosed apoptotic bodies which are rapidly engulfed by macrophages or neighboring cells. Although the morphological features of apoptotic cells are well studied, the biochemical events that control apoptosis are not understood. Programmed cell death is triggered by a variety of pathways that are initiated by different stimuli including noxious agents, DNA damage, the activation of TNF receptors, or the withdrawl of growth factors. The central process of programmed cell death involves a cascade of biochemical events that begins with the initiation of a family of cysteine proteases, including the interleukin-1-{Beta}-converting enzyme, CPP-32, and Apopain. The ratio of Bax, a death-inducer gene, to Bcl-2, an apoptosis suppressor gene, determines whether or not the main apoptotic pathyway is blocked. Apoptosis is suppressed if the ratio of Bcl-2/Bax is > 1, and cells undergo apoptosis if the ratio is < 1. The overexpression of Bcl-2 has been shown to block the apoptotic program triggered by a variety of agents. Therefore, Bcl-2 must be involved in blocking the central pathway of the cell death program. In conclusion, this study showed that high levels of Bcl-2 were detected in some mucous cells at specific time points during mucous cell metaplasia, and this expression was reduced at later time points or was absent after remodeling of this epithelium.

Members of the bcl-2 and caspase families regulate nuclear degeneration during chick lens fibre differentiation.

Science.gov (United States)

Wride, M A; Parker, E; Sanders, E J

1999-09-01

The optical clarity of the lens is ensured by the programmed removal of nuclei and other organelles from the lens fibre cells during development. The morphology of the degenerating nuclei is similar to that observed during apoptosis and is accompanied by DNA fragmentation. Proteins encoded by the bcl-2 proto-oncogene family are important in either promoting or inhibiting apoptosis, and caspases are involved in downstream proteolytic events. Here, the expression of bcl-2 family members (bcl-2, bax, bad, and bcl-x(s/l)) and caspases-1, -2, -3, -4, and -6 was investigated through a range of stages of chick lens development using immunocytochemistry, Western blotting, and affinity labelling for caspases using biotinylated caspase inhibitors. Using differentiating lens epithelial cell cultures, it was demonstrated that the addition to cultures of synthetic peptide inhibitors of caspases -1, -2, -4, -6, and -9 brought about a 50-70% reduction in the number of degenerating nuclei per unit area of culture, as assessed by image analysis. These effects were comparable to those seen when general inhibitors of caspases were added to cultures. On the other hand, inhibitors of caspases-3 and -8 were not effective in significantly reducing the number of TUNEL-labelled nuclei. Expression of the caspase substrates poly(ADP-ribose) polymerase (PARP) and the 45-kDa subunit of DNA fragmentation factor (DFF 45) was also observed in the developing lens. Western blots of cultures to which caspase inhibitors were added revealed alterations in the PARP cleavage pattern, but not in that of DFF. These results demonstrate a role for members of the bcl-2 family and caspases in the degeneration of lens fibre cell nuclei during chick secondary lens fibre development and support the proposal that this process has many characteristics in common with apoptosis. Copyright 1999 Academic Press.

RBP2 Promotes Adult Acute Lymphoblastic Leukemia by Upregulating BCL2.

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Xiaoming Wang

Full Text Available Despite recent increases in the cure rate of acute lymphoblastic leukemia (ALL, adult ALL remains a high-risk disease that exhibits a high relapse rate. In this study, we found that the histone demethylase retinoblastoma binding protein-2 (RBP2 was overexpressed in both on-going and relapse cases of adult ALL, which revealed that RBP2 overexpression was not only involved in the pathogenesis of ALL but that its overexpression might also be related to relapse of the disease. RBP2 knockdown induced apoptosis and attenuated leukemic cell viability. Our results demonstrated that BCL2 is a novel target of RBP2 and supported the notion of RBP2 being a regulator of BCL2 expression via directly binding to its promoter. As the role of RBP2 in regulating apoptosis was confirmed, RBP2 overexpression and activation of BCL2 might play important roles in ALL development and progression.

One-dimensional long-range percolation: A numerical study

Science.gov (United States)

Gori, G.; Michelangeli, M.; Defenu, N.; Trombettoni, A.

2017-07-01

In this paper we study bond percolation on a one-dimensional chain with power-law bond probability C /rd +σ , where r is the distance length between distinct sites and d =1 . We introduce and test an order-N Monte Carlo algorithm and we determine as a function of σ the critical value Cc at which percolation occurs. The critical exponents in the range 0 values for Cc are compared with a known exact bound, while the critical exponent ν is compared with results from mean-field theory, from an expansion around the point σ =1 and from the ɛ -expansion used with the introduction of a suitably defined effective dimension deff relating the long-range model with a short-range one in dimension deff. We finally present a formulation of our algorithm for bond percolation on general graphs, with order N efficiency on a large class of graphs including short-range percolation and translationally invariant long-range models in any spatial dimension d with σ >0 .

Resonant long-range interactions between polar macromolecules

International Nuclear Information System (INIS)

Preto, Jordane; Pettini, Marco

2013-01-01

Motivated by its prospective biological relevance, the issue of resonant long-range interactions between two molecules displaying oscillating dipole moments is reinvestigated within the framework of classical electrodynamics. In particular, our findings shed new light on Fröhlich's theory of selective long-range interactions between biomolecules. First, terms of a very long-range kind – which have never been reported so far – are found in the interaction potential, due to field retardation. Second, at variance with a long-standing belief, it is shown that sizable resonant long-range interactions may exist only if the interacting system is out of thermal equilibrium.

Bcl-2 and N-Myc Coexpression Increases IGF-IR and Features of Malignant Growth in Neuroblastoma Cell Lines

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Rama Jasty

2001-01-01

Full Text Available The bcl-2 and c-myc oncogenes cooperate to transform multiple cell types. In the pediatric malignancy NB2, Bcl2 is highly expressed. In tumors with a poor prognosis, N-Myc, a protein homologous to c-Myc, is overexpressed as a result of gene amplification. The present study was designed to determine whether Bcl-2 cooperates with N-Myc to bestow a tumorigenic phenotype to neuroblastoma (NB cells. NB cell lines that at baseline express neither Bcl-2 nor N-Myc were stably transfected to express these gene products. In this model, we found Bcl-2 rescues N-Myc-expressing cells from apoptosis induced by serum withdrawal. Coexpression of Bcl-2 and N-Myc supports growth in low serum conditions and anchorage-independent growth in soft agar. Similarly, in vivo tumorigenic and angiogenic activity was dependent on coexpression. Our data further suggests that the mechanism underlying these changes involves the receptor for insulin growth factor type I (IGF-IR.

BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L).

Science.gov (United States)

Maiuri, Maria Chiara; Criollo, Alfredo; Tasdemir, Ezgi; Vicencio, José Miguel; Tajeddine, Nicolas; Hickman, John A; Geneste, Olivier; Kroemer, Guido

2007-01-01

Beclin 1 has recently been identified as novel BH3-only protein, meaning that it carries one Bcl-2-homology-3 (BH3) domain. As other BH3-only proteins, Beclin 1 interacts with anti-apoptotic multidomain proteins of the Bcl-2 family (in particular Bcl-2 and its homologue Bcl-X(L)) by virtue of its BH3 domain, an amphipathic alpha-helix that binds to the hydrophobic cleft of Bcl-2/Bcl-X(L). The BH3 domains of other BH3-only proteins such as Bad, as well as BH3-mimetic compounds such as ABT737, competitively disrupt the inhibitory interaction between Beclin 1 and Bcl-2/Bcl-X(L). This causes autophagy of mitochondria (mitophagy) but not of the endoplasmic reticulum (reticulophagy). Only ER-targeted (not mitochondrion-targeted) Bcl-2/Bcl-X(L) can inhibit autophagy induced by Beclin 1, and only Beclin 1-Bcl-2/Bcl-X(L) complexes present in the ER (but not those present on heavy membrane fractions enriched in mitochondria) are disrupted by ABT737. These findings suggest that the Beclin 1-Bcl-2/Bcl-X(L) complexes that normally inhibit autophagy are specifically located in the ER and point to an organelle-specific regulation of autophagy. Furthermore, these data suggest a spatial organization of autophagy and apoptosis control in which BH3-only proteins exert two independent functions. On the one hand, they can induce apoptosis, by (directly or indirectly) activating the mitochondrion-permeabilizing function of pro-apoptotic multidomain proteins from the Bcl-2 family. On the other hand, they can activate autophagy by liberating Beclin 1 from its inhibition by Bcl-2/Bcl-X(L) at the level of the endoplasmic reticulum.

Effect of Bcl-2 rs956572 polymorphism on age-related gray matter volume changes.

Directory of Open Access Journals (Sweden)

Mu-En Liu

Full Text Available The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female with a mean age of 56.2±22.0 years (range: 21-92. Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001. Moreover, the downward slope was steeper among the Bcl-2 rs956572 A-allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum.

Enzymatic cellulose oxidation is linked to lignin by long-range electron transfer

DEFF Research Database (Denmark)

Westereng, Bjorge; Cannella, David; Wittrup Agger, Jane

2015-01-01

in biological systems are only partly understood. We show here that insoluble high molecular weight lignin functions as a reservoir of electrons facilitating LPMO activity. The electrons are donated to the enzyme by long-range electron transfer involving soluble low molecular weight lignins present in plant...... cell walls. Electron transfer was confirmed by electron paramagnetic resonance spectroscopy showing that LPMO activity on cellulose changes the level of unpaired electrons in the lignin. The discovery of a long-range electron transfer mechanism links the biodegradation of cellulose and lignin and sheds...

Travel: a long-range goal of retired women.

Science.gov (United States)

Staats, Sara; Pierfelice, Loretta

2003-09-01

The authors surveyed retired persons (predominately women) with regard to their immediate, intermediate, and long-range activities following retirement. As predicted, leisure travel emerged as a frequent long-range goal for persons retired more than 5 years. The travel activity preferences of long-retired older women present challenges and opportunities to both researchers and marketers. Length of trips and frequency of trips have been predicted from regression models, with trip length in particular being well predicted by the problem of daily life hassles. A theoretical model of continued post-retirement travel is presented as a variant of Solomon's opponent process theory of affect (R. L. Solomon, 1980). The authors suggest that to the degree that places traveled to are varied and different, older people may remain stimulated and continue to enjoy retirement.

The studies on thyrocyte apoptosis and expression of Bcl-2 and Bax in Hashimoto's thyroiditis

International Nuclear Information System (INIS)

Zhao Yaping; Wang Jialing; Fan Zhiyong; Liu Zehong; Wu HeJun; Zhou Wei; Jia Meizhai

2003-01-01

To investigate the thyrocyte apoptosis, the expression of Bcl-2, Bax and the relationship between apoptosis and the pathogenesis in Hashimoto's thyroiditis (HT), 41 HT thyroid and 10 normal thyroid specimens were selected. The level of apoptosis was detected by TUNEL methods. The expression and distribution of Bcl-2 and Bax were detected using immunohistochemical methods and analyzed by Mias99 pathological image system. Immunohistochemical staining was carried out using S-P kit. The Result showed that an increased level of apoptosis was observed in Hashimoto's glands. The apoptosis mainly distributed in thyroid follicles destruction area. This was associated with increased Bax expression. The strongly positive Bcl-2 staining was observed in the thyrocyte of intact thyroid follicles. The ratios of positive granule area and total light density of Bcl-2 to those of Bax in HT thyroid follicle area were lower than those in normal thyroid. The apoptosis of thyrocyte induced by dysregulation of Bcl-2 and Bax may be involved in the pathogeneses of HT

Identification of an HLA-A*0201 restricted Bcl2-derived epitope expressed on tumors

DEFF Research Database (Denmark)

Wang, Mingjun; Johansen, Britta; Nissen, Mogens H

2006-01-01

A large number of human tumor-associated antigen-derived peptides have been identified that are recognized by CTLs in a MHC-I restricted fashion. The apoptosis inhibitory protein Bcl2 is overexpressed in many human cancers as part of their neoplastic phenotype. Since inhibition or loss of Bcl2...... from the amino acid sequence of the Bcl2 protein and its binding affinity for HLA-A*0201 was confirmed using a biochemical binding assay. We here demonstrate that the 9-mer peptide Bcl2(85-93) induces specific CTL reactivity in immunized C57-A2K(b) or -A2D(b) tg mice. These Bcl2(85-93) specific CTLs...... react with and lyse Bcl2-expressing human colon carcinoma CCL220 cells which have been transfected with a chimeric HLA-A*0201/H2-K(b) DNA construct similar to that expressed in the transgenic mice. Based on these observations, we suggest that Bcl2(85-93) may be a target for immune therapy....

Pan-Bcl-2 inhibitor obatoclax delays cell cycle progression and blocks migration of colorectal cancer cells.

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Bruno Christian Koehler

Full Text Available Despite the fact that new treatment regimes have improved overall survival of patients challenged by colorectal cancer (CRC, prognosis in the metastatic situation is still restricted. The Bcl-2 family of proteins has been identified as promising anti cancer drug target. Even though small molecules targeting Bcl-2 proteins are in clinical trials, little is known regarding their effects on CRC. The aim of this study was to preclinically investigate the value of ABT-737 and Obatoclax as anticancer drugs for CRC treatment. The effects of the BH3-mimetics ABT-737 and Obatoclax on CRC cells were assessed using viability and apoptosis assays. Wound healing migration and boyden chamber invasion assays were applied. 3-dimensional cell cultures were used for long term assessment of invasion and proliferation. Clinically relevant concentrations of pan-Bcl-2 inhibitor Obatoclax did not induce cell death. In contrast, the BH3-mimetic ABT-737 induced apoptosis in a dose dependent manner. Obatoclax caused a cell line specific slowdown of CRC cell growth. Furthermore, Obatoclax, but not ABT-737, recovered E-Cadherin expression and led to impaired migration and invasion of CRC cells. The proliferative capacity and invasiveness of CRC cells was strikingly inhibited by low dose Obatoclax in long term 3-dimensional cell cultures. Obatoclax, but not ABT-737, caused a G1-phase arrest accompanied by a downregulation of Cyclin D1 and upregulation of p27 and p21. Overexpression of Mcl-1, Bcl-xL or Bcl-2 reversed the inhibitory effect of Obatoclax on migration but failed to restore the proliferative capacity of Obatoclax-treated CRC cells. The data presented indicate broad and multifaceted antitumor effects of the pan-Bcl-2 inhibitor Obatoclax on CRC cells. In contrast to ABT-737, Obatoclax inhibited migration, invasion and proliferation in sublethal doses. In summary, this study recommends pan-Bcl-2 inhibition as a promising approach for clinical trials in CRC.

The Bcl-2 Family in Host-Virus Interactions.

Science.gov (United States)

Kvansakul, Marc; Caria, Sofia; Hinds, Mark G

2017-10-06

Members of the B cell lymphoma-2 (Bcl-2) family are pivotal arbiters of mitochondrially mediated apoptosis, a process of fundamental importance during tissue development, homeostasis, and disease. At the structural and mechanistic level, the mammalian members of the Bcl-2 family are increasingly well understood, with their interplay ultimately deciding the fate of a cell. Dysregulation of Bcl-2-mediated apoptosis underlies a plethora of diseases, and numerous viruses have acquired homologs of Bcl-2 to subvert host cell apoptosis and autophagy to prevent premature death of an infected cell. Here we review the structural biology, interactions, and mechanisms of action of virus-encoded Bcl-2 proteins, and how they impact on host-virus interactions to ultimately enable successful establishment and propagation of viral infections.

Reactivating Fetal Hemoglobin Expression in Human Adult Erythroblasts Through BCL11A Knockdown Using Targeted Endonucleases

Directory of Open Access Journals (Sweden)

Carmen F Bjurström

2016-01-01

Full Text Available We examined the efficiency, specificity, and mutational signatures of zinc finger nucleases (ZFNs, transcriptional activator-like effector nucleases (TALENs, and clustered regularly interspaced short palindromic repeat (CRISPR/Cas9 systems designed to target the gene encoding the transcriptional repressor BCL11A, in human K562 cells and human CD34+ progenitor cells. ZFNs and TALENs were delivered as in vitro transcribed mRNA through electroporation; CRISPR/Cas9 was codelivered by Cas9 mRNA with plasmid-encoded guideRNA (gRNA (pU6.g1 or in vitro transcribed gRNA (gR.1. Analyses of efficacy revealed that for these specific reagents and the delivery methods used, the ZFNs gave rise to more allelic disruption in the targeted locus compared to the TALENs and CRISPR/Cas9, which was associated with increased levels of fetal hemoglobin in erythroid cells produced in vitro from nuclease-treated CD34+ cells. Genome-wide analysis to evaluate the specificity of the nucleases revealed high specificity of this specific ZFN to the target site, while specific TALENs and CRISPRs evaluated showed off-target cleavage activity. ZFN gene-edited CD34+ cells had the capacity to engraft in NOD-PrkdcSCID-IL2Rγnull mice, while retaining multi-lineage potential, in contrast to TALEN gene-edited CD34+ cells. CRISPR engraftment levels mirrored the increased relative plasmid-mediated toxicity of pU6.g1/Cas9 in hematopoietic stem/progenitor cells (HSPCs, highlighting the value for the further improvements of CRISPR/Cas9 delivery in primary human HSPCs.

Estradiol increases the Bax/Bcl-2 ratio and induces apoptosis in the anterior pituitary gland.

Science.gov (United States)

Zaldivar, Verónica; Magri, María Laura; Zárate, Sandra; Jaita, Gabriela; Eijo, Guadalupe; Radl, Daniela; Ferraris, Jimena; Pisera, Daniel; Seilicovich, Adriana

2009-01-01

Estrogens are recognized as acting as modulators of pituitary cell renewal, sensitizing cells to mitogenic and apoptotic signals, thus participating in anterior pituitary homeostasis during the estrous cycle. The balance of pro- and antiapoptotic proteins of the Bcl-2 family is known to regulate cell survival and apoptosis. In order to understand the mechanisms underlying apoptosis during the estrous cycle, we evaluated the expression of the proapoptotic protein Bax and the antiapoptotic proteins Bcl-2 and Bcl-xL in the anterior pituitary gland in cycling female rats as well as the influence of estradiol on the expression of these proteins in anterior pituitary cells of ovariectomized rats. As determined by Western blot, the expression of Bax was higher in anterior pituitary glands from rats at proestrus than at diestrus I, Bcl-2 protein levels showed no difference and Bcl-xL expression was lower, thus increasing the Bax/Bcl-2 ratio at proestrus. Assessed by annexin V binding and flow cytometry, the percentage of apoptotic anterior pituitary cells was higher in rats at proestrus than at diestrus I. Chronic estrogen treatment in ovariectomized rats enhanced the Bax/Bcl-2 ratio and induced apoptosis. Moreover, incubation of cultured anterior pituitary cells from ovariectomized rats with 17beta-estradiol for 24 h increased the Bax/Bcl-2 ratio, decreased Bcl-xL expression and induced apoptosis. Our results demonstrate that estradiol increases the ratio between proapoptotic and antiapoptotic proteins of the Bcl-2 family. This effect could participate in the sensitizing action of estrogens to proapoptotic stimuli and therefore be involved in the high apoptotic rate observed at proestrus in the anterior pituitary gland.

Heart rate, multiple body temperature, long-range and long-life telemetry system for free-ranging animals

Science.gov (United States)

Lund, G. F.; Westbrook, R. M.; Fryer, T. B.

1980-01-01

The design details and rationale for a versatile, long-range, long-life telemetry data acquisition system for heart rates and body temperatures at multiple locations from free-ranging animals are presented. The design comprises an implantable transmitter for short to medium range transmission, a receiver retransmitter collar to be worn for long-range transmission, and a signal conditioner interface circuit to assist in signal discrimination and demodulation of receiver or tape-recorded audio outputs. Implanted electrodes are used to obtain an ECG, from which R-wave characteristics are selected to trigger a short RF pulse. Pulses carrying heart rate information are interrupted periodically by a series of pulse interval modulated RF pulses conveying temperature information sensed at desired locations by thermistors. Pulse duration and pulse sequencing are used to discriminate between heart rate and temperature pulses as well as radio frequency interference. The implanted transmitter may be used alone for medium and short-range tracking, or with a receiver-transmitter collar that employs commercial tracking equipment for transmissions of up to 12 km. A system prototype has been tested on a dog.

Long-range spin deformations around quasiparticles

International Nuclear Information System (INIS)

Godfrey, M.; Gunn, M.

1989-01-01

The quasi-particle formed by a hole in a Heisenberg antiferromagnet has an associated long-range spin distortion whose amplitude increases with the velocity of the hole. The authors show that the existence and properties of this distortion follow from simple classical arguments based on the long-wavelength equations of motion for the spin system. A similar long-range distortion is found in the quantum-mechanical problem of an electron exchange coupled to a Heisenberg antiferromagnet

Bcl-2 overexpression: effects on transmembrane calcium movement

International Nuclear Information System (INIS)

Rangaswami, Arun A.; Premack, Brett; Walleczek, Jan; Killoran, Pamela; Gardner, Phyllis; Knox, Susan J.

1996-01-01

Purpose/Objective: High levels of expression of the proto-oncogene bcl-2 and its 26 kD protein product Bcl-2 have been correlated with the inhibition of apoptosis and the increased resistance of tumor cells to cytotoxic drugs and ionizing radiation. Unfortunately, the specific mechanism of action of Bcl-2 remains poorly understood. In the studies described here, the role of intracellular calcium fluxes and plasma membrane calcium cycling in the induction of apoptosis, and the effect of Bcl-2 expression on the modulation of transmembrane calcium fluxes following treatment of cells with cytotoxic agents were studied. The relationship between intracellular calcium release, capacitive calcium entry, and the plasma membrane potential were also investigated. Materials and Methods: Human B-cell lymphoma (PW) and human promyelocytic leukemia (HL60) cell lines were transfected with Bcl-2 and a control vector. The Bcl-2 transfectants over expressed the Bcl-2 onco-protein and were more resistant to irradiation than the control cells. Cells were loaded with fluorescent indicators indo-1 and fura-2 AM to quantify the cytosolic calcium concentration and subsequent calcium responses to a variety of cytotoxic stimuli, including the microsomal ATPase inhibitor, thapsigargin, using fluorometric measurements. Comparisons of resting and stimulated cytosolic calcium concentrations were made between the parental, neomycin control, and bcl-2 transfected cells. In order to determine the actual calcium influx rate, cells were loaded with either indo-1 or fura-2 and then exposed to 0.1 mM extracellular manganese, which enters the cells through calcium influx channels and quenches the fluorescent signal in proportion to the calcium influx rate. In order to determine the role of the membrane potential in driving calcium influx, cells were treated with either 0.1 μM Valinomycin or isotonic potassium chloride to either hyper polarize or depolarize the resting membrane potential, and the

Long-range PCR facilitates the identification of PMS2-specific mutations.

Science.gov (United States)

Clendenning, Mark; Hampel, Heather; LaJeunesse, Jennifer; Lindblom, Annika; Lockman, Jan; Nilbert, Mef; Senter, Leigha; Sotamaa, Kaisa; de la Chapelle, Albert

2006-05-01

Mutations within the DNA mismatch repair gene, "postmeiotic segregation increased 2" (PMS2), have been associated with a predisposition to hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome). The presence of a large family of highly homologous PMS2 pseudogenes has made previous attempts to sequence PMS2 very difficult. Here, we describe a novel method that utilizes long-range PCR as a way to preferentially amplify PMS2 and not the pseudogenes. A second, exon-specific, amplification from diluted long-range products enables us to obtain a clean sequence that shows no evidence of pseudogene contamination. This method has been used to screen a cohort of patients whose tumors were negative for the PMS2 protein by immunohistochemistry and had not shown any mutations within the MLH1 gene. Sequencing of the PMS2 gene from 30 colorectal and 11 endometrial cancer patients identified 10 novel sequence changes as well as 17 sequence changes that had previously been identified. In total, putative pathologic mutations were detected in 11 of the 41 families. Among these were five novel mutations, c.705+1G>T, c.736_741del6ins11, c.862_863del, c.1688G>T, and c.2007-1G>A. We conclude that PMS2 mutation detection in selected Lynch syndrome and Lynch syndrome-like patients is both feasible and desirable. Published 2006 Wiley-Liss, Inc.

Combined Targeting of BCL-2 and BCR-ABL Tyrosine Kinase Eradicates Chronic Myeloid Leukemia Stem Cells

Science.gov (United States)

Mak, Po Yee; Mu, Hong; Zhou, Hongsheng; Mak, Duncan H.; Schober, Wendy; Leverson, Joel D.; Zhang, Bin; Bhatia, Ravi; Huang, Xuelin; Cortes, Jorge; Kantarjian, Hagop; Konopleva, Marina

2016-01-01

BCR-ABL tyrosine kinase inhibitors (TKIs) are effective against chronic myeloid leukemia (CML), but they rarely eliminate CML stem cells. Disease relapse is common upon therapy cessation, even in patients with complete molecular responses. Furthermore, once CML progresses to blast crisis (BC), treatment outcomes are dismal. We hypothesized that concomitant targeting of BCL-2 and BCR-ABL tyrosine kinase could overcome these limitations. We demonstrate increased BCL-2 expression at the protein level in bone marrow cells, particularly in Lin−Sca-1+cKit+ cells of inducible CML in mice as determined by CyTOF mass cytometry. Further, selective inhibition of BCL-2, aided by TKI-mediated MCL-1 and BCL-XL inhibition, markedly decreased leukemic Lin−Sca-1+cKit+ cell numbers and long-term stem cell frequency, and prolonged survival in a murine CML model. Additionally, this combination effectively eradicated CD34+CD38−, CD34+CD38+, and quiescent stem/progenitor CD34+ cells from BC CML patient samples. Our results suggest that BCL-2 is a key survival factor for CML stem/progenitor cells and that combined inhibition of BCL-2 and BCR-ABL tyrosine kinase has the potential to significantly improve depth of response and cure rates of chronic phase and BC CML. PMID:27605552

Propofol-induced rno-miR-665 targets BCL2L1 and influences apoptosis in rodent developing hippocampal astrocytes.

Science.gov (United States)

Sun, Wen-Chong; Liang, Zuo-Di; Pei, Ling

2015-12-01

Propofol exerts neurotoxic effects on the developing mammalian brains, but the underlying molecular mechanism remains unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression at the post-transcriptional level. However, in specific types of neurocytes, the detailed functions of miRNAs were not entirely understood. We investigated the potential role of miRNAs in astrocyte pathogenesis caused by propofol. We performed genome-wide microRNA expression profiling in immature cultured hippocampal astrocytes by microarray analysis and predicted their targets and functions using bioinformatics tools. The functional effects of one differentially expressed miRNA were examined experimentally in relation to astrocyte viability. The results showed that 13 miRNAs were significantly differentially expressed after both short-term exposure to high-concentration propofol (10 μg/ml for 1h) and long-term exposure to low-concentration propofol (0.9 μg/ml for 48 h), including rno-miR-665, differing significantly between the 2. Bioinformatics predicted putative binding sites for rno-miR-665 existing in the 3'-untranslated region of Bcl-2-like protein 1 BCL2L1 (Bcl-xl) mRNA. Moreover, such relationship was assessed by luciferase reporter assay, qRT-PCR and western blot. Rno-miR-665 which was significantly up-regulated by propofol can suppress BCL2L1 and elevate cleaved caspase-3 expression in immature astrocytes in vitro. Apoptosis of developing hippocampal astrocytes was thus significantly influenced by propofol or rno-miR-665, or both. Taken together, rno-miR-665 is involved in the neurotoxicity induced by propofol via a caspase-3 mediated mechanism by negatively regulating BCL2L1. It might act as an alternative therapeutic target for treatment of neurological disorders in peadiatric prolonged anesthesia or sedation with propofol clinically. Copyright © 2015. Published by Elsevier B.V.

Bcl-2 antisense therapy in B-cell malignancies.

Science.gov (United States)

Chanan-Khan, Asher

2005-07-01

Bcl-2 is an apoptosis regulating protein, overexpression of which is associated with chemotherapy resistant disease, aggressive clinical course, and poor survival in patients with B-cell lymphoproliferative disorders. Overexpression of Bcl-2 protein results in an aberrant intrinsic apoptotic pathway that confers a protective effect on malignant cells against a death signal (e.g., chemotherapy or radiotherapy). Downregulation of this oncoprotein, thus, represents a possible new way to target clinically aggressive disease. Preclinical studies have shown that this oncoprotein can be effectively decreased by Bcl-2 antisense in malignant lymphoid cells and can reverse chemotherapy resistance, as well as enhance the anti-apoptotic potential of both chemotherapeutic and biologic agents. Ongoing clinical trials are exploring the role of Bcl-2 downregulation with oblimersen (Bcl-2 antisense) in patients with non-Hodgkin's lymphoma, chronic lymphocytic leukemia and multiple myeloma. Early results from these studies are promising and support the proof of the principle. As these studies are completed and mature data emerges, the role of Bcl-2 antisense therapy in the treatment of B-cell malignancies will become clearer.

Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy

Energy Technology Data Exchange (ETDEWEB)

Lee, Dong-Hwa; Ha, Ji-Hyang [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Kim, Yul [Department of Bio and Brain Engineering, KAIST, Daejeon 305-701 (Korea, Republic of); Bae, Kwang-Hee [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Park, Jae-Yong [Department of Physiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751 (Korea, Republic of); Choi, Wan Sung [Department of Anatomy and Neurobiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751 (Korea, Republic of); Yoon, Ho Sup [Division of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637511 (Singapore); Park, Sung Goo; Park, Byoung Chul [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of); Yi, Gwan-Su, E-mail: gsyi@kaist.ac.kr [Department of Bio and Brain Engineering, KAIST, Daejeon 305-701 (Korea, Republic of); Chi, Seung-Wook, E-mail: swchi@kribb.re.kr [Medical Proteomics Research Center, KRIBB, Daejeon 305-806 (Korea, Republic of)

2011-05-20

Highlights: {yields} Identification of a conserved BH3 motif in C-terminal coiled coil region of nCLU. {yields} The nCLU BH3 domain binds to BH3 peptide-binding grooves in both Bcl-X{sub L} and Bcl-2. {yields} A conserved binding mechanism of nCLU BH3 and the other pro-apoptotic BH3 peptides with Bcl-X{sub L}. {yields} The absolutely conserved Leu323 and Asp328 of nCLU BH3 domain are critical for binding to Bcl-X{sub L.} {yields} Molecular understanding of the pro-apoptotic function of nCLU as a novel BH3-only protein. -- Abstract: Clusterin (CLU) is a multifunctional glycoprotein that is overexpressed in prostate and breast cancers. Although CLU is known to be involved in the regulation of apoptosis and cell survival, the precise molecular mechanism underlying the pro-apoptotic function of nuclear CLU (nCLU) remains unclear. In this study, we identified a conserved BH3 motif in C-terminal coiled coil (CC2) region of nCLU by sequence analysis and characterized the molecular interaction of the putative nCLU BH3 domain with anti-apoptotic Bcl-2 family proteins by nuclear magnetic resonance (NMR) spectroscopy. The chemical shift perturbation data demonstrated that the nCLU BH3 domain binds to pro-apoptotic BH3 peptide-binding grooves in both Bcl-X{sub L} and Bcl-2. A structural model of the Bcl-X{sub L}/nCLU BH3 peptide complex reveals that the binding mode is remarkably similar to those of other Bcl-X{sub L}/BH3 peptide complexes. In addition, mutational analysis confirmed that Leu323 and Asp328 of nCLU BH3 domain, absolutely conserved in the BH3 motifs of BH3-only protein family, are critical for binding to Bcl-X{sub L}. Taken altogether, our results suggest a molecular basis for the pro-apoptotic function of nCLU by elucidating the residue specific interactions of the BH3 motif in nCLU with anti-apoptotic Bcl-2 family proteins.

Cannabinoids Regulate Bcl-2 and Cyclin D2 Expression in Pancreatic β Cells.

Directory of Open Access Journals (Sweden)

Jihye Kim

Full Text Available Recent reports have shown that cannabinoid 1 receptors (CB1Rs are expressed in pancreatic β cells, where they induce cell death and cell cycle arrest by directly inhibiting insulin receptor activation. Here, we report that CB1Rs regulate the expression of the anti-apoptotic protein Bcl-2 and cell cycle regulator cyclin D2 in pancreatic β cells. Treatment of MIN6 and βTC6 cells with a synthetic CB1R agonist, WIN55,212-2, led to a decrease in the expression of Bcl-2 and cyclin D2, in turn inducing cell cycle arrest in G0/G1 phase and caspase-3-dependent apoptosis. Additionally, genetic deletion and pharmacological blockade of CB1Rs after injury in mice led to increased levels of Bcl-2 and cyclin D2 in pancreatic β cells. These findings provide evidence for the involvement of Bcl-2 and cyclin D2 mediated by CB1Rs in the regulation of β-cell survival and growth, and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and growth in diabetes.

Bcl-2 prevents loss of mitochondria in CCCP-induced apoptosis

International Nuclear Information System (INIS)

Graaf, Aniek O. de; Heuvel, Lambert P. van den; Dijkman, Henry B.P.M.; Abreu, Ronney A. de; Birkenkamp, Kim U.; Witte, Theo de; Reijden, Bert A. van der; Smeitink, Jan A.M.; Jansen, Joop H.

2004-01-01

Bcl-2 family proteins regulate apoptosis at the level of mitochondria. To examine the mechanism of Bcl-2 function, we investigated the effects of the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) on two hematopoietic cell lines and Bcl-2 overexpressing transfectants. CCCP directly interferes with mitochondrial function and induces apoptosis. We show that Bcl-2 inhibits apoptosis and that the antiapoptotic effect of Bcl-2 takes place upstream of caspase activation and nuclear changes associated with apoptosis, since these were markedly inhibited in cells overexpressing Bcl-2. Bcl-2 does not prevent the decrease in mitochondrial membrane potential nor the alterations in cellular ATP content induced by CCCP in FL5.12 and Jurkat cells. A higher number of mitochondria was observed in untreated Bcl-2 transfected cells compared to parental cells, as shown by electron microscopy. Exposure to CCCP induced a dramatic decrease in the number of mitochondria and severely disrupted mitochondrial ultrastructure, with apparent swelling and loss of cristae in parental cells. Bcl-2 clearly diminished the disruption of mitochondrial structure and preserved a higher number of mitochondria. These data suggest that CCCP induces apoptosis by structural disruption of mitochondria and that Bcl-2 prevents apoptosis and mitochondrial degeneration by preserving mitochondrial integrity

Bcl-2 prevents loss of mitochondria in CCCP-induced apoptosis.

Science.gov (United States)

de Graaf, Aniek O; van den Heuvel, Lambert P; Dijkman, Henry B P M; de Abreu, Ronney A; Birkenkamp, Kim U; de Witte, Theo; van der Reijden, Bert A; Smeitink, Jan A M; Jansen, Joop H

2004-10-01

Bcl-2 family proteins regulate apoptosis at the level of mitochondria. To examine the mechanism of Bcl-2 function, we investigated the effects of the protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) on two hematopoietic cell lines and Bcl-2 overexpressing transfectants. CCCP directly interferes with mitochondrial function and induces apoptosis. We show that Bcl-2 inhibits apoptosis and that the antiapoptotic effect of Bcl-2 takes place upstream of caspase activation and nuclear changes associated with apoptosis, since these were markedly inhibited in cells overexpressing Bcl-2. Bcl-2 does not prevent the decrease in mitochondrial membrane potential nor the alterations in cellular ATP content induced by CCCP in FL5.12 and Jurkat cells. A higher number of mitochondria was observed in untreated Bcl-2 transfected cells compared to parental cells, as shown by electron microscopy. Exposure to CCCP induced a dramatic decrease in the number of mitochondria and severely disrupted mitochondrial ultrastructure, with apparent swelling and loss of cristae in parental cells. Bcl-2 clearly diminished the disruption of mitochondrial structure and preserved a higher number of mitochondria. These data suggest that CCCP induces apoptosis by structural disruption of mitochondria and that Bcl-2 prevents apoptosis and mitochondrial degeneration by preserving mitochondrial integrity.

Nitric oxide and bcl-2 mediated the apoptosis induced by nickel(II) in human T hybridoma cells

International Nuclear Information System (INIS)

Guan Fuqin; Zhang Dongmei; Wang Xinchang; Chen Junhui

2007-01-01

Although effects of nickel(II) on the immune system have long been recognized, little is known about the effects of nickel(II) on the induction of apoptosis and related signaling events in T cells. In the present study, we investigated the roles and signaling pathways of nickel(II) in the induction of apoptosis in a human T cell line jurkat. The results showed that the cytotoxic effects of Ni involved significant morphological changes and chromosomal condensation (Hoechst 33258 staining). Analyses of hypodiploid cells and FITC-Annexin V and PI double staining showed significant increase of apoptosis in jurkat cells 6, 12 and 24 h after nickel(II) treatment. Flow cytometry analysis also revealed that the loss of mitochondrial membrane potential (MMP) occurred concomitantly with the onset of NiCl 2 -induced apoptosis. Induction of apoptotic cell death by nickel was mediated by reduction of bcl-2 expression. Furthermore, nickel stimulated the generation of nitric oxide (NO). These results suggest that nickel(II) chloride induces jurkat cells apoptosis via nitric oxide generation, mitochondrial depolarization and bcl-2 suppression

Long-range dispersion interactions. I. Formalism for two heteronuclear atoms

International Nuclear Information System (INIS)

Zhang, J.-Y.; Mitroy, J.

2007-01-01

A general procedure for systematically evaluating the long-range dispersion interaction between two heteronuclear atoms in arbitrary states is outlined. The C 6 dispersion parameter can always be written in terms of sum rules involving oscillator strengths only and formulas for a number of symmetry cases are given. The dispersion coefficients for excited alkali-metal atoms interacting with the ground-state H and He are tabulated

Predicting long-range transport: a systematic evaluation of two multimedia transport models.

Science.gov (United States)

Bennett, D H; Scheringer, M; McKone, T E; Hungerbühler, K

2001-03-15

The United Nations Environment Program has recently developed criteria to identify and restrict chemicals with a potential for persistence and long-range transport (persistent organic pollutants or POPs). There are many stakeholders involved, and the issues are not only scientific but also include social, economic, and political factors. This work focuses on one aspect of the POPs debate, the criteria for determining the potential for long-range transport (LRT). Our goal is to determine if current models are reliable enough to support decisions that classify a chemical based on the LRT potential. We examine the robustness of two multimedia fate models for determining the relative ranking and absolute spatial range of various chemicals in the environment. We also consider the effect of parameter uncertainties and the model uncertainty associated with the selection of an algorithm for gas-particle partitioning on the model results. Given the same chemical properties, both models give virtually the same ranking. However, when chemical parameter uncertainties and model uncertainties such as particle partitioning are considered, the spatial range distributions obtained for the individual chemicals overlap, preventing a distinct rank order. The absolute values obtained for the predicted spatial range or travel distance differ significantly between the two models for the uncertainties evaluated. We find that to evaluate a chemical when large and unresolved uncertainties exist, it is more informative to use two or more models and include multiple types of uncertainty. Model differences and uncertainties must be explicitly confronted to determine how the limitations of scientific knowledge impact predictions in the decision-making process.

Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab.

Science.gov (United States)

Akyurek, Nalan; Uner, Aysegul; Benekli, Mustafa; Barista, Ibrahim

2012-09-01

Diffuse large B-cell lymphomas (DLBCLs) are a biologically heterogeneous group in which various gene alterations have been reported. The aim of this study was to investigate the frequency and prognostic impact of BCL2, BCL6, and MYC rearrangements in cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (R-CHOP)-treated DLBCL cases. Tissue microarrays were constructed from 239 cases of DLBCL, and the expressions of CD10, BCL6, MUM1/IRF4, and BCL2 were evaluated by immunohistochemistry. MYC, BCL2, and BCL6 rearrangements were investigated by interphase fluorescence in situ hybridization on tissue microarrays. Survival analysis was constructed from 145 R-CHOP-treated patients. MYC, BCL2, and BCL6 rearrangements were detected in 14 (6%), 36 (15%), and 69 (29%) of 239 DLBCL patients. Double or triple rearrangements were detected in 7 (3%) of 239 DLBCL cases. Of these, 4 had BCL2 and MYC, 2 had BCL6 and MYC, and 1 had BCL2, BCL6, and MYC rearrangements. The prognosis of these cases was extremely poor, with a median survival of 9 months. MYC rearrangement was associated with significantly worse overall survival (P = .01), especially for the cases with GC phenotype (P = .009). BCL6 rearrangement also predicted significantly shorter overall survival (P = .04), especially for the non-GC phenotype (P = .03). BCL2 rearrangement had no prognostic impact on outcome. International Prognostic Index (P = .004) and MYC rearrangement (P = .009) were independent poor prognostic factors. Analysis of MYC gene rearrangement along with BCL2 and BCL6 is critical in identifying high-risk patients with poor prognosis. Copyright © 2011 American Cancer Society.

Passive long range acousto-optic sensor

Science.gov (United States)

Slater, Dan

2006-08-01

Alexander Graham Bell's photophone of 1880 was a simple free space optical communication device that used the sun to illuminate a reflective acoustic diaphragm. A selenium photocell located 213 m (700 ft) away converted the acoustically modulated light beam back into sound. A variation of the photophone is presented here that uses naturally formed free space acousto-optic communications links to provide passive multichannel long range acoustic sensing. This system, called RAS (remote acoustic sensor), functions as a long range microphone with a demonstrated range in excess of 40 km (25 miles).

Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.

Science.gov (United States)

Cadet, J L; Ordonez, S V; Ordonez, J V

1997-02-01

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.

rno-miR-665 targets BCL2L1 (Bcl-xl) and increases vulnerability to propofol in developing astrocytes.

Science.gov (United States)

Sun, Wen-Chong; Pei, Ling

2016-07-01

Propofol exerts a cytotoxic influence over immature neurocytes. Our previous study revealed that clinically relevant doses of propofol accelerated apoptosis of primary cultured astrocytes of developing rodent brains via rno-miR-665 regulation. However, the role of rno-miR-665 during the growth spurt of neonatal rodent brains in vivo is still uncertain. Post-natal day 7 (P7) rats received a single injection of propofol 30 mg/kg intraperitoneally (i.p.), and neuroapoptosis of hippocampal astrocytes was analyzed by immunofluorescence and scanning electron microscopy. The differential expression of rno-miR-665, BCL2L1 (Bcl-xl), and cleaved caspase 3 (CC3) was surveyed by qRT-PCR and western blotting. In addition, the utility of A-1155463, a highly potent and BCL2L1-selective antagonist, was aimed to assess the contribution of BCL2L1 for neuroglial survival. Following the intraventricular injection of lentivirus rno-miR-665, neuroprotection was detected by 5-point scale measurement. The single dose of propofol 30 mg/kg triggered dose-dependent apoptosis of developing hippocampal astrocytes. Meanwhile, propofol triggered both rno-miR-665 and CC3, and depressed BCL2L1, which was predicted as one target gene of rno-miR-665. Combination treatment with A-1155463 and propofol induced lower mRNA and protein levels of BCL2L1 and more CC3 activation than propofol treatment alone in vivo. The lentivirus-mediated knockdown of rno-miR-665 elevated BCL2L1 and attenuated CC3 levels, whereas up-regulation of rno-miR-665 suppressed BCL2L1 and induced CC3 expression in vivo. More importantly, rno-miR-665 antagomir infusion improved neurological outcomes of pups receiving propofol during the brain growth spurt. Rno-miR-665, providing a potential target for alternative therapeutics for pediatric anesthesia, is susceptible to propofol by negatively targeting antiapoptotic BCL2L1. Relatively little is known about the association between exposure of astrocytes to brief propofol

Unitarity corrections to short-range order long-range rapidity correlations

CERN Document Server

Capella, A

1978-01-01

Although the effective hadronic forces have short range in rapidity space, one nevertheless expects long-range dynamical correlations induced by unitarity constraints. This paper contains a thorough discussion of long-range rapidity correlations in high-multiplicity events. In particular, the authors analyze in detail the forward- backward multiplicity correlations, measured recently in the whole CERN ISR energy range. They find from these data that the normalized variance of the number n of exchanged cut Pomerons, ((n/(n)-1)/sup 2/) , is most probably in the range 0.32 to 0.36. They show that such a number is obtained from Reggeon theory in the eikonal approximation. The authors also predict a very specific violation of local compensation of charge in multiparticle events: The violation should appear in the fourth-order zone correlation function and is absent in the second-order correlation function, the only one measured until now. (48 refs).

Long-range correlation and market segmentation in bond market

Science.gov (United States)

Wang, Zhongxing; Yan, Yan; Chen, Xiaosong

2017-09-01

This paper investigates the long-range auto-correlations and cross-correlations in bond market. Based on Detrended Moving Average (DMA) method, empirical results present a clear evidence of long-range persistence that exists in one year scale. The degree of long-range correlation related to maturities has an upward tendency with a peak in short term. These findings confirm the expectations of fractal market hypothesis (FMH). Furthermore, we have developed a method based on a complex network to study the long-range cross-correlation structure and applied it to our data, and found a clear pattern of market segmentation in the long run. We also detected the nature of long-range correlation in the sub-period 2007-2012 and 2011-2016. The result from our research shows that long-range auto-correlations are decreasing in the recent years while long-range cross-correlations are strengthening.

Overexpression of the human BCL-2 gene product results in growth enhancement of Epstein-Barr virus-immortalized B cells

International Nuclear Information System (INIS)

Tsujimoto, Yoshihide

1989-01-01

The biological activity of the human BCL-2 gene product was analyzed in an Epstein-Barr virus (EBV)-infected human lymphoblastoid B-cell line transfected with BCL-2 sequences driven by the simian virus 40 promoter and enhancer. Overproduction of the BCL-2 protein conferred a selective growth advantage to the EBV-infected B cells as compared with control transfectants in low-serum medium and also after seeding at limiting dilution but did not render the cells tumorigenic in athymic nude mice. This growth enhancement was also seen in cells transfected with the BCL-2 gene with its own promoter juxtaposed to the immunoglobulin heavy chain gene enhancer, which represents the translocated form of the BCL-2 gene observed in follicular lymphomas with the t(14;18) translocation. The growth advantage of EBV-infected B cells overproducing the BCL-2 protein is neither due to the enhanced growth factor production nor due to an enhanced sensitivity of the BCL-2 transfectants to interleukins 1 or 6, although both lymphokines are known to stimulate proliferation of EBV-infected B-cell lines. The growth advantage of EBV-infected B-cell lines. The growth advantage of EBV-infected B cells by overproduction of the BCL-2 protein suggests the direct involvement of the BCL-2 gene product in the pathogenesis of follicular lymphoma

Bcl-2 protein level in blood of patients with acute myeloid leukaemia ...

African Journals Online (AJOL)

(AML), bcl-2 being an anti-apoptotic protein incriminated in cancer. ... resistant to apoptosis, defining this protein as a factor of bad prognosis in AML. Moreover, the determination ..... of the molecular mechanisms of physiological ... long term survival in breast cancer, Am. J. Pathol. ... Burkitt subtype at presentation, and is not.

A computer simulation of a long-range CWFM radar showing the tradeoffs of performance as a function of range

Science.gov (United States)

Gordy, Robert S.; Zoledziowski, Severyn

2011-06-01

This paper describes a study of the operation of a long range CWFM radar using "System View" software for modeling and simulation. The System View software is currently offered by Agilent. The models that were studied include: a model illustrating the basic principle of operation of the CWFM radar, the range resolution of the radar, the effect of long range processing and the resultant approach with the tradeoff of detected range resolution due to Doppler frequency shift as a function of range distance. The study was performed as part of the design of an airborne CWFM radar. The radar can be designed with a single antenna or a dual antenna. The dual antenna approach is presented in this paper.

Bcl-x(L) expression in vivo in rheumatoid synovium.

LENUS (Irish Health Repository)

Busteed, S

2012-02-03

To examine the expression of the apoptosis regulatory protein, Bcl-x(L), in the synovium of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Immunohistochemistry for Bcl-x(L) was carried out on synovial samples from patients with RA and OA. Reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot analysis were performed to qualitatively examine the expression of Bcl-x(L). Bcl-x(L) expression was detected in the lining, endothelium and inflammatory cells of both RA (n=20) and OA (n=10) samples. However, there was significantly more expression in the lining of RA synovium compared to OA (77 vs 61%, p<0.05). Many of the positive cells in the RA subsynovium were noted to be plasma cells. There was a significant correlation between Bcl-x(L) expression and the number of inflammatory cells in the subsynovium of RA and OA patients (r (s)=0.376, p<0.05, n=30). Age and disease duration did not correlate with Bcl-x(L) expression in rheumatoid patients. Bcl-x(L) may play a role in the extended survival of synoviocytes and inflammatory cells in rheumatoid synovium.

Apoptosis and the BCL-2 gene family - patterns of expression and prognostic value in STAGE I and II follicular center lymphoma

International Nuclear Information System (INIS)

Logsdon, Mark D.; Meyn, Raymond E.; Besa, Pelayo C.; Pugh, William C.; Stephens, L. Clifton; Peters, Lester J.; Milas, Luka; Cox, James D.; Cabanillas, Fernando; Brisbay, Shawn; Andersen, Margret; McDonnell, Timothy J.

1999-01-01

Purpose: The prognostic significance of spontaneous levels of apoptosis and Bcl-2, Bax, and Bcl-x protein expression in follicular center lymphoma (FCL) is unknown. The objectives of this retrospective study were (1) to investigate the relationship between pretreatment apoptosis levels and long-term treatment outcome in patients with Stage I and II FCL; (2) to define the incidence and patterns of Bax and Bcl-x protein expression in human FC; and (3) to determine the relationship of Bcl-2, Bax, and Bcl-x expression with spontaneous apoptosis levels and clinical outcome in localized FCL. Methods and Materials: Between 1974 and 1988, 144 patients with Stage I or II FCL were treated. Hematoxylin and eosin (H and E) stained tissue sections of pretreatment specimens were retrieved for 96 patients. Treatment consisted of regional radiation therapy (XRT) for 25 patients, combined modality therapy (CMT) consisting of combination chemotherapy and XRT for 57 patients, and other treatments for 14 patients. Median follow-up for living patients was nearly 12 years. The apoptotic index (AI) was calculated by dividing the number of apoptotic cells by the total number of cells counted and multiplying by 100. Expression of Bcl-2, Bax, and Bcl-x proteins was assessed using immunohistochemistry. Results: The mean and median AI values for the entire group were 0.53 and 0.4, respectively (range: 0-5.2). The AI strongly correlated with cytologic grade, with mean AI values of 0.25 for grade 1, 0.56 for grade 2, and 0.84 for grade 3 (p < 0.0005; Kendall correlation). A positive correlation was present between grouped AI and grouped mitotic index (MI) (p = 0.014). For patients treated with CMT, an AI < 0.4 correlated with improved freedom from relapse (FFR) (p = 0.0145) and overall survival (OS) (p = 0.0081). An AI < 0.4 did not correlate with clinical outcome for the entire cohort or for patients receiving XRT only. Staining of tumor follicles for the Bcl-2 protein was positive, variable

Mapping of the bcl-2 oncogene on mouse chromosome 1.

Science.gov (United States)

Mock, B A; Givol, D; D'Hoostelaere, L A; Huppi, K; Seldin, M F; Gurfinkel, N; Unger, T; Potter, M; Mushinski, J F

1988-01-01

Two bcl-2 alleles have been identified in inbred strains of mice by restriction fragment length polymorphism (RFLP). Analysis of a bcl-2 RFLP in a series of bilineal congenic strains (C.D2), developed as a tool for chromosomal mapping studies, revealed linkage of bcl-2 to the Idh-1/Pep-3 region of murine chromosome 1. The co-segregation of bcl-2 alleles with allelic forms of two other chromosome 1 loci, Ren-1,2 and Spna-1, in a set of back-cross progeny, positions bcl-2 7.8 cM centromeric from Ren-1,2.

Nonsyndromic cleft lip with or without cleft palate: Evidence of linkage to BCL3 in 17 multigenerational families

Energy Technology Data Exchange (ETDEWEB)

Stein, J.; Hecht, T. [Univ. of Texas, Houston, TX (United States); Stal, S. [Texas Children`s Hospital, Houston, TX (United States)] [and others

1995-08-01

Nonsyndromic cleft lip with or without cleft palate (CL/P) is a common craniofacial developmental defect. Recent segregation analyses have suggested that major genes play a role in the etiology of CL/P. Linkage to 22 candidate genes was tested in 11 multigenerational families with CL/P, and 21 of these candidates were excluded. APOC2, 19q13.1, which is linked to the proto-oncogene BCL3, gave suggestive evidence for linkage to CL/P. The study was expanded to include a total of 39 multigenerational CL/P families. Linkage was tested in all families, using anonymous marker, D19S178, and intragenic markers in BCL3 and APOC2. Linkage was tested under two models, autosomal dominant with reduced penetrance and affecteds-only model. Both models showed evidence of heterogeneity, with 43% of families linked at zero recombination to BCL3 when marker data from BCL3 and APOC2 were included. A maximum multipoint LOD score of 7.00 at BCL3 was found among the 17 families that had posterior probabilities {ge}50% in favor of linkage. The transmission disequilibrium test provided additional evidence for linkage with the 3 allele of BCL3 more often transmitted to affected children. These results suggest that BCL3, or a nearby gene, plays a role in the etiology of CL/P in some families. 39 refs., 8 figs., 4 tabs.

Characterizing short-range vs. long-range spatial correlations in dislocation distributions

International Nuclear Information System (INIS)

Chevy, Juliette; Fressengeas, Claude; Lebyodkin, Mikhail; Taupin, Vincent; Bastie, Pierre; Duval, Paul

2010-01-01

Hard X-ray diffraction experiments have provided evidence of a strongly heterogeneous distribution of dislocation densities along the axis of cylindrical ice single crystals oriented for basal slip in torsion creep. The dislocation arrangements showed a complex scale-invariant character, which was analyzed by means of statistical and multifractal techniques. A trend to decreasing autocorrelation of the dislocation distribution was observed as deformation proceeds. At low strain levels, long-range spatial correlations control the distribution, but short-range correlations in relation with cross-slip progressively prevail when strain increases. This trend was reproduced by a model based on field dislocation dynamics, a theory accounting for both long-range elastic interactions and short-range interactions through transport of dislocation densities.

Characterizing short-range vs. long-range spatial correlations in dislocation distributions

Energy Technology Data Exchange (ETDEWEB)

Chevy, Juliette, E-mail: juliette.chevy@gmail.com [Laboratoire de Glaciologie et Geophysique de l' Environnement-CNRS, 54 rue Moliere, 38402 St. Martin d' Heres (France)] [Laboratoire Science et Ingenierie des Materiaux et Procedes, Grenoble INP-CNRS-UJF, BP 75, 38402 St. Martin d' Heres Cedex (France); Fressengeas, Claude; Lebyodkin, Mikhail; Taupin, Vincent [Laboratoire de Physique et Mecanique des Materiaux, Universite Paul Verlaine-Metz/CNRS, Ile du Saulcy, 57045 Metz Cedex (France); Bastie, Pierre [Laboratoire de Spectrometrie Physique, BP 87, 38402 St. Martin d' Heres Cedex (France)] [Institut Laue Langevin, BP 156, 38042 Grenoble Cedex 9 (France); Duval, Paul [Laboratoire de Glaciologie et Geophysique de l' Environnement-CNRS, 54 rue Moliere, 38402 St. Martin d' Heres (France)

2010-03-15

Hard X-ray diffraction experiments have provided evidence of a strongly heterogeneous distribution of dislocation densities along the axis of cylindrical ice single crystals oriented for basal slip in torsion creep. The dislocation arrangements showed a complex scale-invariant character, which was analyzed by means of statistical and multifractal techniques. A trend to decreasing autocorrelation of the dislocation distribution was observed as deformation proceeds. At low strain levels, long-range spatial correlations control the distribution, but short-range correlations in relation with cross-slip progressively prevail when strain increases. This trend was reproduced by a model based on field dislocation dynamics, a theory accounting for both long-range elastic interactions and short-range interactions through transport of dislocation densities.

BCL2 genotypes and prostate cancer survival

Energy Technology Data Exchange (ETDEWEB)

Renner, Wilfried [Medical University of Graz, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz (Austria); Langsenlehner, Uwe [GKK Outpatient Department, Division of Internal Medicine, Graz (Austria); Krenn-Pilko, Sabine; Langsenlehner, Tanja [Medical University of Graz, Department of Therapeutic Radiology and Oncology, Graz (Austria); Eder, Petra [University Hospital Wuerzburg, Department of Internal Medicine I, Wuerzburg (Germany)

2017-06-15

The antiapoptotic B-cell lymphoma 2 (BCL2) gene is a key player in cancer development and progression. A functional single-nucleotide polymorphism (c.-938C>A, rs2279115) in the inhibitory P2 BCL2 gene promoter has been associated with clinical outcomes in various types of cancer. Aim of the present study was to analyze the role of BCL2-938C>A genotypes in prostate cancer mortality. The association between BCL2-938C>A (rs2279115) genotypes and prostate cancer outcome was studied within the prospective PROCAGENE study comprising 702 prostate cancer patients. During a median follow-up time of 92 months, 120 (17.1%) patients died. A univariate Cox regression model showed a significant association of the CC genotype with reduced cancer-specific survival (CSS; hazard ratio, HR, 2.13, 95% confidence interval, CI, 1.10-4.12; p = 0.024) and overall survival (OS; HR 2.34, 95% CI 1.58-3.47; p < 0.001). In a multivariate Cox regression model including age at diagnosis, risk group, and androgen deprivation therapy, the CC genotype remained a significant predictor of poor CSS (HR 2.05, 95% CI 1.05-3.99; p = 0.034) and OS (HR 2.25, 95% CI 1.51-3.36; p < 0.001). This study provides evidence that the homozygous BCL2-938 CC genotype is associated with OS and C in prostate cancer patients. (orig.) [German] Das antiapoptotische Gen B cell lymphoma 2 (BCL2) spielt eine Schluesselrolle in der Entstehung und Progression von Krebserkrankungen. Ein funktioneller Einzelnukleotid-Polymorphismus (c.-938C>A, rs2279115) im inhibitorischen P2-BCL2-Promotor wurde mit dem klinischen Outcome verschiedener Krebserkrankungen verknuepft. Ziel der vorliegenden Studie war die Untersuchung der Rolle von BCL2-938C>A-Genotypen fuer die Mortalitaet bei Patienten mit Prostatakarzinom. Der Zusammenhang zwischen BCL2-938C>A-Genotypen (rs2279115) und dem Outcome bei Prostatakrebs wurde in der prospektiven PROCAGENE-Studie, die 702 Patienten mit Prostatakarzinom umfasste, untersucht. Waehrend der medianen

Effect of Bcl-xL overexpression on sialylation of Fc-fusion protein in recombinant Chinese hamster ovary cell cultures.

Science.gov (United States)

Lee, Jong Hyun; Kim, Yeon-Gu; Lee, Gyun Min

2015-01-01

The sialic acid of glycoproteins secreted by recombinant Chinese hamster ovary (rCHO) cells can be impaired by sialidase under culture conditions which promote the extracellular accumulation of this enzyme. To investigate the effect of Bcl-xL overexpression on the sialylation of glycoproteins produced in rCHO cell culture, two rCHO cell lines producing the same Fc-fusion protein, which were derived from DUKX-B11 and DG44, respectively, were engineered to have regulated Bcl-xL overexpression using the Tet-off system. For both cell lines, Bcl-xL overexpression improved cell viability and extended culture longevity in batch cultures. As a result, a maximum Fc-fusion protein titer increased by Bcl-xL overexpression though the extent of titer enhancement differed between the two cell lines. With Bcl-xL overexpression, the sialylation of Fc-fusion protein, which was assessed by isoelectric focusing gel and sialic acid content analyses, decreased more slowly toward the end of batch cultures. This was because Bcl-xL overexpression delayed the extracellular accumulation of sialidase activity by reducing cell lysis during batch cultures. Taken together, Bcl-xL overexpression in rCHO cell culture increased Fc-fusion protein production and also reduced the impairment of sialylation of Fc-fusion protein by maintaining high viability during batch cultures. © 2015 American Institute of Chemical Engineers.

XIAP impairs mitochondrial function during apoptosis by regulating the Bcl-2 family in renal cell carcinoma.

Science.gov (United States)

Chen, Chao; Liu, Tian Shu; Zhao, Si Cong; Yang, Wen Zheng; Chen, Zong Ping; Yan, Yong

2018-05-01

Efficient apoptosis requires Bcl-2 family-mediated mitochondrial outer membrane permeabilization (MOMP), which releases pro-apoptotic proteins to the cytosol, activating apoptosis and inhibiting X-linked inhibitor of apoptosis protein (XIAP). XIAP is a member of the inhibitors of apoptosis protein family whose expression is elevated in many cancer types and participates in the release of pro-apoptotic proteins. To explore the association between XIAP and the Bcl-2 family, and the influence of XIAP on mitochondria, RNA interference of XIAP was performed in Caki-1 cells and the dynamic change in the levels of related proteins was compared with the original Caki-1 cells upon induction of apoptosis. Upon knockdown of XIAP, the release of cytochrome c (Cyt-c), second mitochondria-derived activator of caspase (Smac) and apoptotic protease activating factor 1 (Apaf-1) from mitochondria proceeded normally, whereas in Caki-1 cells, the release of these pro-apoptotic proteins was significantly prolonged, and incomplete. Downregulation of XIAP through small interfering RNA resulted in an increase of apoptosis and a marked decrease in Bcl-2 and Bcl-xl levels at 3 h. Additionally, the regulation of the level of XIAP protein affected the specific ratios of Bcl-2/Bax and Bcl-xl/Bax, which play decisive roles in cell death. In the present study, it was revealed that XIAP can feed back to mitochondria, delaying Cyt-c and Apaf-1 release. Furthermore, XIAP can limit the release of its inhibitor Smac with the involvement of Bcl-2 family proteins.

Problem of long-range forces in the computer simulation of condensed media

International Nuclear Information System (INIS)

Ceperely, D.

1980-07-01

Simulation (both Monte Carlo and molecular dynamical) has become a powerful tool in the study of classical systems of particles interacting with short-range pair potentials. For systems involving long-range forces (e.g., Coulombic, dipolar, hydrodynamic) it is a different story. Relating infinite-system properties to the results of computer simulation involving relatively small numbers of particles, periodically replicated, raises difficult and challenging problems. The purpose of the workshop was to bring together a group of scientists, all of whom share a strong direct interest in clearly formulating and resolving these problems. There were 46 participants, most of whom have been actively engaged in simulations of Hamiltonian models of condensed media. A few participants were scientists who are not primarily concerned, themselves, with simulation, but who are deeply involved in the theory of such models

Linear response theory for long-range interacting systems in quasistationary states.

Science.gov (United States)

Patelli, Aurelio; Gupta, Shamik; Nardini, Cesare; Ruffo, Stefano

2012-02-01

Long-range interacting systems, while relaxing to equilibrium, often get trapped in long-lived quasistationary states which have lifetimes that diverge with the system size. In this work, we address the question of how a long-range system in a quasistationary state (QSS) responds to an external perturbation. We consider a long-range system that evolves under deterministic Hamilton dynamics. The perturbation is taken to couple to the canonical coordinates of the individual constituents. Our study is based on analyzing the Vlasov equation for the single-particle phase-space distribution. The QSS represents a stable stationary solution of the Vlasov equation in the absence of the external perturbation. In the presence of small perturbation, we linearize the perturbed Vlasov equation about the QSS to obtain a formal expression for the response observed in a single-particle dynamical quantity. For a QSS that is homogeneous in the coordinate, we obtain an explicit formula for the response. We apply our analysis to a paradigmatic model, the Hamiltonian mean-field model, which involves particles moving on a circle under Hamiltonian dynamics. Our prediction for the response of three representative QSSs in this model (the water-bag QSS, the Fermi-Dirac QSS, and the Gaussian QSS) is found to be in good agreement with N-particle simulations for large N. We also show the long-time relaxation of the water-bag QSS to the Boltzmann-Gibbs equilibrium state. © 2012 American Physical Society

Phospholipase D1 increases Bcl-2 expression during neuronal differentiation of rat neural stem cells.

Science.gov (United States)

Park, Shin-Young; Ma, Weina; Yoon, Sung Nyo; Kang, Min Jeong; Han, Joong-Soo

2015-01-01

We studied the possible role of phospholipase D1 (PLD1) in the neuronal differentiation, including neurite formation of neural stem cells. PLD1 protein and PLD activity increased during neuronal differentiation. Bcl-2 also increased. Downregulation of PLD1 by transfection with PLD1 siRNA or a dominant-negative form of PLD1 (DN-PLD1) inhibited both neurite outgrowth and Bcl-2 expression. PLD activity was dramatically reduced by a PLCγ (phospholipase Cγ) inhibitor (U73122), a Ca(2+)chelator (BAPTA-AM), and a PKCα (protein kinase Cα) inhibitor (RO320432). Furthermore, treatment with arachidonic acid (AA) which is generated by the action of PLA2 (phospholipase A2) on phosphatidic acid (a PLD1 product), increased the phosphorylation of p38 MAPK and CREB, as well as Bcl-2 expression, indicating that PLA2 is involved in the differentiation process resulting from PLD1 activation. PGE2 (prostaglandin E2), a cyclooxygenase product of AA, also increased during neuronal differentiation. Moreover, treatment with PGE2 increased the phosphorylation of p38 MAPK and CREB, as well as Bcl-2 expression, and this effect was inhibited by a PKA inhibitor (Rp-cAMP). As expected, inhibition of p38 MAPK resulted in loss of CREB activity, and when CREB activity was blocked with CREB siRNA, Bcl-2 production also decreased. We also showed that the EP4 receptor was required for the PKA/p38MAPK/CREB/Bcl-2 pathway. Taken together, these observations indicate that PLD1 is activated by PLCγ/PKCα signaling and stimulate Bcl-2 expression through PLA2/Cox2/EP4/PKA/p38MAPK/CREB during neuronal differentiation of rat neural stem cells.

Long range trajectories

Energy Technology Data Exchange (ETDEWEB)

Allen, P. W.; Jessup, E. A.; White, R. E. [Air Resources Field Research Office, Las Vegas, Nevada (United States)

1967-07-01

A single air molecule can have a trajectory that can be described with a line, but most meteorologists use single lines to represent the trajectories of air parcels. A single line trajectory has the disadvantage that it is a categorical description of position. Like categorized forecasts it provides no qualification, and no provision for dispersion in case the parcel contains two or more molecules which may take vastly different paths. Diffusion technology has amply demonstrated that an initial aerosol cloud or volume of gas in the atmosphere not only grows larger, but sometimes divides into puffs, each having a different path or swath. Yet, the average meteorologist, faced with the problem of predicting the future motion of a cloud, usually falls back on the line trajectory approach with the explanation that he had no better tool for long range application. In his more rational moments, he may use some arbitrary device to spread his cloud with distance. One such technique has been to separate the trajectory into two or more trajectories, spaced about the endpoint of the original trajectory after a short period of travel, repeating this every so often like a chain reaction. This has the obvious disadvantage of involving a large amount of labor without much assurance of improved accuracy. Another approach is to draw a circle about the trajectory endpoint, to represent either diffusion or error. The problem then is to know what radius to give the circle and also whether to call it diffusion or error. Meteorologists at the Nevada Test Site (NTS) are asked frequently to provide advice which involves trajectory technology, such as prediction of an aerosol cloud path, reconstruction of the motion of a volume of air, indication of the dilution, and the possible trajectory prediction error over great distances. Therefore, we set out, nearly three years ago, to provide some statistical knowledge about the status of our trajectory technology. This report contains some of the

Bcl-2 and Bcl-xL overexpression inhibits cytochrome c release, activation of multiple caspases, and virus release following coxsackievirus B3 infection

International Nuclear Information System (INIS)

Carthy, Christopher M.; Yanagawa, Bobby; Luo Honglin; Granville, David J.; Yang, Decheng; Cheung, Paul; Cheung, Caroline; Esfandiarei, Mitra; Rudin, Charles M.; Thompson, Craig B.; Hunt, David W.C.; McManus, Bruce M.

2003-01-01

Coxsackievirus B3, a cytopathic virus in the family Picornaviridae, induces degenerative changes in host cell morphology. Here we demonstrate cytochrome c release and caspases-2, -3, -6, -7, -8, and -9 processing. Enforced Bcl-2 and Bcl-xL expression markedly reduced release of cytochrome c, presentation of the mitochondrial epitope 7A6, and depressed caspase activation following infection. In comparison, cell death using TRAIL ligand caused caspase-8 processing prior to cytochrome c release and executioner caspases and cell death was only partially rescued by Bcl-2 and Bcl-xL overexpression. Disruption of the mitochondrial inner membrane potential following CVB3 infection was not inhibited by zVAD.fmk treatment. Bcl-2 or Bcl-xL overexpression or zVAD.fmk treatment delayed the loss of host cell viability and decreased progeny virus release following infection. Our data suggest that mitochondrial release of cytochrome c may be an important early event in caspase activation in CVB3 infection, and, as such, may contribute to the loss of host-cell viability and progeny virus release

miR-326 targets antiapoptotic Bcl-xL and mediates apoptosis in human platelets.

Directory of Open Access Journals (Sweden)

Shifang Yu

Full Text Available Platelets play crucial roles in hemostasis, thrombosis, wound healing, inflammation, angiogenesis, and tumor metastases. Because they are anucleated blood cells, platelets lack nuclear DNA, but they do contain mitochondrial DNA, which plays a key role in regulating apoptosis. Recent evidence has suggested that miRNAs are also involved in regulating gene expression and apoptosis in platelets. Our previous study showed that the expression of miR-326 increased visibly when apheresis platelets were stored in vitro. The antiapoptotic Bcl-2 family regulator Bcl-xL has been identified as a putative target of miR-326. In the present study, dual reporter luciferase assays were used to characterize the function of miR-326 in the regulation of the apoptosis of platelet cells. These assays demonstrated that miR-326 bound to the 3'-translated region of Bcl-xL. To directly assess the functional effects of miR-326 expression, levels of Bcl-xL and the apoptotic status of stored apheresis platelets were measured after transfection of miR-326 mimic or inhibitor. Results indicated that miR-326 inhibited Bcl-xL expression and induced apoptosis in stored platelets. Additionally, miR-326 inhibited Bcl-2 protein expression and enhanced Bak expression, possibly through an indirect mechanism, though there was no effect on the expression of Bax. The effect of miR-326 appeared to be limited to apoptosis, with no significant effect on platelet activation. These results provide new insight into the molecular mechanisms affecting differential platelet gene regulation, which may increase understanding of the role of platelet apoptosis in multiple diseases.

Memory traces of long-range coordinated oscillations in the sleeping human brain.

Science.gov (United States)

Piantoni, Giovanni; Van Der Werf, Ysbrand D; Jensen, Ole; Van Someren, Eus J W

2015-01-01

Cognition involves coordinated activity across distributed neuronal networks. Neuronal activity during learning triggers cortical plasticity that allows for reorganization of the neuronal network and integration of new information. Animal studies have shown post-learning reactivation of learning-elicited neuronal network activity during subsequent sleep, supporting consolidation of the reorganization. However, no previous studies, to our knowledge, have demonstrated reactivation of specific learning-elicited long-range functional connectivity during sleep in humans. We here show reactivation of learning-induced long-range synchronization of magnetoencephalography power fluctuations in human sleep. Visuomotor learning elicited a specific profile of long-range cortico-cortical synchronization of slow (0.1 Hz) fluctuations in beta band (12-30 Hz) power. The parieto-occipital part of this synchronization profile reappeared in delta band (1-3.5 Hz) power fluctuations during subsequent sleep, but not during the intervening wakefulness period. Individual differences in the reactivated synchronization predicted postsleep performance improvement. The presleep resting-state synchronization profile was not reactivated during sleep. The findings demonstrate reactivation of long-range coordination of neuronal activity in humans, more specifically of reactivation of coupling of infra-slow fluctuations in oscillatory power. The spatiotemporal profile of delta power fluctuations during sleep may subserve memory consolidation by echoing coordinated activation elicited by prior learning. © 2014 Wiley Periodicals, Inc.

Spontaneous Lorentz violation and the long-range gravitational preferred-frame effect

International Nuclear Information System (INIS)

Graesser, Michael L.; Jenkins, Alejandro; Wise, Mark B.

2005-01-01

Lorentz-violating operators involving Standard Model fields are tightly constrained by experimental data. However, bounds are more model-independent for Lorentz violation appearing in purely gravitational couplings. The spontaneous breaking of Lorentz invariance by the vacuum expectation value of a vector field selects a universal rest frame. This affects the propagation of the graviton, leading to a modification of Newton's law of gravity. We compute the size of the long-range preferred-frame effect in terms of the coefficients of the two-derivative operators in the low-energy effective theory that involves only the graviton and the Goldstone bosons

Putative cruciform DNA structures at BCL6 breakpoint region may explain BCL6 translocation in diffuse large B-Cell lymphoma

International Nuclear Information System (INIS)

Bhatelia, Khyati D.; Nambiar, Mridula; Choudhary, Bibha; Raghvan, Sathees C.

2010-01-01

Cancer is a disease characterized by uncontrolled proliferation of cells, caused by genetic alterations such as chromosomal translocations, which are present in almost all hematological malignancies. Diffuse Large B-cell Lymphoma (DLBL) is the most common non-Hodgkin's lymphoma, comprising 40-50% of all lymphomas both in India and worldwide, and is characterized by BCL6 chromosomal translocation. However, the mechanism of this translocation is completely unknown. By mapping of translocation breakpoints from patients, we have identified three breakpoint cluster regions at 5' UTR of BCL6 gene. Bioinformatics analysis of cluster II, which possesses majority of breakpoints, this region may form cruciform DNA structures. Gel mobility shift assays using oligomeric DNA from the region suggested that a portion of cluster II folded into hairpin structures. Mutations to the wild type sequences disrupted hairpin formation. Circular dichroism studies on BCL6 oligomers resulted in a spectra containing two overlapping peaks at 265 nm and 285 nm, confirming hairpin structure. Further, the structure was destroyed upon heating, and reformed when appropriate conditions were provided. P1 nuclease assay in conjunction with KMnO 4 probing suggested that the structure possessed an eight nucleotide double-stranded stem and a nine nucleotide loop. To further understand the mechanism of BCL6 translocation in vivo, human cells were transfected with episomes harboring cluster II region and the results obtained will be discussed. Hence, our results suggest the formation of a putative cruciform DNA structure at BCL6 breakpoint region and that may facilitate breakage at BCL6 gene explaining chromosomal translocations in DLBL. (author)

Heteronuclear Long-Range Correlation

DEFF Research Database (Denmark)

Sørensen, Ole W.

The lecture will cover heteronuclear long-range correlation techniques like HMBC, H2BC, and HAT HMBC with the emphasis on determining the number of covalent bonds between two spins being correlated. H2BC and HMBC spectra are quite complementary as a peak can be strong in one of the two spectra...

Ancient Origin of the CARD–Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions

Directory of Open Access Journals (Sweden)

Jens Staal

2018-05-01

Full Text Available The CARD–coiled coil (CC/Bcl10/MALT1-like paracaspase (CBM signaling complexes composed of a CARD–CC family member (CARD-9, -10, -11, or -14, Bcl10, and the type 1 paracaspase MALT1 (PCASP1 play a pivotal role in immunity, inflammation, and cancer. Targeting MALT1 proteolytic activity is of potential therapeutic interest. However, little is known about the evolutionary origin and the original functions of the CBM complex. Type 1 paracaspases originated before the last common ancestor of planulozoa (bilaterians and cnidarians. Notably in bilaterians, Ecdysozoa (e.g., nematodes and insects lacks Bcl10, whereas other lineages have a Bcl10 homolog. A survey of invertebrate CARD–CC homologs revealed such homologs only in species with Bcl10, indicating an ancient common origin of the entire CBM complex. Furthermore, vertebrate-like Syk/Zap70 tyrosine kinase homologs with the ITAM-binding SH2 domain were only found in invertebrate organisms with CARD–CC/Bcl10, indicating that this pathway might be related to the original function of the CBM complex. Moreover, the type 1 paracaspase sequences from invertebrate organisms that have CARD–CC/Bcl10 are more similar to vertebrate paracaspases. Functional analysis of protein–protein interactions, NF-κB signaling, and CYLD cleavage for selected invertebrate type 1 paracaspase and Bcl10 homologs supports this scenario and indicates an ancient origin of the CARD–CC/Bcl10/paracaspase signaling complex. By contrast, many of the known MALT1-associated activities evolved fairly recently, indicating that unknown functions are at the basis of the protein conservation. As a proof-of-concept, we provide initial evidence for a CBM- and NF-κB-independent neuronal function of the Caenorhabditis elegans type 1 paracaspase malt-1. In conclusion, this study shows how evolutionary insights may point at alternative functions of MALT1.

Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6

Directory of Open Access Journals (Sweden)

Nina Kerres

2017-09-01

Full Text Available The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL. Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

Continuous limit of discrete systems with long-range interaction

International Nuclear Information System (INIS)

Tarasov, Vasily E

2006-01-01

Discrete systems with long-range interactions are considered. Continuous medium models as continuous limit of discrete chain system are defined. Long-range interactions of chain elements that give the fractional equations for the medium model are discussed. The chain equations of motion with long-range interaction are mapped into the continuum equation with the Riesz fractional derivative. We formulate the consistent definition of continuous limit for the systems with long-range interactions. In this paper, we consider a wide class of long-range interactions that give fractional medium equations in the continuous limit. The power-law interaction is a special case of this class

BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells

Science.gov (United States)

Lagadinou, Eleni D.; Sach, Alexander; Callahan, Kevin; Rossi, Randall M.; Neering, Sarah J.; Minhajuddin, Mohammad; Ashton, John M.; Pei, Shanshan; Grose, Valerie; O’Dwyer, Kristen M.; Liesveld, Jane L.; Brookes, Paul S.; Becker, Michael W.; Jordan, Craig T.

2013-01-01

Summary Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally-defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly over-express BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation. PMID:23333149

Correlation of mammographical imaging signs with the expression of bcl-2 and bax proteins in breast cancer

International Nuclear Information System (INIS)

Zhang Yili; Du Hongwen; Zhang Yun; Zhang Yuelang; Kuang Fangjun; Guo Zuomin

2004-01-01

Objective: To discuss the correlation of mammographical imaging signs with the expression of bcl-2 and bax proteins in breast cancer for early diagnosis and forecast of its prognoses. Methods: Fifty-four breast cancers and 26 benign diseases were proved by pathologic methods and all cases underwent mammography. Immunohistochemical technique was used to measure the expression of bcl-2 and bax proteins in these tissues. The correlation of imaging signs with the expression of bcl-2 and bax proteins in breast cancer and benign lesion was analyzed. Results: The expression of bcl-2 or bax protein in the breast cancer was higher than that in breast benign diseases (χ 2 =15.116, 11.361, P 2 =10.358, 12.818, P 2 =10.996, 10.667, P 2 =10.405, P 2 =6.841, P<0.05). Conclusion: Some imaging signs of breast cancer were closely related to the expression of bcl-2 and bax proteins and these signs could reflect the biological behavior of tumor cells and prognoses. Therefore it could be helpful to the early diagnosis and treatment of breast cancer. (authors)

Report of the Long-Range Planning Committee

International Nuclear Information System (INIS)

1984-01-01

This is the final report of the Long-Range Planning Committee of the Lawrence Livermore National Laboratory. It describes the make-up, purpose, working assumptions, and activities of the Committee and discusses the work done by the Committee on defense matters, energy, a number of additional topics, and future long-range planning activities

Spectral long-range interaction of temporal incoherent solitons.

Science.gov (United States)

Xu, Gang; Garnier, Josselin; Picozzi, Antonio

2014-02-01

We study the interaction of temporal incoherent solitons sustained by a highly noninstantaneous (Raman-like) nonlinear response. The incoherent solitons exhibit a nonmutual interaction, which can be either attractive or repulsive depending on their relative initial distance. The analysis reveals that incoherent solitons exhibit a long-range interaction in frequency space, which is in contrast with the expected spectral short-range interaction described by the usual approach based on the Raman-like spectral gain curve. Both phenomena of anomalous interaction and spectral long-range behavior of incoherent solitons are described in detail by a long-range Vlasov equation.

G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma

NARCIS (Netherlands)

van de Donk, N. W. C. J.; de Weerdt, O.; Veth, G.; Eurelings, M.; van Stralen, E.; Frankel, S. R.; Hagenbeek, A.; Bloem, A. C.; Lokhorst, H. M.

2004-01-01

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame.

Opposite role of Bax and BCL-2 in the anti-tumoral responses of the immune system

International Nuclear Information System (INIS)

Bougras, Gwenola; Cartron, Pierre-François; Gautier, Fabien; Martin, Stéphane; LeCabellec, Marité; Meflah, Khaled; Gregoire, Marc; Vallette, François M

2004-01-01

The relative role of anti apoptotic (i.e. Bcl-2) or pro-apoptotic (e.g. Bax) proteins in tumor progression is still not completely understood. The rat glioma cell line A15A5 was stably transfected with human Bcl-2 and Bax transgenes and the viability of theses cell lines was analyzed in vitro and in vivo. In vitro, the transfected cell lines (huBax A15A5 and huBcl-2 A15A5) exhibited different sensitivities toward apoptotic stimuli. huBax A15A5 cells were more sensitive and huBcl-2 A15A5 cells more resistant to apoptosis than mock-transfected A15A5 cells (pCMV A15A5). However, in vivo, in syngenic rat BDIX, these cell lines behaved differently, as no tumor growth was observed with huBax A15A5 cells while huBcl-2 A15A5 cells formed large tumors. The immune system appeared to be involved in the rejection of huBax A15A5 cells since i) huBax A15A5 cells were tumorogenic in nude mice, ii) an accumulation of CD8+ T-lymphocytes was observed at the site of injection of huBax A15A5 cells and iii) BDIX rats, which had received huBax A15A5 cells developed an immune protection against pCMV A15A5 and huBcl-2 A15A5 cells. We show that the expression of Bax and Bcl-2 controls the sensitivity of the cancer cells toward the immune system. This sensitization is most likely to be due to an increase in immune induced cell death and/or the amplification of an anti tumour immune response

Long-range interactions in lattice field theory

International Nuclear Information System (INIS)

Rabin, J.M.

1981-06-01

Lattice quantum field theories containing fermions can be formulated in a chirally invariant way provided long-range interactions are introduced. It is established that in weak-coupling perturbation theory such a lattice theory is renormalizable when the corresponding continuum theory is, and that the continuum theory is indeed recovered in the perturbative continuum limit. In the strong-coupling limit of these theories one is led to study an effective Hamiltonian describing a Heisenberg antiferromagnet with long-range interactions. Block-spin renormalization group methods are used to find a critical rate of falloff of the interactions, approximately as inverse distance squared, which separates a nearest-neighbor-antiferromagnetic phase from a phase displaying identifiable long-range effects. A duality-type symmetry is present in some block-spin calculations

Long-range interactions in lattice field theory

Energy Technology Data Exchange (ETDEWEB)

Rabin, J.M.

1981-06-01

Lattice quantum field theories containing fermions can be formulated in a chirally invariant way provided long-range interactions are introduced. It is established that in weak-coupling perturbation theory such a lattice theory is renormalizable when the corresponding continuum theory is, and that the continuum theory is indeed recovered in the perturbative continuum limit. In the strong-coupling limit of these theories one is led to study an effective Hamiltonian describing a Heisenberg antiferromagnet with long-range interactions. Block-spin renormalization group methods are used to find a critical rate of falloff of the interactions, approximately as inverse distance squared, which separates a nearest-neighbor-antiferromagnetic phase from a phase displaying identifiable long-range effects. A duality-type symmetry is present in some block-spin calculations.

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

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Shishkina, Galina T; Kalinina, Tatyana S; Bulygina, Veta V; Lanshakov, Dmitry A; Babluk, Ekaterina V; Dygalo, Nikolay N

2015-01-01

Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

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Galina T Shishkina

Full Text Available Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg, and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg. Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

The Role of Bcl-2 Family Proteins in Therapy Responses of Malignant Astrocytic Gliomas: Bcl2L12 and Beyond

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Fotini M. Kouri

2012-01-01

Full Text Available Glioblastoma (GBM is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs, revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12, as important regulators of therapy-induced cell death. This review will discuss the multi-faceted modi operandi of Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins.

Inhibition of doxorubicin-induced senescence by PPARδ activation agonists in cardiac muscle cells: cooperation between PPARδ and Bcl6.

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Paola Altieri

Full Text Available Senescence and apoptosis are two distinct cellular programs that are activated in response to a variety of stresses. Low or high doses of the same stressor, i.e., the anticancer drug doxorubicin, may either induce apoptosis or senescence, respectively, in cardiac muscle cells. We have demonstrated that PPARδ, a ligand-activated transcriptional factor that controls lipid metabolism, insulin sensitivity and inflammation, is also involved in the doxorubicin-induced senescence program. This occurs through its interference with the transcriptional repressor protein B cell lymphoma-6 (Bcl6. Low doses of doxorubicin increase the expression of PPARδ that sequesters Bcl6, thus preventing it from exerting its anti-senescent effects. We also found that L-165041, a specific PPARδ activator, is highly effective in protecting cardiomyocytes from doxorubicin-induced senescence through a Bcl6 related mechanism. In fact, L-165041 increases Bcl6 expression via p38, JNK and Akt activation, and at the same time it induces the release of Bcl6 from PPARδ, thereby enabling Bcl6 to bind to its target genes. L-165041 also prevented apoptosis induced by higher doses of doxorubicin. However, while experiments performed with siRNA analysis techniques very clearly showed the weight of Bcl6 in the cellular senescence program, no role was found for Bcl6 in the anti-apoptotic effects of L-165041, thus confirming that senescence and apoptosis are two very distinct stress response cellular programs. This study increases our understanding of the molecular mechanism of anthracycline cardiotoxicity and suggests a potential role for PPARδ agonists as cardioprotective agents.

Unusual features of long-range density fluctuations in glass-forming organic liquids: A Rayleigh and Rayleigh-Brillouin light scattering study

International Nuclear Information System (INIS)

Patkowski, A.; Fischer, E. W.; Steffen, W.; Glaser, H.; Baumann, M.; Ruths, T.; Meier, G.

2001-01-01

A new feature of glass-forming liquids, i.e., long-range density fluctuations of the order of 100 nm, has been extensively characterized by means of static light scattering, photon correlation spectroscopy and Rayleigh-Brillouin spectroscopy in orthoterphenyl (OTP) and 1,1-di(4 # prime#-methoxy-5 # prime#methyl-phenyl)-cyclohexane (BMMPC). These long-range density fluctuations result in the following unusual features observed in a light scattering experiment, which are not described by the existing theories: (i) strong q-dependent isotropic excess Rayleigh intensity, (ii) additional slow component in the polarized photon correlation function, and (iii) high Landau-Placzek ratio. These unusual features are equilibrium properties of the glass-forming liquids and depend only on temperature, provided that the sample has been equilibrated long enough. The temperature-dependent equilibration times were measured for BMMPC and are about 11 orders of magnitude longer than the α process. It was found that the glass-forming liquid OTP may occur in two states: with and without long-range density fluctuations ('clusters'). We have characterized the two states by static and dynamic light scattering in the temperature range from T g to T g +200 K. The relaxation times of the α process as well as the parameters of the Brillouin line are identical in both OTP with and without clusters. The α process (density fluctuations) in OTP was characterized by measuring either the polarized (VV) or depolarized (VH) correlation function, which are practically identical and q-independent. This feature, which is commonly observed in glass-forming liquids, is not fully explained by the existing theories

Long range correlations in condensed matter

International Nuclear Information System (INIS)

Bochicchio, R.C.

1990-01-01

Off diagonal long range order (ODLRO) correlations are strongly related with the generalized Bose-Einstein condensation. Under certain boundary conditions, one implies the other. These phenomena are of great importance in the description of quantum situations with a macroscopic manifestation (superfluidity, superconductivity, etc.). Since ion pairs are not bosons, the definition of ODLRO is modified. The information contained with the 2-particle propagator (electron pairs) and the consequences that lead to pairs statistics are shown in this presentation. The analogy between long range correlations and fluids is also analyzed. (Author). 17 refs

Bcl-2 antisense therapy in B-cell malignant proliferative disorders.

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Chanan-Khan, Asher; Czuczman, Myron S

2004-08-01

Overexpression of Bcl-2 oncogene has been clinically associated with an aggressive clinical course, chemotherapy and radiotherapy resistance, and poor survival in patients with malignant B-cell disorders. Patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma, or non-Hodgkin's lymphoma have limited therapeutic options. Preclinical and early clinical data have shown that Bcl-2 oncoprotein can be decreased by Bcl-2 antisense therapy. Also, downregulation of Bcl-2 protein can result in reversal of chemotherapy resistance and improved antitumor activity of biologic agents. Various clinical trials are evaluating the role of targeting Bcl-2 as a mechanism to enhance the antitumor potential of chemotherapy and immunotherapy. Early results from these clinical studies are encouraging and confirm the proof of principle for antisense therapy. As current data mature, these trials will hopefully validate preliminary results and establish Bcl-2 antisense as an important addition to the current armamentarium used in the treatment of patients with B-cell neoplasms.

Characterization of a TK6-Bcl-xL gly-159-ala Human Lymphoblast Clone

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Chyall, L.: Gauny, S.; Kronenberg, A.

2006-01-01

TK6 cells are a well-characterized human B-lymphoblast cell line derived from WIL-2 cells. A derivative of the TK6 cell line that was stably transfected to express a mutated form of the anti-apoptotic protein Bcl-xL (TK6-Bcl-xL gly-159- ala clone #38) is compared with the parent cell line. Four parameters were evaluated for each cell line: growth under normal conditions, plating efficiency, and frequency of spontaneous mutation to 6‑thioguanine resistance (hypoxanthine phosphoribosyl transferase locus) or trifluorothymidine resistance (thymidine kinase locus). We conclude that the mutated Bcl-xL protein did not affect growth under normal conditions, plating efficiency or spontaneous mutation frequencies at the thymidine kinase (TK) locus. Results at the hypoxanthine phosphoribosyl transferase (HPRT) locus were inconclusive. A mutant fraction for TK6‑Bcl-xL gly-159-ala clone #38 cells exposed to 150cGy of 160kVp x-rays was also calculated. Exposure to x-irradiation increased the mutant fraction of TK6‑Bcl-xL gly-159-ala clone #38 cells.

Long-range GABAergic connections distributed throughout the neocortex and their possible function

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Nobuaki eTamamaki

2010-12-01

Full Text Available Features and functions of long range GABAergic projection neurons in the developing cerebral cortex have been reported previously, although until now their significance in the adult cerebral cortex has remained uncertain. The septo-hippocampal circuit is one exception – in this system, long range mature GABAergic projection neurons have been well analyzed and their contribution to the generation of theta-oscillatory behavior in the hippocampus has been documented. To have a clue to the function of the GABAergic projection neurons in the neocortex, we view the long range GABAergic projections those participating in the cortico-cortical, cortico-fugal, and afferent projections in the cerebral cortex. Then, we consider the possibility that the GABAergic projection neurons are involved in the generation, modification, and/or synchronization of oscillations in mature neocortical neuron activity. When markers that identify the GABAergic projection neurons are examined in anatomical and developmental studies, it is clear that neuronal NO synthetase (nNOS-immunoreactivity can readily identify GABAergic projection fibers (i.e. those longer than 1.5 mm. To elucidate the role of the GABAergic projection neurons in the neocortex, it will be necessary to clarify the network constructed by nNOS-positive GABAergic projection neurons and their postsynaptic targets. Thus, our long-range goals will be to label and manipulate (including deleting the GABAergic projection neurons using genetic tools driven by a nNOS promoter. We recognize that this may be a complex endeavor, as most excitatory neurons in the murine neocortex express nNOS transiently. Nevertheless, additional studies characterizing long range GABAergic projection neurons will have great value to the overall understanding of mature cortical function.

Long-range antigravity

Energy Technology Data Exchange (ETDEWEB)

Macrae, K.I.; Riegert, R.J. (Maryland Univ., College Park (USA). Center for Theoretical Physics)

1984-10-01

We consider a theory in which fermionic matter interacts via long-range scalar, vector and tensor fields. In order not to be in conflict with experiment, the scalar and vector couplings for a given fermion must be equal, as is natural in a dimensionally reduced model. Assuming that the Sun is not approximately neutral with respect to these new scalar-vector charges, and if the couplings saturate the experimental bounds, then their strength can be comparable to that of gravity. Scalar-vector fields of this strength can compensate for a solar quadrupole moment contribution to Mercury's anomalous perihelion precession.

Long-range antigravity

International Nuclear Information System (INIS)

Macrae, K.I.; Riegert, R.J.

1984-01-01

We consider a theory in which fermionic matter interacts via long-range scalar, vector and tensor fields. In order not to be in conflict with experiment, the scalar and vector couplings for a given fermion must be equal, as is natural in a dimensionally reduced model. Assuming that the Sun is not approximately neutral with respect to these new scalar-vector charges, and if the couplings saturate the experimental bounds, then their strength can be comparable to that of gravity. Scalar-vector fields of this strength can compensate for a solar quadrupole moment contribution to Mercury's anomalous perihelion precession. (orig.)

Cyanide-induced death of dopaminergic cells is mediated by uncoupling protein-2 up-regulation and reduced Bcl-2 expression

International Nuclear Information System (INIS)

Zhang, X.; Li, L.; Zhang, L.; Borowitz, J.L.; Isom, G.E.

2009-01-01

Cyanide is a potent inhibitor of mitochondrial oxidative metabolism and produces mitochondria-mediated death of dopaminergic neurons and sublethal intoxications that are associated with a Parkinson-like syndrome. Cyanide toxicity is enhanced when mitochondrial uncoupling is stimulated following up-regulation of uncoupling protein-2 (UCP-2). In this study, the role of a pro-survival protein, Bcl-2, in cyanide-mediated cell death was determined in a rat dopaminergic immortalized mesencephalic cell line (N27 cells). Following pharmacological up-regulation of UCP-2 by treatment with Wy14,643, cyanide reduced cellular Bcl-2 expression by increasing proteasomal degradation of the protein. The increased turnover of Bcl-2 was mediated by an increase of oxidative stress following UCP-2 up-regulation. The oxidative stress involved depletion of mitochondrial glutathione (mtGSH) and increased H 2 O 2 generation. Repletion of mtGSH by loading cells with glutathione ethyl ester reduced H 2 O 2 generation and in turn blocked the cyanide-induced decrease of Bcl-2. To determine if UCP-2 mediated the response, RNAi knock down was conducted. The RNAi decreased cyanide-induced depletion of mtGSH, reduced H 2 O 2 accumulation, and inhibited down-regulation of Bcl-2, thus blocking cell death. To confirm the role of Bcl-2 down-regulation in the cell death, it was shown that over-expression of Bcl-2 by cDNA transfection attenuated the enhancement of cyanide toxicity after UCP-2 up-regulation. It was concluded that UCP-2 up-regulation sensitizes cells to cyanide by increasing cellular oxidative stress, leading to an increase of Bcl-2 degradation. Then the reduced Bcl-2 levels sensitize the cells to cyanide-mediated cell death.

Cloning and characterization of a potato StAN11 gene involved in anthocyanin biosynthesis regulation.

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Li, Wang; Wang, Bing; Wang, Man; Chen, Min; Yin, Jing-Ming; Kaleri, Ghullam Murtaza; Zhang, Rui-Jie; Zuo, Tie-Niu; You, Xiong; Yang, Qing

2014-04-01

Anthocyanins are a class of products of plant secondary metabolism and are responsible for tubers color in potato. The biosynthesis of anthocyanins is a complex biological process, in which multiple genes are involved including structural genes and regulatory genes. In this study, StAN11, a WD40-repeat gene, was cloned from potato cultivar Chieftain (Solanum tuberosum L.). StAN11 (HQ599506) contained no intron and its open reading frame (ORF) was 1,029 bp long, encoding a putative protein of 342 amino acids. In order to verify its role in anthocyanin biosynthesis, StAN11 was inserted behind the CaMV-35S promoter of pCMBIA1304 and the recombination vector was introduced into the potato cultivar Désirée plants by Agrobacterium-mediated transformation. The color of transgenic tuber skin was significantly deepened, compared to the wild-type control, which was highly consistent with the accumulation of anthocyanin and expression of StAN11 in transgenic lines tuber skin. Further analysis on the expression of Flavonone-3-hydroxylase (F3H), Dihydroflavonol reductase (DFR), Anthocyanidin synthase (ANS), and Flavonoid 3-O-glucosyl transferase (3GT) in transgenic plants revealed that only DFR was upregulated. This result suggested that StAN11 regulated anthocyanin biosynthesis in potato by controlling DFR expression and accumulation of anthocyanin could be increased through overexpression of StAN11 in the tubers with the genetic background of anthocyanin biosynthesis. © 2013 Institute of Botany, Chinese Academy of Sciences.

Energetic heavy ions overcome tumor radioresistance caused by overexpression of Bcl-2

International Nuclear Information System (INIS)

Hamada, Nobuyuki; Hara, Takamitsu; Omura-Minamisawa, Motoko; Funayama, Tomoo; Sakashita, Tetsuya; Sora, Sakura; Yokota, Yuichiro; Nakano, Takashi

2008-01-01

Background and purpose: Overexpression of Bcl-2 is frequent in human cancers and has been associated with radioresistance. Here we investigated the potential impact of heavy ions on Bcl-2 overexpressing tumors. Materials and methods: Bcl-2 cells (Bcl-2 overexpressing HeLa cells) and Neo cells (neomycin resistant gene-expressing HeLa cells) exposed to γ-rays or heavy ions were assessed for the clonogenic survival, apoptosis and cell cycle distribution. Results: Whereas Bcl-2 cells were more resistant to γ-rays (0.2 keV/μm) and helium ions (16.2 keV/μm) than Neo cells, heavy ions (76.3-1610 keV/μm) yielded similar survival regardless of Bcl-2 overexpression. Carbon ions (108 keV/μm) decreased the difference in the apoptotic incidence between Bcl-2 and Neo cells, and prolonged G 2 /M arrest that occurred more extensively in Bcl-2 cells than in Neo cells. Conclusions: High-LET heavy ions overcome tumor radioresistance caused by Bcl-2 overexpression, which may be explained at least in part by the enhanced apoptotic response and prolonged G 2 /M arrest. Thus, heavy-ion therapy may be a promising modality for Bcl-2 overexpressing radioresistant tumors

Combined Targeting of JAK2 and Bcl-2/Bcl-xL to Cure Mutant JAK2-Driven Malignancies and Overcome Acquired Resistance to JAK2 Inhibitors

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Michaela Waibel

2013-11-01

Full Text Available To design rational therapies for JAK2-driven hematological malignancies, we functionally dissected the key survival pathways downstream of hyperactive JAK2. In tumors driven by mutant JAK2, Stat1, Stat3, Stat5, and the Pi3k and Mek/Erk pathways were constitutively active, and gene expression profiling of TEL-JAK2 T-ALL cells revealed the upregulation of prosurvival Bcl-2 family genes. Combining the Bcl-2/Bcl-xL inhibitor ABT-737 with JAK2 inhibitors mediated prolonged disease regressions and cures in mice bearing primary human and mouse JAK2 mutant tumors. Moreover, combined targeting of JAK2 and Bcl-2/Bcl-xL was able to circumvent and overcome acquired resistance to single-agent JAK2 inhibitor treatment. Thus, inhibiting the oncogenic JAK2 signaling network at two nodal points, at the initiating stage (JAK2 and the effector stage (Bcl-2/Bcl-xL, is highly effective and provides a clearly superior therapeutic benefit than targeting just one node. Therefore, we have defined a potentially curative treatment for hematological malignancies expressing constitutively active JAK2.

Long range implantation by MEVVA metal ion source

International Nuclear Information System (INIS)

Zhang Tonghe; Wu Yuguang; Ma Furong; Liang Hong

2001-01-01

Metal vapor vacuum arc (MEVVA) source ion implantation is a new technology used for achieving long range ion implantation. It is very important for research and application of the ion beam modification of materials. The results show that the implanted atom diffusion coefficient increases in Mo implanted Al with high ion flux and high dose. The implanted depth is 311.6 times greater than that of the corresponding ion range. The ion species, doses and ion fluxes play an important part in the long-range implantation. Especially, thermal atom chemistry have specific effect on the long-range implantation during high ion flux implantation at transient high target temperature

Dual targeting of MDM2 and BCL2 as a therapeutic strategy in neuroblastoma.

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Van Goethem, Alan; Yigit, Nurten; Moreno-Smith, Myrthala; Vasudevan, Sanjeev A; Barbieri, Eveline; Speleman, Frank; Shohet, Jason; Vandesompele, Jo; Van Maerken, Tom

2017-08-22

Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner. The venetoclax/idasanutlin combination was consistently found to be highly synergistic in a diverse panel of neuroblastoma cell lines, including cells with high MCL1 expression levels. A more pronounced induction of apoptosis was found to underlie the synergistic interaction, as evidenced by caspase-3/7 and cleaved PARP measurements. Mice carrying orthotopic xenografts of neuroblastoma cells treated with both idasanutlin and venetoclax had drastically lower tumor weights than mice treated with either treatment alone. In conclusion, these data strongly support the further evaluation of dual BCL2/MDM2 targeting as a therapeutic strategy in neuroblastoma.

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

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Deng, Jiusheng; Park, Dongkyoo; Wang, Mengchang; Nooka, Ajay; Deng, Qiaoya; Matulis, Shannon; Kaufman, Jonathan; Lonial, Sagar; Boise, Lawrence H; Galipeau, Jacques; Deng, Xingming

2016-05-10

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.

Bcl-2 silencing attenuates hypoxia-induced apoptosis resistance in pulmonary microvascular endothelial cells.

Science.gov (United States)

Cao, Yongmei; Jiang, Zhen; Zeng, Zhen; Liu, Yujing; Gu, Yuchun; Ji, Yingying; Zhao, Yupeng; Li, Yingchuan

2016-01-01

Pulmonary arterial hypertension (PAH) is a life-threatening disorder that ultimately causes heart failure. While the underlying causes of this condition are not well understood, previous studies suggest that the anti-apoptotic nature of pulmonary microvascular endothelial cells (PMVECs) in hypoxic environments contributes to PAH pathogenesis. In this study, we focus on the contribution of Bcl-2 and hypoxia response element (HRE) to apoptosis-resistant endothelial cells and investigate the mechanism. PMVECs obtained from either normal rats or apoptosis-resistant PMVECs obtained from PAH rats were transduced with recombinant lentiviral vectors carrying either Bcl-2-shRNA or HRE combined Bcl-2-shRNA, and then cultured these cells for 24 h under hypoxic (5% O2) or normoxic (21% O2) conditions. In normal PMVECs, Bcl-2-shRNA or HRE combined with Bcl-2-shRNA transduction successfully decreased Bcl-2 expression, while increasing apoptosis as well as caspase-3 and P53 expression in a normoxic environment. In a hypoxic environment, the effects of Bcl-2-shRNA treatment on cell apoptosis, and on Bcl-2, caspase-3, P53 expression were significantly suppressed. Conversely, HRE activation combined with Bcl-2-shRNA transduction markedly enhanced cell apoptosis and upregulated caspase-3 and P53 expression, while decreasing Bcl-2 expression. Furthermore, in apoptosis-resistant PMVECs, HRE-mediated Bcl-2 silencing effectively enhanced cell apoptosis and caspase-3 activity. The apoptosis rate was significantly depressed when Lv-HRE-Bcl-2-shRNA was combined with Lv-P53-shRNA or Lv-caspase3-shRNA transduction in a hypoxic environment. These results suggest that HRE-mediated Bcl-2 inhibition can effectively attenuate hypoxia-induced apoptosis resistance in PMVECs by downregulating Bcl-2 expression and upregulating caspase-3 and P53 expression. This study therefore reveals critical insight into potential therapeutic targets for treating PAH.

Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential.

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Chen, Ying-Bei; Aon, Miguel A; Hsu, Yi-Te; Soane, Lucian; Teng, Xinchen; McCaffery, J Michael; Cheng, Wen-Chih; Qi, Bing; Li, Hongmei; Alavian, Kambiz N; Dayhoff-Brannigan, Margaret; Zou, Shifa; Pineda, Fernando J; O'Rourke, Brian; Ko, Young H; Pedersen, Peter L; Kaczmarek, Leonard K; Jonas, Elizabeth A; Hardwick, J Marie

2011-10-17

Mammalian Bcl-x(L) protein localizes to the outer mitochondrial membrane, where it inhibits apoptosis by binding Bax and inhibiting Bax-induced outer membrane permeabilization. Contrary to expectation, we found by electron microscopy and biochemical approaches that endogenous Bcl-x(L) also localized to inner mitochondrial cristae. Two-photon microscopy of cultured neurons revealed large fluctuations in inner mitochondrial membrane potential when Bcl-x(L) was genetically deleted or pharmacologically inhibited, indicating increased total ion flux into and out of mitochondria. Computational, biochemical, and genetic evidence indicated that Bcl-x(L) reduces futile ion flux across the inner mitochondrial membrane to prevent a wasteful drain on cellular resources, thereby preventing an energetic crisis during stress. Given that F(1)F(O)-ATP synthase directly affects mitochondrial membrane potential and having identified the mitochondrial ATP synthase β subunit in a screen for Bcl-x(L)-binding partners, we tested and found that Bcl-x(L) failed to protect β subunit-deficient yeast. Thus, by bolstering mitochondrial energetic capacity, Bcl-x(L) may contribute importantly to cell survival independently of other Bcl-2 family proteins.

Bcl-2 Protein Expression in Egyptian Acute Myeloid Leukemia

International Nuclear Information System (INIS)

El-Shakankiry, N.; El-Sayed, Gh.M.M.; El-Maghraby, Sh.; Moneer, M.M.

2009-01-01

Objective: The primary cause of treatment failure in acute myeloid leukemia (AML) is the emergence of both resistant disease and early relapse. The bcl-2 gene encodes a 26-kDa protein that promotes cell survival by blocking programmed cell death (apoptosis). In the present study, bcl-2 protein expression was evaluated in newly diagnosed AML patients and correlated with the induction of remission and overall survival (OS), in an attempt to define patients who might benefit from modified therapeutic strategies. Patients and methods: Pretreatment cellular bcl-2 protein expression was measured in bone marrow samples obtained from 68 patients of newly diagnosed acute myeloid leukemia and 10 healthy controls by western blotting. Results: The mean bcl-2 protein expression was significantly higher in patients (0.68610.592) compared to controls (0.313±0.016) (p=0.002). The overall survival for patients with mean bcl-2 expression of less, and more than or equal to 0.315, was 67% and 56%, respectively, with no significant difference between the two groups 0»=0.86). Conclusion: Even though we did not observe a significant difference in overall survival between patients with high and low levels of bcl-2, modulation of this protein might still be considered as an option for enhancing the effectiveness of conventional chemotherapy.

THE EXPRESSION OF Bcl-2 AND PRO-CASPASE 3 IN HEAD AND NECK SQUAMOUS CELL CARCINOMA

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Andrej Cör

2002-12-01

Full Text Available Background. Head and neck squamous cell carcinoma (HNSCC is the sixth most common cancer and accounts for 6% of cancers worldwide. A better understanding of its biology could lead to improved treatment options. Generally, the goal of cancer treatment is to abolish cell proliferation and to induce necrotic or aptoptotic cell death. Apoptosis has been recognized as a key mechanism of tumour cell elimination. Different apoptotic signals converge to induce caspase cascade activation. Caspase 3 is the central executioner caspase and is necessary for effective apoptotic cell death. Bcl-2 protein family regulates apoptosis. The Bcl-2 protein itself is a product of a proto-oncogene and has an antiapoptotic action.Methods. In our study, the expression of Bcl-2 and pro-caspase 3 by immunohistochemistry in 28 HNSCC graded into well, moderately and poorly differentiated cancers were investigated.Results. Our results of Bcl-2 expression confirm and extend previous reports in which Bcl-2 over-expression has been recognised as an important parameter in HNSCC biological behaviour. Three of 28 tumours (11% showed significant Bcl-2 expression. Two of them were poorly and one was moderately differentiated. Pro-caspase 3 immunoreactivity was confined mainly to the cytoplasm. Absent or low pro-caspase 3 immunoreactivity was found only in 1 of 6 well differentiated and in 1of 10 moderately differentiated tumours in contrast to 5 of 12 poorly differentiated tumours. In six of 12 poorly differentiated tumours procasapse 3 immunoreactivity was strongly positive. In two cases hyperplastic epithelium was strongly positive in contrast to adjacent HNSCC in the same slide which was completely negative for pro-caspase 3.Conclusions. Our results indicate downregulation of pro-caspase 3 expression, especially in poorly differentiated HNSCC. Further studies are needed to test whether this is related to HNSCC behaviour and predict treatment outcome.

Long-range Self-interacting Dark Matter in the Sun

International Nuclear Information System (INIS)

Chen, Jing; Liang, Zheng-Liang; Wu, Yue-Liang; Zhou, Yu-Feng

2015-01-01

We investigate the implications of the long-rang self-interaction on both the self-capture and the annihilation of the self-interacting dark matter (SIDM) trapped in the Sun. Our discussion is based on a specific SIDM model in which DM particles self-interact via a light scalar mediator, or Yukawa potential, in the context of quantum mechanics. Within this framework, we calculate the self-capture rate across a broad region of parameter space. While the self-capture rate can be obtained separately in the Born regime with perturbative method, and in the classical limits with the Rutherford formula, our calculation covers the gap between in a non-perturbative fashion. Besides, the phenomenology of both the Sommerfeld-enhanced s- and p-wave annihilation of the solar SIDM is also involved in our discussion. Moreover, by combining the analysis of the Super-Kamiokande (SK) data and the observed DM relic density, we constrain the nuclear capture rate of the DM particles in the presence of the dark Yukawa potential. The consequence of the long-range dark force on probing the solar SIDM turns out to be significant if the force-carrier is much lighter than the DM particle, and a quantitative analysis is provided

Influence of long-range Coulomb interaction in velocity map imaging.

Science.gov (United States)

Barillot, T; Brédy, R; Celep, G; Cohen, S; Compagnon, I; Concina, B; Constant, E; Danakas, S; Kalaitzis, P; Karras, G; Lépine, F; Loriot, V; Marciniak, A; Predelus-Renois, G; Schindler, B; Bordas, C

2017-07-07

The standard velocity-map imaging (VMI) analysis relies on the simple approximation that the residual Coulomb field experienced by the photoelectron ejected from a neutral or ion system may be neglected. Under this almost universal approximation, the photoelectrons follow ballistic (parabolic) trajectories in the externally applied electric field, and the recorded image may be considered as a 2D projection of the initial photoelectron velocity distribution. There are, however, several circumstances where this approximation is not justified and the influence of long-range forces must absolutely be taken into account for the interpretation and analysis of the recorded images. The aim of this paper is to illustrate this influence by discussing two different situations involving isolated atoms or molecules where the analysis of experimental images cannot be performed without considering long-range Coulomb interactions. The first situation occurs when slow (meV) photoelectrons are photoionized from a neutral system and strongly interact with the attractive Coulomb potential of the residual ion. The result of this interaction is the formation of a more complex structure in the image, as well as the appearance of an intense glory at the center of the image. The second situation, observed also at low energy, occurs in the photodetachment from a multiply charged anion and it is characterized by the presence of a long-range repulsive potential. Then, while the standard VMI approximation is still valid, the very specific features exhibited by the recorded images can be explained only by taking into consideration tunnel detachment through the repulsive Coulomb barrier.

UMER: An analog computer for dynamics of swarms interacting via long-range forces

International Nuclear Information System (INIS)

Kishek, R.A.; Bai, G.; Bernal, S.; Feldman, D.; Godlove, T.F.; Haber, I.; O'Shea, P.G.; Quinn, B.; Papadopoulos, C.; Reiser, M.; Stratakis, D.; Tian, K.; Tobin, C.J.; Walter, M.

2006-01-01

Some of the most challenging and interesting problems in nature involve large numbers of objects or particles mutually interacting through long-range forces. Examples range from galaxies and plasmas to flocks of birds and traffic flow on a highway. Even in cases where the form of the interacting force is precisely known, such as the 1/r 2 -dependent Coulomb and gravitational forces, such problems present a formidable theoretical and modeling challenge for large numbers of interacting bodies. This paper reports on a newly constructed, scaled particle accelerator that will serve as an experimental testbed for the dynamics of swarms interacting through long-range forces. Primarily designed for intense beam dynamics studies for advanced accelerators, the University of Maryland Electron Ring (UMER) design is described in detail and an update on commissioning is provided. An example application to a system other than a charged particle beam is discussed

Eliminating Legionella by inhibiting BCL-XL to induce macrophage apoptosis.

Science.gov (United States)

Speir, Mary; Lawlor, Kate E; Glaser, Stefan P; Abraham, Gilu; Chow, Seong; Vogrin, Adam; Schulze, Keith E; Schuelein, Ralf; O'Reilly, Lorraine A; Mason, Kylie; Hartland, Elizabeth L; Lithgow, Trevor; Strasser, Andreas; Lessene, Guillaume; Huang, David C S; Vince, James E; Naderer, Thomas

2016-02-24

Human pathogenic Legionella replicate in alveolar macrophages and cause a potentially lethal form of pneumonia known as Legionnaires' disease(1). Here, we have identified a host-directed therapeutic approach to eliminate intracellular Legionella infections. We demonstrate that the genetic deletion, or pharmacological inhibition, of the host cell pro-survival protein BCL-XL induces intrinsic apoptosis of macrophages infected with virulent Legionella strains, thereby abrogating Legionella replication. BCL-XL is essential for the survival of Legionella-infected macrophages due to bacterial inhibition of host-cell protein synthesis, resulting in reduced levels of the short-lived, related BCL-2 pro-survival family member, MCL-1. Consequently, a single dose of a BCL-XL-targeted BH3-mimetic therapy, or myeloid cell-restricted deletion of BCL-XL, limits Legionella replication and prevents lethal lung infections in mice. These results indicate that repurposing BH3-mimetic compounds, originally developed to induce cancer cell apoptosis, may have efficacy in treating Legionnaires' and other diseases caused by intracellular microbes.

Age differences in visual search for compound patterns: long- versus short-range grouping.

Science.gov (United States)

Burack, J A; Enns, J T; Iarocci, G; Randolph, B

2000-11-01

Visual search for compound patterns was examined in observers aged 6, 8, 10, and 22 years. The main question was whether age-related improvement in search rate (response time slope over number of items) was different for patterns defined by short- versus long-range spatial relations. Perceptual access to each type of relation was varied by using elements of same contrast (easy to access) or mixed contrast (hard to access). The results showed large improvements with age in search rate for long-range targets; search rate for short-range targets was fairly constant across age. This pattern held regardless of whether perceptual access to a target was easy or hard, supporting the hypothesis that different processes are involved in perceptual grouping at these two levels. The results also point to important links between ontogenic and microgenic change in perception (H. Werner, 1948, 1957).

Memory and long-range correlations in chess games

Science.gov (United States)

Schaigorodsky, Ana L.; Perotti, Juan I.; Billoni, Orlando V.

2014-01-01

In this paper we report the existence of long-range memory in the opening moves of a chronologically ordered set of chess games using an extensive chess database. We used two mapping rules to build discrete time series and analyzed them using two methods for detecting long-range correlations; rescaled range analysis and detrended fluctuation analysis. We found that long-range memory is related to the level of the players. When the database is filtered according to player levels we found differences in the persistence of the different subsets. For high level players, correlations are stronger at long time scales; whereas in intermediate and low level players they reach the maximum value at shorter time scales. This can be interpreted as a signature of the different strategies used by players with different levels of expertise. These results are robust against the assignation rules and the method employed in the analysis of the time series.

Hexavalent chromium-induced apoptosis of granulosa cells involves selective sub-cellular translocation of Bcl-2 members, ERK1/2 and p53

International Nuclear Information System (INIS)

Banu, Sakhila K.; Stanley, Jone A.; Lee, JeHoon; Stephen, Sam D.; Arosh, Joe A.; Hoyer, Patricia B.; Burghardt, Robert C.

2011-01-01

Hexavalent chromium (CrVI) has been widely used in industries throughout the world. Increased usage of CrVI and atmospheric emission of CrVI from catalytic converters of automobiles, and its improper disposal causes various health hazards including female infertility. Recently we have reported that lactational exposure to CrVI induced a delay/arrest in follicular development at the secondary follicular stage. In order to investigate the underlying mechanism, primary cultures of rat granulosa cells were treated with 10 μM potassium dichromate (CrVI) for 12 and 24 h, with or without vitamin C pre-treatment for 24 h. The effects of CrVI on intrinsic apoptotic pathway(s) were investigated. Our data indicated that CrVI: (i) induced DNA fragmentation and increased apoptosis, (ii) increased cytochrome c release from the mitochondria to cytosol, (iii) downregulated anti-apoptotic Bcl-2, Bcl-XL, HSP70 and HSP90; upregulated pro-apoptotic BAX and BAD, (iv) altered translocation of Bcl-2, Bcl-XL, BAX, BAD, HSP70 and HSP90 to the mitochondria, (v) upregulated p-ERK and p-JNK, and selectively translocated p-ERK to the mitochondria and nucleus, (vi) activated caspase-3 and PARP, and (vii) increased phosphorylation of p53 at ser-6, ser-9, ser-15, ser-20, ser-37, ser-46 and ser-392, increased p53 transcriptional activation, and downregulated MDM-2. Vitamin C pre-treatment mitigated CrVI effects on apoptosis and related pathways. Our study, for the first time provides a clear insight into the effect of CrVI on multiple pathways that lead to apoptosis of granulosa cells which could be mitigated by vitamin C.

Long-range correlations in rectal temperature fluctuations of healthy infants during maturation.

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Georgette Stern

Full Text Available BACKGROUND: Control of breathing, heart rate, and body temperature are interdependent in infants, where instabilities in thermoregulation can contribute to apneas or even life-threatening events. Identifying abnormalities in thermoregulation is particularly important in the first 6 months of life, where autonomic regulation undergoes critical development. Fluctuations in body temperature have been shown to be sensitive to maturational stage as well as system failure in critically ill patients. We thus aimed to investigate the existence of fractal-like long-range correlations, indicative of temperature control, in night time rectal temperature (T(rec patterns in maturing infants. METHODOLOGY/PRINCIPAL FINDINGS: We measured T(rec fluctuations in infants every 4 weeks from 4 to 20 weeks of age and before and after immunization. Long-range correlations in the temperature series were quantified by the correlation exponent, alpha using detrended fluctuation analysis. The effects of maturation, room temperature, and immunization on the strength of correlation were investigated. We found that T(rec fluctuations exhibit fractal long-range correlations with a mean (SD alpha of 1.51 (0.11, indicating that T(rec is regulated in a highly correlated and hence deterministic manner. A significant increase in alpha with age from 1.42 (0.07 at 4 weeks to 1.58 (0.04 at 20 weeks reflects a change in long-range correlation behavior with maturation towards a smoother and more deterministic temperature regulation, potentially due to the decrease in surface area to body weight ratio in the maturing infant. alpha was not associated with mean room temperature or influenced by immunization CONCLUSIONS: This study shows that the quantification of long-range correlations using alpha derived from detrended fluctuation analysis is an observer-independent tool which can distinguish developmental stages of night time T(rec pattern in young infants, reflective of maturation of

Expression of bcl-2 in the Epithelial Lining of Odontogenic Keratocysts

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Gh. Jahanshahi

2006-03-01

Full Text Available Statement of Problem: The aggressive nature and high recurrence rate of Odontogenic Keratocysts (OKCs may be due to unknown factors inherent in the epithelium or because of enzymatic activity in the fibrous wall. Bcl-2 protein is characterized by its ability to inhibit apoptosis.Purpose: The aim of the present study was to analyze the expression of bcl-2 protein in OKCs and to compare it with the more common radicular and dentigerous cysts. The possible relationship between inflammation and bcl-2 expression was also investigated.Materials and Methods: Formalin fixed paraffin-embedded tissue sections of 20 OKCs, 20 radicular and 20 dentigerous cysts were immunohistochemically analyzed for immunoreactivity of the bcl-2 protein.Results: Bcl-2 expression was observed in 19 OKCs (95%, one radicular cyst (5%and one dentigerous cyst (5%. There was no statistically significant relationship between inflammation and the number of bcl-2 positive cells. Immunoreactivity was mainly noted in the basal or basal/supra basal layers.Conclusion: Considering the fact that bcl-2 over expression may lead to increased survival of epithelial cells, present study may demonstrate a possible relationship between the aggressive nature of OKC and the intrinsic growth potential of its lining epithelium. Furthermore a basal/supra basal distribution of bcl-2 positive cells was seen in some odontogenic keratocysts which may have a significant impact on the behavior of this cyst.

Inhibition of oxygen-glucose deprivation-induced apoptosis of human adipose-derived stem cells by genetic modification with antiapoptotic protein bcl-2.

Science.gov (United States)

Cui, Ziwei; Shen, Liangyun; Lin, Yue; Wang, Shuqin; Zheng, Dongfeng; Tan, Qian

2014-08-01

Adipose-derived stem cells (ADSCs) have become a promising tool for a wide range of cell-based therapies. However, transplanted ADSCs do not survive well under ischemic conditions. In this study we aimed to inhibit oxygen-glucose deprivation (OGD)-induced apoptosis of human ADSCs by genetic modification with antiapoptotic protein Bcl-2. After isolation and culture, the phenotypes of human ADSCs at passage 3 were analyzed by flow cytometry. Then, genetic modification of ADSCs with Bcl-2 was carried out. Bcl-2 gene transfection was verified by Western blot analysis and multipotent differentiation properties were evaluated in Bcl-2-modified ADSCs (Bcl-2-ADSCs). Apoptosis was evaluated by a TUNEL assay under ischemic conditions induced by OGD. Apoptotic nuclei were also assessed and quantified by Hoechst staining. The cultured ADSCs expressed stem cell-associated markers CD29, CD34, CD44, and CD90, but not fibroblast marker HLA-DR or hematopoietic stem cell marker CD133. The Bcl-2 gene was transferred into ADSCs efficiently, and Bcl-2-ADSCs differentiated into adipocytes, chondrocytes, and osteoblasts. In addition, Bcl-2 overexpression reduced the percentage of apoptotic Bcl-2-ADSCs by 38 % under OGD. Our results indicate that Bcl-2 overexpression through gene transfection inhibits apoptosis of ADSCs under ischemic conditions. This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Resources and Long-Range Forecasts

Science.gov (United States)

Smith, Waldo E.

1973-01-01

The author argues that forecasts of quick depletion of resources in the environment as a result of overpopulation and increased usage may not be free from error. Ignorance still exists in understanding the recovery mechanisms of nature. Long-range forecasts are likely to be wrong in such situations. (PS)

Down the Road...Long Range Planning for Automation.

Science.gov (United States)

Texas State Library, Austin. Dept. of Library Development.

The materials in this manual/workbook were prepared to assist participants in a workshop on long-range planning for library automation. Chapters cover the following topics: (1) "What Is Long-Range Planning?" (2) "Why Plan?" (3) "Who Needs to Participate?" (4) "Planning to Plan"; (5) "Determining Needs"; (6) "Description and Introduction"; (7)…

A better understanding of long-range temporal dependence of traffic flow time series

Science.gov (United States)

Feng, Shuo; Wang, Xingmin; Sun, Haowei; Zhang, Yi; Li, Li

2018-02-01

Long-range temporal dependence is an important research perspective for modelling of traffic flow time series. Various methods have been proposed to depict the long-range temporal dependence, including autocorrelation function analysis, spectral analysis and fractal analysis. However, few researches have studied the daily temporal dependence (i.e. the similarity between different daily traffic flow time series), which can help us better understand the long-range temporal dependence, such as the origin of crossover phenomenon. Moreover, considering both types of dependence contributes to establishing more accurate model and depicting the properties of traffic flow time series. In this paper, we study the properties of daily temporal dependence by simple average method and Principal Component Analysis (PCA) based method. Meanwhile, we also study the long-range temporal dependence by Detrended Fluctuation Analysis (DFA) and Multifractal Detrended Fluctuation Analysis (MFDFA). The results show that both the daily and long-range temporal dependence exert considerable influence on the traffic flow series. The DFA results reveal that the daily temporal dependence creates crossover phenomenon when estimating the Hurst exponent which depicts the long-range temporal dependence. Furthermore, through the comparison of the DFA test, PCA-based method turns out to be a better method to extract the daily temporal dependence especially when the difference between days is significant.

Quantifying indices of short- and long-range white matter connectivity at each cortical vertex.

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Maria Carmela Padula

Full Text Available Several neurodevelopmental diseases are characterized by impairments in cortical morphology along with altered white matter connectivity. However, the relationship between these two measures is not yet clear. In this study, we propose a novel methodology to compute and display metrics of white matter connectivity at each cortical point. After co-registering the extremities of the tractography streamlines with the cortical surface, we computed two measures of connectivity at each cortical vertex: the mean tracts' length, and the proportion of short- and long-range connections. The proposed measures were tested in a clinical sample of 62 patients with 22q11.2 deletion syndrome (22q11DS and 57 typically developing individuals. Using these novel measures, we achieved a fine-grained visualization of the white matter connectivity patterns at each vertex of the cortical surface. We observed an intriguing pattern of both increased and decreased short- and long-range connectivity in 22q11DS, that provides novel information about the nature and topology of white matter alterations in the syndrome. We argue that the method presented in this study opens avenues for additional analyses of the relationship between cortical properties and patterns of underlying structural connectivity, which will help clarifying the intrinsic mechanisms that lead to altered brain structure in neurodevelopmental disorders.

Expression of Bcl-2, Melan A and HMB-45 in Dysplastic Nevi.

Science.gov (United States)

Patrascu, Oana Maria; Costache, Mariana; Dumitru, Adrian Vasile; Mehotin, Corina Nicoleta; Sajin, Maria; Lazaroiu, Anca Mihaela

2016-03-01

From the first recognition of dysplastic nevi as a pathology per se, many debates have been raised and many histological and immunohistological studies have been conducted in order to establish the true significance of these lesions. Therefore, the aim of this study was to establish if there is a correlation between HMB-45, Melan A and Bcl-2 expression and the grade of dysplasia, as well as between the marker's staining patterns. Ten dysplastic nevi from six female patients were selected and their histological features (size, dysplasia), as well as the immunohistological staining patterns, were studied (HMB-45, Melan A, Bcl-2). The Pearson correlation coefficient and regression was calculated with Windows Excel Data Analysis. We demonstrated that there was a notable correlation between the dysplasia and the size of the lesions (r(8)= 0.62 with p-value= 0.052), and also between Melan A and Bcl-2 (a r(6)= 0.73, p0.05). We can affirm, at least in our cases, there is a correlation between the grade of dysplasia and the size of the lesion, and also, that there is a correlation between Melan A and Bcl-2 staining, explained by MITF gene. These results were only partial concordant with those in other studies, therefore a larger number of cases is recommended to be further analyzed in order to clearly draw a conclusion.

Emitting recombination of BCl molecules with chlorine atoms, resulting from dissociation of boron trichloride molecules under action of pulse CO2-laser radiation

International Nuclear Information System (INIS)

Nikonorov, A.P.; Moskvitina, E.N.; Kuzyakov, Yu.Ya.; Stepanov, P.I.

1983-01-01

Luminescence in BCl 3 is investigated. The results of measurements of gas temperature, BCl molecules concentration, and luminescence absolute intensity at boron trichloride presure of 40 mm pH and density of laser pulse energy from 1.7 up to 4.0 J/cm 2 are obtained. Nature of uninterrupted spectrum is considered. It is established that luminescence appearing in the BCl 3 under action of pulse CO 2 -laser is caused by reaction of emitting recombination of BCl molecules with chlorine atoms. Rate constant of this reaction in the range of 2300-3100 K is determined

Quinacrine induces apoptosis in human leukemia K562 cells via p38 MAPK-elicited BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression

International Nuclear Information System (INIS)

Changchien, Jung-Jung; Chen, Ying-Jung; Huang, Chia-Hui; Cheng, Tian-Lu; Lin, Shinne-Ren; Chang, Long-Sen

2015-01-01

Although previous studies have revealed the anti-cancer activity of quinacrine, its effect on leukemia is not clearly resolved. We sought to explore the cytotoxic effect and mechanism of quinacrine action in human leukemia K562 cells. Quinacrine induced K562 cell apoptosis accompanied with ROS generation, mitochondrial depolarization, and down-regulation of BCL2L1 and BCL2. Upon exposure to quinacrine, ROS-mediated p38 MAPK activation and ERK inactivation were observed in K562 cells. Quinacrine-induced cell death and mitochondrial depolarization were suppressed by the p38MAPK inhibitor SB202190 and constitutively active MEK1 over-expression. Activation of p38 MAPK was shown to promote BCL2 degradation. Further, ERK inactivation suppressed c-Jun-mediated transcriptional expression of BCL2L1. Over-expression of BCL2L1 and BCL2 attenuated quinacrine-evoked mitochondrial depolarization and rescued the viability of quinacrine-treated cells. Taken together, our data indicate that quinacrine-induced K562 cell apoptosis is mediated through mitochondrial alterations triggered by p38 MAPK-mediated BCL2 down-regulation and suppression of ERK/c-Jun-mediated BCL2L1 expression. - Highlights: • Quinacrine induces K562 cell apoptosis via down-regulation of BCL2 and BCL2L1. • Quinacrine induces p38 MAPK activation and ERK inactivation in K562 cells. • Quinacrine elicits p38 MAPK-mediated BCL2 down-regulation. • Quinacrine suppresses ERK/c-Jun-mediated BCL2L1 expression

Long-Range Correlations in Sentence Series from A Story of the Stone.

Science.gov (United States)

Yang, Tianguang; Gu, Changgui; Yang, Huijie

2016-01-01

A sentence is the natural unit of language. Patterns embedded in series of sentences can be used to model the formation and evolution of languages, and to solve practical problems such as evaluating linguistic ability. In this paper, we apply de-trended fluctuation analysis to detect long-range correlations embedded in sentence series from A Story of the Stone, one of the greatest masterpieces of Chinese literature. We identified a weak long-range correlation, with a Hurst exponent of 0.575±0.002 up to a scale of 104. We used the structural stability to confirm the behavior of the long-range correlation, and found that different parts of the series had almost identical Hurst exponents. We found that noisy records can lead to false results and conclusions, even if the noise covers a limited proportion of the total records (e.g., less than 1%). Thus, the structural stability test is an essential procedure for confirming the existence of long-range correlations, which has been widely neglected in previous studies. Furthermore, a combination of de-trended fluctuation analysis and diffusion entropy analysis demonstrated that the sentence series was generated by a fractional Brownian motion.

Long-Range Correlations in Sentence Series from A Story of the Stone.

Directory of Open Access Journals (Sweden)

Tianguang Yang

Full Text Available A sentence is the natural unit of language. Patterns embedded in series of sentences can be used to model the formation and evolution of languages, and to solve practical problems such as evaluating linguistic ability. In this paper, we apply de-trended fluctuation analysis to detect long-range correlations embedded in sentence series from A Story of the Stone, one of the greatest masterpieces of Chinese literature. We identified a weak long-range correlation, with a Hurst exponent of 0.575±0.002 up to a scale of 104. We used the structural stability to confirm the behavior of the long-range correlation, and found that different parts of the series had almost identical Hurst exponents. We found that noisy records can lead to false results and conclusions, even if the noise covers a limited proportion of the total records (e.g., less than 1%. Thus, the structural stability test is an essential procedure for confirming the existence of long-range correlations, which has been widely neglected in previous studies. Furthermore, a combination of de-trended fluctuation analysis and diffusion entropy analysis demonstrated that the sentence series was generated by a fractional Brownian motion.

Stochastic processes and long range dependence

CERN Document Server

Samorodnitsky, Gennady

2016-01-01

This monograph is a gateway for researchers and graduate students to explore the profound, yet subtle, world of long-range dependence (also known as long memory). The text is organized around the probabilistic properties of stationary processes that are important for determining the presence or absence of long memory. The first few chapters serve as an overview of the general theory of stochastic processes which gives the reader sufficient background, language, and models for the subsequent discussion of long memory. The later chapters devoted to long memory begin with an introduction to the subject along with a brief history of its development, followed by a presentation of what is currently the best known approach, applicable to stationary processes with a finite second moment. The book concludes with a chapter devoted to the author’s own, less standard, point of view of long memory as a phase transition, and even includes some novel results. Most of the material in the book has not previously been publis...

Measured long-range repulsive Casimir–Lifshitz forces

Science.gov (United States)

Munday, J. N.; Capasso, Federico; Parsegian, V. Adrian

2014-01-01

Quantum fluctuations create intermolecular forces that pervade macroscopic bodies1–3. At molecular separations of a few nanometres or less, these interactions are the familiar van der Waals forces4. However, as recognized in the theories of Casimir, Polder and Lifshitz5–7, at larger distances and between macroscopic condensed media they reveal retardation effects associated with the finite speed of light. Although these long-range forces exist within all matter, only attractive interactions have so far been measured between material bodies8–11. Here we show experimentally that, in accord with theoretical prediction12, the sign of the force can be changed from attractive to repulsive by suitable choice of interacting materials immersed in a fluid. The measured repulsive interaction is found to be weaker than the attractive. However, in both cases the magnitude of the force increases with decreasing surface separation. Repulsive Casimir–Lifshitz forces could allow quantum levitation of objects in a fluid and lead to a new class of switchable nanoscale devices with ultra-low static friction13–15. PMID:19129843

Short-range/Long-range Integrated Target (SLIT) for Video Guidance Sensor Rendezvous and Docking

Science.gov (United States)

Roe, Fred D. (Inventor); Bryan, Thomas C. (Inventor)

2009-01-01

A laser target reflector assembly for mounting upon spacecraft having a long-range reflector array formed from a plurality of unfiltered light reflectors embedded in an array pattern upon a hemispherical reflector disposed upon a mounting plate. The reflector assembly also includes a short-range reflector array positioned upon the mounting body proximate to the long-range reflector array. The short-range reflector array includes three filtered light reflectors positioned upon extensions from the mounting body. The three filtered light reflectors retro-reflect substantially all incident light rays that are transmissive by their monochromatic filters and received by the three filtered light reflectors. In one embodiment the short-range reflector array is embedded within the hemispherical reflector,

Long-range correlations from colour confinement

International Nuclear Information System (INIS)

Jurkiewicz, J.; Zenczykowski, P.

1979-01-01

A class of independent parton emission models is generalized by the introduction of the colour degrees of freedom. In the proposed models colour confinement extorts strong long-range forward-backward correlations, the rise of one-particle inclusive distribution and the KNO scaling. It leads to the analytically calculable definite asymptotic predictions for the D/ ratio which depends only on the choice of the colour group. Multiplicity distribution develops a remarkably long tail. (author)

Atherosclerosis-Associated Endothelial Cell Apoptosis by MiR-429-Mediated Down Regulation of Bcl-2

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Tao Zhang

2015-10-01

Full Text Available Background/Aims: Endothelial cell injury and subsequent apoptosis play a key role in the development and pathogenesis of atherosclerosis, which is hallmarked by dysregulated lipid homeostasis, aberrant immunity and inflammation, and plaque-instability-associated coronary occlusion. Nevertheless, our understanding of the mechanisms underlying endothelial cell apoptosis is still limited. MicroRNA-429 (miR-29 is a known cancer suppressor that promotes cancer cell apoptosis. However, it is unknown whether miR-429 may be involved in the development of atherosclerosis through similar mechanisms. We addressed these questions in the current study. Methods: We examined the levels of endothelial cell apoptosis in ApoE (-/- mice suppled with high-fat diet (HFD, a mouse model for atherosclerosis (simplified as HFD mice. We analyzed the levels of anti-apoptotic protein Bcl-2 and the levels of miR-429 in the purified CD31+ endothelial cells from mouse aorta. Prediction of the binding between miR-429 and 3'-UTR of Bcl-2 mRNA was performed by bioinformatics analyses and confirmed by a dual luciferase reporter assay. The effects of miR-429 were further analyzed in an in vitro model using oxidized low-density lipoprotein (ox-LDL-treated human aortic endothelial cells (HAECs. Results: HFD mice developed atherosclerosis in 12 weeks, while the control ApoE (-/- mice that had received normal diet (simplified as NOR mice did not. HFD mice had significantly lower percentage of endothelial cells and significantly higher percentage of mesenchymal cells in the aorta than NOR mice. Significantly higher levels of endothelial cell apoptosis were detected in HFD mice, resulting from decreases in Bcl-2 protein, but not mRNA. The decreases in Bcl-2 in endothelial cells were due to increased levels of miR-429, which suppressed the translation of Bcl-2 mRNA via 3'-UTR binding. These in vivo findings were reproduced in vitro on ox-LDL-treated HAECs. Conclusion: Atherosclerosis

Long-range contributions to double beta decay revisited

Energy Technology Data Exchange (ETDEWEB)

Helo, J.C. [Universidad Técnica Federico Santa María, Centro-Científico-Tecnológico de Valparaíso,Casilla 110-V, Valparaíso (Chile); Departamento de Física, Facultad de Ciencias, Universidad de La Serena, Avenida Cisternas 1200, La Serena (Chile); Hirsch, M. [HEP Group, Instituto de Física Corpuscular,C.S.I.C./Universitat de València Edificio Institutos de Investigacion,Parc Cientific de Paterna, Apartado 22085, E-46071 València (Spain); Ota, T. [Department of Physics, Saitama University,Shimo-Okubo 255, 338-8570 Saitama-Sakura (Japan)

2016-06-01

We discuss the systematic decomposition of all dimension-7 (d=7) lepton number violating operators. These d=7 operators produce momentum enhanced contributions to the long-range part of the 0νββ decay amplitude and thus are severely constrained by existing half-live limits. In our list of possible models one can find contributions to the long-range amplitude discussed previously in the literature, such as the left-right symmetric model or scalar leptoquarks, as well as some new models not considered before. The d=7 operators generate Majorana neutrino mass terms either at tree-level, 1-loop or 2-loop level. We systematically compare constraints derived from the mass mechanism to those derived from the long-range 0νββ decay amplitude and classify our list of models accordingly. We also study one particular example decomposition, which produces neutrino masses at 2-loop level, can fit oscillation data and yields a large contribution to the long-range 0νββ decay amplitude, in some detail.

SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

Energy Technology Data Exchange (ETDEWEB)

Jauharoh, Siti Nur Aisyah [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Faculty of Medicine and Health Science, Syarif Hidayatullah State Islamic University, Jakarta 15412 (Indonesia); Saegusa, Jun; Sugimoto, Takeshi [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Ardianto, Bambang [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Department of Child Health, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55282 (Indonesia); Kasagi, Shimpei; Sugiyama, Daisuke; Kurimoto, Chiyo [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Tokuno, Osamu; Nakamachi, Yuji [Department of Laboratory Medicine, Kobe University Hospital, Hyogo 650-0017 (Japan); Kumagai, Shunichi [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Kawano, Seiji, E-mail: sjkawano@med.kobe-u.ac.jp [Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine, Hyogo 650-0017 (Japan); Department of Laboratory Medicine, Kobe University Hospital, Hyogo 650-0017 (Japan)

2012-01-06

Highlights: Black-Right-Pointing-Pointer Ro52{sup low} HeLa cells are resistant to apoptosis upon various stimulations. Black-Right-Pointing-Pointer Ro52 is upregulated by IFN-{alpha}, etoposide, or IFN-{gamma} and anti-Fas Ab. Black-Right-Pointing-Pointer Ro52-mediated apoptosis is independent of p53. Black-Right-Pointing-Pointer Ro52 selectively regulates Bcl-2 expression. -- Abstract: SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjoegren's syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52's role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52{sup low} HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H{sub 2}O{sub 2}- or diamide-induced oxidative stress, IFN-{alpha}, IFN-{gamma} and anti-Fas antibody, etoposide, or {gamma}-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity.

SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production

International Nuclear Information System (INIS)

Jauharoh, Siti Nur Aisyah; Saegusa, Jun; Sugimoto, Takeshi; Ardianto, Bambang; Kasagi, Shimpei; Sugiyama, Daisuke; Kurimoto, Chiyo; Tokuno, Osamu; Nakamachi, Yuji; Kumagai, Shunichi; Kawano, Seiji

2012-01-01

Highlights: ► Ro52 low HeLa cells are resistant to apoptosis upon various stimulations. ► Ro52 is upregulated by IFN-α, etoposide, or IFN-γ and anti-Fas Ab. ► Ro52-mediated apoptosis is independent of p53. ► Ro52 selectively regulates Bcl-2 expression. -- Abstract: SS-A/Ro52 (Ro52), an autoantigen in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome, has E3 ligase activity to ubiquitinate proteins that protect against viral infection. To investigate Ro52’s role during stress, we transiently knocked it down in HeLa cells by siRo52 transfection. We found that Ro52 low HeLa cells were significantly more resistant to apoptosis than wild-type HeLa cells when stimulated by H 2 O 2 - or diamide-induced oxidative stress, IFN-α, IFN-γ and anti-Fas antibody, etoposide, or γ-irradiation. Furthermore, Ro52-mediated apoptosis was not influenced by p53 protein level in HeLa cells. Depleting Ro52 in HeLa cells caused Bcl-2, but not other Bcl-2 family molecules, to be upregulated. Taken together, our data showed that Ro52 is a universal proapoptotic molecule, and that its proapoptotic effect does not depend on p53, but is exerted through negative regulation of the anti-apoptotic protein Bcl-2. These findings shed light on a new physiological role for Ro52 that is important to intracellular immunity.

Long-range correlation in cosmic microwave background radiation.

Science.gov (United States)

Movahed, M Sadegh; Ghasemi, F; Rahvar, Sohrab; Tabar, M Reza Rahimi

2011-08-01

We investigate the statistical anisotropy and gaussianity of temperature fluctuations of Cosmic Microwave Background (CMB) radiation data from the Wilkinson Microwave Anisotropy Probe survey, using the Multifractal Detrended Fluctuation Analysis, Rescaled Range, and Scaled Windowed Variance methods. Multifractal Detrended Fluctuation Analysis shows that CMB fluctuations has a long-range correlation function with a multifractal behavior. By comparing the shuffled and surrogate series of CMB data, we conclude that the multifractality nature of the temperature fluctuation of CMB radiation is mainly due to the long-range correlations, and the map is consistent with a gaussian distribution.

The BH3 α-Helical Mimic BH3-M6 Disrupts Bcl-XL, Bcl-2, and MCL-1 Protein-Protein Interactions with Bax, Bak, Bad, or Bim and Induces Apoptosis in a Bax- and Bim-dependent Manner*

Science.gov (United States)

Kazi, Aslamuzzaman; Sun, Jiazhi; Doi, Kenichiro; Sung, Shen-Shu; Takahashi, Yoshinori; Yin, Hang; Rodriguez, Johanna M.; Becerril, Jorge; Berndt, Norbert; Hamilton, Andrew D.; Wang, Hong-Gang; Sebti, Saïd M.

2011-01-01

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-XL, and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-XL and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-XL, Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-XL/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-XL, Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612. PMID:21148306

Analyse bioinformatique des protéines BCL-2 et développement de la base de connaissance dédiée, BCL2DB

OpenAIRE

Rech de Laval , Valentine

2013-01-01

BCL-2 proteins play an essential role in the decision of life or death of animal cells. They control the induction of apoptosis (programmed cell death) in the mitochondrial pathway via regulators having opposite functions: anti- or pro-apoptotic. Proteins containing one or more Bcl-2 homology domains (BHl-4) are systematically classified in this family. Through bioinformatics and phylogenetic analysis, we revisited the different criteria for protein inclusion in the BCL-2 group and proposed a...

Discovery and molecular characterization of a Bcl-2-regulated cell death pathway in schistosomes.

Science.gov (United States)

Lee, Erinna F; Clarke, Oliver B; Evangelista, Marco; Feng, Zhiping; Speed, Terence P; Tchoubrieva, Elissaveta B; Strasser, Andreas; Kalinna, Bernd H; Colman, Peter M; Fairlie, W Douglas

2011-04-26

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2-regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2-like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with "BH3 mimetic" drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment.

Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy

International Nuclear Information System (INIS)

Lee, Kyung-Hun; Noh, Dong-Young; Heo, Dae Seog; Ha, Sung Whan; Bang, Yung-Jue; Im, Seock-Ah; Oh, Do-Youn; Lee, Se-Hoon; Chie, Eui Kyu; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Park, In Ae

2007-01-01

Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. A cohort of 151 curatively resected stage III breast cancer patients (M:F = 3:148, median age 46 years) who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS) and overall survival (OS). Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. The median follow-up duration was 36 months, and 37 patients (24.5%) experienced a recurrence. Univariate analyses indicated that the tumor size (P = 0.038) and the number of involved lymph nodes (P < 0.001) significantly affected the recurrences. However, the type of surgery, the histology, histologic grade, the presence of endolymphatic emboli, and a close resection margin did not. Moreover, ER positivity (P = 0.013), bcl-2 positivity (P = 0.002) and low p53 expression (P = 0.032) were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P < 0.001), negative bcl-2 expression (HR 2.895; P = 0.030), and c-erbB2 over-expression (HR 3.535; P = 0.001) as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+) subgroup. Moreover, OS was significantly affected by ER, bcl

Long-range order in canary song.

Science.gov (United States)

Markowitz, Jeffrey E; Ivie, Elizabeth; Kligler, Laura; Gardner, Timothy J

2013-01-01

Bird songs range in form from the simple notes of a Chipping Sparrow to the rich performance of the nightingale. Non-adjacent correlations can be found in the syntax of some birdsongs, indicating that the choice of what to sing next is determined not only by the current syllable, but also by previous syllables sung. Here we examine the song of the domesticated canary, a complex singer whose song consists of syllables, grouped into phrases that are arranged in flexible sequences. Phrases are defined by a fundamental time-scale that is independent of the underlying syllable duration. We show that the ordering of phrases is governed by long-range rules: the choice of what phrase to sing next in a given context depends on the history of the song, and for some syllables, highly specific rules produce correlations in song over timescales of up to ten seconds. The neural basis of these long-range correlations may provide insight into how complex behaviors are assembled from more elementary, stereotyped modules.

Prognostic significance of bcl-2 expression in stage III breast cancer patients who had received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy

Directory of Open Access Journals (Sweden)

Kim Dong-Wan

2007-04-01

Full Text Available Abstract Background Bcl-2 is positively regulated by hormonal receptor pathways in breast cancer. A study was conducted to assess the prognostic significances of clinico-pathologic variables and of ER, PR, p53, c-erbB2, bcl-2, or Ki-67 as markers of relapse in breast cancer patients who had received the identical adjuvant therapy at a single institution. Methods A cohort of 151 curatively resected stage III breast cancer patients (M:F = 3:148, median age 46 years who had 4 or more positive lymph nodes and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T as adjuvant chemotherapy was analyzed for clinico-pathologic characteristics including disease-free survival (DFS and overall survival (OS. Patients with positive ER and/or PR expression received 5 years of tamoxifen following AC/T. The protein expressions of biomarkers were assessed immunohistochemically. Results The median follow-up duration was 36 months, and 37 patients (24.5% experienced a recurrence. Univariate analyses indicated that the tumor size (P = 0.038 and the number of involved lymph nodes (P P = 0.013, bcl-2 positivity (P = 0.002 and low p53 expression (P = 0.032 were found to be significantly associated with a prolonged DFS. Furthermore, multivariate analysis identified 10 or more involved lymph nodes (HR 7.366; P P = 0.030, and c-erbB2 over-expression (HR 3.535; P = 0.001 as independent indicators of poorer DFS. In addition, bcl-2 expression was found to be significantly correlated with the expressions of ER and PR, and inversely correlated with the expressions of p53, c-erbB2 and Ki-67. Patients with bcl-2 expression had a significantly longer DFS than those without, even in the ER (+ subgroup. Moreover, OS was significantly affected by ER, bcl-2 and c-erbB2. Conclusion Bcl-2 is an independent prognostic factor of DFS in curatively resected stage III breast cancer patients and appears to be a useful prognostic factor in combination with c-erbB2 and the

Immunohistochemical assessment of Survivin and Bcl3 expression as potential biomarkers for NF-κB activation in the Barrett metaplasia-dysplasia-adenocarcinoma sequence.

Science.gov (United States)

Puccio, Ignazio; Khan, Saif; Butt, Adil; Graham, David; Sehgal, Vinay; Patel, Dominic; Novelli, Marco; Lovat, Laurence B; Rodriguez-Justo, Manuel; Hamoudi, Rifat A

2018-02-01

Non-dysplastic Barrett's oesophagus (NDBE) occurs as a consequence of an inflammatory response triggered through prolonged gastro-oesophageal reflux and it may precede the development of oesophageal adenocarcinoma. NF-κB activation as a result of the inflammatory response has been shown in NDBE, but the possible mechanism involved in the process is unknown. The aim of this study was to assess, using immunohistochemistry, Survivin and Bcl3 expression as potential biomarkers for NF-κB activation along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Survivin is an NF-κB-inducible anti-apoptotic protein, and Bcl3 is a negative regulator of NF-κB. There was progressive upregulation of Survivin expression along the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. Bcl3 expression was upregulated in non-dysplastic Barrett's oesophagus, low-grade, high-grade dysplasia and oesophageal adenocarcinoma when compared to squamous group. The study shows the differential expression of Bcl3 between the squamous and Barrett's stage, suggesting that Bcl3 could be a surrogate marker for early event involving constitutive NF-κB activation. In addition, the study suggests that NF-κB activation may infer resistance to apoptosis through the expression of anti-apoptotic genes such as Survivin, which showed progressive increase in expression throughout the oesophageal metaplasia-dysplasia-adenocarcinoma sequence. This ability to avoid apoptosis may underlie the persistence and malignant predisposition of Barrett's metaplasia. © 2018 The Authors. International Journal of Experimental Pathology © 2018 International Journal of Experimental Pathology.

Properties of short-range and long-range correlation energy density functionals from electron-electron coalescence

International Nuclear Information System (INIS)

Gori-Giorgi, Paola; Savin, Andreas

2006-01-01

The combination of density-functional theory with other approaches to the many-electron problem through the separation of the electron-electron interaction into a short-range and a long-range contribution is a promising method, which is raising more and more interest in recent years. In this work some properties of the corresponding correlation energy functionals are derived by studying the electron-electron coalescence condition for a modified (long-range-only) interaction. A general relation for the on-top (zero electron-electron distance) pair density is derived, and its usefulness is discussed with some examples. For the special case of the uniform electron gas, a simple parametrization of the on-top pair density for a long-range only interaction is presented and supported by calculations within the ''extended Overhauser model.'' The results of this work can be used to build self-interaction corrected short-range correlation energy functionals

Predictive value of bcl-2 immunoreactivity in prostate cancer patients treated with radiotherapy

International Nuclear Information System (INIS)

Bylund, A.; Widmark, A.; Stattin, P.; Bergh, A.

1998-01-01

Background and purpose: Recent experimental evidence suggests that overexpression of bcl-2, a protein functioning by blocking apoptosis, may influence the treatment outcome in human tumours, including prostate cancer. To test the clinical implications of this hypothesis, tumours from patients with prostate cancer treated with external beam radiotherapy were investigated for bcl-2 immunoreactivity (IR) and correlated with prognosis and treatment outcome. Materials and methods: Bcl-2 IR was evaluated in archival tumour specimens obtained through transurethral resection from 42 patients with localized prostate cancer (T0-T4, N0 and M0). Bcl-2 IR expression was related to stage, grade and cancer-specific survival. Specimens were obtained prior to administrating routine radiotherapy for all patients. Results: Bcl-2 IR was present in 19/42 (45%) tumours. The bcl-2-positive patients had a significantly longer cancer-specific survival than the bcl-2-negative patients (10.3 versus 3.4 years, P<0.04). At follow-up (7-19 years), nine patients were still alive, 26 patients had died of prostate cancer and seven patients had died of other causes. Conclusions: This study indicates that pre-treatment bcl-2 overexpression is related to a favourable outcome in prostate cancer treated with radiotherapy. Low bcl-2 along with a high stage may be a predictor of poor prognosis and these patients might benefit from additional treatment. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

Clusterin silencing sensitizes pancreatic cancer MIA-PaCa-2 cells to gmcitabine via regulation of NF-kB/Bcl-2 signaling.

Science.gov (United States)

Xu, Miao; Chen, Xiumei; Han, Yanling; Ma, Chunqing; Ma, Lin; Li, Shirong

2015-01-01

Clusterin (CLU) is known as a multifunctional protein involved in a variety of physiological processes including lipid transport, epithelial cell differentiation, tumorigenesis, and apoptosis. Our recent study has demonstrated that knockdown of clusterin sensitizes pancreatic cancer cell lines to gmcitabine treatment. However the details of this survival mechanism remain undefined. Of the various downstream targets of CLU, we examined activation of the NF-kB transcription factor and subsequent transcriptional regulation of BCL-2 gene in pancreatic cancer cell MIA-PaCa-2. The MIA-PaCa-2 cells were transfected with an antisense oligonucleotide (ASO) against clusterin, which led to a decreased protein level of the antiapoptotic gene BCL-2. Furthermore, inhibition of CLU decreased the function of NF-kB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway increased the apoptotic effect of gmcitabine chemotherapy. Re-activated NF-kB resulted in attenuation of ASO-induced effects, followed by the bcl-2 upregulation, and bcl-2 re-inhibition resulted in attenuation of Re-activated NF-kB -induced effects. Animals injected with ASO CLU in MIA-PaCa-2 cells combined with gmcitabine treatment had fewer tumors than gmcitabine or ASO CLU alone. These findings suggest that knockdown of CLU sensitized MIA-PaCa-2 cells to gmcitabine chemotherapy through modulating NF-Kb/bcl-2 pathway.

ENSEMBLE methods to reconcile disparate national long range dispersion forecasts

DEFF Research Database (Denmark)

Mikkelsen, Torben; Galmarini, S.; Bianconi, R.

2003-01-01

ENSEMBLE is a web-based decision support system for real-time exchange and evaluation of national long-range dispersion forecasts of nuclear releases with cross-boundary consequences. The system is developed with the purpose to reconcile among disparatenational forecasts for long-range dispersion...... emergency and meteorological forecasting centres, which may choose to integrate them directly intooperational emergency information systems, or possibly use them as a basis for future system development.......ENSEMBLE is a web-based decision support system for real-time exchange and evaluation of national long-range dispersion forecasts of nuclear releases with cross-boundary consequences. The system is developed with the purpose to reconcile among disparatenational forecasts for long-range dispersion....... ENSEMBLE addresses the problem of achieving a common coherent strategy across European national emergency management when national long-range dispersion forecasts differ from one another during an accidentalatmospheric release of radioactive material. A series of new decision-making “ENSEMBLE” procedures...

ENSEMBLE methods to reconcile disparate national long range dispersion forecasts

OpenAIRE

Mikkelsen, Torben; Galmarini, S.; Bianconi, R.; French, S.

2003-01-01

ENSEMBLE is a web-based decision support system for real-time exchange and evaluation of national long-range dispersion forecasts of nuclear releases with cross-boundary consequences. The system is developed with the purpose to reconcile among disparatenational forecasts for long-range dispersion. ENSEMBLE addresses the problem of achieving a common coherent strategy across European national emergency management when national long-range dispersion forecasts differ from one another during an a...

The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.

Science.gov (United States)

Kazi, Aslamuzzaman; Sun, Jiazhi; Doi, Kenichiro; Sung, Shen-Shu; Takahashi, Yoshinori; Yin, Hang; Rodriguez, Johanna M; Becerril, Jorge; Berndt, Norbert; Hamilton, Andrew D; Wang, Hong-Gang; Sebti, Saïd M

2011-03-18

A critical hallmark of cancer cell survival is evasion of apoptosis. This is commonly due to overexpression of anti-apoptotic proteins such as Bcl-2, Bcl-X(L), and Mcl-1, which bind to the BH3 α-helical domain of pro-apoptotic proteins such as Bax, Bak, Bad, and Bim, and inhibit their function. We designed a BH3 α-helical mimetic BH3-M6 that binds to Bcl-X(L) and Mcl-1 and prevents their binding to fluorescently labeled Bak- or Bim-BH3 peptides in vitro. Using several approaches, we demonstrate that BH3-M6 is a pan-Bcl-2 antagonist that inhibits the binding of Bcl-X(L), Bcl-2, and Mcl-1 to multi-domain Bax or Bak, or BH3-only Bim or Bad in cell-free systems and in intact human cancer cells, freeing up pro-apoptotic proteins to induce apoptosis. BH3-M6 disruption of these protein-protein interactions is associated with cytochrome c release from mitochondria, caspase-3 activation and PARP cleavage. Using caspase inhibitors and Bax and Bak siRNAs, we demonstrate that BH3-M6-induced apoptosis is caspase- and Bax-, but not Bak-dependent. Furthermore, BH3-M6 disrupts Bcl-X(L)/Bim, Bcl-2/Bim, and Mcl-1/Bim protein-protein interactions and frees up Bim to induce apoptosis in human cancer cells that depend for tumor survival on the neutralization of Bim with Bcl-X(L), Bcl-2, or Mcl-1. Finally, BH3-M6 sensitizes cells to apoptosis induced by the proteasome inhibitor CEP-1612.

B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins.

Science.gov (United States)

Renault, Thibaud T; Elkholi, Rana; Bharti, Archana; Chipuk, Jerry E

2014-09-19

The B cell lymphoma-2 (BCL-2) family is the key mediator of cellular sensitivity to apoptosis during pharmacological interventions for numerous human pathologies, including cancer. There is tremendous interest to understand how the proapoptotic BCL-2 effector members (e.g. BCL-2-associated X protein, BAX) cooperate with the BCL-2 homology domain only (BH3-only) subclass (e.g. BCL-2 interacting mediator of death, BIM; BCL-2 interacting-domain death agonist, BID) to induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis and whether these mechanisms may be pharmacologically exploited to enhance the killing of cancer cells. Indeed, small molecule inhibitors of the anti-apoptotic BCL-2 family members have been designed rationally. However, the success of these "BH3 mimetics" in the clinic has been limited, likely due to an incomplete understanding of how these drugs function in the presence of multiple BCL-2 family members. To increase our mechanistic understanding of how BH3 mimetics cooperate with multiple BCL-2 family members in vitro, we directly compared the activity of several BH3-mimetic compounds (i.e. ABT-263, ABT-737, GX15-070, HA14.1, TW-37) in biochemically defined large unilamellar vesicle model systems that faithfully recapitulate BAX-dependent mitochondrial outer membrane permeabilization. Our investigations revealed that the presence of BAX, BID, and BIM differentially regulated the ability of BH3 mimetics to derepress proapoptotic molecules from anti-apoptotic proteins. Using mitochondria loaded with fluorescent BH3 peptides and cells treated with inducers of cell death, these differences were supported. Together, these data suggest that although the presence of anti-apoptotic BCL-2 proteins primarily dictates cellular sensitivity to BH3 mimetics, additional specificity is conferred by proapoptotic BCL-2 proteins. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Evaluation of multiple bio-pathological factors in colorectal adenocarcinomas: independent prognostic role of p53 and bcl-2.

Science.gov (United States)

Buglioni, S; D'Agnano, I; Cosimelli, M; Vasselli, S; D'Angelo, C; Tedesco, M; Zupi, G; Mottolese, M

1999-12-22

About 40% of patients with colorectal carcinoma will develop local or distant tumour recurrences. Integrated analyses of bio-pathological markers, predictive of tumour aggressiveness, may offer a more rational approach to planning adjuvant therapy. To this end, we analysed the correlation between p53 accumulation, Bcl-2 expression, DNA ploidy, cell proliferation and conventional clinico-pathological parameters by testing the prognostic significance of these variables in a series of 171 colorectal carcinoma patients with long-term follow-up. The relationships among the various bio-pathological parameters, analysed by multiple correspondence analysis, showed 2 different clinico-biological profiles. The first, characterised by p53 negativity, Bcl-2 positivity, diploidy, low percentage of cells in S-phase (%S-phase), a low Ki-67 score, is associated with Dukes' A-B stage, well differentiated tumours and lack of relapse. The second, defined by p53 positivity, Bcl-2 negativity, aneuploidy, high %S-phase and elevated Ki-67 score, correlates with Dukes' C-D stage, poorly differentiated tumours and presence of relapse. When these parameters were examined according to Kaplan-Meier's method, significantly shorter disease-free (DFS) and overall survival (OS) were also observed in patients bearing p53 positive and Bcl-2 negative tumours, in Dukes' B stage. In multivariate analysis, p53 accumulation and Bcl-2 expression emerged as independent predictors of a worse and better clinical outcome, respectively. Our results indicate that, in colorectal adenocarcinomas, a biological profile, based on the combined evaluation of p53 and Bcl-2, may be useful for identifying high risk patients to be enrolled in an adjuvant setting, mainly in an early stage of the disease. Int. J. Cancer (Pred. Oncol.) 84:545-552, 1999. Copyright 1999 Wiley-Liss, Inc.

Laser long-range remote-sensing program experimental results

Science.gov (United States)

Highland, Ronald G.; Shilko, Michael L.; Fox, Marsha J.; Gonglewski, John D.; Czyzak, Stanley R.; Dowling, James A.; Kelly, Brian; Pierrottet, Diego F.; Ruffatto, Donald; Loando, Sharon; Matsuura, Chris; Senft, Daniel C.; Finkner, Lyle; Rae, Joe; Gallegos, Joe

1995-12-01

A laser long range remote sensing (LRS) program is being conducted by the United States Air Force Phillips Laboratory (AF/PL). As part of this program, AF/PL is testing the feasibility of developing a long path CO(subscript 2) laser-based DIAL system for remote sensing. In support of this program, the AF/PL has recently completed an experimental series using a 21 km slant- range path (3.05 km ASL transceiver height to 0.067 km ASL target height) at its Phillips Laboratory Air Force Maui Optical Station (AMOS) facility located on Maui, Hawaii. The dial system uses a 3-joule, (superscript 13)C isotope laser coupled into a 0.6 m diameter telescope. The atmospheric optical characterization incorporates information from an infrared scintillometer co-aligned to the laser path, atmospheric profiles from weather balloons launched from the target site, and meteorological data from ground stations at AMOS and the target site. In this paper, we report a description of the experiment configuration, a summary of the results, a summary of the atmospheric conditions and their implications to the LRS program. The capability of such a system for long-range, low-angle, slant-path remote sensing is discussed. System performance issues relating to both coherent and incoherent detection methods, atmospheric limitations, as well as, the development of advanced models to predict performance of long range scenarios are presented.

Molecular basis of Bcl-X(L-p53 interaction: insights from molecular dynamics simulations.

Directory of Open Access Journals (Sweden)

Nagakumar Bharatham

Full Text Available Bcl-X(L, an antiapoptotic Bcl-2 family protein, plays a central role in the regulation of the apoptotic pathway. Heterodimerization of the antiapoptotic Bcl-2 family proteins with the proapoptotic family members such as Bad, Bak, Bim and Bid is a crucial step in the apoptotic regulation. In addition to these conventional binding partners, recent evidences reveal that the Bcl-2 family proteins also interact with noncanonical binding partners such as p53. Our previous NMR studies showed that Bcl-X(L: BH3 peptide and Bcl-X(L: SN15 peptide (a peptide derived from residues S15-N29 of p53 complex structures share similar modes of bindings. To further elucidate the molecular basis of the interactions, here we have employed molecular dynamics simulations coupled with MM/PBSA approach. Bcl-X(L and other Bcl-2 family proteins have 4 hydrophobic pockets (p1-p4, which are occupied by four systematically spaced hydrophobic residues (h1-h4 of the proapoptotic Bad and Bak BH3 peptides. We observed that three conserved hydrophobic residues (F19, W23 and L26 of p53 (SN15 peptide anchor into three hydrophobic pockets (p2-p4 of Bcl-X(L in a similar manner as BH3 peptide. Our results provide insights into the novel molecular recognition by Bcl-X(L with p53.

CC genotype of anti-apoptotic gene BCL-2 (-938 C/A) is an independent prognostic marker of unfavorable clinical outcome in patients with non-small-cell lung cancer.

Science.gov (United States)

Javid, J; Mir, R; Mirza, M; Imtiyaz, A; Prasant, Y; Mariyam, Z; Julka, P K; Mohan, A; Lone, M; Ray, P C; Saxena, A

2015-04-01

B cell lymphoma 2 (BCL-2) gene is a well-known regulator of apoptosis and a key element in cancer development and progression. A regulatory (-938C>A, rs2279115) single-nucleotide polymorphism in the inhibitory P2 BCL-2 gene promoter generates significantly different BCL-2 promoter activities and has been associated with different clinical outcomes in various malignancies. The aim of the present study was to analyze the possible influence of the (-938C>A) SNP on the risk and survival of Indian patients suffering from NSCLC. A hospital-based case-control study of 155 age- and sex-matched patients diagnosed with NSCLC and 155 cancer-free controls was conducted and genotyped by performing PIRA-PCR to elucidate the putative association between clinical outcome and genotypes of BCL-2 (-938C>A, rs2279115). The association of the polymorphism with the survival of NSCLC patients was analyzed by Kaplan-Meier curves. In Indian NSCLC, patients increased risk of developing NSCLC was found to be associated with BCL-2 (-938) CC genotype, [OR 3.68 (1.92-6.79), RR 1.87 (1.35-2.57) and RD 31.03 (16.79-45.27) p 0.00006 for CC and OR 2.08 (1.18-3.66), RR 1.36 (1.08-1.71) and RD 17.74 (4.68-30.81) p 0.01 for AC genotype]. Patients homozygous for C allele exhibited a significant poor overall survival compared with patients displaying AC + CC or AC or AA genotype [median survival (months) 8 vs. 11 vs. 14 vs. 35.5 (p A) polymorphism. Genetic polymorphism in the inhibitory P2 promoter region of anti-apoptotic BCL-2 genes contributes to the risk of developing non-small-cell lung cancer in Indian population. BCL-2 (-938CC) genotype was an independent adverse prognostic factor for patients with NSCLC.

Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL.

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Zhuo Zhan

Full Text Available Cyclin A-Cdk2, a cell cycle regulated Ser/Thr kinase, plays important roles in a variety of apoptoticprocesses. However, the mechanism of cyclin A-Cdk2 regulated apoptosis remains unclear. Here, we demonstrated that Rad9, a member of the BH3-only subfamily of Bcl-2 proteins, could be phosphorylated by cyclin A-Cdk2 in vitro and in vivo. Cyclin A-Cdk2 catalyzed the phosphorylation of Rad9 at serine 328 in HeLa cells during apoptosis induced by etoposide, an inhibitor of topoisomeraseII. The phosphorylation of Rad9 resulted in its translocation from the nucleus to the mitochondria and its interaction with Bcl-xL. The forced activation of cyclin A-Cdk2 in these cells by the overexpression of cyclin A,triggered Rad9 phosphorylation at serine 328 and thereby promoted the interaction of Rad9 with Bcl-xL and the subsequent initiation of the apoptotic program. The pro-apoptotic effects regulated by the cyclin A-Cdk2 complex were significantly lower in cells transfected with Rad9S328A, an expression vector that encodes a Rad9 mutant that is resistant to cyclin A-Cdk2 phosphorylation. These findings suggest that cyclin A-Cdk2 regulates apoptosis through a mechanism that involves Rad9phosphorylation.

Effective theory and breakdown of conformal symmetry in a long-range quantum chain

Science.gov (United States)

Lepori, L.; Vodola, D.; Pupillo, G.; Gori, G.; Trombettoni, A.

2016-11-01

We deal with the problem of studying the symmetries and the effective theories of long-range models around their critical points. A prominent issue is to determine whether they possess (or not) conformal symmetry (CS) at criticality and how the presence of CS depends on the range of the interactions. To have a model, both simple to treat and interesting, where to investigate these questions, we focus on the Kitaev chain with long-range pairings decaying with distance as power-law with exponent α. This is a quadratic solvable model, yet displaying non-trivial quantum phase transitions. Two critical lines are found, occurring respectively at a positive and a negative chemical potential. Focusing first on the critical line at positive chemical potential, by means of a renormalization group approach we derive its effective theory close to criticality. Our main result is that the effective action is the sum of two terms: a Dirac action SD, found in the short-range Ising universality class, and an "anomalous" CS breaking term SAN. While SD originates from low-energy excitations in the spectrum, SAN originates from the higher energy modes where singularities develop, due to the long-range nature of the model. At criticality SAN flows to zero for α > 2, while for α limit α → ∞ the ELI is restored. In order to test the validity of the determined effective theory, we compared the two-fermion static correlation functions and the von Neumann entropy obtained from them with the ones calculated on the lattice, finding agreement. These results explain two observed features characteristic of long-range models, the hybrid decay of static correlation functions within gapped phases and the area-law violation for the von Neumann entropy. The proposed scenario is expected to hold in other long-range models displaying quasiparticle excitations in ballistic regime. From the effective theory one can also see that new phases emerge for α model, are not altered. This also shows

Crosstalk between Bcl-2 family and Ras family small GTPases: potential cell fate regulation?

International Nuclear Information System (INIS)

Kang, Jia; Pervaiz, Shazib

2013-01-01

Cell fate regulation is a function of diverse cell signaling pathways that promote cell survival and or inhibit cell death execution. In this regard, the role of the Bcl-2 family in maintaining a tight balance between cell death and cell proliferation has been extensively studied. The conventional dogma links cell fate regulation by the Bcl-2 family to its effect on mitochondrial permeabilization and apoptosis amplification. However, recent evidence provide a novel mechanism for death regulation by the Bcl-2 family via modulating cellular redox metabolism. For example overexpression of Bcl-2 has been shown to contribute to a pro-oxidant intracellular milieu and down-regulation of cellular superoxide levels enhanced death sensitivity of Bcl-2 overexpressing cells. Interestingly, gene knockdown of the small GTPase Rac1 or pharmacological inhibition of its activity also reverted death phenotype in Bcl-2 expressing cells. This appears to be a function of an interaction between Bcl-2 and Rac1. Similar functional associations have been described between the Bcl-2 family and other members of the Ras superfamily. These interactions at the mitochondria provide novel opportunities for strategic therapeutic targeting of drug-resistant cancers.

Deregulated expression of A1, Bcl-2, Bcl-xL, and Mcl-1 antiapoptotic proteins and Bid, Bad, and Bax proapoptotic genes in polycythemia vera patients

Directory of Open Access Journals (Sweden)

Elainy Patricia Lino Gasparotto

2011-12-01

Full Text Available Apoptosis deregulation might have a role in the pathophysiology of polycythemia vera (PV. This study evaluated Bcl-2 molecule expression in CD34+ cells and leukocytes in 12 PV patients. Gene expression was investigated by real time PCR using SybrGreen Quantitect kit and protein expression was evaluated by western-blotting. JAK2 V617F mutation was detected according to Baxter et al (2005. CD34+ cells from PV patients presented higher levels of A1 and Mcl-1 expression (median: 22.6 and 5.2, respectively in comparison with controls (0.9 and 0.5, p=0.004 and p=0.020; while Bcl-2 and Bcl-xL expression decreased in PV patients (0.18 and 1.19 compared with controls (1.39 and 2.01, p=0.006 and p=0.020. CD34+ cells in PV patients showed an elevated Bid expression (14.4 in comparison with healthy subjects (1.0; p=0.002. Patients' leukocytes showed an A1 augmentation (7.41, p=0.001 and a reduced expression of Bax (0.19; p=0.040 and Bad (0.2; p=0.030. There was no correlation between JAK2 V617F allele burden and molecular expression. PV patients showed alterations in Bcl-2 members' expression, which may interfere with control of apoptotic machinery and contribute to disease pathogenesis.A desregulação da apoptose parece participar da fisiopatologia da policitemia vera (PV. Este estudo avaliou a expressão das moléculas da família Bcl-2 em células hematopoéticas CD34 + e leucócitos de 12 pacientes com PV. Foram realizados: a quantificação da expressão gênica por PCR em tempo real utilizando kit Sybrgreen Quantitect, avaliação da expressão de proteínas por western-blot e detecção da mutação JAK2 V617F segundo Baxter et al. (2005. Células CD34 + dos pacientes com PV apresentaram maior expressão de A1 e Mcl-1 (mediana: 22,6 e 5,2, respectivamente em comparação com controles (0,9 e 0,5, p = 0,004 e p = 0,020 e expressão de Bcl-2 e Bcl-xL diminuída nestes pacientes (0,18 e 1,19 em relação aos controles (1,39 e 2,01, p = 0,006 e p = 0

Long-Range Piping Inspection by Ultrasonic Guided Waves

International Nuclear Information System (INIS)

Joo, Young Sang; Lim, Sa Hoe; Eom, Heung Seop; Kim, Jae Hee

2005-01-01

The ultrasonic guided waves are very promising for the long-range inspection of large structures because they can propagate a long distance along the structures such as plates, shells and pipes. The guided wave inspection could be utilized for an on-line monitoring technique when the transmitting and receiving transducers are positioned at a remote point on the structure. The received signal has the information about the integrity of the monitoring area between the transmitting and receiving transducers. On-line monitoring of a pipe line using an ultrasonic guided wave can detect flaws such as corrosion, erosion and fatigue cracking at an early stage and collect useful information on the flaws. However the guided wave inspection is complicated by the dispersive characteristics for guided waves. The phase and group velocities are a function of the frequency-thickness product. Therefore, the different frequency components of the guided waves will travel at different speeds and the shape of the received signal will changed as it propagates along the pipe. In this study, we analyze the propagation characteristics of guided wave modes in a small diameter pipe of nuclear power plant and select the suitable mode for a long-range inspection. And experiments will be carried out for the practical application of a long-range inspection in a 26m long pipe by using a high-power ultrasonic inspection system

Bcl-xL stimulates Bax relocation to mitochondria and primes cells to ABT-737.

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Renault, Thibaud T; Teijido, Oscar; Missire, Florent; Ganesan, Yogesh Tengarai; Velours, Gisèle; Arokium, Hubert; Beaumatin, Florian; Llanos, Raul; Athané, Axel; Camougrand, Nadine; Priault, Muriel; Antonsson, Bruno; Dejean, Laurent M; Manon, Stéphen

2015-07-01

Bax cytosol-to-mitochondria translocation is a central event of the intrinsic pathway of apoptosis. Bcl-xL is an important regulator of this event and was recently shown to promote the retrotranslocation of mitochondrial Bax to the cytosol. The present study identifies a new aspect of the regulation of Bax localization by Bcl-xL: in addition to its role in Bax inhibition and retrotranslocation, we found that, like with Bcl-2, an increase of Bcl-xL expression levels led to an increase of Bax mitochondrial content. This finding was substantiated both in pro-lymphocytic FL5.12 cells and a yeast reporting system. Bcl-xL-dependent increase of mitochondrial Bax is counterbalanced by retrotranslocation, as we observed that Bcl-xLΔC, which is unable to promote Bax retrotranslocation, was more efficient than the full-length protein in stimulating Bax relocation to mitochondria. Interestingly, cells overexpressing Bcl-xL were more sensitive to apoptosis upon treatment with the BH3-mimetic ABT-737, suggesting that despite its role in Bax inhibition, Bcl-xL also primes mitochondria to permeabilization and cytochrome c release. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeted BCL2 inhibition effectively inhibits neuroblastoma tumour growth

NARCIS (Netherlands)

Lamers, Fieke; Schild, Linda; den Hartog, Ilona J. M.; Ebus, Marli E.; Westerhout, Ellen M.; Ora, Ingrid; Koster, Jan; Versteeg, Rogier; Caron, Huib N.; Molenaar, Jan J.

2012-01-01

Genomic aberrations of key regulators of the apoptotic pathway have hardly been identified in neuroblastoma. We detected high BCL2 mRNA and protein levels in the majority of neuroblastoma tumours by Affymetrix expression profiling and Tissue Micro Array analysis. This BCL2 mRNA expression is

Long-range beam-beam experiments in the relativistic heavy ion collider

International Nuclear Information System (INIS)

Calaga, R; Fischer, W; Milas, N; Robert-Demolaize, G

2014-01-01

Long-range beam-beam effects are a potential limit to the LHC performance with the nominal design parameters, and certain upgrade scenarios under discussion. To mitigate long-range effects, current carrying wires parallel to the beam were proposed and space is reserved in the LHC for such wires. Two current carrying wires were installed in RHIC to study the effect of strong long-range beam-beam effects in a collider, as well as test the compensation of a single long-range interaction. The experimental data were used to benchmark simulations. We summarize this work

Primary central nervous system diffuse large B-cell lymphoma shows an activated B-cell-like phenotype with co-expression of C-MYC, BCL-2, and BCL-6.

Science.gov (United States)

Li, Xiaomei; Huang, Ying; Bi, Chengfeng; Yuan, Ji; He, Hong; Zhang, Hong; Yu, QiuBo; Fu, Kai; Li, Dan

2017-06-01

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, whose main prognostic factor is closely related to germinal center B-cell-like subtype (GCB- DLBCL) or activated B-cell-like type (non-GCB-DLBCL). The most common type of primary central nervous system lymphoma is diffuse large B-cell type with poor prognosis and the reason is unclear. This study aims to stratify primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) according to the cell-of-origin (COO) and to investigate the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53, further to elucidate the reason why primary central nervous system diffuse large B-cell lymphoma possesses a poor clinical outcome as well. Nineteen cases of primary central nervous system DLBCL were stratified according to immunostaining algorithms of Hans, Choi and Meyer (Tally) and we investigated the multiple proteins expression of C-MYC, BCL-6, BCL-2, TP53. The Epstein-Barr virus and Borna disease virus infection were also detected. Among nineteen cases, most (15-17 cases) were assigned to the activated B-cell-like subtype, highly expression of C-MYC (15 cases, 78.9%), BCL-2 (10 cases, 52.6%), BCL-6 (15 cases, 78.9%). Unfortunately, two cases were positive for PD-L1 while PD-L2 was not expressed in any case. Two cases infected with BDV but no one infected with EBV. In conclusion, most primary central nervous system DLBCLs show an activated B-cell-like subtype characteristic and have multiple expressions of C-MYC, BCL-2, BCL-6 protein, these features might be significant factor to predict the outcome and guide treatment of PCNS-DLBCLs. Copyright © 2017 Elsevier GmbH. All rights reserved.

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

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Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

2011-01-01

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial outer-membrane permeabilization. Because Bcl-2 proteins have been successfully targeted with “BH3 mimetic” drugs, particularly in the treatment of cancer, we investigated whether schistosome apoptosis pathways could provide targets for future antischistosomal drug discovery efforts. Accordingly, we showed that a schistosome prosurvival protein, sjA, binds ABT-737, a well-characterized BH3 mimetic. A crystal structure of sjA bound to a BH3 peptide provides direct evidence for the feasibility of developing BH3 mimetics to target Bcl-2 prosurvival proteins in schistosomes, suggesting an alternative application for this class of drugs beyond cancer treatment. PMID:21444803

Apoptosis and BCL-2 expression as predictors of survival in radiation-treated non-small-cell lung cancer

International Nuclear Information System (INIS)

Hwang, Jun-Hwa; Lim, Sung-Chul; Kim, Young-Chul; Park, Kyung-Ok; Ahn, Sung-Ja; Chung, Woong-Ki

2001-01-01

Objectives: We assessed the role of apoptosis and the expression of bcl-2, p53, and c-myc oncoproteins in pretreatment histologic specimens as a predictor of response to radiation therapy and survival in non-small-cell lung cancer (NSCLC) patients. Methods: Pretreatment biopsy specimens of 68 patients with NSCLC (62 squamous cell carcinoma, 6 adenocarcinoma) were stained with hematoxylin and eosin. From 5 high-powered fields, the apoptotic index (AI) was calculated as the ratio of apoptotic tumor cells to the total number of tumor cells. Bcl-2, p53, and c-myc oncoprotein expression was detected by immunohistochemical staining. Results: Twenty-nine cases showed partial or complete remission, whereas 39 showed no response. AI ranged from 0.2 to 12.0% (mean ± SD; 4.3±2.6%, median 4.0%). There was no difference in AI between responders (4.0±2.3) and nonresponders (4.5±2.8, p>0.05). However, in the responders, AI was correlated with the degree of change in tumor volume (r=0.41, p<0.05). In an analysis of 53 subjects who survived more than 1 month after the completion of radiation therapy, the patients with a higher AI (n=27, MST=22.8 m) survived longer than those with a lower AI (n=26, MST=9.2, log-rank, p=0.03). Patients expressing bcl-2 had poorer survival (n=22, MST=6.0 m) than patients without bcl-2 (n=31, 22.8 m, p<0.003). According to multivariate analysis, three variables, bcl-2 expression, AI, and response to radiation, were independent prognostic factors for survival. Conclusion: A low level of spontaneous apoptosis and expression of apoptosis blocking bcl-2 protein in pretreatment histology predict a poor prognosis for radiation-treated NSCLC patients

Current transport properties and phase diagram of a Kitaev chain with long-range pairing

Science.gov (United States)

Giuliano, Domenico; Paganelli, Simone; Lepori, Luca

2018-04-01

We describe a method to probe the quantum phase transition between the short-range topological phase and the long-range topological phase in the superconducting Kitaev chain with long-range pairing, both exhibiting subgap modes localized at the edges. The method relies on the effects of the finite mass of the subgap edge modes in the long-range regime (which survives in the thermodynamic limit) on the single-particle scattering coefficients through the chain connected to two normal leads. Specifically, we show that, when the leads are biased at a voltage V with respect to the superconducting chain, the Fano factor is either zero (in the short-range correlated phase) or 2 e (in the long-range correlated phase). As a result, we find that the Fano factor works as a directly measurable quantity to probe the quantum phase transition between the two phases. In addition, we note a remarkable "critical fractionalization effect" in the Fano factor, which is exactly equal to e along the quantum critical line. Finally, we note that a dual implementation of our proposed device makes it suitable as a generator of large-distance entangled two-particle states.

Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior.

Science.gov (United States)

Shishkina, Galina T; Kalinina, Tatyana S; Berezova, Inna V; Dygalo, Nikolay N

2012-01-01

Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Long range supergravity coupling strengths

International Nuclear Information System (INIS)

Kenyon, I.R.

1991-01-01

A limit of 2x10 -13 has recently been deduced for the fractional difference between the gravitational masses of the K 0 and anti K 0 mesons. This limit is applied here to put stringent limits on the strengths of the long range vector-scalar gravitational couplings envisaged in supergravity theories. A weaker limit is inferred from the general relativistic fit to the precession of the orbit of the pulsar PSR1913+16. (orig.)

Long-range interaction between spins

International Nuclear Information System (INIS)

Naik, P.C.; Pradhan, T.

1981-01-01

It is shown that invariance of Lagrangian field theory under a class of the coordinate-dependent Lorentz group of transformations requires the introduction of a massless axial vector gauge field which gives rise to a super-weak long-range spin-spin force between particles in vacuum. Recent experiments demonstrating repulsion and attraction between circularly polarised laser beams are interpreted to be due to such a force enhanced by spin polarisation of sodium vapour, through which these beams pass. (author)

Phospho-Bcl-xL(Ser62) influences spindle assembly and chromosome segregation during mitosis.

Science.gov (United States)

Wang, Jianfang; Beauchemin, Myriam; Bertrand, Richard

2014-01-01

Functional analysis of a series of phosphorylation mutants reveals that Bcl-xL(Ser62Ala) influences cell entry into anaphase and mitotic exit in taxol-exposed cells compared with cells expressing wild-type Bcl-xL or a series of other phosphorylation mutants, an effect that appears to be independent of its anti-apoptotic activity. During normal mitosis progression, Bcl-xL(Ser62) is strongly phosphorylated by PLK1 and MAPK14/SAPKp38α at the prometaphase, metaphase, and the anaphase boundaries, while it is de-phosphorylated at telophase and cytokinesis. Phospho-Bcl-xL(Ser62) localizes in centrosomes with γ-tubulin and in the mitotic cytosol with some spindle-assembly checkpoint signaling components, including PLK1, BubR1, and Mad2. In taxol- and nocodazole-exposed cells, phospho-Bcl-xL(Ser62) also binds to Cdc20- Mad2-, BubR1-, and Bub3-bound complexes, while Bcl-xL(Ser62Ala) does not. Silencing Bcl-xL expression and expressing the phosphorylation mutant Bcl-xL(Ser62Ala) lead to an increased number of cells harboring mitotic spindle defects including multipolar spindle, chromosome lagging and bridging, aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h. Together, the data indicate that during mitosis, Bcl-xL(Ser62) phosphorylation impacts on spindle assembly and chromosome segregation, influencing chromosome stability. Observations of mitotic cells harboring aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h were also made with cells expressing the phosphorylation mutant Bcl-xL(Ser49Ala) and dual mutant Bcl-xL(Ser49/62Ala).

Long-range correlations in PbPb collisions at 158 a *GeV

CERN Document Server

Alt, C; Baatar, B; Barna, D; Bartke, J; Betev, L; Bialkowska, H; Blume, C; Boimska, B; Botje, M; Bracinik, J; Bramm, R; Brun, R; Buncic, P; Cerny, V; Christakoglou, P; Chvala, O; Cramer, J G; Csato, P; Darmenov, N; Dimitrov, A; Dinkelaker, P; Eckardt, V; Farantatos, G; Flierl, D; Fodor, Z; Foka, P; Freund, P; Friese, V; Gal, J; Gazdzicki, M; Georgopoulos, G; Gladysz, E; Grebieszkow, K; Hegyi, S; Hohne, C; Kadija, K; Karev, A; Kliemant, M; Kniege, S; Kolesnikov, V I; Kollegger, T; Kornas, E; Korus, R; Kowalski, M; Kraus, I; Kreps, M; van Leeuwen, M; Levai, P; Litov, L; Lungwitz, B; Makariev, M; Malakhov, A I; Mateev, M; Mayes, B W; Melkumov, G L; Meurer, C; Mischke, A; Mitrovski, M; Molnar, J; Mrowczynski, S; Palla, G; Panagiotou, A D; Panayotov, D; Petridis, A; Pikna, M; Pinsky, L; Puhlhofer, F; Renfordt, R; Richard, A; Roland, C; Roland, G; Rybczynski, M; Rybicki, A; Sandoval, A; Schmitz, N; Seyboth, P; Sikler, F; Sitar, B; Skrzypczak, E; Stefanek, G; Stock, R; Strobele, H; Susa, T; Szentpetery, I; Sziklai, J; Trubnikov, V; Varga, D; Vassiliou, M; Veres, G l; Vesztergombi, G; Vranie, D; Wetzler, A; Wlodarczyk, Z; Yoo, l K; Zaranek, J; Zimanyi, J; Feofilov, G; Kolevatov, R; Kondratiev, V; Naumenko, P; Vechernin, V

2005-01-01

We present the 1st results of the event-by-event study of long-range correlations between event mean Pt and charged particle multiplicity using NA49 experimental data in two separated rapidity intervals in 158 A *Ge V Pb Pb collisions at the CERN SPS. Noticeable long range correlations are found. The most striking feature is the negative Prn correlation observed for the central PbPb collisions. Results are compared to the predictions of the HIJING event generator and of the String Fusion Model favoring a string fusion hypothesis.

Long-range interactions among three alkali-metal atoms

International Nuclear Information System (INIS)

Marinescu, M.; Starace, A.F.

1996-01-01

The long-range asymptotic form of the interaction potential surface for three neutral alkali-metal atoms in their ground states may be expressed as an expansion in inverse powers of inter-nuclear distances. The first leading powers are proportional to the dispersion coefficients for pairwise atomic interactions. They are followed by a term responsible for a three body dipole interaction. The authors results consist in evaluation of the three body dipole interaction coefficient between three alkali-metal atoms. The generalization to long-range n atom interaction terms will be discussed qualitatively

Coenzyme Q10 Protects Hippocampal Neurons Against Ischemia/Reperfusion Injury via Modulation of BAX/Bcl-2 Expression

Directory of Open Access Journals (Sweden)

M Zamani

2012-12-01

Full Text Available Introduction : Preliminary studies confirmed reduction in cell death following treatment with antioxidants. According to this finding we study the relationship between consumption of CoQ10 and expression of bax and bcl2 in hippocampus following ischemia/reperfusion as proteins involved in cell programmed death or apoptosis.Material & methods : We studied the protective role of CoQ10 against Ischemia-Reperfusion. Experimental design includes four groups: intact, ischemic control, sham control and treatment groups with CoQ10. The mice treated with CoQ10 as Pre - Treatment for a week. Then, ischemia induced by common carotid artery ligation and following the reduction in inflammation (a week the mice post-treated with CoQ10.Nissl staining applied to counting necrotic cells of hippocampus and the western blotting performed to measurement the bax and bcl2 expression.Results :. Cell death was significantly lower when mice treated with CoQ10. Bax expression was significantly high in ischemic group but in treatment group was less and reversely the bcl2 expression in ischemic group was lower than treatment and vehicle groups.Conclusion : Ischemia for 15 minutes induced cell death in hippocampus with more potent effect on CA1. CoQ10 intake significantly reduced cell death and prevented the expression of bax while inducing an increase in expression of bcl2.

Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis

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Yongxing Gong

2017-02-01

Full Text Available Mutation of the PARK2 gene can promote both Parkinson's Disease and cancer, yet the underlying mechanisms of how PARK2 controls cellular physiology is incompletely understood. Here, we show that the PARK2 tumor suppressor controls the apoptotic regulator BCL-XL and modulates programmed cell death. Analysis of approximately 10,000 tumor genomes uncovers a striking pattern of mutual exclusivity between PARK2 genetic loss and amplification of BCL2L1, implicating these genes in a common pathway. PARK2 directly binds to and ubiquitinates BCL-XL. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL both in vitro and in vivo, and cancer-specific mutations in PARK2 abrogate the ability of the ubiquitin E3 ligase to target BCL-XL for degradation. Furthermore, PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Thus, like genes at the nodal points of growth arrest pathways such as p53, the PARK2 tumor suppressor is able to exert its antiproliferative effects by regulating both cell cycle progression and programmed cell death.

Long-range interactions in dilute granular systems

NARCIS (Netherlands)

Müller, M.K

2008-01-01

In this thesis, on purpose, we focussed on the most challenging, longest ranging potentials. We analyzed granular media of low densities obeying 1/r long-range interaction potentials between the granules. Such systems are termed granular gases and differ in their behavior from ordinary gases by

Critical human-factors issues in nuclear-power regulation and a recommended comprehensive human-factors long-range plan. Executive summary

International Nuclear Information System (INIS)

Hopkins, C.O.; Snyder, H.L.; Price, H.E.; Hornick, R.J.; Mackie, R.R.; Smillie, R.J.; Sugarman, R.C.

1982-08-01

This comprehensive long-range human factors plan for nuclear reactor regulation was developed by a Study Group of the Human Factors Society, Inc. This Study Group was selected by the Executive Council of the Society to provide a balanced, experienced human factors perspective to the applications of human factors scientific and engineering knowledge to nuclear power generation. The report is presented in three volumes. Volume 1 contains an Executive Summary of the 18-month effort and its conclusions. Volume 2 summarizes all known nuclear-related human factors activities, evaluates these activities wherever adequate information is available, and describes the recommended long-range (10-year) plan for human factors in regulation. Volume 3 elaborates upon each of the human factors issues and areas of recommended human factors involvement contained in the plan, and discusses the logic that led to the recommendations

Exploring flavor-dependent long-range forces in long-baseline neutrino oscillation experiments

Science.gov (United States)

Chatterjee, Sabya Sachi; Dasgupta, Arnab; Agarwalla, Sanjib Kumar

2015-12-01

The Standard Model gauge group can be extended with minimal matter content by introducing anomaly free U(1) symmetry, such as L e - L μ or L e - L τ . If the neutral gauge boson corresponding to this abelian symmetry is ultra-light, then it will give rise to flavor-dependent long-range leptonic force, which can have significant impact on neutrino oscillations. For an instance, the electrons inside the Sun can generate a flavor-dependent long-range potential at the Earth surface, which can suppress the ν μ → ν e appearance probability in terrestrial experiments. The sign of this potential is opposite for anti-neutrinos, and affects the oscillations of (anti-)neutrinos in different fashion. This feature invokes fake CP-asymmetry like the SM matter effect and can severely affect the leptonic CP-violation searches in long-baseline experiments. In this paper, we study in detail the possible impacts of these long-range flavor-diagonal neutral current interactions due to L e - L μ symmetry, when (anti-)neutrinos travel from Fermilab to Homestake (1300 km) and CERN to Pyhäsalmi (2290 km) in the context of future high-precision superbeam facilities, DUNE and LBNO respectively. If there is no signal of long-range force, DUNE (LBNO) can place stringent constraint on the effective gauge coupling α eμ < 1.9 × 10-53 (7.8 × 10-54) at 90% C.L., which is almost 30 (70) times better than the existing bound from the Super-Kamiokande experiment. We also observe that if α eμ ≥ 2 × 10-52, the CP-violation discovery reach of these future facilities vanishes completely. The mass hierarchy measurement remains robust in DUNE (LBNO) if α eμ < 5 × 10-52 (10-52).

A Review on Structures and Functions of Bcl-2 Family Proteins from Homo sapiens.

Science.gov (United States)

Sivakumar, Dakshinamurthy; Sivaraman, Thirunavukkarasu

2016-01-01

Cancer cells evade apoptosis, which is regulated by proteins of Bcl-2 family in the intrinsic pathways. Numerous experimental three-dimensional (3D) structures of the apoptotic proteins and the proteins bound with small chemical molecules/peptides/proteins have been reported in the literature. In this review article, the 3D structures of the Bcl-2 family proteins from Homo sapiens and as well complex structures of the anti-apoptotic proteins bound with small molecular inhibitors reported in the literature to date have been comprehensively listed out and described in detail. Moreover, the molecular mechanisms by which the Bcl-2 family proteins modulate the apoptotic processes and strategies for designing antagonists to anti-apoptotic proteins have been concisely discussed.

Peculiar long-range supercurrent in superconductor-ferromagnet-superconductor junction containing a noncollinear magnetic domain in the ferromagnetic region

Energy Technology Data Exchange (ETDEWEB)

Meng, Hao, E-mail: menghao1982@shu.edu.cn [School of Physics and Telecommunication Engineering, Shaanxi University of Technology, Hanzhong 723001 (China); National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093 (China); Wu, Xiuqiang [National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing 210093 (China); Ren, Yajie [School of Physics and Telecommunication Engineering, Shaanxi University of Technology, Hanzhong 723001 (China)

2015-01-14

We study the supercurrent in clean superconductor-ferromagnet-superconductor heterostructure containing a noncollinear magnetic domain in the ferromagnetic region. It is demonstrated that the magnetic domain can lead to a spin-flip scattering process, which reverses the spin orientations of the singlet Cooper pair and simultaneously changes the sign of the corresponding electronic momentum. If the ferromagnetic layers on both sides of magnetic domain have the same features, the long-range proximity effect will take place. That is because the singlet Cooper pair will create an exact phase-cancellation effect and gets an additional π phase shift as it passes through the entire ferromagnetic region. Then, the equal spin triplet pair only exists in the magnetic domain region and can not diffuse into the other two ferromagnetic layers. So, the supercurrent mostly arises from the singlet Cooper pairs, and the equal spin triplet pairs are not involved. This result can provide a approach for generating the long-range supercurrent.

Induction of Apoptosis by the Severe Acute Respiratory Syndrome Coronavirus 7a Protein Is Dependent on Its Interaction with the Bcl-XL Protein▿

Science.gov (United States)

Tan, Ying-Xim; Tan, Timothy H. P.; Lee, Marvin J.-R.; Tham, Puay-Yoke; Gunalan, Vithiagaran; Druce, Julian; Birch, Chris; Catton, Mike; Fu, Nai Yang; Yu, Victor C.; Tan, Yee-Joo

2007-01-01

The severe acute respiratory syndrome coronavirus (SARS-CoV) 7a protein, which is not expressed by other known coronaviruses, can induce apoptosis in various cell lines. In this study, we show that the overexpression of Bcl-XL, a prosurvival member of the Bcl-2 family, blocks 7a-induced apoptosis, suggesting that the mechanism for apoptosis induction by 7a is at the level of or upstream from the Bcl-2 family. Coimmunoprecipitation experiments showed that 7a interacts with Bcl-XL and other prosurvival proteins (Bcl-2, Bcl-w, Mcl-1, and A1) but not with the proapoptotic proteins (Bax, Bak, Bad, and Bid). A good correlation between the abilities of 7a deletion mutants to induce apoptosis and to interact with Bcl-XL was observed, suggesting that 7a triggers apoptosis by interfering directly with the prosurvival function of Bcl-XL. Interestingly, amino acids 224 and 225 within the C-terminal transmembrane domain of Bcl-XL are essential for the interaction with the 7a protein, although the BH3 domain of Bcl-XL also contributes to this interaction. In addition, fractionation experiments showed that 7a colocalized with Bcl-XL at the endoplasmic reticulum as well as the mitochondria, suggesting that they may form complexes in different membranous compartments. PMID:17428862

The effect of radiation on bcl-2 and bax in hyperplastic prostatic tissues

International Nuclear Information System (INIS)

Ma Qingjie; Li Yuxin; Gu Xinquan; Cao Xia; Zhao Jie; Kong Xiangbo; Cai Shanyu

2004-01-01

Aim: To investigate the expressions of bcl-2 and bax in benign prostatic hyperplasia (BPH) and the effect of β-rays on bcl-2 and bax. Methods: The expressions of bcl-2 and bax are studied by means of immunohistochemical method in 9 normal prostate (NP) and 15 BPH and 35 patients treated with 90Sr/90Y Prostatic Hyperplasia Applicator. Results: The expressions of bcl-2 in epithelia of NP and BPH are higher than that in stroma P<0.01=. The expressions of bcl-2 in epithelia and stroma of BPH are higher than that in NP P<0.01=. The expressions of bax in epithelia of NP are higher than that in BPH P<0.05=. However ,the expressions of bcl-2 in epithelia and stroma of BPH are higher than bax P<0.01 =. Compared with the control group, the expressions of bcl-2 in epithelia and stroma of BPH treated with 90Sr/90Y Prostatic Hyperplasia Applicator decreased and the expressions of bax increased P<0.01=. Conclusion: bcl-2 gene and bax gene play an important role in the regulation of prostatic apoptosis and the treatment of β-rays can accelerate the apoptosis of prostatic tissues. (authors)

Look Ahead: Long-Range Learning Plans

Science.gov (United States)

Weinstein, Margery

2010-01-01

Faced with an unsteady economy and fluctuating learning needs, planning a learning strategy designed to last longer than the next six months can be a tall order. But a long-range learning plan can provide a road map for success. In this article, four companies (KPMG LLP, CarMax, DPR Construction, and EMC Corp.) describe their learning plans, and…

Long-range-corrected Rung 3.5 density functional approximations

Science.gov (United States)

Janesko, Benjamin G.; Proynov, Emil; Scalmani, Giovanni; Frisch, Michael J.

2018-03-01

Rung 3.5 functionals are a new class of approximations for density functional theory. They provide a flexible intermediate between exact (Hartree-Fock, HF) exchange and semilocal approximations for exchange. Existing Rung 3.5 functionals inherit semilocal functionals' limitations in atomic cores and density tails. Here we address those limitations using range-separated admixture of HF exchange. We present three new functionals. LRC-ωΠLDA combines long-range HF exchange with short-range Rung 3.5 ΠLDA exchange. SLC-ΠLDA combines short- and long-range HF exchange with middle-range ΠLDA exchange. LRC-ωΠLDA-AC incorporates a combination of HF, semilocal, and Rung 3.5 exchange in the short range, based on an adiabatic connection. We test these in a new Rung 3.5 implementation including up to analytic fourth derivatives. LRC-ωΠLDA and SLC-ΠLDA improve atomization energies and reaction barriers by a factor of 8 compared to the full-range ΠLDA. LRC-ωΠLDA-AC brings further improvement approaching the accuracy of standard long-range corrected schemes LC-ωPBE and SLC-PBE. The new functionals yield highest occupied orbital energies closer to experimental ionization potentials and describe correctly the weak charge-transfer complex of ethylene and dichlorine and the hole-spin distribution created by an Al defect in quartz. This study provides a framework for more flexible range-separated Rung 3.5 approximations.

Observation of field-induced long-range order in disordered Sr14Cu24O41

International Nuclear Information System (INIS)

Ohsugi, S.; Matsumoto, S.; Kitaoka, Y.; Matsuda, M.; Uehara, M.; Nagata, T.; Akimitsu, J.

2004-01-01

Field-induced magnetic order in a structural disordered single-crystal Sr 14 Cu 24 O 41 (Sr 14 -B) has been observed in the Cu-nuclear magnetic resonance (NMR) measurements for the ladder sites below 20 K under the magnetic field H∼11 T. For the Zhang Rice (ZR) sites in the chains, the spectrum splits below 20 K due to an appearance of the internal field, whereas that of less disordered Sr 14 -A does not. This gives an evidence of three-dimensional (3D) long-range (LR) ordering in Sr 14 -B below T N ∼20 K under H∼11 T

Force induced unzipping of DNA with long range correlated noise

International Nuclear Information System (INIS)

Lam, Pui-Man; Zhen, Yi

2011-01-01

We derive and solve a Fokker–Planck equation for the stationary distribution of the free energy, in a model of unzipping of double-stranded DNA under external force. The autocorrelation function of the random DNA sequence can be of a general form, including long range correlations. In the case of Ornstein–Uhlenbeck noise, characterized by a finite correlation length, our result reduces to the exact result of Allahverdyan et al, with the average number of unzipped base pairs going as (X) ∼ 1/f 2 in the white noise limit, where f is the deviation from the critical force. In the case of long range correlated noise, where the integrated autocorrelation is divergent, we find that (X) is finite at f = 0, with its value decreasing as the correlations become of longer range. This shows that long range correlations actually stabilize the DNA sequence against unzipping. Our result is also in agreement with the findings of Allahverdyan et al obtained using numerical generation of the long range correlated noise

Micro-Economics of Apoptosis in Cancer: ncRNAs Modulation of BCL-2 Family Members.

Science.gov (United States)

Villanova, Lidia; Careccia, Silvia; De Maria, Ruggero; Fiori, Micol E

2018-03-23

In the last few years, non-coding RNAs (ncRNAs) have been a hot topic in cancer research. Many ncRNAs were found to regulate the apoptotic process and to play a role in tumor cell resistance to treatment. The apoptotic program is on the frontline as self-defense from cancer onset, and evasion of apoptosis has been classified as one of the hallmarks of cancer responsible for therapy failure. The B-cell lymphoma 2 (BCL-2) family members are key players in the regulation of apoptosis and mediate the activation of the mitochondrial death machinery in response to radiation, chemotherapeutic agents and many targeted therapeutics. The balance between the pro-survival and the pro-apoptotic BCL-2 proteins is strictly controlled by ncRNAs. Here, we highlight the most common mechanisms exerted by microRNAs, long non-coding RNAs and circular RNAs on the main mediators of the intrinsic apoptotic cascade with particular focus on their significance in cancer biology.

Gene conversion is strongly induced in human cells by double-strand breaks and is modulated by the expression of BCL-XL

International Nuclear Information System (INIS)

Wiese, Claudia; Pierce, Andrew J.; Gauny, Stacey S.; Jasin, Maria; Kronenberg, Amy

2001-01-01

Homology-directed repair (HDR) of DNA double-strand breaks (DSBs) is a well-established mechanism that contributes to the maintenance of genomic stability in rodent cells, and it has been assumed that HDR is of similar importance in the repair of DSBs in human cells. However, in addition to promoting genomic stability, some outcomes of homologous recombination can be deleterious, suggesting that factors exist to regulate HDR. We previously demonstrated that overexpression of BCL-2 or BCL-xL enhanced the frequency of x-ray-induced mutations involving the TK1 locus, including loss of heterozygosity (LOH) events presumed to arise by mitotic recombination. The present study was designed to test whether HDR is a prominent DSB repair pathway in human cells, and to directly determine whether ectopic expression of BCL-xL affects HDR. We used the B-lymphoblastoid cell line TK6, which expresses wild-type TP53 and resembles normal lymphocytes in undergoing apoptosis following genotoxic stress. U sing isogenic derivatives of TK6 cells (TK6-neo, TK6-bcl-xL), we find that a DSB in an integrated HDR reporter stimulates gene conversion 40-50-fold in TK6-neo cells, demonstrating that a DSB can be efficiently repaired by gene conversion in human cells. Significantly, DSB-induced gene conversion events are 3- to 4-fold more frequent in BCL-xL overexpressing cells. The results demonstrate that HDR plays an important role in maintaining genomic integrity in human cells and that ectopic expression of BCL-xL enhances HDR of DSBs. To our knowledge, this is the first study to highlight a function for BCL-xL in modulating DSB repair in human cells

Conformal invariance in the long-range Ising model

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Miguel F. Paulos

2016-01-01

Full Text Available We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Conformal Invariance in the Long-Range Ising Model

CERN Document Server

Paulos, Miguel F; van Rees, Balt C; Zan, Bernardo

2016-01-01

We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Conformal invariance in the long-range Ising model

Energy Technology Data Exchange (ETDEWEB)

Paulos, Miguel F. [CERN, Theory Group, Geneva (Switzerland); Rychkov, Slava, E-mail: slava.rychkov@lpt.ens.fr [CERN, Theory Group, Geneva (Switzerland); Laboratoire de Physique Théorique de l' École Normale Supérieure (LPTENS), Paris (France); Faculté de Physique, Université Pierre et Marie Curie (UPMC), Paris (France); Rees, Balt C. van [CERN, Theory Group, Geneva (Switzerland); Zan, Bernardo [Institute of Physics, Universiteit van Amsterdam, Amsterdam (Netherlands)

2016-01-15

We consider the question of conformal invariance of the long-range Ising model at the critical point. The continuum description is given in terms of a nonlocal field theory, and the absence of a stress tensor invalidates all of the standard arguments for the enhancement of scale invariance to conformal invariance. We however show that several correlation functions, computed to second order in the epsilon expansion, are nontrivially consistent with conformal invariance. We proceed to give a proof of conformal invariance to all orders in the epsilon expansion, based on the description of the long-range Ising model as a defect theory in an auxiliary higher-dimensional space. A detailed review of conformal invariance in the d-dimensional short-range Ising model is also included and may be of independent interest.

Long-Range Nondestructive Testing System, Phase I

Data.gov (United States)

National Aeronautics and Space Administration — This proposal is for the development of a long range, multi-point non-destructive system for the detection of subsurface flaws in metallic and composite materials of...

PPAR-γ Silencing Inhibits the Apoptosis of A549 Cells by Upregulating Bcl-2

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Jingyu YANG

2013-03-01

Full Text Available Background and objective Drug resistance is the one of primary causes of death in patients with lung cancer, PPAR-γ could induce the apoptosis and reverse drug resistance. The aim of this study is to investigate the expression of PPAR-γ on cisplatin sensitivity and apoptosis response of human lung cancer cell line A549. Methods Reconstruction of PPAR-γ silencing A549 cells (A549/PPAR-γ(- by siRNA. MTT assay was employed to determine the effect of cisplatin on the proliferation of A549/PPAR-γ(-, flow cytometry to determine the effect of cisplatin on the cell apoptosis, Western blot to determine the change of phosphorylation of Akt, caspase-3 and expression of bcl-2/bax. Finally, RT-PCR was employed to determine the transcriptional level of bcl-2. Results Two PPAR-γ silencing A549 cell clones were established successfully, and the expression of PPAR-γ was downregulated significantly as confirmed by RT-PCR and Western blot. After PPAR-γ silencing, the resistance of these two A549 clones to cisplatin was increased by 1.29-fold and 1.60-fold respectively. Flow cytometry showed that the apoptosis rate was decreased, and Western Blot showed that the phosphorylation of Akt and expression of bcl-2/bax were upregulated, caspase-3 was downregulated. Finally, RT-PCR showed that the transcriptional level of bcl-2 was upregulated as well. Conclusion Downregulation of PPAR-γ in A549 cells led to increase of cisplatin resistance. One of the mechanisms was upregulatin of phosphorylation of Akt and expression of bcl-2, which inhibited the apoptosis of cells. The downregulation of PPAR-γ is a possible mechanism that leads to the clinical drug resistance of cancer.

Long-Range Coulomb Effect in Intense Laser-Driven Photoelectron Dynamics.

Science.gov (United States)

Quan, Wei; Hao, XiaoLei; Chen, YongJu; Yu, ShaoGang; Xu, SongPo; Wang, YanLan; Sun, RenPing; Lai, XuanYang; Wu, ChengYin; Gong, QiHuang; He, XianTu; Liu, XiaoJun; Chen, Jing

2016-06-03

In strong field atomic physics community, long-range Coulomb interaction has for a long time been overlooked and its significant role in intense laser-driven photoelectron dynamics eluded experimental observations. Here we report an experimental investigation of the effect of long-range Coulomb potential on the dynamics of near-zero-momentum photoelectrons produced in photo-ionization process of noble gas atoms in intense midinfrared laser pulses. By exploring the dependence of photoelectron distributions near zero momentum on laser intensity and wavelength, we unambiguously demonstrate that the long-range tail of the Coulomb potential (i.e., up to several hundreds atomic units) plays an important role in determining the photoelectron dynamics after the pulse ends.

Long-Range Research Plan, FY 1985-FY 1989

International Nuclear Information System (INIS)

1984-09-01

The Long-Range Research Plan (LRRP) was prepared by the Office of Nuclear Regulatory Research (RES) to assist the NRC in coordinating its long-range research planning with the short-range budget cycles. The LRRP lays out programmatic approaches for research to help resolve regulatory issues. The plan will be updated annually. This document is divided into the following sections: operating reactor inspection, maintenance, and repair; equipment qualification; seismic research; reactor operations and risk; thermal-hydraulic transients; severe accidents; advanced concepts; radiation protection and health effects; and waste management. The following are also listed as appendices: unresolved safety issues and TMI action plan items, priorities for research program, research program outline, and research utilization report. A glossary of acronyms is included

The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells.

Science.gov (United States)

Lian, Jiqin; Karnak, David; Xu, Liang

2010-11-01

Bcl-2 is a key dual regulator of autophagy and apoptosis, but how the level of Bcl-2 influences the cellular decision between autophagy and apoptosis is unclear. The natural BH3-mimetic (-)-gossypol preferentially induces autophagy in androgen-independent (AI) prostate cancer cells that have high levels of Bcl-2 and are resistant to apoptosis, whereas apoptosis is preferentially induced in androgen-dependent or -independent cells with low Bcl-2. (-)-Gossypol induces autophagy via blocking Bcl-2-Beclin 1 interaction at the endoplasmic reticulum (ER), together with downregulating Bcl-2, upregulating Beclin 1 and activating the autophagic pathway. Furthermore, (-)-gossypol-induced autophagy is Beclin 1- and Atg5-dependent. These results provide new insights into the mode of cell death induced by Bcl-2 inhibitors, which could facilitate the rational design of clinical trials by selecting patients who are most likely to benefit from the Bcl-2-targeted molecular therapy.

Pivotal role of hMT+ in long-range disambiguation of interhemispheric bistable surface motion.

Science.gov (United States)

Duarte, João Valente; Costa, Gabriel Nascimento; Martins, Ricardo; Castelo-Branco, Miguel

2017-10-01

It remains an open question whether long-range disambiguation of ambiguous surface motion can be achieved in early visual cortex or instead in higher level regions, which concerns object/surface segmentation/integration mechanisms. We used a bistable moving stimulus that can be perceived as a pattern comprehending both visual hemi-fields moving coherently downward or as two widely segregated nonoverlapping component objects (in each visual hemi-field) moving separately inward. This paradigm requires long-range integration across the vertical meridian leading to interhemispheric binding. Our fMRI study (n = 30) revealed a close relation between activity in hMT+ and perceptual switches involving interhemispheric segregation/integration of motion signals, crucially under nonlocal conditions where components do not overlap and belong to distinct hemispheres. Higher signal changes were found in hMT+ in response to spatially segregated component (incoherent) percepts than to pattern (coherent) percepts. This did not occur in early visual cortex, unlike apparent motion, which does not entail surface segmentation. We also identified a role for top-down mechanisms in state transitions. Deconvolution analysis of switch-related changes revealed prefrontal, insula, and cingulate areas, with the right superior parietal lobule (SPL) being particularly involved. We observed that directed influences could emerge either from left or right hMT+ during bistable motion integration/segregation. SPL also exhibited significant directed functional connectivity with hMT+, during perceptual state maintenance (Granger causality analysis). Our results suggest that long-range interhemispheric binding of ambiguous motion representations mainly reflect bottom-up processes from hMT+ during perceptual state maintenance. In contrast, state transitions maybe influenced by high-level regions such as the SPL. Hum Brain Mapp 38:4882-4897, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley

EGFR and Bcl-2 in gastric mucosa of children infected with Helicobacter pylori

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Ewa Ryszczuk

2016-03-01

Full Text Available Aim: The aim of the study was to evaluate the expression of EGFR and Bcl-2 proteins as inhibitory markers of apoptosis in surface epithelial cells and gland cells of antral gastric mucosa in children infected with Helicobacter pylori according to the severity and activity of antral gastritis and to assess the correlation between the number of cells expressing EGFR and the number of cells expressing Bcl-2 in H. pylori infected children.Materials and methods: The study included 44 children: 68.2% with chronic gastritis and positive IgG against H. pylori, and 31.8% with functional disorders of the gastrointestinal tract and with normal IgG against H. pylori. The evaluation of EGFR expression in gastric mucosa was performed immunohistochemically using monoclonal mouse anti-EGFR antibody. The polyclonal antibody was used to determine the expression of anti-Bcl-2.Results: A significant increase in the number of cells expressing EGFR and Bcl-2 protein was found in the epithelial cells in severe as well as mild and moderate gastritis in the group of children infected with H. pylori. An increase in the number of cells expressing EGFR and Bcl-2 protein was also found in the epithelial cells in group I according to the activity of gastritis. There was a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children.Conclusion: Increased expression of EGFR and Bcl-2 proteins in the epithelial cells and a statistically significant positive correlation between the numbers of cells expressing EGFR and Bcl-2 in H. pylori infected children could suggest increased regeneration abilities of gastric mucosa.

No dramatic age-related loss of hair cells and spiral ganglion neurons in Bcl-2 over-expression mice or Bax null mice

Directory of Open Access Journals (Sweden)

Ohlemiller Kevin K

2010-07-01

Full Text Available Abstract Age-related decline of neuronal function is associated with age-related structural changes. In the central nervous system, age-related decline of cognitive performance is thought to be caused by synaptic loss instead of neuronal loss. However, in the cochlea, age-related loss of hair cells and spiral ganglion neurons (SGNs is consistently observed in a variety of species, including humans. Since age-related loss of these cells is a major contributing factor to presbycusis, it is important to study possible molecular mechanisms underlying this age-related cell death. Previous studies suggested that apoptotic pathways were involved in age-related loss of hair cells and SGNs. In the present study, we examined the role of Bcl-2 gene in age-related hearing loss. In one transgenic mouse line over-expressing human Bcl-2, there were no significant differences between transgenic mice and wild type littermate controls in their hearing thresholds during aging. Histological analysis of the hair cells and SGNs showed no significant conservation of these cells in transgenic animals compared to the wild type controls during aging. These data suggest that Bcl-2 overexpression has no significant effect on age-related loss of hair cells and SGNs. We also found no delay of age-related hearing loss in mice lacking Bax gene. These findings suggest that age-related hearing loss is not through an apoptotic pathway involving key members of Bcl-2 family.

Strong asymmetry for surface modes in nonlinear lattices with long-range coupling

International Nuclear Information System (INIS)

Martinez, Alejandro J.; Vicencio, Rodrigo A.; Molina, Mario I.

2010-01-01

We analyze the formation of localized surface modes on a nonlinear cubic waveguide array in the presence of exponentially decreasing long-range interactions. We find that the long-range coupling induces a strong asymmetry between the focusing and defocusing cases for the topology of the surface modes and also for the minimum power needed to generate them. In particular, for the defocusing case, there is an upper power threshold for exciting staggered modes, which depends strongly on the long-range coupling strength. The power threshold for dynamical excitation of surface modes increases (decreases) with the strength of long-range coupling for the focusing (defocusing) cases. These effects seem to be generic for discrete lattices with long-range interactions.

Fractality Evidence and Long-Range Dependence on Capital Markets: a Hurst Exponent Evaluation

Science.gov (United States)

Oprean, Camelia; Tănăsescu, Cristina

2014-07-01

Since the existence of market memory could implicate the rejection of the efficient market hypothesis, the aim of this paper is to find any evidence that selected emergent capital markets (eight European and BRIC markets, namely Hungary, Romania, Estonia, Czech Republic, Brazil, Russia, India and China) evince long-range dependence or the random walk hypothesis. In this paper, the Hurst exponent as calculated by R/S fractal analysis and Detrended Fluctuation Analysis is our measure of long-range dependence in the series. The results reinforce our previous findings and suggest that if stock returns present long-range dependence, the random walk hypothesis is not valid anymore and neither is the market efficiency hypothesis.

The function of BCL9 in Wnt/β-catenin signaling and colorectal cancer cells

International Nuclear Information System (INIS)

Roche, Marc de la; Worm, Jesper; Bienz, Mariann

2008-01-01

Most cases of colorectal cancer are initiated by hyperactivation of the Wnt/β-catenin pathway due to mutations in the APC tumour suppressor, or in β-catenin itself. A recently discovered component of this pathway is Legless, which is essential for Wnt-induced transcription during Drosophila development. Limited functional information is available for its two mammalian relatives, BCL9 and B9L/BCL9-2: like Legless, these proteins bind to β-catenin, and RNAi-mediated depletion of B9L/BCL9-2 has revealed that this protein is required for efficient β-catenin-mediated transcription in mammalian cell lines. No loss-of-function data are available for BCL9. We have used overexpression of dominant-negative forms of BCL9, and RNAi-mediated depletion, to study its function in human cell lines with elevated Wnt pathway activity, including colorectal cancer cells. We found that BCL9 is required for efficient β-catenin-mediated transcription in Wnt-stimulated HEK 293 cells, and in the SW480 colorectal cancer cell line whose Wnt pathway is active due to APC mutation. Dominant-negative mutants of BCL9 indicated that its function depends not only on its β-catenin ligand, but also on an unknown ligand of its C-terminus. Finally, we show that BCL9 and B9L are both Wnt-inducible genes, hyperexpressed in colorectal cancer cell lines, indicating that they are part of a positive feedback loop. BCL9 is required for efficient β-catenin-mediated transcription in human cell lines whose Wnt pathway is active, including colorectal cancer cells, indicating its potential as a drug target in colorectal cancer

Real world data on young patients with high-risk diffuse large B-cell lymphoma treated with R-CHOP or R-CHOEP - MYC, BCL2 and BCL6 as prognostic biomarkers

DEFF Research Database (Denmark)

Pedersen, Mette Ølgod; Gang, Anne Ortved; Brown, Peter

2017-01-01

BACKGROUND: Double expression of MYC and BCL2 proteins (DE) and double-hit MYC+BCL2/BCL6 translocations (DH) were established as important biomarkers in patients with diffuse large B-cell lymphoma (DLBCL) by the 2016 revision of the World Health Organization classification of lymphoid neoplasms...... in situ hybridization (FISH). RESULTS: DE with MYC>75% and BCL2>85% was an independent negative prognostic marker of progression free survival (PFS) in patients treated with R-CHOP but not R-CHOEP (peffect of DE for response (PFS) to R...

Bcl-2 expression during the development and degeneration of RCS rat retinae.

Science.gov (United States)

Sharma, R K

2001-12-14

In various hereditary retinal degenerations, including that in Royal College of Surgeons (RCS) rats, the photoreceptors ultimately die by apoptosis. Bcl-2 is one of the genes, which regulates apoptosis and is thought to promote survival of cells. This study has investigated the developmental expression of Bcl-2 in RCS rat, which is a well-studied animal model for hereditary retinal degeneration. An antibody against Bcl-2 was used for its immunohistochemical localization in dystrophic RCS rat retinae from postnatal (PN) days 4, 7, 13, 35, 45, 70, 202 and 14 months. Results were compared with Bcl-2 localization in congenic non-dystrophic rats from PN 4, 7, 13, 44, 202 and 14 months. Bcl-2 immunoreactivity in non-dystrophic retinae was already present in PN 4 retinae in the nerve fiber layer (presumably in the endfeet of immature Müller cells) and in the proximal parts of certain radially aligned neuroepithelial cells/immature Müller cell radial processes. With increasing age the immunoreactivity in relatively more mature Müller cell radial processes spread distally towards the outer retina and between PN 13 and 44 it reached the adult distribution. No cell bodies in the ganglion cell layer were found to be immunoreactive. Expression of Bcl-2 immunoreactivity in dystrophic RCS rat retinae closely resembled that of non-dystrophic retinae. No immunoreactivity was seen in photoreceptors or retinal pigment epithelium in dystrophic or non-dystrophic retinae. In conclusion, Bcl-2 expression is not altered, either in terms of its chronology or the cell type expressing it, during retinal degeneration in RCS rats.

The role of BCL-2 and glutathione in an antioxidant pathway to prevent radiation-induced apoptosis

International Nuclear Information System (INIS)

Vlachaki, Maria T.; Meyn, Raymond E.

1997-01-01

Objective: The expression of the bcl-2 gene has been associated with resistance to radiation induced apoptosis. There is evidence that the bcl-2 protein acts in the antioxidant pathways to block the effects of reactive oxygen spieces that mediate apoptosis possibly by increasing the levels of intracellular glutathione. Our hypothesis is that pretreatment of radiation-sensitive cells, known to lack bcl-2 expression, with antioxidants will reduce radiation-induced apoptosis. For this purpose, the apoptotic response to radiation and the intracellular levels of glutathione were tested before and after pretreatment with antioxidants in two murine lymphoma cell lines, a radiation resistant-bcl-2 expressing (Ly-ar) line and a radiation sensitive (Ly-as) line. Methods and Materials: Ly-ar and Ly-as cells were irradiated at 0,1,2,3 and 4 hours before collection. The intracellular levels of reduced (GSH) and oxidized (GSSG) glutathione were determined by the use of the fluorescent dye ophthalaldehyde. Ly-as cells were pretreated with dihydrolipoic acid and lipoamide for 1 hour before irradiation. Apoptosis response was measured by the DNA fragmentation assay. The radiation dose was 2.5 Gy. Results: After irradiation, the apoptotic rate of Ly-ar and Ly-as cells is 11-19% and 66-87% respectively. Ly-ar cells have higher intracellular GSH and GSSG levels compared to Ly-as cells by 69.9% and 91.9% respectively and the GSH/GSSG ratio in Ly-ar and Ly-as cells is 17.09 and 15.09 respectively (a difference of 13.25%). GSH levels do not change during the first three hours after irradiation; however there is a 46% reduction at four hours after irradiation, a time at which the Ly-as cells have already fragmented their DNA. Pretreatment of cells with dihydrolipoic acid or lipoamide at concentrations of 4mM and 2mM respectively was toxic and resulted in cell death in the absence of irradiation. Conclusions: GSH and GSSG levels are elevated in radiation-resistant murine lymphoma cells

Long Range Aircraft Trajectory Prediction

OpenAIRE

Magister, Tone

2009-01-01

The subject of the paper is the improvement of the aircraft future trajectory prediction accuracy for long-range airborne separation assurance. The strategic planning of safe aircraft flights and effective conflict avoidance tactics demand timely and accurate conflict detection based upon future four–dimensional airborne traffic situation prediction which is as accurate as each aircraft flight trajectory prediction. The improved kinematics model of aircraft relative flight considering flight ...

Bcl-2 overexpression prevents 99mTc-MIBI uptake in breast cancer cell lines

International Nuclear Information System (INIS)

Aloj, Luigi; Zannetti, Antonella; Caraco, Corradina; Del Vecchio, Silvana; Salvatore, Marco

2004-01-01

We have previously shown a correlation between the absence of technetium-99m methoxyisobutylisonitrile ( 99m Tc-MIBI) uptake and overexpression of the anti-apoptotic protein Bcl-2 in human breast carcinoma. To establish a direct cause-effect relationship between Bcl-2 overexpression and reduced 99m Tc-MIBI uptake, MCF-7 and T47D breast cancer cell lines were stably transfected with the human Bcl-2 gene to increase intracellular protein levels and tested for 99m Tc-MIBI uptake. All clones overexpressing Bcl-2 showed a dramatic reduction of 99m Tc-MIBI uptake as compared with mock transfected control cells. Tracer uptake was promptly and partially restored by induction of apoptosis with staurosporine treatment. After 4.5 h of staurosporine treatment, a tenfold increase in 99m Tc-MIBI uptake was observed in treated as compared with untreated Bcl-2 overexpressing cells. Our findings provide a rational basis for the development of an in vivo test to detect Bcl-2 overexpression in human tumours. (orig.)

Scintillation mitigation for long-range surveillance video

CSIR Research Space (South Africa)

Delport, JP

2010-09-01

Full Text Available Atmospheric turbulence is a naturally occurring phenomenon that can severely degrade the quality of long-range surveillance video footage. Major effects include image blurring, image warping and temporal wavering of objects in the scene. Mitigating...

Observed Orbit Effects during Long Range Beam-Beam Studies

CERN Document Server

Alemany, R; Buffat, X; Calaga, R; Fitterer, M; Giachino, R; Hemelsoet, GH; Herr, W; Papotti, G; Pieloni, T; Poyer, M; Schaumann, M; Trad, G; Wollmann, D

2012-01-01

Possible limitations due to long range beam-beam effects at the LHC have been studied and are presented in this note. With a larger number of bunches and collisions in all interaction points, the crossing angles were reduced to enhance long range beam-beam effects. The analysis of the effects on the dynamic aperture and losses are documented in [1]. This note concentrates on the bunch-by-bunch orbit effects observed during the experiment.

Long-range correlations and universality in plasma edge turbulence

International Nuclear Information System (INIS)

Milligen, B.Ph. van; Pedrosa, M.A.; Carreras, B.A.

1999-01-01

Long-range correlations in turbulence, associated with self-similarity of the fluctuations, are a signature of transport by avalanches as occurs in Self-Organized Critical systems. We have investigated long-range correlations in plasma edge fluctuations in a variety of fusion devices, using the Rescaled-Range and similar techniques. We find that the degree of self-similarity in confining devices is high and similar between devices, and much different from non-confining devices where it is low. Likewise, we find that turbulent spectra show a high degree of similarity between devices. These findings strongly indicate the existence of universality in plasma edge (ohmic) turbulence, and demonstrate its non-Gaussian character. (author)

Coenzyme Q10 Protects Hippocampal Neurons against Ischemia/ Reperfusion Injury via Modulation of BAX/Bcl-2 Expression

Directory of Open Access Journals (Sweden)

Mohammad Zamani

2012-09-01

Full Text Available Introduction: Preliminary studies have con.rmed reduction in cell death following treatment with antioxidants. According to this .nding we study the relationship between consumption of CoQ10 and expression of Bax and Bcl2 in hippocampus following ischemia/reperfusion as proteins involved in cell programmed death or apoptosis. Methods: We studied the protective role of CoQ10 against ischemia-reperfusion. Experimental design includes four groups:  intact, ischemic control, sham control and treatment group with CoQ10. The mice were pre-treated with CoQ10 for a week, then ischemia was induced by common carotid artery ligation and following the reduction in in.ammation (a week the mice was treated with CoQ10.  Nissl staining was applied for counting the necrotic cells of hippocampus and the western blot was performed to measure the Bax and Bcl2 expression.Results: Cell death was signi.cantly lower when mice were treated with CoQ10. Bax expression was signi.cantly high in the ischemic group but low in the treatment group, and the bcl2 expression was lower in the ischemic group than the treatment and the vehicle groups.Discussion: Ischemia for 15 minutes induced cell death in hippocampus with more potent effect on CA1. CoQ10 intake signi.cantly reduced cell death and prevented the expression of Bax while inducing an increase in expression of bcl2.

Empirical study of long-range connections in a road network offers new ingredient for navigation optimization models

Science.gov (United States)

Wang, Pu; Liu, Like; Li, Xiamiao; Li, Guanliang; González, Marta C.

2014-01-01

Navigation problem in lattices with long-range connections has been widely studied to understand the design principles for optimal transport networks; however, the travel cost of long-range connections was not considered in previous models. We define long-range connection in a road network as the shortest path between a pair of nodes through highways and empirically analyze the travel cost properties of long-range connections. Based on the maximum speed allowed in each road segment, we observe that the time needed to travel through a long-range connection has a characteristic time Th ˜ 29 min, while the time required when using the alternative arterial road path has two different characteristic times Ta ˜ 13 and 41 min and follows a power law for times larger than 50 min. Using daily commuting origin-destination matrix data, we additionally find that the use of long-range connections helps people to save about half of the travel time in their daily commute. Based on the empirical results, we assign a more realistic travel cost to long-range connections in two-dimensional square lattices, observing dramatically different minimum average shortest path but similar optimal navigation conditions.

Cycloheximide and actinomycin D delay death and affect bcl-2, bax, and Ice gene expression in astrocytes under in vitro ischemia.

Science.gov (United States)

Yu, Albert Cheung Hoi; Yung, Hon Wa; Hui, Michael Hung Kit; Lau, Lok Ting; Chen, Xiao Qian; Collins, Richard A

2003-10-15

An in vitro ischemia model was established and the effect of the metabolic inhibitors cycloheximide (CHX) and actinomycin D (ActD) on apoptosis in astrocytes under ischemia studied. CHX decreased by 75% the number of cells dying after 6 hr of ischemia compared with control cultures. TdT-mediated dUTP nick end labelling (TUNEL) staining of comparable cultures was reduced by 40%. ActD decreased cell death by 60% compared with controls. The number of TUNEL-positive cells was reduced by 38%. The nuclear shrinkage in TUNEL-positive astrocytes in control cultures did not occur in ActD-treated astrocytes, indicating that nuclear shrinkage and DNA fragmentation during apoptosis are two unrelated processes. Expression of bcl-2 (alpha and beta), bax, and Ice in astrocytes under similar ischemic conditions, as measured by quantitative reverse transcription-polymerase chain reaction, indicated that ischemia down-regulated bcl-2 (alpha and beta) and bax. Ice was initially down-regulated from 0 to 4 hr, before returning to control levels after 8 hr of ischemia. ActD decreased the expression of these genes. CHX reduced the expression of bcl-2 (alpha and beta) but increased bax and Ice expression. It is hypothesized that the balance of proapoptotic (Bad, Bax) and antiapoptotic (Bcl-2, Bcl-Xl) proteins determines apoptosis. The data suggest that the ratio of Bcl-2/Bad in astrocytes following ActD and CHX treatment does not decrease as much in untreated cells during ischemia. Our data indicate that it is the ratio of Bcl-2 family members that plays a critical role in determining ischemia-induced apoptosis. It is also important to note that ischemia-induced apoptosis involves the regulation of RNA and protein synthesis. Copyright 2003 Wiley-Liss, Inc.

Imaging using long range dipolar field effects

International Nuclear Information System (INIS)

Gutteridge, Sarah

2002-01-01

The work in this thesis has been undertaken by the author, except where indicated in reference, within the Magnetic Resonance Centre, at the University of Nottingham during the period from October 1998 to March 2001. This thesis details the different characteristics of the long range dipolar field and its application to magnetic resonance imaging. The long range dipolar field is usually neglected in nuclear magnetic resonance experiments, as molecular tumbling decouples its effect at short distances. However, in highly polarised samples residual long range components have a significant effect on the evolution of the magnetisation, giving rise to multiple spin echoes and unexpected quantum coherences. Three applications utilising these dipolar field effects are documented in this thesis. The first demonstrates the spatial sensitivity of the signal generated via dipolar field effects in structured liquid state samples. The second utilises the signal produced by the dipolar field to create proton spin density maps. These maps directly yield an absolute value for the water content of the sample that is unaffected by relaxation and any RF inhomogeneity or calibration errors in the radio frequency pulses applied. It has also been suggested that the signal generated by dipolar field effects may provide novel contrast in functional magnetic resonance imaging. In the third application, the effects of microscopic susceptibility variation on the signal are studied and the relaxation rate of the signal is compared to that of a conventional spin echo. (author)

The BCL6 RD2 Domain Governs Commitment of Activated B Cells to Form Germinal Centers

Directory of Open Access Journals (Sweden)

Chuanxin Huang

2014-09-01

Full Text Available To understand how the Bcl6 transcriptional repressor functions in the immune system, we disrupted its RD2 repression domain in mice. Bcl6RD2MUT mice exhibit a complete loss of germinal center (GC formation but retain normal extrafollicular responses. Bcl6RD2MUT antigen-engaged B cells migrate to the interfollicular zone and interact with cognate T helper cells. However, these cells fail to complete early GC-commitment differentiation and coalesce as nascent GC aggregates. Bcl6 directly binds and represses trafficking receptors S1pr1 and Gpr183 by recruiting Hdac2 through the RD2 domain. Deregulation of these genes impairs B cell migration and may contribute to GC failure in Bcl6RD2MUT mice. The development of functional GC-TFH cells was partially impaired in Bcl6RD2MUT mice. In contrast to Bcl6−/− mice, Bcl6RD2MUT animals experience no inflammatory disease or macrophage deregulation. These results reveal an essential role for RD2 repression in early GC commitment and striking biochemical specificity in Bcl6 control of humoral and innate immune-cell phenotypes.

Alternative long-ranged charge optimized many-body potential for aluminium.

Science.gov (United States)

Mo, Yunjie; He, Yingyou; Feng, Xiaofang; Jiang, Shaoji

2017-12-06

A new COMB3 potential was developed for aluminium, which focuses on long-range interaction and phase transition. The potential was developed by fitting the equilibrium lattice properties of different phases and defects to ensure its transferability to general systems. The quality of the potential was tested in several problems and compared with the EAM potential as well as the published COMB3 potential, the effect of the cutoff method was studied in detail to demonstrate the necessity to extend the cutoff region. Systems of strong deformations along the Bain path, under a trigonal strain and with planar stacking faults were calculated and the present potential performed as well as the EAM potential. At last, a surface process that involves adsorption and diffusion was studied using the present potential.

A short and long range study of mullite-zirconia-zircon composites

Energy Technology Data Exchange (ETDEWEB)

Rendtorff, Nicolas M.; Conconi, Maria S.; Aglietti, Esteban F. [Centro de Tecnologia de Recursos Minerales y Ceramica (CETMIC: CONICET-CIC) (Argentina); Chain, Cecilia Y.; Pasquevich, Alberto F. [Universidad Nacional de La Plata, Departamento de Fisica, IFLP, Facultad de Ciencias Exactas (Argentina); Rivas, Patricia C. [CONICET (Argentina); Martinez, Jorge A., E-mail: toto@fisica.unlp.edu.ar; Caracoche, Maria C. [Universidad Nacional de La Plata, Departamento de Fisica, IFLP, Facultad de Ciencias Exactas (Argentina)

2010-06-15

In the field of refractory materials, ceramics containing mullite-zirconia are the basis of those most used in the industry of glass and steel. It is known that the addition of zircon improves the behavior of the refractory used in service. Knowing that some mullite-zirconia composites properties as fracture strength and the elastic modulus E are associated with the material microstructure integrity, the eventual thermal decomposition of zircon into zirconia and silica could seriously alter the material elastic properties. In this paper the phase content of a series of mullite-zirconia-zircon (3Al{sub 2}O{sub 3}.2SiO{sub 2}-ZrO{sub 2}-ZrSiO{sub 4}) composites is determined at atomic level via perturbed angular correlations (PAC) and compared with that derived from the long range X-ray diffraction technique. PAC results on the as-prepared materials indicate that all nominal zircon is present and that it involves two types of nanoconfigurations, one of them describing aperiodic regions. The thermomechanical properties already reported for these materials could be related to the crystalline to aperiodic zircon concentrations ratio they exhibit.

Born to be Alive: A Role for the BCL-2 Family in Melanoma Tumor Cell Survival, Apoptosis, and Treatment

Energy Technology Data Exchange (ETDEWEB)

Anvekar, Rina A.; Asciolla, James J.; Missert, Derek J.; Chipuk, Jerry E., E-mail: jerry.chipuk@mssm.edu [Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY (United States); Department of Dermatology, Mount Sinai School of Medicine, New York, NY (United States); The Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY (United States)

2011-10-13

The global incidence of melanoma has dramatically increased during the recent decades, yet the advancement of primary and adjuvant therapies has not kept a similar pace. The development of melanoma is often centered on cellular signaling that hyper-activates survival pathways, while inducing a concomitant blockade to cell death. Aberrations in cell death signaling not only promote tumor survival and enhanced metastatic potential, but also create resistance to anti-tumor strategies. Chemotherapeutic agents target melanoma tumor cells by inducing a form of cell death called apoptosis, which is governed by the BCL-2 family of proteins. The BCL-2 family is comprised of anti-apoptotic proteins (e.g., BCL-2, BCL-xL, and MCL-1) and pro-apoptotic proteins (e.g., BAK, BAX, and BIM), and their coordinated regulation and function are essential for optimal responses to chemotherapeutics. Here we will discuss what is currently known about the mechanisms of BCL-2 family function with a focus on the signaling pathways that maintain melanoma tumor cell survival. Importantly, we will critically evaluate the literature regarding how chemotherapeutic strategies directly impact on BCL-2 family function and offer several suggestions for future regimens to target melanoma and enhance patient survival.

Fluctuation-induced long-range interactions in polymer systems

International Nuclear Information System (INIS)

Semenov, A N; Obukhov, S P

2005-01-01

We discover a new universal long-range interaction between solid objects in polymer media. This polymer-induced interaction is directly opposite to the van der Waals attraction. The predicted effect is deeply related to the classical Casimir interactions, providing a unique example of universal fluctuation-induced repulsion rather than normal attraction. This universal repulsion comes from the subtracted soft fluctuation modes in the ideal counterpart of the real polymer system. The effect can also be interpreted in terms of subtracted (ghost) large-scale polymer loops. We establish the general expressions for the energy of polymer-induced interactions for arbitrary solid particles in a concentrated polymer system. We find that the correlation function of the polymer density in a concentrated solution of very long chains follows a scaling law rather than an exponential decay at large distances. These novel universal long-range interactions can be of importance in various polymer systems. We discuss the ways to observe/simulate these fluctuation-induced effects

Study of beam-beam long range compensation with octupoles

CERN Document Server

AUTHOR|(CDS)2068329; Pieloni, Tatiana; Buffat, Xavier; Tambasco, Claudia

2017-01-01

Long range beam-beam effects are responsible for particle losses and define fundamental operational parameters of colliders (i.e. crossing angles, intensities, emittances, ${\\beta}$${^∗}$). In this study we propose octuple magnets as a possible scheme to efficiently compensate long-range beam-beam interactions with a global correction scheme. The impact and improvements on the dynamic aperture of colliding beams together with estimates of the luminosity potentials are dis- cussed for the HL-LHC upgrade and extrapolations made for the FCC project.

Testing for long-range dependence in world stock markets

OpenAIRE

Cajueiro, Daniel Oliveira; Tabak, Benjamin Miranda

2008-01-01

In this paper, we show a novel approach to rank stock market indices in terms of weak form efficiency using state of the art methodology in statistical physics. We employ the R/S and V/S methodologies to test for long-range dependence in equity returns and volatility. Empirical results suggests that although emerging markets possess stronger long-range dependence in equity returns than developed economies, this is not true for volatility. In the case of volatility, Hurst exponents...

Long-Range Big Quantum-Data Transmission

Science.gov (United States)

Zwerger, M.; Pirker, A.; Dunjko, V.; Briegel, H. J.; Dür, W.

2018-01-01

We introduce an alternative type of quantum repeater for long-range quantum communication with improved scaling with the distance. We show that by employing hashing, a deterministic entanglement distillation protocol with one-way communication, one obtains a scalable scheme that allows one to reach arbitrary distances, with constant overhead in resources per repeater station, and ultrahigh rates. In practical terms, we show that, also with moderate resources of a few hundred qubits at each repeater station, one can reach intercontinental distances. At the same time, a measurement-based implementation allows one to tolerate high loss but also operational and memory errors of the order of several percent per qubit. This opens the way for long-distance communication of big quantum data.

BCL2-like 11 intron 2 deletion polymorphism is not associated with non-small cell lung cancer risk and prognosis.

Science.gov (United States)

Cho, Eun Na; Kim, Eun Young; Jung, Ji Ye; Kim, Arum; Oh, In Jae; Kim, Young Chul; Chang, Yoon Soo

2015-10-01

BCL2-Like 11(BIM), which encodes a BH3-only protein, is a major pro-apoptotic molecule that facilitates cell death. We hypothesized that a BIM intron 2 deletion polymorphism increases lung cancer risk and predicts poor prognosis in non-small lung cancer (NSCLC) patients. We prospectively recruited 450 lung cancer patients and 1:1 age, sex, and smoking status matched control subjects from February 2013 to April 2014 among patients treated at Severance, Gangnam Severance, and Chonnam Hwasoon Hospital. The presence of a 2903-bp genomic DNA deletion polymorphism of intron 2 of BIM was analyzed by PCR and validated by sequencing. Odds ratios were calculated by chi-square tests and survival analysis with Kaplan-Meier estimation. Sixty-nine out of 450 (15.3%) lung cancer patients carried the BIM deletion polymorphism, while 66 out of 450 (14.7%) control subjects carried the BIM deletion polymorphism, with an odds ratio of for lung cancer of 1.054 (95% CI; 0.731-1.519). We categorized 406 NSCLC patients according to the presence of the polymorphism and found that there were no statistically significant differences in age, sex, histologic type, or stage between subjects with and without the deletion polymorphism. The BIM deletion polymorphism did not influence overall survival (OS) or progression free survival (PFS) in our sample (OS; 37.6 vs 34.4 months (P=0.759), PFS; 49.6 vs 26.0 months (P=0.434)). These findings indicate that the BIM deletion polymorphism is common in Korean NSCLC patients but does not significantly affect the intrinsic biologic function of BH3-only protein. Furthermore, the BIM deletion polymorphism did not predict clinical outcomes in patients with NSCLC. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Discovery and molecular characterization of a Bcl-2–regulated cell death pathway in schistosomes

OpenAIRE

Lee, Erinna F.; Clarke, Oliver B.; Evangelista, Marco; Feng, Zhiping; Speed, Terence P.; Tchoubrieva, Elissaveta B.; Strasser, Andreas; Kalinna, Bernd H.; Colman, Peter M.; Fairlie, W. Douglas

2011-01-01

Schistosomiasis is an infectious disease caused by parasites of the phylum platyhelminthe. Here, we describe the identification and characterization of a Bcl-2–regulated apoptosis pathway in Schistosoma japonicum and S. mansoni. Genomic, biochemical, and cell-based mechanistic studies provide evidence for a tripartite pathway, similar to that in humans including BH3-only proteins that are inhibited by prosurvival Bcl-2–like molecules, and Bax/Bak-like proteins that facilitate mitochondrial ou...

Plastic downregulation of the transcriptional repressor BCL6 during maturation of human dendritic cells

International Nuclear Information System (INIS)

Pantano, Serafino; Jarrossay, David; Saccani, Simona; Bosisio, Daniela; Natoli, Gioacchino

2006-01-01

Dendritic cell (DC) maturation links peripheral events initiated by the encounter with pathogens to the activation and expansion of antigen-specific T lymphocytes in secondary lymphoid organs. Here, we describe an as yet unrecognized modulator of human DC maturation, the transcriptional repressor BCL6. We found that both myeloid and plasmacytoid DCs constitutively express BCL6, which is rapidly downregulated following maturation triggered by selected stimuli. Both in unstimulated and maturing DCs, control of BCL6 protein levels reflects the convergence of several mechanisms regulating BCL6 stability, mRNA transcription and nuclear export. By regulating the induction of several genes implicated in the immune response, including inflammatory cytokines, chemokines and survival genes, BCL6 may represent a pivotal modulator of the afferent branch of the immune response

Fast long-range connections in transportation networks

International Nuclear Information System (INIS)

Palhares Viana, Matheus; Fontoura Costa, Luciano da

2011-01-01

Multidimensional scaling is applied in order to visualize an analogue of the small-world effect implied by edges having different displacement velocities in transportation networks. Our findings are illustrated for two real-world systems, namely the London urban network (streets and underground) and the US highway network enhanced by some of the main US airlines routes. We also show that the travel time in these two networks is drastically changed by attacks targeting the edges with large displacement velocities. - Highlights: → Multidimensional scaling used to visualize the effects of fast long-range connections. → Fast long-range connections are important to decrease the average travel time. → The average travel time diverges quickly when the network is under target attacks.

Empirical study of long-range connections in a road network offers new ingredient for navigation optimization models

International Nuclear Information System (INIS)

Wang, Pu; Liu, Like; Li, Xiamiao; Li, Guanliang; González, Marta C

2014-01-01

Navigation problem in lattices with long-range connections has been widely studied to understand the design principles for optimal transport networks; however, the travel cost of long-range connections was not considered in previous models. We define long-range connection in a road network as the shortest path between a pair of nodes through highways and empirically analyze the travel cost properties of long-range connections. Based on the maximum speed allowed in each road segment, we observe that the time needed to travel through a long-range connection has a characteristic time T h  ∼ 29 min, while the time required when using the alternative arterial road path has two different characteristic times T a  ∼ 13 and 41 min and follows a power law for times larger than 50 min. Using daily commuting origin–destination matrix data, we additionally find that the use of long-range connections helps people to save about half of the travel time in their daily commute. Based on the empirical results, we assign a more realistic travel cost to long-range connections in two-dimensional square lattices, observing dramatically different minimum average shortest path 〈l〉 but similar optimal navigation conditions. (paper)

Long-range hybrid ridge and trench plasmonic waveguides

Energy Technology Data Exchange (ETDEWEB)

Bian, Yusheng [State Key Laboratory for Mesoscopic Physics, Department of Physics, Peking University, Beijing 100871 (China); Gong, Qihuang, E-mail: qhgong@pku.edu.cn [State Key Laboratory for Mesoscopic Physics, Department of Physics, Peking University, Beijing 100871 (China); Collaborative Innovation Center of Quantum Matter, Beijing 100871 (China)

2014-06-23

We report a class of long-range hybrid plasmon polariton waveguides capable of simultaneously achieving low propagation loss and tight field localization at telecommunication wavelength. The symmetric (quasi-symmetric) hybrid configurations featuring high-refractive-index-contrast near the non-uniform metallic nanostructures enable significantly improved optical performance over conventional hybrid waveguides, exhibiting considerably longer propagation distances and dramatically enhanced figure of merits for similar degrees of confinement. Compared to their traditional long-range plasmonic counterparts, the proposed hybrid waveguides put much less stringent requirements on index-matching conditions, demonstrating nice performance under a wide range of physical dimensions and robust characteristics against certain fabrication imperfections. Studies concerning crosstalk between adjacent identical waveguides further reveal their potential for photonic integrations. In addition, alternative configurations with comparable guiding properties to the structures in our case studies are also proposed, which can potentially serve as attractive prototypes for numerous high-performance nanophotonic components.

Boundary layer parameterizations and long-range transport

International Nuclear Information System (INIS)

Irwin, J.S.

1992-01-01

A joint work group between the American Meteorological Society (AMS) and the EPA is perusing the construction of an air quality model that incorporates boundary layer parameterizations of dispersion and transport. This model could replace the currently accepted model, the Industrial Source Complex (ISC) model. The ISC model is a Gaussian-plume multiple point-source model that provides for consideration of fugitive emissions, aerodynamic wake effects, gravitational settling and dry deposition. A work group of several Federal and State agencies is perusing the construction of an air quality modeling system for use in assessing and tracking visibility impairment resulting from long-range transport of pollutants. The modeling system is designed to use the hourly vertical profiles of wind, temperature and moisture resulting from a mesoscale meteorological processor that employs four dimensional data assimilation (FDDA). FDDA involves adding forcing functions to the governing model equations to gradually ''nudge'' the model state toward the observations (12-hourly upper air observations of wind, temperature and moisture, and 3-hourly surface observations of wind and moisture). In this way it is possible to generate data sets whose accuracy, in terms of transport, precipitation, and dynamic consistency is superior to both direct interpolation of synoptic-scale analyses of observations and purely predictive mode model result. (AB) ( 19 refs.)

The Frontiers of Nuclear Science: A Long-Range Plan

Energy Technology Data Exchange (ETDEWEB)

None, None

2007-12-01

In a letter dated July 17, 2006, the Department of Energy’s (DOE) Office of Science for Nuclear Physics and the National Science Foundation’s (NSF) Mathematical and Physical Sciences Directorate charged the Nuclear Science Advisory Committee (NSAC) to “conduct a study of the opportunities and priorities for U.S. nuclear physics research and recommend a long range plan that will provide a framework for coordinated advancement of the nation’s nuclear science research programs over the next decade.” This request set in motion a bottom-up review and forward look by the nuclear science community. With input from this community-wide process, a 59 member working group, which included the present NSAC members, gathered at the beginning of May, 2007, to develop guidance on how to optimize the future research directions for the field based on the projected resources outlined in the charge letter from DOE and NSF. A new long range plan—The Frontiers of Nuclear Science—grew out of this meeting. For the last decade, the top priority for nuclear science has been to utilize the flagship facilities that were built with investments by the nation in the 1980s and 1990s. Research with these facilities has led to many significant new discoveries that have changed our understanding of the world in which we live. But new discoveries demand new facilities, and the successes cannot continue indefinitely without new investment.

Expression of Bcl-2 family proteins and spontaneous apoptosis in normal human testis.

Science.gov (United States)

Oldereid, N B; Angelis, P D; Wiger, R; Clausen, O P

2001-05-01

We investigated the frequency of spontaneous apoptosis and expression of the Bcl-2 family of proteins during normal spermatogenesis in man. Testicular tissue with both normal morphology and DNA content was obtained from necro-donors and fixed in Bouin's solution. A TdT-mediated dUTP end-labelling method (TUNEL) was used for the detection of apoptotic cells. Expression of apoptosis regulatory Bcl-2 family proteins and of p53 and p21(Waf1) was assessed by immunohistochemistry. Germ cell apoptosis was detected in all testes and was mainly seen in primary spermatocytes and spermatids and in a few spermatogonia. Bcl-2 and Bak were preferentially expressed in the compartments of spermatocytes and differentiating spermatids, while Bcl-x was preferentially expressed in spermatogonia. Bax showed a preferential expression in nuclei of round spermatids, whereas Bad was only seen in the acrosome region of various stages of spermatids. Mcl-1 staining was weak without a particular pattern, whereas expression of Bcl-w, p53 and p21(Waf1) proteins was not detected by immunohistochemistry. The results show that spontaneous apoptosis occurs in all male germ cell compartments in humans. Bcl-2 family proteins are distributed preferentially within distinct germ cell compartments suggesting a specific role for these proteins in the processes of differentiation and maturation during human spermatogenesis.

Efficient Long-Range Hole Transport Through G-Quadruplexes.

Science.gov (United States)

Wu, Jingyuan; Meng, Zhenyu; Lu, Yunpeng; Shao, Fangwei

2017-10-09

DNA offers a means of long-range charge transport for biology and electric nanodevices. Here, a series of tetra-stranded G-quadruplexes were assembled within a dendritic DNA architecture to explore oxidative charge transport (hole transport) through the G-quadruplex. Efficient charge transport was achieved over 28 Å upon UV irradiation. Over a longer G-quadruplex bridge, hole transport was escalated to a higher efficiency, which resulted in a higher yield than that of the optimal duplex DNA for charge transport, that is, the adenine tract. Efficient long-range hole transport suggests tetra-stranded G-quadruplexes, instead of an oxidation hotspot, hold better potential as an electron conduit than duplex DNA. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Segmentation of time series with long-range fractal correlations

Science.gov (United States)

Bernaola-Galván, P.; Oliver, J.L.; Hackenberg, M.; Coronado, A.V.; Ivanov, P.Ch.; Carpena, P.

2012-01-01

Segmentation is a standard method of data analysis to identify change-points dividing a nonstationary time series into homogeneous segments. However, for long-range fractal correlated series, most of the segmentation techniques detect spurious change-points which are simply due to the heterogeneities induced by the correlations and not to real nonstationarities. To avoid this oversegmentation, we present a segmentation algorithm which takes as a reference for homogeneity, instead of a random i.i.d. series, a correlated series modeled by a fractional noise with the same degree of correlations as the series to be segmented. We apply our algorithm to artificial series with long-range correlations and show that it systematically detects only the change-points produced by real nonstationarities and not those created by the correlations of the signal. Further, we apply the method to the sequence of the long arm of human chromosome 21, which is known to have long-range fractal correlations. We obtain only three segments that clearly correspond to the three regions of different G + C composition revealed by means of a multi-scale wavelet plot. Similar results have been obtained when segmenting all human chromosome sequences, showing the existence of previously unknown huge compositional superstructures in the human genome. PMID:23645997

Segmentation of time series with long-range fractal correlations.

Science.gov (United States)

Bernaola-Galván, P; Oliver, J L; Hackenberg, M; Coronado, A V; Ivanov, P Ch; Carpena, P

2012-06-01

Segmentation is a standard method of data analysis to identify change-points dividing a nonstationary time series into homogeneous segments. However, for long-range fractal correlated series, most of the segmentation techniques detect spurious change-points which are simply due to the heterogeneities induced by the correlations and not to real nonstationarities. To avoid this oversegmentation, we present a segmentation algorithm which takes as a reference for homogeneity, instead of a random i.i.d. series, a correlated series modeled by a fractional noise with the same degree of correlations as the series to be segmented. We apply our algorithm to artificial series with long-range correlations and show that it systematically detects only the change-points produced by real nonstationarities and not those created by the correlations of the signal. Further, we apply the method to the sequence of the long arm of human chromosome 21, which is known to have long-range fractal correlations. We obtain only three segments that clearly correspond to the three regions of different G + C composition revealed by means of a multi-scale wavelet plot. Similar results have been obtained when segmenting all human chromosome sequences, showing the existence of previously unknown huge compositional superstructures in the human genome.

Long-range alpha detector (LRAD)

International Nuclear Information System (INIS)

MacArthur, D.W.; McAtee, J.L.

1991-01-01

Historically, alpha detectors have been limited by the very short range of alpha particles in air and by relatively poor sensitivity, even if the particles are intercepted. Of necessity, these detectors are operated in a vacuum or in close proximity to the source if reasonable efficiency is desired. In our new long-range alpha detector (LRAD), alpha particles interact with the ambient air, producing ionization in the air at the rate of about 30,000 ion pairs per MeV of alpha energy. These charges can be transported over significant distances (several meters) in a moving current of air generated by a small fan. An ion chamber located in front of the fan measures the current carried by the moving ions. The LRAD-based monitor is more sensitive and more thorough than conventional monitors. We present current LRAD sensitivity limits and results, practical monitor designs, and proposed uses for LRAD monitors. 4 refs., 7 figs

Protein phosphatase 2A mediates JS-K-induced apoptosis by affecting Bcl-2 family proteins in human hepatocellular carcinoma HepG2 cells.

Science.gov (United States)

Liu, Ling; Huang, Zile; Chen, Jingjing; Wang, Jiangang; Wang, Shuying

2018-04-25

Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K-induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342 + /PI + dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up-regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A-C by siRNA could abolish the activation of PP2A-C, down-regulation of anti-apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins. © 2018 Wiley Periodicals, Inc.

Bcl-w Enhances Mesenchymal Changes and Invasiveness of Glioblastoma Cells by Inducing Nuclear Accumulation of β-Catenin

Science.gov (United States)

Lee, Woo Sang; Woo, Eun Young; Kwon, Junhye; Park, Myung-Jin; Lee, Jae-Seon; Han, Young-Hoon; Bae, In Hwa

2013-01-01

Bcl-w a pro-survival member of the Bcl-2 protein family, is expressed in a variety of cancer types, including gastric and colorectal adenocarcinomas, as well as glioblastoma multiforme (GBM), the most common and lethal brain tumor type. Previously, we demonstrated that Bcl-w is upregulated in gastric cancer cells, particularly those displaying infiltrative morphology. These reports propose that Bcl-w is strongly associated with aggressive characteristic, such as invasive or mesenchymal phenotype of GBM. However, there is no information from studies of the role of Bcl-w in GBM. In the current study, we showed that Bcl-w is upregulated in human glioblastoma multiforme (WHO grade IV) tissues, compared with normal and glioma (WHO grade III) tissues. Bcl-w promotes the mesenchymal traits of glioblastoma cells by inducing vimentin expression via activation of transcription factors, β-catenin, Twist1 and Snail in glioblastoma U251 cells. Moreover, Bcl-w induces invasiveness by promoting MMP-2 and FAK activation via the PI3K-p-Akt-p-GSK3β-β-catenin pathway. We further confirmed that Bcl-w has the capacity to induce invasiveness in several human cancer cell lines. In particular, Bcl-w-stimulated β-catenin is translocated into the nucleus as a transcription factor and promotes the expression of target genes, such as mesenchymal markers or MMPs, thereby increasing mesenchymal traits and invasiveness. Our findings collectively indicate that Bcl-w functions as a positive regulator of invasiveness by inducing mesenchymal changes and that trigger their aggressiveness of glioblastoma cells. PMID:23826359

Butyrate down regulates BCL-XL and sensitizes human fibroblasts to radiation and chemotherapy induced apoptosis

International Nuclear Information System (INIS)

Chung, Diana H.; Ljungman, Mats; Zhang Fenfen; Chen Feng; McLaughlin, William P.

1997-01-01

Purpose/Objective: Butyrate is a short chain fatty acid that has been implicated in the induction of cell cycle arrest, cell differentiation and apoptosis. The purpose of this study was to determine if butyrate treatment sensitizes cells to radiation or chemotherapy induced apoptosis. Materials and Methods: Normal neonatal human diploid fibroblasts were used throughout this study. Apoptosis was scored and quantified using three different methods. First, cell morphology using propidium iodide and fluorescence microscopy was used to qualitatively determine apoptosis and to quantify the percentage of cells undergoing apoptosis. Second, apoptosis induced DNA degradation was scored by quantifying the amount of cells appearing in a sub-G1 peak using fixed and PI-stained cells and flow cytometry. Third, apoptosis-induced DNA degradation was examined by using an assay involving direct lysis of cells in the wells of agarose gels followed by conventional gel electrophoresis. Western blotting was used to quantify the cellular levels of the apoptosis regulators, Bcl-2, Bcl-XL and Bax. Results: Human diploid fibroblasts, which were resistant to radiation induced apoptosis, were found to undergo massive apoptosis when radiation was combined with butyrate treatment. Sensitization was obtained when butyrate was added before or after radiation although the combination of both pre and post-treatment was the most effective. Butyrate was also found to enhance UV light and cisplatin-induced apoptosis. These findings correlated with a reduction of the apoptosis antagonist Bcl-XL. Bcl-XL levels significantly dropped in a time and dose dependent manner. In addition, butyrate effectively blocked UV-induced accumulation of p53. Conclusion: Our results suggest that butyrate may be an attractive agent to use in combination with radiation or chemotherapy to lower the apoptotic threshold of tumor cells, regardless of the p53 status of the tumor cells

Long-range transport and deposition of sulfur in Asia

International Nuclear Information System (INIS)

Arndt, R.L.; Carmichael, G.R.

1995-01-01

The long range transport of sulfur in Asia is analyzed through the use of a multi-dimensional acid deposition model. The air quality of this region is heavily influenced by the combination of Asia's growing population, its expanding economy, and the associated systems of energy consumption and production. These factors combined with a shift to using indigenous coal as the primary fuel source for the region, will result in increased emissions of pollutants into the environment. By the year 2020 sulfur emissions from Asia are projected to exceed the combined emissions from Europe and North America. The authors have estimated sulfur deposition in Asia on a one-by-one degree spatial resolution in the region from Pakistan to Japan and from Indonesia to Mongolia using a 3-layer Lagrangian model. Deposition in excess of 10 g S/m 2 is predicted in south-central China. The relationship between emission source and receptor has been developed into a deposition matrix and examples of the source-receptor relationship are presented. 11 refs., 2 figs., 2 tabs

Gauge hierarchy and long range forces

International Nuclear Information System (INIS)

Pal, P.B.; Keung, Wai-Yee; Chang, D.

1990-01-01

With the aid of simple examples, we show how a long range attractive force can arise in a gauge theory with a hierarchy. The force is due to the exchange of a Higgs boson whose mass and matter couplings are both naturally suppressed by the hierarchical mass ratio. Such bosons appear if there is an accidental global symmetry in the low-energy renormalizable Lagrangian after the high energy symmetry breaking. 6 refs

A Study on Techniques for Focusing Circumferential Array Guided Waves for Long Range Inspection of Pipes

International Nuclear Information System (INIS)

Kang, To; Kim, Hak Joon; Song, Sung Jin; Cho, Young Do; Lee, Dong Hoon; Cho, Hyun Joon

2009-01-01

Ultrasonic guided waves have been widely utilized for long range inspection of structures. Especially, development of array guided waves techniques and its application for long range gas pipe lines(length of from hundreds meters to few km) were getting increased. In this study, focusing algorithm for array guided waves was developed in order to improve long range inspectability and accuracy of the array guided waves techniques for long range inspection of gas pipes, and performance of the developed techniques was verified by experiments using the developed array guided wave system. As a result, S/N ratio of array guided wave signals obtained with the focusing algorithm was increased higher than that of signals without focusing algorithm

UTag: Long-range Ultra-wideband Passive Radio Frequency Tags

Energy Technology Data Exchange (ETDEWEB)

Dowla, F

2007-03-14

Long-range, ultra-wideband (UWB), passive radio frequency (RF) tags are key components in Radio Frequency IDentification (RFID) system that will revolutionize inventory control and tracking applications. Unlike conventional, battery-operated (active) RFID tags, LLNL's small UWB tags, called 'UTag', operate at long range (up to 20 meters) in harsh, cluttered environments. Because they are battery-less (that is, passive), they have practically infinite lifetimes without human intervention, and they are lower in cost to manufacture and maintain than active RFID tags. These robust, energy-efficient passive tags are remotely powered by UWB radio signals, which are much more difficult to detect, intercept, and jam than conventional narrowband frequencies. The features of long range, battery-less, and low cost give UTag significant advantage over other existing RFID tags.

Relationships Between Long-Range Lightning Networks and TRMM/LIS Observations

Science.gov (United States)

Rudlosky, Scott D.; Holzworth, Robert H.; Carey, Lawrence D.; Schultz, Chris J.; Bateman, Monte; Cummins, Kenneth L.; Cummins, Kenneth L.; Blakeslee, Richard J.; Goodman, Steven J.

2012-01-01

Recent advances in long-range lightning detection technologies have improved our understanding of thunderstorm evolution in the data sparse oceanic regions. Although the expansion and improvement of long-range lightning datasets have increased their applicability, these applications (e.g., data assimilation, atmospheric chemistry, and aviation weather hazards) require knowledge of the network detection capabilities. The present study intercompares long-range lightning data with observations from the Lightning Imaging Sensor (LIS) aboard the Tropical Rainfall Measurement Mission (TRMM) satellite. The study examines network detection efficiency and location accuracy relative to LIS observations, describes spatial variability in these performance metrics, and documents the characteristics of LIS flashes that are detected by the long-range networks. Improved knowledge of relationships between these datasets will allow researchers, algorithm developers, and operational users to better prepare for the spatial and temporal coverage of the upcoming GOES-R Geostationary Lightning Mapper (GLM).

Mott scattering as a probe of long range QCD

International Nuclear Information System (INIS)

Bertulani, C.A.; Balantekin, A.B.

1993-12-01

We investigate the possibility of using the Mott scattering between identical nuclei to assess the existence of long range QCD, e.g., a color Van der Waals interaction, as suggested recently. Among other effects which were not considered before, the tail of the nuclear potential, emission of radiation by Bremsstrahlung, atomic screening, emission of delta-electrons, and the quasi-molecule binding are included in our calculations. We show that the sum of these effects can explain the observed shift in the Mott oscillations in a recent experiment. (orig.)

Long-range forecasting of intermittent streamflow

OpenAIRE

F. F. van Ogtrop; R. W. Vervoort; G. Z. Heller; D. M. Stasinopoulos; R. A. Rigby

2011-01-01

Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a statistical model to forecast streamflow up to 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS) to determine th...

Long-range forecasting of intermittent streamflow

OpenAIRE

F. F. van Ogtrop; R. W. Vervoort; G. Z. Heller; D. M. Stasinopoulos; R. A. Rigby

2011-01-01

Long-range forecasting of intermittent streamflow in semi-arid Australia poses a number of major challenges. One of the challenges relates to modelling zero, skewed, non-stationary, and non-linear data. To address this, a probabilistic statistical model to forecast streamflow 12 months ahead is applied to five semi-arid catchments in South Western Queensland. The model uses logistic regression through Generalised Additive Models for Location, Scale and Shape (GAMLSS) to determine the probabil...

Long-range terms in atomic collisions

International Nuclear Information System (INIS)

McGuire, J.H.; Weaver, O.L.

1986-01-01

Various separations, or ''gauge choices,'' are possible for the decomposition of the total Hamiltonian into electronic and internuclear terms. We show that, for one particular choice, all long-range Coulomb terms are associated with the internuclear motion. The potential then associated with electronic transitions is non-Coulombic. Some practical consequences of this gauge choice are discussed

Highly selective SiO2 etching over Si3N4 using a cyclic process with BCl3 and fluorocarbon gas chemistries

Science.gov (United States)

Matsui, Miyako; Kuwahara, Kenichi

2018-06-01

A cyclic process for highly selective SiO2 etching with atomic-scale precision over Si3N4 was developed by using BCl3 and fluorocarbon gas chemistries. This process consists of two alternately performed steps: a deposition step using BCl3 mixed-gas plasma and an etching step using CF4/Ar mixed-gas plasma. The mechanism of the cyclic process was investigated by analyzing the surface chemistry at each step. BCl x layers formed on both SiO2 and Si3N4 surfaces in the deposition step. Early in the etching step, the deposited BCl x layers reacted with CF x radicals by forming CCl x and BF x . Then, fluorocarbon films were deposited on both surfaces in the etching step. We found that the BCl x layers formed in the deposition step enhanced the formation of the fluorocarbon films in the CF4 plasma etching step. In addition, because F radicals that radiated from the CF4 plasma reacted with B atoms while passing through the BCl x layers, the BCl x layers protected the Si3N4 surface from F-radical etching. The deposited layers, which contained the BCl x , CCl x , and CF x components, became thinner on SiO2 than on Si3N4, which promoted the ion-assisted etching of SiO2. This is because the BCl x component had a high reactivity with SiO2, and the CF x component was consumed by the etching reaction with SiO2.

Thermodynamic study on co-deposition of ZrB2–SiC from ZrCl4–BCl3–CH3SiCl3–H2–Ar system

International Nuclear Information System (INIS)

Deng, Juanli; Cheng, Laifei; Zheng, Guopeng; Su, Kehe; Zhang, Litong

2012-01-01

Thermodynamics phase diagram of ZrB 2 –SiC co-deposited from precursors of ZrCl 4 –BCl 3 –CH 3 SiCl 3 (methyltrichlorosilane, MTS)–H 2 –Ar has been investigated in detail by using the FactSage code and its embedded database (130 species being involved). The yields of condensed phases in the co-deposition process have been examined as the functions of the inject reactant ratios of BCl 3 / (BCl 3 + MTS) and H 2 / (ZrCl 4 + BCl 3 + MTS), and the temperature at a fixed pressure of 5 kPa. The results show that their yields strongly depend on the molar ratios of the inject reactants and the temperature. Consequently, the pure ZrB 2 –SiC composite without free C, B 4 C, ZrC and ZrSi can be co-deposited under the ideal condition by adjusting the reactant ratios and the temperature. The gas-phase equilibrium concentration distribution shows that the high input amount of H 2 is favorable for the co-deposition of ZrB 2 and SiC at a fixed ratio of ZrCl 4 :BCl 3 :MTS:Ar. In the end, the theoretical results can lay down guidelines for increasing the experimental yields of ZrB 2 and SiC. - Highlights: ► The exact ratio of ZrB 2 and SiC could be obtained by adjusting input gas ratios. ► The other condensed phase species could appear under some suitable conditions ► The H 2 acting as reaction species directly influences the deposition process. ► The high H 2 input amount is favorable for the co-deposition of ZrB 2 and SiC. ► The flow rate range of the H 2 pump should be increased in the experimental study.

Long-range alpha detector

International Nuclear Information System (INIS)

MacArthur, D.W.; McAtee, J.L.

1991-01-01

Historically, alpha-particle and alpha-contamination detectors have been limited by the very short range of alpha particles in air and by relatively poor sensitivity even if the particles are intercepted. Alpha detectors have had to be operated in a vacuum or in close proximity to the source if reasonable efficiency is desired. Alpha particles interact with the ambient air, producing ionization in the air at the rate of ∼30,000 ion pairs per mega-electron-volt of alpha energy. These charges can be transported over significant distances (several meters) in a moving current of air generated by a small fan. An ion chamber located in front of the fan measures the current carried by the moving ions. The long-range alpha detector (LRAD) offers several advantages over more traditional alpha detectors. First and foremost, it can operate efficiently even if the contamination is not easily accessible. Second, ions generated by contamination in crevices and other unmonitorable locations can be detected if the airflow penetrates those areas. Third, all of the contamination on a large surface will generate ions that can be detected in a single detector; hence, the detector's sensitivity to distributed sources is not limited by the size of the probe. Finally, a simple ion chamber can detect very small electric currents, making this technique potentially quite sensitive

Stress Hormone Cortisol Enhances Bcl2 Like-12 Expression to Inhibit p53 in Hepatocellular Carcinoma Cells.

Science.gov (United States)

Wu, Weizhong; Liu, Sanguang; Liang, Yunfei; Zhou, Zegao; Bian, Wei; Liu, Xueqing

2017-12-01

The pathogenesis of hepatocellular carcinoma (HC) is unclear. It is suggested that psychological stress associates with the pathogenesis of liver cancer. Bcl2-like protein 12 (Bcl2L12) suppresses p53 protein. This study tests a hypothesis that the major stress hormone, cortisol, inhibits the expression of p53 in HC cells (HCC) via up regulating the expression of Bcl2L12. Peripheral blood samples were collected from patients with HC to be analyzed for the levels of cortisol. HCC were cultured to assess the role of cortisol in the regulation of the expression of Bcl2L12 and p53 in HCC. We observed that the serum cortisol levels were higher in HC patients. Expression of Bcl2L12 in HCC was correlated with serum cortisol. Cortisol enhanced the Bcl2L12 expression in HCC. Bcl2L12 binding to the TP53 promoter was correlated with p53 expression in HCC. Cortisol increased the Bcl2L12 expression in HCC to inhibit p53 expression. Stress hormone cortisol suppresses p53 in HCC via enhancing Bcl2L12 expression in HCC. The results suggest that cortisol may be a therapeutic target for the treatment of HC.

Serial Determination of bcl-2 Major Breakpoint Region (MBR) Rearrangement, t(14;18) (q32;q21), in the Bone Marrow and Peripheral Blood for Stages I - III Follicular Lymphoma after Central Lymphatic Irradiation (CLI) - A Preliminary Report

International Nuclear Information System (INIS)

Ha, C.S.; Cabanillas, F.; Lee, M.; Besa, P.C.; McLaughlin, P.W.; Cox, J.D.

1995-01-01

Purpose/Objective: About (2(3)) of all cases of follicular lymphoma have rearrangement of bcl-2 MBR through t(14;18) (q32;q21). This arrangement could serve as a sensitive marker for follicular lymphoma cells. The objectives of this study are two fold: 1) To assess complete molecular response rate of stages I-III follicular lymphoma to CLI by detection of PCR amplifiable bcl-2 MBR rearrangement in the bone marrow and peripheral blood before and after CLI. 2) To assess the significance of the molecular response as a prognostic indicator. Materials and Methods: 13 patients with stages I-III follicular lymphoma were treated with CLI as a part of a prospective randomized protocol comparing CLI with chemotherapy. Bone marrow and peripheral blood samples were obtained from the patients before initiation of CLI. By using the PCR technique, the DNA sequences from the bone marrow and peripheral blood samples that flank the bcl-2 MBR involved in t(14;18) (q32;q21) were amplified. For the patients who had positive PCR result, bone marrow and blood samples were followed at regular intervals during and after CLI. The patients with negative PCR result prior to CLI did not have follow-up PCR analysis. The results of the PCR amplification were correlated with clinical findings. Results: All 13 patients achieved clinical complete response after CLI. No patient has relapsed with a median follow-up period of 11 months (range 5 to 24 months). Pretreatment PCR results are available in 13 patients for peripheral blood and in 9 patients for bone marrow. (7(13)) blood and (5(9)) bone marrow samples were PCR-positive for bcl-2 MBR rearrangement. All 5 patients with positive pretreatment bone marrow also had positive pretreatment peripheral blood. (6(7)) patients with positive pretreatment blood PCR converted to negative within 2,3,5,6,6, and 10 months from the 1st day of CLI. The 7th patient has no follow-up PCR available yet. Follow-up PCR results from the pretreatment bone

Real world data on young patients with high-risk diffuse large B-cell lymphoma treated with R-CHOP or R-CHOEP - MYC, BCL2 and BCL6 as prognostic biomarkers.

Directory of Open Access Journals (Sweden)

Mette Ølgod Pedersen

Full Text Available Double expression of MYC and BCL2 proteins (DE and double-hit MYC+BCL2/BCL6 translocations (DH were established as important biomarkers in patients with diffuse large B-cell lymphoma (DLBCL by the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Whether this applies to the subgroup of young patients with high risk DLBCL is not known. We previously found that in a uniform retrospective population-based cohort of patients aged 18-60 years with high-risk DLBCL, the addition of etoposide to R-CHOP chemotherapy (R-CHOEP resulted in improved survival mainly in patients with germinal center B-cell like (GCB immunophenotype. The aim of this study was to investigate the prognostic and predictive value of DE and DH in this patient cohort.Data on all young Danish patients diagnosed with de novo high-risk DLBCL 2004-2008 and treated with R-CHOP or R-CHOEP were obtained from the Danish Lymphoma database (n = 159. Tumor samples were available from 103 patients. MYC and BCL2 proteins were analyzed with quantitative immunohistochemistry (IHC using different cut off values. MYC-, BCL2- and BCL6-translocations were examined with fluorescent in situ hybridization (FISH.DE with MYC>75% and BCL2>85% was an independent negative prognostic marker of progression free survival (PFS in patients treated with R-CHOP but not R-CHOEP (p<0.001, also after exclusion of patients with DH. A predictive effect of DE for response (PFS to R-CHOEP vs. R-CHOP was almost significant (p = 0.07. DH was not prognostic in this patient cohort.In young patients with high-risk DLBCL, treatment with R-CHOEP may overcome the negative prognostic impact of DE observed in patients treated with R-CHOP.

The anti-apoptotic members of the Bcl-2 family are attractive tumor-associated antigens

DEFF Research Database (Denmark)

Straten, Per thor; Andersen, Mads Hald; Andersen, Mads Hald

2010-01-01

Anti-apoptotic members of the Bcl-2 family (Bcl-2, Bcl-X(L) and Mcl-2) are pivotal regulators of apoptotic cell death. They are all highly overexpressed in cancers of different origin in which they enhance the survival of the cancer cells. Consequently, they represent prime candidates for anti-ca...

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside.

Science.gov (United States)

Vela, Laura; Marzo, Isabel

2015-08-01

Bcl-2 proteins are key determinants in the life-death balance. In recent years, proteins in this family have been identified as drug targets in the design of new anti-tumor therapies. Advances in the knowledge of the mechanism of action of anti-apoptotic and pro-apoptotic members of the Bcl-2 family have enabled the development of the so-called 'BH3 mimetics'. These compounds act by inhibiting anti-apoptotic proteins of the family, imitating the function of the BH3-only subset of pro-apoptotic members. Combinations of BH3-mimetics with anti-tumor drugs are being evaluated in both preclinical models and clinical trials. Recent advances in these approaches will be reviewed. Copyright © 2015 Elsevier Ltd. All rights reserved.

RNA interference suppression of A100A4 reduces the growth and metastatic phenotype of human renal cancer cells via NF-kB-dependent MMP-2 and bcl-2 pathway.

Science.gov (United States)

Yang, X-C; Wang, X; Luo, L; Dong, D-H; Yu, Q-C; Wang, X-S; Zhao, K

2013-06-01

of lung metastases was inhibited by 89% (p kB, MMP-2 and bcl-2 suppression. We conclude that S100A4 plays a crucial role in proliferation and migratory/invasive processes in human RCC by a mechanism involving activation of NF-kB-bcl-2 and NF-kB-MMP-2 pathway.

Bcl-2 family-regulated apoptosis in health and disease

Directory of Open Access Journals (Sweden)

Grant Dewson

2010-04-01

Full Text Available Grant Dewson, Ruth M KluckMolecular Genetics of Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, AustraliaAbstract: Apoptotic cell death is essential for embryonic development, tissue homeostasis, and a well-functioning immune system, with aberrant apoptosis contributing to numerous disease conditions. Inadequate cell death is a major contributing factor to tumorigenesis, while excess cell death contributes to neurodegeneration and autoimmune disease. The major pathway of apoptotic cell death, the mitochondrial pathway, is controlled by the Bcl-2 family of proteins. The members of this family, more than 17 in humans, share significant sequence and structural homology, and fulfil either prosurvival or proapoptotic roles. Specific interactions between these functionally polar proteins, and their relative expression levels, govern the susceptibility of each cell to toxic insults. Here we review the current understanding on how apoptotic cell death is controlled by this important protein family. We also discuss how excessive or insufficient cell death can contribute to disease, and how targeting the Bcl-2 family offers novel therapeutic opportunities.Keywords: apoptosis, Bcl-2, cancer, cytochrome c, mitochondria

A light-up probe targeting for Bcl-2 2345 G-quadruplex DNA with carbazole TO

Science.gov (United States)

Gu, Yingchun; Lin, Dayong; Tang, Yalin; Fei, Xuening; Wang, Cuihong; Zhang, Baolian; Zhou, Jianguo

2018-02-01

As its significant role, the selective recognition of G-quadruplex with specific structures and functions is important in biological and medicinal chemistry. Carbazole derivatives have been reported as a kind of fluorescent probe with many excellent optical properties. In the present study, the fluorescence of the dye (carbazole TO) increased almost 70 fold in the presence of bcl-2 2345 G4 compared to that alone in aqueous buffer condition with almost no fluorescence and 10-30 fold than those in the presence of other DNAs. The binding study results by activity inhibition of G4/Hemin peroxidase experiment, NMR titration and molecular docking simulation showed the high affinity and selectivity to bcl-2 2345 G4 arises from its end-stacking interaction with G-quartet. It is said that a facile approach with excellent sensitive, good selectivity and quick response for bcl-2 2345 G-quadruplex was developed and may be used for antitumor recognition or antitumor agents.

Long range diffusion of hydrogen in yttrium

International Nuclear Information System (INIS)

Anderson, I.S.; Scherrer, P.; Ross, D.K.

1989-01-01

The diffusion of H in single crystals of YH 0.2 is investigated by means of Quasielastic neutron scattering between 593 K and 695 K. Individual jump rates giving rise to long range and local diffusion are determined. (orig.)

Force-induced unzipping of DNA with long-range correlated sequence

OpenAIRE

Allahverdyan, A. E.; Gevorkian, Zh. S.

2002-01-01

We consider force-induced unzipping transition for a heterogeneous DNA model with a long-range correlated base-sequence. It is shown that as compared to the uncorrelated situation, long-range correlations smear the unzipping phase-transition, change its universality class and lead to non-self-averaging: the averaged behavior strongly differs from the typical ones. Several basic scenarios for this typical behavior are revealed and explained. The results can be relevant for explaining the biolo...

Structure function analysis of long-range correlations in plasma turbulence

International Nuclear Information System (INIS)

Yu, C.X.; Gilmore, M.; Peebles, W.A.; Rhodes, T.L.

2003-01-01

Long-range correlations (temporal and spatial) have been predicted in a number of different turbulence models, both analytical and numerical. These long-range correlations are thought to significantly affect cross-field turbulent transport in magnetically confined plasmas. The Hurst exponent, H - one of a number of methods to identify the existence of long-range correlations in experimental data - can be used to quantify self-similarity scalings and correlations in the mesoscale temporal range. The Hurst exponent can be calculated by several different algorithms, each of which has particular advantages and disadvantages. One method for calculating H is via structure functions (SFs). The SF method is a robust technique for determining H with several inherent advantages that has not yet been widely used in plasma turbulence research. In this article, the SF method and its advantages are discussed in detail, using both simulated and measured fluctuation data from the DIII-D tokamak [J. L. Luxon and L. G. Davis, Fusion Technol. 8, 441 (1985)]. In addition, it is shown that SFs used in conjunction with rescaled range analysis (another method for calculating H) can be used to mitigate the effects of coherent modes in some cases

Enhanced dopaminergic differentiation of human neural stem cells by synergistic effect of Bcl-xL and reduced oxygen tension

DEFF Research Database (Denmark)

Krabbe, Christina; Courtois, Elise; Jensen, Pia

2009-01-01

Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic different......Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic...... days at 20% oxygen, hVMbcl-x(L) cultures contained proportionally more tyrosine hydroxylase(TH)-positive cells than hVM1 control cultures. This difference was significantly potentiated from 11 +/- 0.8% to 17.2 +/- 0.2% of total cells when the oxygen tension was lowered to 3%. Immunocytochemistry and Q...

Effect of Bcl-2/Bax gene expression on apoptosis of spermatogenic cells of mouse testes induced by low dose radiation

International Nuclear Information System (INIS)

Liu Guangwei; Wang Chunyan; Lu Zhe; Liu Shunchun; Gong Shouliang

2003-01-01

The different kinds of spermatogenic cells were separated using density gradient centrifugation and their apoptosis and Bcl-2 and Bax protein expression were measured with flow cytometry and immunohistochemical method, respectively. The results showed the apoptosis in all kinds of spermatogenic cells induced by low dose radiation (LDR) had a obvious regularity. When the doses were 0.025 and 0.05 Gy, spermatogonia apoptosis was dominant. With the increase of irradiation dose (0.075-0.2 Gy), spermatocytes also showed an apoptotic change, but the apoptotic percentage of spermatogonia was significantly higher than that of spermatocytes. Moreover, the apoptosis of spermatids and spermatozoa scarcely occurred after LDR. Bax protein was primarily expressed in spermatogonia and spermatocytes, and the former was significantly higher than that of the latter after LDR. With the increase of irradiation dose, Bax protein expression showed a upgrading tendency, but that of spermatids and spermatozoa scarcely occurred. Bcl-2 protein was primarily expressed in spermatids and spermatozoa, but the Bcl-2 protein expressions of spermatogonia and spermatocytes scarcely occurred after LDR. These results imply that the interacting regulation of Bcl-2 and Bax gene expression might be involved in selective apoptosis of spermatogenic cells induced by LDR, which provided an experimental evidence for further exploring the apoptotic mechanism of adaptive response of spermatogenic cells by LDR

Regional and long-range transport of air pollution

International Nuclear Information System (INIS)

Sandroni, S.

1987-01-01

The Course lectures presented are organised in four sections: atmospheric transport, conversion, deposition of atmospheric trace constituents and associated problems; conventional and sophisticated techniques for atmospheric sounding (e.g., Sodar, Lidar, Cospec, tetroons, instrument-carrying aircraft) and simulation techniques (non-reactive tracers); models available for various applications (long-range episodes, long-term averages, photochemical and deposition processes); a comparison of performances of different models and the linearity problem in the formation of acid deposition

Long-range Coulomb interactions in low energy (e,2e) data

International Nuclear Information System (INIS)

Waterhouse, D.

2000-01-01

Full text: Proper treatment of long-range Coulomb interactions has confounded atomic collision theory since Schrodinger first presented a quantum-mechanical model for atomic interactions. The long-range Coulomb interactions are difficult to include in models in a way that treats the interaction sufficiently well but at the same time ensures the calculation remains tractable. An innovative application of an existing multi-parameter (e,2e) data acquisition system will be described. To clarify the effects of long-range Coulomb interactions, we will report the correlations and interactions that occur at low energy, observed by studying the energy sharing between outgoing electrons in the electron-impact ionisation of krypton

Pad A treatability study long-range project plan

International Nuclear Information System (INIS)

Mousseau, J.D.

1991-06-01

This plan addresses the work to be accomplished by the Pad A Treatability Study Project. The purpose of this project is to investigate potential treatment and separation technologies, identify the best technologies, and to demonstrate by both lab- and pilot-scale demonstration, the most applicable remedial technologies for treating plutonium-contaminated salts at the Pad A site located at the Subsurface Disposal Area (SDA) at the Radioactive Waste Management Complex (RWMC) a the Idaho National Engineering Laboratory (INEL). The conduct of this project will be supported by other DOE laboratories, universities, and private industries, who will provide support for near-term demonstrations of treatment and separation technologies. The purpose of this long-range planning document is to present the detailed plan for the implementation of the Pad A Treatability Study Project

Long range diffusion of hydrogen in yttrium

Energy Technology Data Exchange (ETDEWEB)

Anderson, I S; Scherrer, P [Paul Scherrer Inst., Villigen (Switzerland); Ross, D K [Birmingham Univ. (UK). Dept. of Physics; Bonnet, J E [Laboratoire pour l' Utilisation du Rayonnement Electromagnetique (LURE), Paris-11 Univ., 91 - Orsay (France)

1989-01-01

The diffusion of H in single crystals of YH{sub 0.2} is investigated by means of Quasielastic neutron scattering between 593 K and 695 K. Individual jump rates giving rise to long range and local diffusion are determined. (orig.).

A plant Bcl-2-associated athanogene is proteolytically activated to confer fungal resistance

Directory of Open Access Journals (Sweden)

Mehdi Kabbage

2016-04-01

Full Text Available The Bcl-2-associated athanogene (BAG family is a multifunctional group of proteins involved in numerous cellular functions ranging from apoptosis to tumorigenesis. These proteins are evolutionarily conserved and encode a characteristic region known as the BAG domain. BAGs function as adapter proteins forming complexes with signaling molecules and molecular chaperones. In humans, a role for BAG proteins has been suggested in tumor growth, HIV infection, and neurodegenerative diseases; as a result, the BAGs are attractive targets for therapeutic interventions, and their expression in cells may serve as a predictive tool for disease development. The Arabidopsis genome contains seven homologs of BAG family proteins (Figure 1, including four with a domain organization similar to animal BAGs (BAG1-4. The remaining three members (BAG5-7 contain a predicted calmodulin-binding motif near the BAG domain, a feature unique to plant BAG proteins that possibly reflects divergent mechanisms associated with plant-specific functions. As reported for animal BAGs, plant BAGs also regulate several stress and developmental processes (Figure 2. The recent article by Li et al. focuses on the role of BAG6 in plant innate immunity. This study shows that BAG6 plays a key role in basal plant defense against fungal pathogens. Importantly, this work further shows that BAG6 is proteolytically activated to induce autophagic cell death and resistance in plants. This finding underscores the importance of proteases in the execution of plant cell death, yet little is known about proteases and their substrates in plants.

Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio

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Azimahtol Hawariah LP

2007-04-01

Full Text Available Abstract Background Zerumbone is a cytotoxic component isolated from Zingiber zerumbet Smith, a herbal plant which is also known as lempoyang. This new anticancer bioactive compound from Z. zerumbet was investigated for its activity and mechanism in human liver cancer cell lines. Results Zerumbone significantly showed an antiproliferative activity upon HepG2 cells with an IC50 of 3.45 ± 0.026 μg/ml. Zerumbone was also found to inhibit the proliferation of non-malignant Chang Liver and MDBK cell lines. However the IC50 obtained was higher compared to the IC50 for HepG2 cells (> 10 μg/ml. The extent of DNA fragmentation was evaluated by the Tdt-mediated dUTP nick end labelling assay which showed that, zerumbone significantly increased apoptosis in HepG2 cells in a time-course manner. In detail, the apoptotic process triggered by zerumbone involved the up-regulation of pro-apoptotic Bax protein and the suppression of anti-apoptotic Bcl-2 protein expression. The changes that occurred in the levels of this antagonistic proteins Bax/Bcl-2, was independent of p53 since zerumbone did not affect the levels of p53 although this protein exists in a functional form. Western blotting analysis for Bax protein was further confirmed qualitatively with an immunoassay that showed the distribution of Bax protein in zerumbone-treated cells. Conclusion Therefore, zerumbone was found to induce the apoptotic process in HepG2 cells through the up and down regulation of Bax/Bcl-2 protein independently of functional p53 activity.

Long-range correlations of different EEG derivations in rats: sleep stage-dependent generators may play a key role

International Nuclear Information System (INIS)

Fang, Guangzhan; Xia, Yang; Lai, Yongxiu; You, Zili; Yao, Dezhong

2010-01-01

For the electroencephalogram (EEG), topographic differences in the long-range temporal correlations would imply that these signals might be affected by specific mechanisms related to the generation of a given neuronal process. So the properties of the generators of various EEG oscillations might be investigated by their spatial differences of the long-range temporal correlations. In the present study, these correlations were characterized with respect to their topography during different vigilance states by detrended fluctuation analysis (DFA). The results indicated that (1) most of the scaling exponents acquired from different EEG derivations for various oscillations were significantly different in each vigilance state; these differences might be resulted from the different quantities and different locations of sleep stage-dependent generators of various neuronal processes; (2) there might be multiple generators of delta and theta over the brain and many of them were sleep stage-dependent; (3) the best site of the frontal electrode in a fronto-parietal bipolar electrode for sleep staging might be above the anterior midline cortex. We suggest that DFA analysis can be used to explore the properties of the generators of a given neuronal oscillation, and the localizations of these generators if more electrodes are involved

Translocation t(11;14 (q13;q32 and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study

Directory of Open Access Journals (Sweden)

Ivyna Bong Pau Ni

2012-09-01

Full Text Available More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR-based translocation detection assay to detect BCL1/JH t(11;14 (q13;q32 in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14 (q13;q32 translocation (n=15 of 105. We found no significant correlation between this translocation with age (P=0.420, gender (P=0.317, ethnicity (P=0.066 or new/relapsed status of multiple myeloma (P=0.412 at 95% confidence interval level by x2 test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14(q13;q32 translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14 (q13;q32 translocation.

A long-range attractive interaction of rotons in superfluid 4He

International Nuclear Information System (INIS)

Nishiyama, Toshiyuki; Sai, Shunkichi

1974-01-01

With the use of the method of the collective description developed by one of the authors (N) for superfluid 4 He, it is shown that a long-range interaction of rotons transmitted by phonons is attractive and yields a resonance state of a roton pair with the binding energy of the order of magnitude 0.12 K which is relevant to the recent experimental results of the Raman scattering. The effect of the short-range mutual interaction of rotons is also discussed. Some comments on the relationship to the other theories of the collective description are made in appendices. (author)

Testing for long-range dependence in the Brazilian term structure of interest rates

International Nuclear Information System (INIS)

Cajueiro, Daniel O.; Tabak, Benjamin M.

2009-01-01

This paper presents empirical evidence of fractional dynamics in interest rates for different maturities for Brazil. A variation of a newly developed test for long-range dependence, the V/S statistic, with a post-blackening bootstrap is employed. Results suggest that Brazilian interest rates possess strong long-range dependence in volatility, even when considering the structural break in 1999. These findings imply that the development of policy models that give rise to long-range dependence in interest rates' volatility could be very useful. The long-short-term interest rates spread has strong long-range dependence, which suggests that traditional tests of expectation hypothesis of the term structure of interest rates may be misspecified.

Role of P53 and BCL-2 in high-risk breast cancer patients treated with adjuvant anthracycline-based chemotherapy.

Science.gov (United States)

Mottolese, M; Benevolo, M; Del Monte, G; Buglioni, S; Papaldo, P; Nisticò, C; Di Filippo, F; Vasselli, S; Vici, P; Botti, C

2000-12-01

Adjuvant therapy has become an integral component of the managment of primary high-risk breast cancer patients. However, a considerable fraction of women receive no benefit from this treatment. This study investigates whether a number of biopathological factors can influence the outcome of patients submitted to adjuvant chemotherapy involving the use of high-dose epirubicin and cyclophosphamide. One hundred and fifty-seven primary breast cancer patients, considered at high risk according to the St. Gallen Meeting Consensus Conference, were evaluated immunohistochemically for estrogen, progesterone receptors, p53, bcl-2, HER-2/neu, and Ki-67, of which the results were correlated with patient outcome. Results obtained demonstrated that p53 is a significant predictor of disease-free survival (DFS P < 0.0001) and overall survival (OS P = 0.0002) both in ductal and lobular carcinomas, whereas bcl-2 expression seems to be of prognostic value only in lobular carcinomas (DFS P = 0.01; OS P = 0.02). This data indicates that in high-risk breast cancer patients the immunohistochemical evaluation of p53 and bcl-2 may be of clinical value in distinguishing different responses to adjuvant anthracycline-based chemotherapy.

Time-Resolved Quantum Cascade Laser Absorption Spectroscopy of Pulsed Plasma Assisted Chemical Vapor Deposition Processes Containing BCl3

Science.gov (United States)

Lang, Norbert; Hempel, Frank; Strämke, Siegfried; Röpcke, Jürgen

2011-08-01

In situ measurements are reported giving insight into the plasma chemical conversion of the precursor BCl3 in industrial applications of boriding plasmas. For the online monitoring of its ground state concentration, quantum cascade laser absorption spectroscopy (QCLAS) in the mid-infrared spectral range was applied in a plasma assisted chemical vapor deposition (PACVD) reactor. A compact quantum cascade laser measurement and control system (Q-MACS) was developed to allow a flexible and completely dust-sealed optical coupling to the reactor chamber of an industrial plasma surface modification system. The process under the study was a pulsed DC plasma with periodically injected BCl3 at 200 Pa. A synchronization of the Q-MACS with the process control unit enabled an insight into individual process cycles with a sensitivity of 10-6 cm-1·Hz-1/2. Different fragmentation rates of the precursor were found during an individual process cycle. The detected BCl3 concentrations were in the order of 1014 molecules·cm-3. The reported results of in situ monitoring with QCLAS demonstrate the potential for effective optimization procedures in industrial PACVD processes.

Reversing multidrug resistance in Caco-2 by silencing MDR1, MRP1, MRP2, and BCL-2/BCL-xL using liposomal antisense oligonucleotides.