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Sample records for 3p 5q 17p

  1. Clonal Ordering of 17p and 5q Allelic Losses in Barrett Dysplasia and Adenocarcinoma

    NASA Astrophysics Data System (ADS)

    Blount, Patricia L.; Meltzer, Stephen J.; Yin, Jing; Huang, Ying; Krasna, Mark J.; Reid, Brian J.

    1993-04-01

    Both 17p and 5q allelic losses appear to be involved in the pathogenesis or progression of many human solid tumors. In colon carcinogenesis, there is strong evidence that the targets of the 17p and 5q allelic losses are TP53, the gene encoding p53, and APC, respectively. It is widely accepted that 5q allelic losses precede 17p allelic losses in the progression to colonic carcinoma. The data, however, supporting this proposed order are largely based on the prevalence of 17p and 5q allelic losses in adenomas and unrelated adenocarcinomas from different patients. We investigated the order in which 17p and 5q allelic losses developed during neoplastic progression in Barrett esophagus by evaluating multiple aneuploid cell populations from the same patient. Using DNA content flow cytometric cell sorting and polymerase chain reaction, 38 aneuploid cell populations from 14 patients with Barrett esophagus who had high grade dysplasia, cancer or both were evaluated for 17p and 5q allelic losses. 17p allelic losses preceded 5q allelic losses in 7 patients, both 17p and 5q allelic losses were present in all aneuploid populations of 4 patients, and only 17p (without 5q) allelic losses were present in the aneuploid populations of 3 patients. In no patient did we find that a 5q allelic loss preceded a 17p allelic loss. Our data suggest that 17p allelic losses typically occur before 5q allelic losses during neoplastic progression in Barrett esophagus.

  2. Targeted sequencing using a 47 gene multiple myeloma mutation panel (M3P) in -17p high risk disease

    PubMed Central

    Kortüm, Klaus M.; Langer, Christian; Monge, Jorge; Bruins, Laura; Egan, Jan B.; Zhu, Yuan X.; Shi, Chang Xin; Jedlowski, Patrick; Schmidt, Jessica; Ojha, Juhi; Bullinger, Lars; Liebisch, Peter; Kull, Miriam; Champion, Mia D.; Van Wier, Scott; Ahmann, Gregory; Rasche, Leo; Knop, Stefan; Fonseca, Rafael; Einsele, Hermann; Stewart, A Keith; Braggio, Esteban

    2015-01-01

    Summary We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM. PMID:25302557

  3. Targeted sequencing using a 47 gene multiple myeloma mutation panel (M(3) P) in -17p high risk disease.

    PubMed

    Kortüm, Klaus M; Langer, Christian; Monge, Jorge; Bruins, Laura; Egan, Jan B; Zhu, Yuan X; Shi, Chang Xin; Jedlowski, Patrick; Schmidt, Jessica; Ojha, Juhi; Bullinger, Lars; Liebisch, Peter; Kull, Miriam; Champion, Mia D; Van Wier, Scott; Ahmann, Gregory; Rasche, Leo; Knop, Stefan; Fonseca, Rafael; Einsele, Hermann; Stewart, A Keith; Braggio, Esteban

    2015-02-01

    We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM. PMID:25302557

  4. Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p, 5q, 11p, 17 and 22.

    PubMed Central

    Foster, K.; Crossey, P. A.; Cairns, P.; Hetherington, J. W.; Richards, F. M.; Jones, M. H.; Bentley, E.; Affara, N. A.; Ferguson-Smith, M. A.; Maher, E. R.

    1994-01-01

    To investigate the role of tumour-suppressor genes on the short arm of chromosome 3 in the mechanism of tumorigenesis in non-familial renal cell carcinoma, we analysed 55 paired blood-tumour DNA samples for allele loss on chromosome 3p and in the region of known or putative tumour-suppressor genes on chromosomes 5, 11, 17 and 22. Sixty-four per cent (35/55) of informative tumours showed loss of heterozygosity (LOH) of at least one locus on the short arm of chromosome 3, compared with only 13% at the p53 tumour-suppressor gene and 6% at 17q21. LOH at chromosome 5q21 and 22q was uncommon (2-3%). Detailed analysis of the regions of LOH on chromosome 3p suggested that, in addition to the VHL gene in chromosome 3p25-p26, mutations in one or more tumour-suppressor genes in chromosome 3p13-p24 may be involved in the pathogenesis of sporadic renal cell carcinoma (RCC). We also confirmed previous suggestions that chromosome 3p allele loss is not a feature of papillary RCC (P < 0.05). Images Figure 2 PMID:8297719

  5. Recent Advances in the 5q- Syndrome

    PubMed Central

    Pellagatti, Andrea; Boultwood, Jacqueline

    2015-01-01

    The 5q- syndrome is the most distinct of the myelodysplastic syndromes (MDS) and patients with this disorder have a deletion of chromosome 5q [del(5q)] as the sole karyotypic abnormality. Several genes mapping to the commonly deleted region of the 5q- syndrome have been implicated in disease pathogenesis in recent years. Haploinsufficiency of the ribosomal gene RPS14 has been shown to cause the erythroid defect in the 5q- syndrome. Loss of the microRNA genes miR-145 and miR-146a has been associated with the thrombocytosis observed in 5q- syndrome patients. Haploinsufficiency of CSNK1A1 leads to hematopoietic stem cell expansion in mice and may play a role in the initial clonal expansion in patients with 5q- syndrome. Moreover, a subset of patients harbor mutation of the remaining CSNK1A1 allele. Mouse models of the 5q- syndrome, which recapitulate the key features of the human disease, indicate that a p53-dependent mechanism underlies the pathophysiology of this disorder. Importantly, activation of p53 has been demonstrated in the human 5q- syndrome. Recurrent TP53 mutations have been associated with an increased risk of disease evolution and with decreased response to the drug lenalidomide in del(5q) MDS patients. Potential new therapeutic agents for del(5q) MDS include the translation enhancer L-leucine. PMID:26075044

  6. Genetics Home Reference: 5q minus syndrome

    MedlinePlus

    ... and management of various health conditions: Diagnostic Tests Drug Therapy Surgery and Rehabilitation Genetic Counseling Palliative Care Related ... in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes. Ann Hematol. 2014 Jan;93( ...

  7. Deletion 5q35.3

    SciTech Connect

    Stratton, R.F.; Tedrowe, N.A.; Tolworthy, J.A.; Patterson, R.M.; Ryan, S.G.; Young, R.S.

    1994-06-01

    The authors report on a 15-month-old boy with a de novo deletion of the terminal band of 5q, macrocephaly, mild retrognathia, anteverted nares with low flat nasal bridge, telecanthus, minor earlobe anomalies, bellshaped chest, diastasis recti, short fingers, and mild developmental delay.

  8. SQSTM1 is a Pathogenic Target of 5q Copy Number Gains in Kidney Cancer

    PubMed Central

    Li, Lianjie; Shen, Chuan; Nakamura, Eijiro; Ando, Kiyohiro; Signoretti, Sabina; Beroukhim, Rameen; Cowley, Glenn S.; Lizotte, Patrick; Liberzon, Ella; Bair, Steven; Root, David E.; Tamayo, Pablo; Tsherniak, Aviad; Cheng, Su-Chun; Tabak, Barbara; Jacobsen, Anders; Hakimi, A. Ari; Schultz, Nikolaus; Ciriello, Giovanni; Sander, Chris; Hsieh, James J.; Kaelin, William G.

    2013-01-01

    SUMMARY Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer and is often linked to loss of chromosome 3p, which harbors the VHL tumor suppressor gene, loss of chromosome 14q, which includes HIF1A, and gain of chromosome 5q. The relevant target(s) on chromosome 5q is not known. Here we show that 5q amplification leads to overexpression of the SQSTM1 oncogene in ccRCC lines and tumors. Overexpression of SQSTM1 in ccRCC lines promoted resistance to redox stress and increased soft agar growth while downregulation of SQSTM1 decreased resistance to redox stress, impaired cellular fitness, and decreased tumor formation. Therefore the selection pressure to amplify 5q in ccRCC is driven, at least partly, by SQSTM1. PMID:24332042

  9. Molecular dissection of the 5q deletion in myelodysplastic syndrome

    PubMed Central

    Ebert, Benjamin L.

    2011-01-01

    The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of Chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haploinsufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q- syndrome. The megakaryocytic and platelet phenotype of the 5q- syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of Chromosome 5q is due to haploinsufficiency of multiple genes. PMID:21943668

  10. Molecular mapping of uncharacteristically small 5q deletions in two patients with the 5q-syndrome: Delineation of the critical region on 5q and identification of a 5q-breakout

    SciTech Connect

    Boultwood, J.; Fidler, C.; Lewis, S.; Littlewood, T.J.; Wainscoat, J.S.; Buckle, V.J. ); Kelly, S. ); Sheridan, H. )

    1994-02-01

    Molecular mapping techniques have defined the region of gene loss in two patients with the 5q-syndrome and uncharacteristically small 5q deletions (5q31-q33). The allelic loss of 10 genes localized to 5q23-qter (centromere-CSF2-EGR1-FGFA-GRL-ADRB2-CSF1R-SPARC-GLUH1-NKSF1-FLT4-telomere) was investigated in peripheral blood cell fractions. Gene dosage experiments demonstrated that CSF2, EGR1, NKSF1, and FLT4 were retained on the 5q-chromosome in both patients and that FGFA was retained in one patient, thus placing these genes outside the critical region. GRL, ADRB2, CSF1R, SPARC, and GLUH1 were shown to be deleted in both patients. The proximal breakpoint is localized between EGR1 and FGFA in one patient and between FGFA and ADRB2 in the other, and the distal breakpoint is localized between GLUH1 and NKSF1 in both patients. Pulsed-field gel electrophoresis was used to map the 5q deletion breakpoints, and breakpoint-specific fragments were detected with FGFA in the granulocyte but not the lymphocyte fraction of one patient. This study has established the critical region of gene loss of the 5q-chromosome in the 5q-syndrome, giving the location for a putative tumor-suppressor gene in the 5.6-Mb region between FGFA and NKSF1. 54 refs., 3 figs., 2 tabs.

  11. Molecular dissection of the 5q deletion in myelodysplastic syndrome.

    PubMed

    Ebert, Benjamin L

    2011-10-01

    The 5q-syndrome is a subtype of myelodysplastic syndrome (MDS) with a defined clinical phenotype associated with heterozygous deletions of chromosome 5q. While no genes have been identified that undergo recurrent homozygous inactivation, functional studies have revealed individual genes that contribute to the clinical phenotype of MDS through haplo-insufficient gene expression. Heterozygous loss of the RPS14 gene on 5q leads to activation of p53 in the erythroid lineage and the macrocytic anemia characteristic of the 5q-syndrome. The megakaryocytic and platelet phenotype of the 5q-syndrome has been attributed to heterozygous deletion of miR145 and miR146a. Murine models have implicated heterozygous loss of APC, EGR1, DIAPH1, and NPM1 in the pathophysiology of del(5q) MDS. These findings indicate that the phenotype of MDS patients with deletions of chromosome 5q is due to haplo-insufficiency of multiple genes. PMID:21943668

  12. 5Q4: Chris Edwards - Child Presence Sensor

    NASA Video Gallery

    Five Questions For (5Q4) Chris Edwards, NASA engineer who was the team lead of a group that invented a child presence sensor designed to alert parents if they've inadvertently left their child in h...

  13. New insights into 5q- syndrome as a ribosomopathy.

    PubMed

    Barlow, Jillian L; Drynan, Lesley F; Trim, Nicola L; Erber, Wendy N; Warren, Alan J; McKenzie, Andrew N J

    2010-11-01

    Myelodysplastic Syndromes (MDS) are a heterogeneous group of acquired clonal bone marrow disorders, characterised by ineffective hematopoiesis. The mechanisms underlying many of these blood disorders have remained elusive due to the difficulty in pinpointing specific gene mutations or haplo-insufficencies, which can occur within large deleted regions. However, there is an increasing interest in the classification of some of these diseases as ribosomopathies. Indeed, studies have implicated Ribosomal Protein (RP) S14 as a strong candidate for haploinsufficiency in 5q- syndrome, a particular form of MDS. Recently, two novel mouse models have provided evidence for the involvement of both RPS14 and the p53 pathway, and specific miRNAs in 5q- syndrome. In this review we will discuss: 5q- syndrome mouse models, the possible mechanisms underlying this blood disorder with respect to the candidate genes and comparisons with other ribosomopathies and the involvement of the p53 pathway in these diseases. PMID:20980806

  14. SMA type 2 unrelated to chromosome 5q13.

    PubMed

    Nevo, Y; Kramer, U; Legum, C; Shomrat, R; Fatal, A; Soffer, D; Harel, S; Shapira, Y

    1998-01-13

    We describe two brothers with clinical and histological findings of type 2 spinal muscular atrophy (SMA) associated with small head circumference (<2%) and normal cognitive development. No survival motor neuron (SMN) or neuronal apoptosis-inhibitory protein (NAIP) deletions were detected in these sibs, and they were discordant for the haplotypes determined by DNA markers flanking the 5q13 SMA locus. These findings support the presence of a distinct anterior horn disease unrelated to 5q13. This entity may have either autosomal recessive or X-linked inheritance. PMID:9450884

  15. I3P Overview

    NASA Video Gallery

    Deborah Diaz, the NASA's Deputy Chief Information Officer, talks about the Information Technology Infrastructure Integration Program (I3P). I3P is NASA's initiative to provide Agency-wide managemen...

  16. 3p deletion syndrome.

    PubMed

    Kaur, Anupam; Khetarpal, S

    2013-08-01

    3p deletion is a rare cytogenetic finding. Here we describe a 3 months old male with congenital malformations. His karyotype revealed 3p deletion 46,XY,del(3)(p25-pter). The child had flexion deformity of wrist and elbow which has never been reported before. PMID:24036645

  17. A locus regulating bronchial hyperresponsiveness maps to chromosome 5q

    SciTech Connect

    Levitt, R.C.; Meyers, D.A.; Bleecker, E.R.

    1994-09-01

    Bronchial hyperresponsiveness (BHR) is one of the hallmarks of asthma. BHR correlates well with asthmatic symptoms and the response to treatment. Moreover, BHR appears to be closely related to airways inflammation. Numerous studies have demonstrated a familial aggregation; however, this phenotype is not likely inherited as a simple Mendelian trait. BHR is also closely associated with total serum IgE levels, as are allergy and asthma. We studied 92 families from Northern Holland ascertained through a parent with asthma who were originally studied between 1962-1970. Since there are a number of candidate genes on chromosome 5q potentially important in producing BHR, families were genotyped for markers in this region. These genes regulate IgE production and the cellular elements that are likely involved in inflammation associated with BHR, allergy and asthma. They include IL-4, IL-3, IL-5, IL-9, IL-12, IL-13 and GM-CSF. Linkage of BHR with markers on 5q was tested using a model free sib-pair method. The data suggest a locus for BHR maps near the cytokine gene cluster on 5q. This region appears critical in producing susceptibility to BHR and possibly to asthma.

  18. Outcome following haematopoietic cell transplantation in patients with myelodysplasia and del (5q) karyotypes.

    PubMed

    Stewart, B; Verdugo, M; Guthrie, K A; Appelbaum, F; Deeg, H J

    2003-12-01

    The deletion (5q) karyotype [del (5q)] in patients with myelodysplastic syndrome (MDS) is considered a good risk feature, while the impact of del (5q) combined with other karyotypic abnormalities [del (5q)+] is less well defined. We analysed the outcome of haematopoietic cell transplants (HCT) in patients with MDS with del (5q) or del (5q)+. Fifty-seven patients, aged 6-72 years, with MDS and del (5q) abnormalities received HCT from related (n = 32) or unrelated (n = 25) donors. By French-American-British (FAB) criteria, 27 patients had refractory anaemia (RA), 10 RA with excess blasts (RAEB), eight RAEB in transformation (RAEB-T) and 12 acute myeloid leukaemia evolving from MDS (tAML). Non-relapse mortality at 1-year post-transplantation was 30% for del (5q) and 38% for del (5q)+ patients. Relapse occurred in one of 20 del (5q) patients and 15 of 37 del (5q)+ patients (P = 0.001). After adjusting for del (5q) status, blast count (<5%) was the only factor significantly associated with relapse-free survival. Patients with del (5q), either as a '5q- syndrome' or with MDS in general, had better outcomes than did patients with del (5q)+. The indication for transplantation in patients with del (5q) was generally severe cytopenias, compared with disease progression to a more advanced FAB stage in patients with del (5q)+. Conceivably, outcome for patients with del (5q)+ would be improved with transplantation earlier in the disease course. PMID:14632779

  19. A Stellar Appulse by Exploding Comet 17P/Holmes

    NASA Astrophysics Data System (ADS)

    Lacerda, Pedro; Jewitt, D.

    2012-10-01

    Comet 17P/Holmes suffered a massive outburst in October 2007. Its total brightness increased from about 17th to 2nd magnitude over a period of only two days as 17P released about 1-10% of its mass into space in the form of dust. Several theories have been proposed to explain the event but the exact cause for the outburst remains unknown. 17P had suffered a similar outburst more than one century ago, which led to its discovery. These unusual and violent explosions have rendered this otherwise unremarkable Jupiter family comet an interesting target of study, because it may provide clues to the activity in other comets. On 29 October 2007, the optocenter of outbursting 17P passed within 1" of a background star. We used observations taken at the Univ. of Hawaii 2.2m telescope located atop Mauna Kea to measure the brightness of the star as it crossed the coma of 17P in an attempt to estimate the optical depth of the dust. The time sampling was 10-15 min. In addition, we used two-band photometry to look for colour variation as the star crossed the dust cloud. These measurements place the most stringent constraints on the extinction optical depth of any cometary coma.

  20. TRANSIENT FRAGMENTS IN OUTBURSTING COMET 17P/HOLMES {sup ,}

    SciTech Connect

    Stevenson, Rachel; Jewitt, David; Kleyna, Jan E-mail: jewitt@ucla.ed

    2010-06-15

    We present results from a wide-field imaging campaign at the Canada-France-Hawaii Telescope to study the spectacular outburst of comet 17P/Holmes in late 2007. Using image-processing techniques we probe inside the spherical dust coma and find 16 fragments having both spatial distribution and kinematics consistent with isotropic ejection from the nucleus. Photometry of the fragments is inconsistent with scattering from monolithic, inert bodies. Instead, each detected fragment appears to be an active cometesimal producing its own dust coma. By scaling from the coma of the primary nucleus of 17P/Holmes, assumed to be 1.7 km in radius, we infer that the 16 fragments have maximum effective radii between {approx}10 m and {approx}100 m on UT 2007 November 6. The fragments subsequently fade at a common rate of {approx}0.2 mag day{sup -1}, consistent with steady depletion of ices from these bodies in the heat of the Sun. Our characterization of the fragments supports the hypothesis that a large piece of material broke away from the nucleus and crumbled, expelling smaller, icy shards into the larger dust coma around the nucleus.

  1. Proteomic studies of pediatric medulloblastoma tumors with 17p deletion.

    PubMed

    Anagnostopoulos, Athanasios K; Papathanassiou, Chrissa; Karamolegou, Kalliopi; Anastasiadou, Ema; Dimas, Konstantinos S; Kontos, Harry; Koutsopoulos, Anastasios; Prodromou, Neofytos; Tzortzatou-Stathopoulou, Fotini; Tsangaris, George Th

    2015-02-01

    CNS tumors are the leading cause of cancer-related death in children. Medulloblastoma is the commonest pediatric CNS malignancy, wherein, despite multimodal therapy with surgery, radiation, and chemotherapy, 5 year survival rates merely approach 60%. Until present, gene expression and cytogenetic studies have produced contradicting findings regarding the molecular background of the specific disease. Through integration of genomics, bioinformatics, and proteomics, the current study aims to shed light at the proteomic-related molecular events responsible for MBL pathophysiology, as well as to provide molecular/protein/pathway answers concerning tumor-onset. Experiments were performed on tissues collected at surgery. With 17p loss being the commonest chromosomal aberrance observed in our sample set, array-CGH were employed to first distinguish for 17p-positive cases. 2-DE coupled to mass spectrometry identification exposed the MBL-specific protein profile. Protein profiles of malignant tissues were compared against profiles of normal cerebellar tissues, and quantitative protein differences were determined. Bioinformatics, functional and database analyses, characterization, and subnetwork profiling generated information on MBL protein interactions. Key molecules of the PI3K/mTOR signaling network were identified via the techniques applied herein. Among the findings IGF2, PI3K, Rictor, MAPKAP1, S6K1, 4EBP1, and ELF4A, as part of the IGF network (implicating PI3K/mTOR), were founded to be deregulated. PMID:25543836

  2. THE OUTBURST OF COMET 17P/HOLMES

    SciTech Connect

    Lin Zhongyi; Lara, Luisa M.; Lin, C.-S.; Ip, W.-H.

    2009-08-15

    Comet 17P/Holmes had a massive outburst at approximately 2007 October 23.8 and its total brightness reached maximum (from m = 17 to m = 2.5) around 2007 October 25, about 1.7 days (42 hr) after the event. Following the first report of this extraordinary cometary outburst, comprehensive observations were obtained at the Lulin Observatory until early 2008 January by using broadband filters and narrowband cometary filters. The separation velocity, as projected on the plane of the sky, between the nucleus and the coma blob produced by the outburst has been estimated to be 0.132 {+-} 0.004 km s{sup -1} from October 25.8 to November 1.6. The expansion speed, also projected on the plane of the sky of the dust shell has been found to be constant at a rate of approximately 0.554 {+-} 0.005 km s{sup -1} from October 25.8 to November 1.6. The color on December 10 is slightly redder than that of the Sun. Our narrowband observations provide information on the production rates of gas species on October 31: log Q (CN) = 27.103 and log Q (C{sub 2}) = 27.349. The resulting abundance ratios show that the comet 17P can be classified as a 'typical comet' in terms of composition.

  3. EXTINCTION IN THE COMA OF COMET 17P/HOLMES

    SciTech Connect

    Lacerda, Pedro; Jewitt, David

    2012-11-20

    On 2007 October 29, the outbursting comet 17P/Holmes passed within 0.''79 of a background star. We recorded the event using optical, narrowband photometry and detect a 3%-4% dip in stellar brightness bracketing the time of closest approach to the comet nucleus. The detected dimming implies an optical depth {tau} Almost-Equal-To 0.04 at 1.''5 from the nucleus and an optical depth toward the nucleus center {tau}{sub n} < 13.3. At the time of our observations, the coma was optically thick only within {rho} {approx}< 0.''01 from the nucleus. By combining the measured extinction and the scattered light from the coma, we estimate a dust red albedo p{sub d} = 0.006 {+-} 0.002 at {alpha} = 16 Degree-Sign phase angle. Our measurements place the most stringent constraints on the extinction optical depth of any cometary coma.

  4. Prenatal detection of 5q14.3 duplication including MEF2C and brain phenotype.

    PubMed

    Cesaretti, Claudia; Spaccini, Luigina; Righini, Andrea; Parazzini, Cecilia; Conte, Giorgio; Crosti, Francesca; Redaelli, Serena; Bulfamante, Gaetano; Avagliano, Laura; Rustico, Mariangela

    2016-05-01

    The 5q14.3 duplication is a rare condition comprising speech and developmental delay, microcephaly, and mild ventriculomegaly. The region 5q14.3 contains several genes but the predominant role for the onset of the neurodevelopmental phenotype has been attributed to MEF2C. We describe the prenatal identification of 5q14.3 duplication, including MEF2C, in a monochorionic twin pregnancy with corpus callosum anomalies, confirmed by autopsy. To the best of our knowledge, this cerebral finding has been observed for the first time in 5q14.3 duplication patients, possibly widening the neurological picture of this scarcely known syndrome. A pathogenetic role of MEF2C overexpression in brain development may be assumed, but further studies are needed. © 2016 Wiley Periodicals, Inc. PMID:26864752

  5. Lingering Grains of Truth around Comet 17P/Holmes

    NASA Astrophysics Data System (ADS)

    Stevenson, R.; Bauer, J. M.; Kramer, E. A.; Grav, T.; Mainzer, A. K.; Masiero, J. R.

    2014-06-01

    Comet 17P/Holmes underwent a massive outburst in 2007 October, brightening by a factor of almost a million in under 48 hr. We used infrared images taken by the Wide-Field Infrared Survey Explorer mission to characterize the comet as it appeared at a heliocentric distance of 5.1 AU almost 3 yr after the outburst. The comet appeared to be active with a coma and dust trail along the orbital plane. We constrained the diameter, albedo, and beaming parameter of the nucleus to 4.135 ± 0.610 km, 0.03 ± 0.01, and 1.03 ± 0.21, respectively. The properties of the nucleus are consistent with those of other Jupiter family comets. The best-fit temperature of the coma was 134 ± 11 K, slightly higher than the blackbody temperature at that heliocentric distance. Using Finson-Probstein modeling, we found that the morphology of the trail was consistent with ejection during the 2007 outburst and was made up of dust grains between 250 μm and a few cm in radius. The trail mass was ~1.2-5.3 × 1010 kg.

  6. Lingering grains of truth around comet 17P/HOLMES

    SciTech Connect

    Stevenson, R.; Bauer, J. M.; Mainzer, A. K.; Masiero, J. R.; Kramer, E. A.; Grav, T.

    2014-06-01

    Comet 17P/Holmes underwent a massive outburst in 2007 October, brightening by a factor of almost a million in under 48 hr. We used infrared images taken by the Wide-Field Infrared Survey Explorer mission to characterize the comet as it appeared at a heliocentric distance of 5.1 AU almost 3 yr after the outburst. The comet appeared to be active with a coma and dust trail along the orbital plane. We constrained the diameter, albedo, and beaming parameter of the nucleus to 4.135 ± 0.610 km, 0.03 ± 0.01, and 1.03 ± 0.21, respectively. The properties of the nucleus are consistent with those of other Jupiter family comets. The best-fit temperature of the coma was 134 ± 11 K, slightly higher than the blackbody temperature at that heliocentric distance. Using Finson-Probstein modeling, we found that the morphology of the trail was consistent with ejection during the 2007 outburst and was made up of dust grains between 250 μm and a few cm in radius. The trail mass was ∼1.2-5.3 × 10{sup 10} kg.

  7. Water outburst activity in Comet 17P/Holmes

    NASA Astrophysics Data System (ADS)

    de Almeida, Amaury A.; Boice, Daniel C.; Picazzio, Enos; Huebner, Walter F.

    2016-08-01

    Cometary outbursts are sporadic events whose mechanisms are not well known where the activity and consequently the brightness can increase hundreds of thousands of times within a few hours to several days. This indicates a dramatic departure from thermal equilibrium between the comet and interplanetary space and is usually documented by "light curves". In a typical cometary outburst, the brightness can increase by 2-5 magnitudes (Whitney, 1955; Gronkowski and Wesolowski, 2015). In only 42 h, Comet 17P/Holmes was reported to brighten from a magnitude of about 17 to about 2.4 at the height of the burst, representing the largest known outburst by a comet. We present the H2O production rate of Holmes for the megaburst occurring between 23 and 24 October 2007. For this, we selected more than 1900 photometric observations from the International Comet Quarterly Archive of Photometric Data (Green, 2007) and use the Semi-Empirical Method of Visual Magnitudes (SEMVM; de Almeida et al., 2007). We clearly show that the comet achieved an average water production rate of 5 × 1029 molecules s-1, corresponding to a water gas loss rate of 14,960 kg s-1, in very good agreement with Schleicher (2009) who derived the water production rate using OH measurements on 1 Nov 2007 (about 8 days after the outburst). We discuss possible physical processes that might cause cometary outbursts and propose a new qualitative mechanism, the Pressurized Obstructed Pore (POP) model. The key feature of POP is the recrystallization of water in the surface regolith as it cools, plugging pores and blocking the release of subsurface gas flow. As the interior gas pressure increases, an outburst is eventually triggered. POP is consistent with current observations and can be tested in the future with observations (e.g., Rosetta in situ measurements) and detailed simulations.

  8. Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome.

    PubMed

    Burwick, Nicholas; Shimamura, Akiko; Liu, Johnson M

    2011-04-01

    A number of human disorders, dubbed ribosomopathies, are linked to impaired ribosome biogenesis or function. These include but are not limited to Diamond Blackfan anemia (DBA), Shwachman Diamond syndrome (SDS), and the 5q- myelodysplastic syndrome (MDS). This review focuses on the latter two non-DBA disorders of ribosome function. Both SDS and 5q- syndrome lead to impaired hematopoiesis and a predisposition to leukemia. SDS, due to bi-allelic mutations of the SBDS gene, is a multi-system disorder that also includes bony abnormalities, and pancreatic and neurocognitive dysfunction. SBDS associates with the 60S subunit in human cells and has a role in subunit joining and translational activation in yeast models. In contrast, 5q- syndrome is associated with acquired haplo-insufficiency of RPS14, a component of the small 40S subunit. RPS14 is critical for 40S assembly in yeast models, and depletion of RPS14 in human CD34(+) cells is sufficient to recapitulate the 5q- erythroid defect. Both SDS and the 5q- syndrome represent important models of ribosome function and may inform future treatment strategies for the ribosomopathies. PMID:21435510

  9. A family with an inverted tandem duplication 5q22.1q23.2.

    PubMed

    Schmidt, T; Bartels, I; Liehr, T; Burfeind, P; Zoll, B; Shoukier, M

    2013-01-01

    Here, we report a 3-year-old boy with short stature, developmental delay and mild facial dysmorphic signs. Karyotype analysis and array-CGH revealed a pure duplication 5q22.1q23.2 with a length of 14.25 Mb. As demonstrated by multicolor-fluorescence in situ hybridization, the duplicated segment was orientated in an inverted tandem manner. One of the 2 older half-brothers of the index patient was intellectually disabled and showed short stature as well. The mother of the siblings was only 149 cm in height. The affected half-brother as well as the mother of the siblings were tested positive for the same duplication. Duplications of the long arm of chromosome 5 are rare. There are 16 reported cases of different 5q segments with a pure duplication and no additional chromosomal imbalance. In order to refine the 5q-duplication phenotype, reported cases were recently classified in 3 groups on the basis of clinical findings and the involved chromosome segments. However, our case does not fit in any of these groups but is placed in the interjacent chromosomal area between 2 of these groups. Overall, this is the second reported family with a duplication of 5q22.1q23.2 and both families share phenotypic features like short stature, facial dysmorphic signs and speech delay. The reported family provides further information for delineating phenotype-genotype correlations of pure duplications of the 5q region. PMID:23051634

  10. Partial trisomy 5q resulting from chromosome 7 insertion: An expansion of the phenotype

    SciTech Connect

    Fries, M.H.; Reilly, P.A.; Williams, T.C.

    1994-09-01

    Partial trisomy 5q has been categorized into three separate phenotypes; however, a distinctive phenotype has not been described for duplications spanning 5q23-q35. We report a case of partial trisomy 5q for this region as a result of a ins(7,5)(q31.3;q23.2q35.1)mat. The liveborn male infant was delivered by emergency cesarean section at 37 weeks after a pregnancy notable for oligohydramnios, with birth weight 1792 g (<3%). Postnatal course was marked by psychomotor delay, failure to thrive, and biopsy demonstrated neonatal giant cell hepatitis with a paucity of intrahepatic bile ducts. His appearance was remarkable for lack of subcutaneous fat, midline displaced hair whorl, bitemporal narrowing with frontal bossing, wide anterior fontanel, widow`s peak, protuberant eyes with periorbital and lid edema, short flat nasal bridge with broad flattened nasal tip, long smooth philtrum, wide mouth with thin lips, wide gingival ridges, micrognathia, posteriorly rotated low-set ears, hepatomegaly, flexion contractions of elbows, and generalized hypertonicity. Urine organic acids, oligosaccharide/mucopolysaccharide screen, and plasma amino acids were negative. GTG-banding on prometaphase chromosomes showed an unbalanced translocation involving chr. 7. This was identified as an insertion of chr. 5 (q23.2q35.1) into distal 7q after FISH using chr. 5 and chr. 7 painting probes. The infant`s mother carries the balanced insertional rearrangement: 46,XX,dir ins(7,5)(q31.3;q23.2q35.1). This phenotype overlaps that of previously described duplications with the addition of giant cell hepatitis, coarsened facial features, gingival thickening, and flexion contractures, suggestive of a yet undiagnosed storage disorder.

  11. Cytogenetic and molecular cytogenetic findings in 43 aneurysmal bone cysts: aberrations of 17p mapped to 17p13.2 by fluorescence in situ hybridization.

    PubMed

    Althof, Pamela A; Ohmori, Kazuo; Zhou, Ming; Bailey, Jacqueline M; Bridge, R Stuart; Nelson, Marilu; Neff, James R; Bridge, Julia A

    2004-05-01

    Aneurysmal bone cyst is a benign, cystic lesion of bone composed of blood-filled spaces separated by fibrous septa. Relatively few cases of aneurysmal bone cyst have been cytogenetically characterized, yet abnormalities of the short arm of chromosome 17 appear to be recurrent. In this study, conventional cytogenetic analysis of 43 aneurysmal bone cyst specimens from 38 patients over a 12-year period revealed clonal chromosomal abnormalities in 12 specimens. Karyotypic anomalies of 17p, including a complex translocation and inversion, were identified in eight of these 12 specimens. In an effort to further define the aberrant 17p breakpoint, fluorescence in situ hybridization (FISH) analyses were performed using a series of probe combinations spanning a 5.1 Mb region between the TP53 (17p13.1) and Miller-Dieker lissencephaly syndrome (17p13.3) gene loci. These studies revealed the critical breakpoint locus at 17p13.2, flanked proximally by an RP11-46I8, RP11-333E1, and RP11-457I18 bacterial artificial chromosome (BAC) probe cocktail and distally by an RP11-198F11 and RP11-115H24 BAC and RP5-1050D4 P1 artificial chromosome (PAC) probe cocktail. Overall, abnormalities of the 17p13.2 locus were identified by metaphase and/or interphase cell FISH analysis in 22 of 35 (63%) aneurysmal bone cyst specimens examined including 26 karyotypically normal specimens. These cytogenetic and molecular cytogenetic findings expand our knowledge of chromosomal alterations in aneurysmal bone cyst, further localize the critically involved 17p breakpoint, and provide an alternative approach (ie FISH) for detecting 17p abnormalities in nondividing cells of aneurysmal bone cysts. The latter could potentially be utilized as an adjunct in diagnostically challenging cases. PMID:15044915

  12. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS.

    PubMed

    Krönke, Jan; Fink, Emma C; Hollenbach, Paul W; MacBeth, Kyle J; Hurst, Slater N; Udeshi, Namrata D; Chamberlain, Philip P; Mani, D R; Man, Hon Wah; Gandhi, Anita K; Svinkina, Tanya; Schneider, Rebekka K; McConkey, Marie; Järås, Marcus; Griffiths, Elizabeth; Wetzler, Meir; Bullinger, Lars; Cathers, Brian E; Carr, Steven A; Chopra, Rajesh; Ebert, Benjamin L

    2015-07-01

    Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)), resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for the therapeutic window of lenalidomide in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4(CRBN). These findings have implications for the clinical activity of lenalidomide and related compounds, and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases. PMID:26131937

  13. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS

    PubMed Central

    Hollenbach, Paul W.; MacBeth, Kyle J.; Hurst, Slater N.; Udeshi, Namrata D.; Chamberlain, Philip P.; Mani, D.R.; Man, Hon Wah; Gandhi, Anita K.; Svinkina, Tanya; Schneider, Rebekka K.; McConkey, Marie; Järås, Marcus; Griffiths, Elizabeth; Wetzler, Meir; Bullinger, Lars; Cathers, Brian E.; Carr, Steven A.; Chopra, Rajesh; Ebert, Benjamin L.

    2015-01-01

    Summary Lenalidomide is a highly effective treatment for myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Here, we demonstrate that lenalidomide induces the ubiquitination of casein kinase 1A1 (CK1α) by the CRL4CRBN E3 ubiquitin ligase, resulting in CK1α degradation. CK1α is encoded by a gene within the common deleted region for del(5q) MDS and haploinsufficient expression sensitizes cells to lenalidomide therapy, providing a mechanistic basis for lenalidomide's therapeutic window in del(5q) MDS. We found that mouse cells are resistant to lenalidomide but that changing a single amino acid in mouse Crbn to the corresponding human residue enables lenalidomide-dependent degradation of CK1α. We further demonstrate that minor side chain modifications in thalidomide and a novel analogue, CC-122, can modulate the spectrum of substrates targeted by CRL4CRBN. These findings have implications for the clinical activity of lenalidomide and related compounds and demonstrate the therapeutic potential of novel modulators of E3 ubiquitin ligases. PMID:26131937

  14. Narrowing and genomic annotation of the commonly deleted region of the 5q- syndrome

    SciTech Connect

    Boultwood, Jacqueline; Fidler, Carrie; Strickson, Amanda J.; Watkins, Fiona; Gama, Susana; Kearney, Lyndal; Tosi, Sabrina; Kasprzyk, Arek; Cheng, Jan-Fang; Jaju, Rina J.; Wainscoat, James S.

    2002-01-15

    The 5q syndrome is the most distinct of the myelodysplastic syndromes, and the molecular basis for this disorder remains unknown. We describe the narrowing of the common deleted region (CDR) of the 5q syndrome to the approximately 1.5-megabases interval at 5q32 flanked by D5S413 and the GLRA1 gene. The Ensemblgene prediction program has been used for the complete genomic annotation of the CDR. The CDR is gene rich and contains 24 known genes and 16 novel (predicted) genes. Of 40 genes in the CDR, 33 are expressed in CD34 cells and, therefore, represent candidate genes since they are expressed within the hematopoietic stem/progenitor cell compartment. A number of the genes assigned to the CDR represent good candidates for the 5q syndrome, including MEGF1, G3BP, and several of the novel gene predictions. These data now afford a comprehensive mutational/expression analysis of all candidate genes assigned to the CDR.

  15. Duplication of 5q21 in a mildly retarded male and his non-retarded mother

    SciTech Connect

    Stallard, R.; Zurcher, V.; Schwartz, S.

    1994-09-01

    Euchromatic autosomal additions to chromosomal complements are typically associated with global effects including mental retardation (MR) and dysmorphism. We report a familial duplication that does not appear to cause consistent, significant effects. A hyperactive male with mild MR was referred for fra(X) testing at 8 yrs. His karyotype was fra(X) negative and normal except for an addition in one 5q. The abnormal 5 was also in the maternal karyotype, but all other parental chromosomes were normal. The addition (=8.5% the length of a 5) was interpreted as a duplication of band 5q21. FISH with Coatasome 5 (Oncor) showed the addition was from 5. The proband`s karyotype was designated 46,XY,dup(5)(q15q22.1)mat; his mother`s, 46,XX,dup(5)(q15q22.1). Single copy probes are being used to test the cytogenetic interpretation. At 39 yrs, the non-retarded, somewhat inattentive mother, who has a high school diploma and subsequent secretarial courses, cares for the proband and his chromosomally normal, but learning disabled sister at home. The family situation is chaotic with reported paternal psychiatric illness and abuse of the proband and his sister. The mother`s father is dead, but her four younger siblings and mother are reportedly normal. Their chromosomes have not been available. The proband was born at 40 weeks following an uneventful pregnancy, with length and weight at the 5-10th centiles. He walked and talked at about one year. At 9 yrs, his ht/wt ratio was 10th centile. Foot length as <3rd centile; soft masses were present on the anterior ankles. He was otherwise physically normal. His estimated I.Q. was 75 and he was severely hyperactive despite Ritalin. This is the first report of a familial duplication in 5q; no identical, isolated case is known. Although additional family members need evaluation, the presence of the dup(5q) in the non-retarded mother suggests that it may not be associated with the proband`s MR.

  16. The 5q deletion size in myeloid malignancies is correlated to additional chromosomal aberrations and to TP53 mutations.

    PubMed

    Stengel, Anna; Kern, Wolfgang; Haferlach, Torsten; Meggendorfer, Manja; Haferlach, Claudia

    2016-10-01

    Deletions in the long arm of chromosome 5 (del(5q)) are recurrent abnormalities in myeloid malignancies. We analyzed del(5q) and accompanying molecular mutations in MDS, MPN and MDS/MPN cases. A high del(5q) frequency was revealed in MDS (1869/11398 cases; 16%), followed by MDS/MPN (37/1107; 3%) and MPN (97/6373; 2%). To investigate potential associations of the del(5q) size with the respective phenotypes, we applied array CGH analyses in selected cohorts of 61 MDS, 22 MDS/MPN and 23 MPN cases. The size varied between 16 and 119 Mb with no differences between the entities. However, MPN and MDS/MPN cases with del(5q) sole showed a significantly smaller del(5q) than cases with additional aberrations. Sequence analysis of 27 genes revealed ≥1 mutation in 91% of patients. The highest mutation frequencies in the total cohort were observed for TP53 (31%), JAK2 (23%) and DNMT3A (18%). The molecular mutation patterns in the del(5q) cohorts were different between the entities but resembled known patterns of cohorts not selected for del(5q). Further, TP53 mutations were significantly more frequent in cases with a larger deletion size (P = 0.003). The results suggest a correlation of large del(5q) with TP53 mutations and with additional chromosomal aberrations possibly contributing to more severe courses of these cases. © 2016 Wiley Periodicals, Inc. PMID:27218649

  17. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  18. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 1 2011-04-01 2011-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  19. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 1 2013-04-01 2013-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  20. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 1 2012-04-01 2012-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... examinations (sections 4p and 17(p) of the Act). A futures association may prescribe different...

  1. 17 CFR 170.10 - Proficiency examinations (sections 4p and 17(p) of the Act).

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 2 2014-04-01 2014-04-01 false Proficiency examinations (sections 4p and 17(p) of the Act). 170.10 Section 170.10 Commodity and Securities Exchanges COMMODITY... Proficiency examinations (sections 4p and 17(p) of the Act). A futures association may prescribe...

  2. Localization of the gene encoding peptidylglycine [alpha]-amidating monooxygenase (PAM) to human chromosome 5q14-5q21

    SciTech Connect

    Ouafik, L.H.; Giraud, P.; Oliver, C. ); Mattei, M.G. ); Eipper, B.A.; Mains, R.E. )

    1993-11-01

    Peptidylglycine [alpha]-amidating monooxygenase (PAM; EC 1.14.17.3) is a multifunctional protein containing two enzymes that act sequentially to catalyze the [alpha]-amidation of neuroendocrine peptides. Southern blot analysis of human placental DNA demonstrated that PAM is encoded by a single gene. The chromosomal localization of the PAM gene was established using in situ hybridization. A 2.2-kb human PAM cDNA hybridized to human metaphase chromosomes revealed a significant clustering of silver grains over chromosome 5 bands q14-q21. The gene encoding another enzyme important in the post-translational processing of neuroendocrine precursors, prohormone convertase 1 (PC1), is localized in the same region (5q15-q21). 14 refs., 2 figs.

  3. A locus regulating total serum IgE maps to chromosome 5q

    SciTech Connect

    Amelung, P.J.; Panhuysen, C.I.M.; Postma, D.S. |

    1994-09-01

    Familial aggregation of allergy has been demonstrated in numerous past studies. However, allergy is a complex disorder which is not inherited as a simple Mendelian trait. Total serum IgE levels correlate with the clinical expression of allergy and asthma and can be utilized as a quantitative measure of the allergic phenotype. We studied 92 families from Northern Holland ascertained through a parent with asthma who were originally studied between 1962-1970. Since there is a large number of candidate genes on chromosome 5q, families were genotyped for markers in this region. These genes either directly or indirectly regulate IgE production and the activation and proliferation of cellular elements that are involved in inflammation associated with allergy and asthma. They include IL-4, IL-3, IL-5, IL-9, IL-12, IL-13 and GM-CSF. Segregation analyses revealed recessive inheritance of `high` levels with a mean for the `low` phenotype of 1.51 (32 IU) and 2.52 (331 IU) for the `high` phenotype. Linkage of log IgE with markers on 5q was tested using the sib-pair and the LOD score methods with the genetic model obtained from the segregation analyses. These results provide evidence for a locus controlling IgE levels near the cytokine gene cluster on 5q. This region appears critical in susceptibility to allergy and asthma.

  4. Lenalidomide for myelodysplastic syndromes with del(5q): how long should it last?

    PubMed

    Vozella, Federico; Latagliata, Roberto; Carmosino, Ida; Volpicelli, Paola; Montagna, Chiara; Romano, Angela; Roberto, Amanda; Finsinger, Paola; Mancini, Marco; Breccia, Massimo; Oliva, Esther; Oliva, Esther

    2015-03-01

    Lenalidomide induces in patients with myelodysplastic syndrome (MDS) and del(5q) erythroid and cytogenetic response rates as high as 75% and 50%, respectively. It is still unclear, however, how long lenalidomide treatment should be continued and whether or not the drug could be interrupted. To assess the feasibility of lenalidomide discontinuation, we revised a cohort of 16 low-risk MDS patients with del(5q) treated at our institute in a phase II multicentric Italian study. Among the 12 responding patients, four discontinued lenalidomide while in complete response. All four patients needed during treatment a permanent lenalidomide reduction from 10 to 5 mg/day because of haematological toxicity (three patients) or grade 3 muscular and bone pain (one patient). At lenalidomide discontinuation after 16, 20, 27 and 20 months from the start, respectively, all four patients were in complete hematologic response and three forth in complete cytogenetic response. Three patients are still in response after 36, 30 and 20 months from lenalidomide discontinuation, respectively: The remaining patient relapsed after 20 months, and she is now receiving a new course of lenalidomide. In conclusion, long-lasting remissions are achievable in MDS patients with del(5q) in complete response after lenalidomide discontinuation. PMID:25950027

  5. Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12

    PubMed Central

    Gretarsdottir, Solveig; Sveinbjörnsdottir, Sigurlaug; Jonsson, Hjörtur H.; Jakobsson, Finnbogi; Einarsdottir, Elisabet; Agnarsson, Uggi; Shkolny, Dana; Einarsson, Gisli; Gudjonsdottir, Herdis M.; Valdimarsson, Einar M.; Einarsson, Olafur B.; Thorgeirsson, Gudmundur; Hadzic, Radinka; Jonsdottir, Sif; Reynisdottir, Sigridur Th.; Bjarnadottir, Sigrun M.; Gudmundsdottir, Thorunn; Gudlaugsdottir, Gudrun J.; Gill, Ramanjit; Lindpaintner, Klaus; Sainz, Jesus; Hannesson, Helgi H.; Sigurdsson, Gunnar Th.; Frigge, Michael L.; Kong, Augustine; Gudnason, Vilmundur; Stefansson, Kari; Gulcher, Jeffrey R.

    2002-01-01

    Stroke is one of the most complex diseases, with several subtypes, as well as secondary risk factors, such as hypertension, hyperlipidemia, and diabetes, which, in turn, have genetic and environmental risk factors of their own. Here, we report the results of a genomewide search for susceptibility genes for the common forms of stroke. We cross-matched a population-based list of patients with stroke in Iceland with an extensive computerized genealogy database clustering 476 patients with stroke within 179 extended pedigrees. Linkage to 5q12 was detected, and the LOD score at this locus meets the criteria for genomewide significance (multipoint allele-sharing LOD score of 4.40, P=3.9×10-6). A 20-cM region on 5q was physically and genetically mapped to obtain accurate marker order and intermarker distances. This locus on 5q12, which we have designated as “STRK1,” does not correspond to known susceptibility loci for stroke or for its risk factors and represents the first mapping of a locus for common stroke. PMID:11833004

  6. Mapping of primary congenital lymphedema to the 5q35.3 region.

    PubMed Central

    Evans, A L; Brice, G; Sotirova, V; Mortimer, P; Beninson, J; Burnand, K; Rosbotham, J; Child, A; Sarfarazi, M

    1999-01-01

    Primary lymphedema is a chronic tissue swelling, most frequently of the lower limbs, resulting from deficient lymphatic drainage. The variability of the affected phenotype, incomplete penetrance, lack of large families, and possible genetic heterogeneity have hampered the identification of causative genes until now. We carried out a genomewide search, using a four-generation North American family with dominantly inherited primary congenital lymphedema (PCL), otherwise known as "Milroy disease," or "hereditary lymphedema type I" (MIM 153100). Linkage to markers from the 5q35.3 region in this and four additional, British families was established. A minimum of 79 directly scorable haplotypes (37 affected) in five families conspicuously segregated with the most telomeric region of 5q35.3, thus suggesting a major locus for PCL in this vicinity. No recombination was observed with D5S408 (Z = 10.03) and D5S2006 (Z = 8.46) with a combined multipoint score of 16.55. While D5S2073 and WIAF-2213 defined the upper centromeric boundary, no recombinants were obtained for the last telomeric marker of D5S2006. Four unaffected subjects were identified as gene carriers and provided an estimated penetrance ratio of.84 for this condition. A few of the positionally mapped genes in the 5q35 region that may potentially be involved in the etiology of this condition are CANX, FGFR4, HK3, and hnRPH1. PMID:9973292

  7. Lenalidomide treatment induced the normalization of marker protein levels in blood plasma of patients with 5q-myelodysplastic syndrome.

    PubMed

    Messingerová, Lucia; Jonášová, Anna; Barančik, Miroslav; Poleková, Lenka; Šereš, Mário; Gibalová, Lenka; Breier, Albert; Sulová, Zdena

    2015-10-01

    A specific type of myelodysplastic syndrome (MDS) is associated with isolated deletion on the long arm of chromosome 5, i.e., 5q-syndrome (del(5q)). The treatment approaches for MDS del(5q) include the immunomodulating drug lenalidomide (LEN). Thirteen MDS del(5q) patients were included in this study. We found elevated activities of lactate dehydrogenase (LDH) and matrix metalloproteinase 9 (MMP-9) in the blood plasma of MDS del(5q) patients as compared with healthy controls. This was stabilized to control values after LEN treatment. Similar behavior we registered also for the thioredoxin and calnexin contents in BP. Peripheral blood mononuclear cells (PBMC) from patients with MDS del(5q) prior to and after treatment with LEN did not exhibit any detectable amount of P-glycoprotein (P-gp) gene transcript. However, we detected a measurable amount of multidrug resistance associated protein 1 (MRP1) mRNA in PBMCs from three patients prior to LEN treatment and in one patient during LEN treatment but it was not present prior to treatment. These data indicated on usefulness of applied protein markers estimation for monitoring of MDS del(5q) patient treatment effectiveness by LEN. Expression of MRP1 seems to be independent on LEN treatment and reflects probably the molecular variability in the ethiopathogenesis of MDS del(5q). PMID:26001289

  8. High-temperature order-disorder transitions in the skutterudites CoGe{sub 1.5}Q{sub 1.5} (Q=S, Te)

    SciTech Connect

    Kaltzoglou, Andreas; Powell, Anthony V.; Knight, Kevin S.; Vaqueiro, Paz

    2013-02-15

    The temperature dependence of anion ordering in the skutterudites CoGe{sub 1.5}Q{sub 1.5} (Q=S, Te) has been investigated by powder neutron diffraction. Both materials adopt a rhombohedral structure at room temperature (space group R3{sup Macron} ) in which the anions are ordered trans to each other within Ge{sub 2}Q{sub 2} rings. In CoGe{sub 1.5}S{sub 1.5}, anion ordering is preserved up to the melting point of 950 Degree-Sign C. However, rhombohedral CoGe{sub 1.5}Te{sub 1.5} undergoes a phase transition at 610 Degree-Sign C involving a change to cubic symmetry (space group Im3{sup Macron }). In the high-temperature modification, there is a statistical distribution of anions over the available sites within the Ge{sub 2}Te{sub 2} rings. The structural transition involves a reduction in the degree of distortion of the Ge{sub 2}Te{sub 2} rings which progressively transform from a rhombus to a rectangular shape. The effect of this transition on the thermoelectric properties has been investigated. - Graphical abstract: Powder neutron diffraction reveals that the skutterudite CoGe{sub 1.5}Te{sub 1.5} undergoes a phase transition at 610 Degree-Sign C, involving the disordering of the anions within the Ge{sub 2}Te{sub 2} rings. Highlights: Black-Right-Pointing-Pointer CoGe{sub 1.5}S{sub 1.5} retains an ordered skutterudite structure up to 950 Degree-Sign C. Black-Right-Pointing-Pointer CoGe{sub 1.5}Te{sub 1.5} undergoes an order-disorder phase transition at 610 Degree-Sign C. Black-Right-Pointing-Pointer Below 610 Degree-Sign C, anions are arranged trans to each other within Ge{sub 2}Te{sub 2} rings. Black-Right-Pointing-Pointer Above 610 Degree-Sign C, anions are statistically distributed within the Ge{sub 2}Te{sub 2} rings. Black-Right-Pointing-Pointer The effect of the phase transition on the thermal conductivity is discussed.

  9. A case of duplication 17p13.1p13.3 confirmed by FISH

    SciTech Connect

    Stephenson, C.F.; Berger, C.S.; Bull, R.M.

    1994-09-01

    There are many reports in the literature of deletions of the p arm of chromosome 17 in the region of p13.3 due to the association with Miller-Dieker Syndrome. However, very little is known about duplications of 17p. We report a duplication of part of 17p in an 8-year-old girl with attention deficit disorder and mild mental retardation. Cytogenetically, the duplicated region appears to include 17p13.1 to p13.3. FISH with a cosmid probe to the Miller-Dieker region at 17p13.3 shows a double hybridization signal, confirming that the duplicated material does indeed include 17q13.3.

  10. Genome-wide association study identifies two new susceptibility loci for colorectal cancer at 5q23.3 and 17q12 in Han Chinese

    PubMed Central

    Lv, Liang; Guo, Yong; Guo, Sutang; Li, Hai; Zhang, Lianhai; Zhou, Yanbing; Jiang, Bo; Ren, Yonghong; Xu, Youchun; Yang, Xiongfei; Liu, Hongxia; Wang, Yirui; Shen, Zhanlong; Qin, Wenyan; Guo, Peng; Jiang, Yuyang; Hu, Zhibin; Shen, Hongbing; Cheng, Jing; Yang, Yinxue; Wang, Shan

    2015-01-01

    Genome-wide association studies (GWAS) have reported a number of loci harboring common variants that influence risk of colorectal cancer (CRC) in European descent. But all the SNPs identified explained a small fraction of total heritability. To identify more genetic factors that modify the risk of CRC, especially Chinese Han specific, we conducted a three-stage GWAS including a screening stage (932 CRC cases and 966 controls) and two independent validations (Stage 2: 1,759 CRC cases and 1,875 controls; Stage 3: 943 CRC cases and 1,838 controls). In the combined analyses, we discovered two novel loci associated with CRC: rs12522693 at 5q23.3 (CDC42SE2-CHSY3, OR = 1.31, P = 2.08 × 10−8) and rs17836917 at 17q12 (ASIC2-CCL2, OR = 0.75, P = 4.55 × 10−8). Additionally, we confirmed two previously reported risk loci, rs6983267 at 8q24.21 (OR = 1.17, P = 7.17 × 10−7) and rs10795668 at 10p14 (OR = 0.86, P = 2.96 × 10−6) in our cohorts. These results bring further insights into the CRC susceptibility and advance our understanding on etiology of CRC. PMID:26515597

  11. Isolation and characterization of candidate genes of the 5q13 region in spinal muscular atrophy

    SciTech Connect

    Lefebvre, S.; Reboullet, S.; Benichou, B.

    1994-09-01

    Based on a fine genetic and physical map of the region deleted in spinal muscular atrophy, we defined the smallest rearrangements encompassing the SMA gene. This interval is entirely contained in the 903D1 YAC clone. Several approaches to identify candidate genes were applied, including the search for interspecies conservation, exon trapping amplification and direct cDNA selection. Combining these strategies, six different cDNA molecules mapping to the YAC contig were isolated. Four cDNA molecules were isolated using the exon trapping system. They map to chromosome 5p and to more than one locus within the 5q13 region. They are homologous to each other and share sequence homology with the {beta}-glucuronidase gene. Based on interspecies conservation, a fifth candidate gene was identified. Sequence analyses of the cDNAs revealed no homologies with any other described genes. This gene mapped to two loci within the 5q13 region. Two other cDNA molecules isolated by direct cDNA selection are also under investigation. Complete characterization and fine physical mapping of those genes with respect to the physical interval defined by the deletions of the SMA region will allow the identification of the disease gene (or genes).

  12. Genetic and radiation hybrid mapping of the hyperekplexia region on chromosome 5q

    SciTech Connect

    Ryan, S.G.; O'Connell, P. ); Dixon, M.J. ); Nigro, M.A. ); Kelts, K.A. ); Markand, O.N. ); Shiang, R.; Wasmuth, J.J. ); Terry, J.C.

    1992-12-01

    Hyperekplexia, or startle disease (STHE), is an autosomal dominant neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to sudden, unexpected acoustic or tactile stimuli. STHE responds dramatically to the benzodiazepine drug clonazepam, which acts at gamma-aminobutyric acid type A (GABA-A) receptors. The STHE locus (STHE) was recently assigned to chromosome 5q, on the basis of tight linkage to the colony-stimulating factor 1-receptor (CSF1-R) locus in a single large family. The authors performed linkage analysis in the original and three additional STHE pedigrees with eight chromosome 5q microsatellite markers and placed several of the most closely linked markers on an existing radiation hybrid (RH) map of the region. The results provide strong evidence for genetic locus homogeneity and assign STHE to a 5.9-cM interval defined by CSF1-R and D5S379, which are separated by an RH map distance of 74 centirays (roughly 2.2-3.7 Mb). Two polymorphic markers (D5S119 and D5S209) lie within this region, but they could not be ordered with respect to STHE. RH mapping eliminated the candidate genes GABRA1 and GABRG2, which encode GABA-A receptor components, by showing that they are telomeric to the target region. 45 refs., 4 figs., 4 tabs.

  13. Las17p-Vrp1p but not Las17p-Arp2/3 interaction is important for actin patch polarization in yeast.

    PubMed

    Rajmohan, Rajamuthiah; Wong, Ming Hwa; Meng, Lei; Munn, Alan L; Thanabalu, Thirumaran

    2009-05-01

    The actin cytoskeleton plays a central role in many important cellular processes such as cell polarization, cell division and endocytosis. The dynamic changes to the actin cytoskeleton that accompany these processes are regulated by actin-associated proteins Wiskott-Aldrich Syndrome Protein (WASP) (known as Las17p in yeast) and WASP-Interacting Protein (WIP) (known as Vrp1p in yeast). Both yeast and human WASP bind to and stimulate the Arp2/3 complex which in turn nucleates assembly of actin monomers into filaments at polarized sites at the cortex. WASP-WIP interaction in yeast and humans are important for Arp2/3 complex stimulation in vitro. It has been proposed that these interactions are also important for polarized actin assembly in vivo. However, the redundancy of actin-associated proteins has made it difficult to test this hypothesis. We have identified two point mutations (L80T and H94L) in yeast WASP that in combination abolish WASP-WIP interaction in yeast. We also identify an N-terminal fragment of Las17p (N-Las17p1-368) able to interact with Vrp1p but not Arp2/3. Using these mutant and truncated forms of yeast WASP we provide novel evidence that WASP interaction with WIP is more important than interaction with Arp2/3 for polarized actin assembly and endocytosis in yeast. PMID:19272406

  14. MEF2C-Related 5q14.3 Microdeletion Syndrome Detected by Array CGH: A Case Report

    PubMed Central

    Shim, Jae Sun; Min, Kyunghoon; Lee, Seung Hoon; Park, Ji Eun; Park, Sang Hee; Kim, MinYoung

    2015-01-01

    Genetic screening is being widely applied to trace the origin of global developmental delay or intellectual disability. The 5q14.3 microdeletion has recently been uncovered as a clinical syndrome presenting with severe intellectual disability, limited walking ability, febrile convulsions, absence of speech, and minor brain malformations. MEF2C was suggested as a gene mainly responsible for the 5q14.3 microdeletion syndrome. We present the case of a 6-year-old girl, who is the first patient in Korea with de novo interstitial microdeletions involving 5q14.3, showing the typical clinical features of 5q14.3 microdeletion syndrome with a smaller size of chromosomal involvement compared to the previous reports. The microdeletion was not detected by subtelomeric multiplex ligation-dependent probe amplification, but by array comparative genomic hybridization, which is advisable for the detection of a small-sized genetic abnormality. PMID:26161356

  15. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.

    PubMed

    Lalani, Seema R; Zhang, Jing; Schaaf, Christian P; Brown, Chester W; Magoulas, Pilar; Tsai, Anne Chun-Hui; El-Gharbawy, Areeg; Wierenga, Klaas J; Bartholomew, Dennis; Fong, Chin-To; Barbaro-Dieber, Tina; Kukolich, Mary K; Burrage, Lindsay C; Austin, Elise; Keller, Kory; Pastore, Matthew; Fernandez, Fabio; Lotze, Timothy; Wilfong, Angus; Purcarin, Gabriela; Zhu, Wenmiao; Craigen, William J; McGuire, Marianne; Jain, Mahim; Cooney, Erin; Azamian, Mahshid; Bainbridge, Matthew N; Muzny, Donna M; Boerwinkle, Eric; Person, Richard E; Niu, Zhiyv; Eng, Christine M; Lupski, James R; Gibbs, Richard A; Beaudet, Arthur L; Yang, Yaping; Wang, Meng C; Xia, Fan

    2014-11-01

    5q31.3 microdeletion syndrome is characterized by neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay, and the minimal critical deletion interval harbors three genes. We describe 11 individuals with clinical features of 5q31.3 microdeletion syndrome and de novo mutations in PURA, encoding transcriptional activator protein Pur-α, within the critical region. These data implicate causative PURA mutations responsible for the severe neurological phenotypes observed in this syndrome. PMID:25439098

  16. Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.

    PubMed

    Kumar, Madhu S; Narla, Anupama; Nonami, Atsushi; Mullally, Ann; Dimitrova, Nadya; Ball, Brian; McAuley, J Randall; Poveromo, Luke; Kutok, Jeffrey L; Galili, Naomi; Raza, Azra; Attar, Eyal; Gilliland, D Gary; Jacks, Tyler; Ebert, Benjamin L

    2011-10-27

    Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome. PMID:21873545

  17. The gene for human glutaredoxin (GLRX) is localized to human chromosome 5q14

    SciTech Connect

    Padilla, C.A.; Holmgren, A.; Bajalica, S.; Lagercrantz, J.

    1996-03-05

    Glutaredoxin is a small protein (12 kDa) catalyzing glutathione-dependent disulfide oxidoreduction reactions in a coupled system with NADPH, GSH, and glutathione reductase. A cDNA encoding the human glutaredoxin gene (HGMW-approved symbol GLRX) has recently been isolated and cloned from a human fetal spleen cDNA library. The screening of a human fetal spleen cDNA library. The screening of a human genomic library in Charon 4A led to the identification of three genomic clones. Using fluorescence in situ hybridization to metaphase chromosomes with one genomic clone as a probe, the human glutaredoxin gene was localized to chromosomal region 5q14. This localization at chromosome 5 was in agreement with the somatic cell hybrid analysis, using DNA from a human-hamster and a human-mouse hybrid panel and using a human glutaredoxin cDNA as a probe. 13 refs., 2 figs.

  18. 5q11.2 deletion in a patient with tracheal agenesis

    PubMed Central

    de Jong, Elisabeth M; Douben, Hannie; Eussen, Bert H; Felix, Janine F; Wessels, Marja W; Poddighe, Pino J; Nikkels, Peter G J; de Krijger, Ronald R; Tibboel, Dick; de Klein, Annelies

    2010-01-01

    Tracheal agenesis (TA) is a rare congenital anomaly of the respiratory tract. Many patients have associated anomalies, suggesting a syndromal phenotype. In a cohort of 12 patients, we aimed to detect copy number variations. In addition to routine cytogenetic analysis, we applied oligonucleotide array comparative genomic hybridization. Our patient cohort showed various copy number variations, of which many were parentally inherited variants. One patient had, in addition to an inherited 16p12.1 deletion, a 3.6 Mb deletion on chromosomal locus 5q11.2. This patient had a syndromic phenotype, including vertebral, anal, cardiovascular and tracheo-oesophageal associated anomalies, and other foregut-related anomalies, such as cartilage rings in the oesophagus and an aberrant right bronchus. No common deletions or duplications are found in our cohort, suggesting that TA is a genetically heterogeneous disorder. PMID:20551993

  19. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies

    SciTech Connect

    Melki, J.; Lefebvre, S.; Burglen, L.; Burlet, P.; Clermont, O.; Reboullet, S.; Benichou, B.; Zeviani, M. ); Millasseau, P. ); Le Paslier, D. )

    1994-06-03

    Spinal muscular atrophies (SMAs) represent the second most common fatal autosomal recessive disorder after cystic fibrosis. Childhood spinal muscular atrophies are divided into severe (type I) and mild forms (types II and III). By a combination of genetic and physical mapping, a yeast artificial chromosome contig of the 5q13 region spanning the disease locus was constructed that showed the presence of low copy repeats in this region. Allele segregation was analyzed at the closest genetic loci detected by markers C212 and C272 in 201 SMA families. Inherited and de novo deletions were observed in nine unrelated SMA patients. Moreover, deletions were strongly suggested in at least 18 percent of SMA type I patients by the observation of marked heterozygosity deficiency for the loci studied. These results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy. 25 refs., 5 figs.

  20. Chromosome 17p deletion in human medulloblastoma: a missing checkpoint in the Hedgehog pathway.

    PubMed

    De Smaele, Enrico; Di Marcotullio, Lucia; Ferretti, Elisabetta; Screpanti, Isabella; Alesse, Edoardo; Gulino, Alberto

    2004-10-01

    Although deregulation of Hedgehog signalling is considered to play a crucial oncogenic role and commonly occurrs in medulloblastoma, genetic lesions in components of this pathway are observed in a minority of cases. The recent identification of a novel putative tumor suppressor (REN(KCTD11)) on chromosome 17p13.2, a region most frequently lost in human medulloblastoma, highlights the role of allelic deletion of the gene in this brain malignancy, leading to the loss of growth inhibitory activity via suppression of Gli-dependent activation of Hedgehog target genes. The presence on 17p13 of another tumor suppressor gene (p53) whose inactivation cooperates with Hedgehog pathway for medulloblastoma formation, suggests that 17p deletion unveils haploinsufficiency conditions leading to abrogation of either direct and indirect checkpoints of Hedgehog signalling in cancer. PMID:15467454

  1. First Direct Measurement of the F17(p,?γ)Ne18 Cross Section

    NASA Astrophysics Data System (ADS)

    Chipps, K. A.; Bardayan, D. W.; Blackmon, J. C.; Chae, K. Y.; Greife, U.; Hatarik, R.; Kozub, R. L.; Matei, C.; Moazen, B. H.; Nesaraja, C. D.; Pain, S. D.; Peters, W. A.; Pittman, S. T.; Shriner, J. F., Jr.; Smith, M. S.

    2009-04-01

    The rate of the F17(p,?γ)Ne18 reaction is important in various astrophysical events. A previous F17(p,?p)F17 measurement identified a 3+ state providing the strongest resonance contribution, but the resonance strength was unknown. We have directly measured the F17(p,?γ)Ne18 reaction using a mixed beam of F17 and O17 at ORNL. The resonance strength for the 3+ resonance in Ne18 was found to be ωγ=33±14(stat)±17(syst)meV, corresponding to a γ width of Γγ=56±24(stat)±30(syst)meV. An upper limit on the direct capture of S(E)≤65keVb was determined at an energy of 800 keV.

  2. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion.

    PubMed

    Chesnais, Virginie; Renneville, Aline; Toma, Andrea; Lambert, Jérôme; Passet, Marie; Dumont, Florent; Chevret, Sylvie; Lejeune, Julie; Raimbault, Anna; Stamatoullas, Aspasia; Rose, Christian; Beyne-Rauzy, Odile; Delaunay, Jacques; Solary, Eric; Fenaux, Pierre; Dreyfus, François; Preudhomme, Claude; Kosmider, Olivier; Fontenay, Michaela

    2016-02-11

    Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. PMID:26626993

  3. Effect of lenalidomide treatment on clonal architecture of myelodysplastic syndromes without 5q deletion

    PubMed Central

    Chesnais, Virginie; Renneville, Aline; Toma, Andrea; Lambert, Jérôme; Passet, Marie; Dumont, Florent; Chevret, Sylvie; Lejeune, Julie; Raimbault, Anna; Stamatoullas, Aspasia; Rose, Christian; Beyne-Rauzy, Odile; Delaunay, Jacques; Solary, Eric; Fenaux, Pierre; Dreyfus, François; Preudhomme, Claude; Kosmider, Olivier

    2016-01-01

    Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug’s effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34+CD38− hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34+CD38− cell–derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379. PMID:26626993

  4. Variation in conserved non-coding sequences on chromosome 5q andsusceptibility to asthma and atopy

    SciTech Connect

    Donfack, Joseph; Schneider, Daniel H.; Tan, Zheng; Kurz,Thorsten; Dubchak, Inna; Frazer, Kelly A.; Ober, Carole

    2005-09-10

    Background: Evolutionarily conserved sequences likely havebiological function. Methods: To determine whether variation in conservedsequences in non-coding DNA contributes to risk for human disease, westudied six conserved non-coding elements in the Th2 cytokine cluster onhuman chromosome 5q31 in a large Hutterite pedigree and in samples ofoutbred European American and African American asthma cases and controls.Results: Among six conserved non-coding elements (>100 bp,>70percent identity; human-mouse comparison), we identified one singlenucleotide polymorphism (SNP) in each of two conserved elements and sixSNPs in the flanking regions of three conserved elements. We genotypedour samples for four of these SNPs and an additional three SNPs each inthe IL13 and IL4 genes. While there was only modest evidence forassociation with single SNPs in the Hutterite and European Americansamples (P<0.05), there were highly significant associations inEuropean Americans between asthma and haplotypes comprised of SNPs in theIL4 gene (P<0.001), including a SNP in a conserved non-codingelement. Furthermore, variation in the IL13 gene was strongly associatedwith total IgE (P = 0.00022) and allergic sensitization to mold allergens(P = 0.00076) in the Hutterites, and more modestly associated withsensitization to molds in the European Americans and African Americans (P<0.01). Conclusion: These results indicate that there is overalllittle variation in the conserved non-coding elements on 5q31, butvariation in IL4 and IL13, including possibly one SNP in a conservedelement, influence asthma and atopic phenotypes in diversepopulations.

  5. A YAC contig of approximately 3 Mb from human chromosome 5q31 [yields] q33

    SciTech Connect

    Li, Xiang; Wang Jabs, E.; Hawkins, A.L.; Griffin, C.A. ); Wise, C.A.; Lovett, M. ); Le Paslier, D. ); Pittler, S.J. )

    1994-02-01

    The human chromosome 5q31-q33 region contains an interesting cluster of growth factor and receptor genes. In addition, several genetic disease loci have been localized within this region, but have not as yet been isolated as molecular clones. These include those loci involved in autosomal dominant limb-girdle muscular dystrophy, diastrophic dysplasia, Treacher Collins syndrome, and myeloid disorders associated with the 5q-syndrome. A yeast artificial chromosome (YAC) contig of this region would assist in the further localization and isolation of these genes. The authors have used YACs isolated from the Washington University and Centre d'Etude du Polymorphisme Humain YAC libraries, including YACs from the large insert (mega) YAC library to build a contig greater than 3 Mb in size. An STS content strategy coupled with limited walking from YAC ends was used to isolate 22 overlapping YACs with as much as sixfold coverage. A total of 20 STSs, derived from genes, anonymous sequences, and vector Alu-PCR or inverse PCR products, were used to compile this contig. The order of loci, centromere-GRL-D5S207-D5S70-D5S545-D5S546-D5S547-D5S68-D5S548-D5S210-D5S549-D5S686- ADRB2-D5S559-CSF1R-D5S551-RPS14-D5S519-SPARC-telomere, was derived from the overlapping clones. This contig and clones derived from it will be useful substrates in selecting candidate cDNAs for the disease loci in this interval. 45 refs., 1 fig., 2 tabs.

  6. Localization of a new autosomal dominant retinitis pigmentosa gene on chromosome 17p screeningof candidate genes

    SciTech Connect

    Greenberg, J.; Goliath, R.; Shugart, Y.Y.

    1994-09-01

    A new gene locus for autosomal dominant retinitis pigmentosa (ADRP) on 17p has been identified in a large South African (SA) family consisting of 28 living affected individuals in 4 successive generations. This is the first ADRP gene to be reported from SA. The human recoverin (RCVN) gene, which codes for a retinal-specific protein important in recovery to the dark state after visual excitation, has been mapped to 17p13.1 and was considered as a prime candidate gene for the disorder in this family. Mutation screening (using 8 different electrophoretic conditions to resolve heteroduplexes and SSCPs) did not produce any evidence of RCVN being involved in the pathogenesis of ADRP in this SA family. In addition, a mobility shift detected within exon 1 of the RCVN gene did not track with the ADRP phenotype. RP patients from 77 SA families and 30 normal individuals are being examined to establish the frequency of this polymorphism in the SA population. Highly polymorphic markers from 17p13 are now being sought in order to establish the minimum region containing this novel ADRP-SA gene. Two additional recently described retinal-expressed cDNAs, guanylyl cyclase and pigment epithelium-derived factor, which map to 17p13.1, will be tested for tight linkage to ADRP-SA.

  7. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 30 2013-07-01 2012-07-01 true pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  8. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 30 2012-07-01 2012-07-01 false pH Effluent limitations under... (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations under continuous monitoring. (a) Where a permittee continuously measures the pH of wastewater pursuant to...

  9. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 29 2014-07-01 2012-07-01 true pH Effluent limitations under continuous monitoring. 401.17 Section 401.17 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations...

  10. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 28 2010-07-01 2010-07-01 true pH Effluent limitations under continuous monitoring. 401.17 Section 401.17 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations...

  11. 40 CFR 401.17 - pH Effluent limitations under continuous monitoring.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 29 2011-07-01 2009-07-01 true pH Effluent limitations under continuous monitoring. 401.17 Section 401.17 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) EFFLUENT GUIDELINES AND STANDARDS GENERAL PROVISIONS § 401.17 pH Effluent limitations...

  12. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

    PubMed Central

    Smith, J. Gustav; Felix, Janine F.; Morrison, Alanna C.; Trompet, Stella; Wilk, Jemma B.; Gidlöf, Olof; Morley, Michael; Joehanes, Roby; Ligthart, Symen; Shan, Xiaoyin; Bis, Joshua C.; Sjögren, Marketa; Ngwa, Julius; Stott, David J.; Aguilar, David; Rice, Kenneth M.; Sesso, Howard D.; Demissie, Serkalem; Buckley, Brendan M.; Taylor, Kent D.; Ford, Ian; Yao, Chen; Liu, Chunyu; Sotoodehnia, Nona; van der Harst, Pim; Stricker, Bruno H. Ch.; Kritchevsky, Stephen B.; Liu, Yongmei; Gaziano, J. Michael; Hofman, Albert; Moravec, Christine S.; Uitterlinden, André G.; Kellis, Manolis; van Meurs, Joyce B.; Margulies, Kenneth B.; Dehghan, Abbas; Levy, Daniel; Olde, Björn; Psaty, Bruce M.; Cupples, L. Adrienne; Jukema, J. Wouter; Djousse, Luc; Franco, Oscar H.; Boerwinkle, Eric; Boyer, Laurie A.; Newton-Cheh, Christopher; Butler, Javed; Vasan, Ramachandran S.; Cappola, Thomas P.; Smith, Nicholas L.

    2016-01-01

    Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure. PMID:27149122

  13. Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure.

    PubMed

    Smith, J Gustav; Felix, Janine F; Morrison, Alanna C; Kalogeropoulos, Andreas; Trompet, Stella; Wilk, Jemma B; Gidlöf, Olof; Wang, Xinchen; Morley, Michael; Mendelson, Michael; Joehanes, Roby; Ligthart, Symen; Shan, Xiaoyin; Bis, Joshua C; Wang, Ying A; Sjögren, Marketa; Ngwa, Julius; Brandimarto, Jeffrey; Stott, David J; Aguilar, David; Rice, Kenneth M; Sesso, Howard D; Demissie, Serkalem; Buckley, Brendan M; Taylor, Kent D; Ford, Ian; Yao, Chen; Liu, Chunyu; Sotoodehnia, Nona; van der Harst, Pim; Stricker, Bruno H Ch; Kritchevsky, Stephen B; Liu, Yongmei; Gaziano, J Michael; Hofman, Albert; Moravec, Christine S; Uitterlinden, André G; Kellis, Manolis; van Meurs, Joyce B; Margulies, Kenneth B; Dehghan, Abbas; Levy, Daniel; Olde, Björn; Psaty, Bruce M; Cupples, L Adrienne; Jukema, J Wouter; Djousse, Luc; Franco, Oscar H; Boerwinkle, Eric; Boyer, Laurie A; Newton-Cheh, Christopher; Butler, Javed; Vasan, Ramachandran S; Cappola, Thomas P; Smith, Nicholas L

    2016-05-01

    Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure. PMID:27149122

  14. De novo 5q35.5 duplication with clinical presentation of Sotos syndrome.

    PubMed

    Kasnauskiene, Jurate; Cimbalistiene, Loreta; Ciuladaite, Zivile; Preiksaitiene, Egle; Kučinskienė, Zita Aušrelė; Hettinger, Joe A; Sismani, Carolina; Patsalis, Philippos C; Kučinskas, Vaidutis

    2011-10-01

    We report on a girl with developmental delay and a de novo 264 kb interstitial duplication in the region of Sotos syndrome at 5q35.3 in the immediate vicinity of critical NSD1 gene, but manifesting the phenotype, of overgrowth both prenatal stage and postnatal, macrocephaly, developmental delay, and resembling that of Sotos syndrome, rather than the recently reported syndrome of reciprocal duplication. The duplication is located right downstream from the NSD1 gene, a region which appears critical for the expression of the gene as regulatory elements might be disrupted or the expression of a not amplified critical gene might be otherwise affected by the duplicated region. Thus,in the process of evaluating identified CNVs attention should be drawn to the possible influence of chromosomal rearrangement on distant genes, which could add additional diversity to genomic disorders. Our case demonstrates that evaluation of the size of chromosomal alteration and gene content are not sufficient for assessment of CNV's pathogenicity and the context of adjacent genes should be considered. PMID:21998857

  15. The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome

    PubMed Central

    Zweier, M.; Rauch, A.

    2012-01-01

    Disorders related to the autosomal transcription factor MEF2C located in 5q14.3 were first described in 2009 and have since evolved to one of the more common microdeletion syndromes. Mutational screening in a larger cohort revealed heterozygous de novo mutations of MEF2C in about 1% of patients with moderate to severe intellectual disability, and the phenotype is similar in patients with intragenic deletions and multigenic microdeletions. Clinically, MEF2C-related disorders are characterized by severe intellectual disability with absent speech and limited walking abilities, hypotonia, seizures, and a variety of minor brain anomalies. The majority of patients show a similar facial gestalt with broad forehead, flat nasal bridge, hypotonic mouth, and small chin, as well as strabismus, but this phenotype is clinically not well recognized. The course of the disease is generally quite uniform, but patients with point mutations and smaller deletions seem to have a higher chance of walking skills and a lower risk of refractory seizures. Patients in whom the microdeletion also includes the RASA1 gene show features of the respective capillary and arterio-venous malformations and fistula syndrome. The phenotypic overlap with Rett syndrome is explained by a shared pathway and, accordingly, diminished MECP2 and CDKL5 expression is measureable in patients with MEF2C defects. Further research of this pathway may therefore eventually lead to a common therapeutic target. PMID:22670137

  16. Faithful expression of the human 5q31 cytokine cluster intransgenic mice

    SciTech Connect

    Lacy, Dee A.; Wang, Zhi-En; Symula, Derek J.; McArthur, CliffordJ.; Rubin, Edward M.; Frazer, Kelly A.; Locksley, Richard M.

    1999-12-03

    ILs 4,5, and 13, cardinal cytokines produced by Th2 cells,are coordinately expressed and clustered in the 150-kb syntenic regions on mouse chromosome 11 and human chromosome 5q31. We analyzed two sets of human yeast artificial chromosome transgenic mice that contained the5931cytokines to assess whether conserved sequences required for their coordinate and cell-specific regulation are contained within the cytokine cluster itself. Human Il-4, IL-13, and Il-5 were expressed under Th2, but not Th1, conditions in vitro. Each of these cytokines was produced during infection with Nippostrongylus brasiliensis, a Th2 inducing stimulus, and human Il-4 was generated after activation of NK T cells in vivo.Consistently fewer cells produced the endogenous mouse cytokines in transgenic than in control mice, suggesting competition for stable expression between the mouse and human genes. These data imply the existence of both conserved trans-activating factors and cis-regulatory elements that underlie the coordinate expression and lineage specificity of the type 2 ctyokine genes in lymphocytes.

  17. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations

    SciTech Connect

    Marsh, D.G.; Neely, J.D.; Ghosh, B.; Freidhoff, L.R.; Ehrlich-Kautzky, E.; Krishnaswamy, G.; Breazeale, D.R.; Beaty, T.H.; Schou, C.

    1994-05-20

    Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (lgE) concentration. No linkage was found between these markers and specific lgE antibody concentrations. Analysis of total lgE within a subset of 128 lgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1., especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates lgE production in a nonantigen-specific (noncognate) fashion. 37 refs., 2 figs., 2 tabs.

  18. A Locus at 5q33.3 Confers Resistance to Tuberculosis in Highly Susceptible Individuals.

    PubMed

    Sobota, Rafal S; Stein, Catherine M; Kodaman, Nuri; Scheinfeldt, Laura B; Maro, Isaac; Wieland-Alter, Wendy; Igo, Robert P; Magohe, Albert; Malone, LaShaunda L; Chervenak, Keith; Hall, Noemi B; Modongo, Chawangwa; Zetola, Nicola; Matee, Mecky; Joloba, Moses; Froment, Alain; Nyambo, Thomas B; Moore, Jason H; Scott, William K; Lahey, Timothy; Boom, W Henry; von Reyn, C Fordham; Tishkoff, Sarah A; Sirugo, Giorgio; Williams, Scott M

    2016-03-01

    Immunosuppression resulting from HIV infection increases the risk of progression to active tuberculosis (TB) both in individuals newly exposed to Mycobacterium tuberculosis (MTB) and in those with latent infections. We hypothesized that HIV-positive individuals who do not develop TB, despite living in areas where it is hyperendemic, provide a model of natural resistance. We performed a genome-wide association study of TB resistance by using 581 HIV-positive Ugandans and Tanzanians enrolled in prospective cohort studies of TB; 267 of these individuals developed active TB, and 314 did not. A common variant, rs4921437 at 5q33.3, was significantly associated with TB (odds ratio = 0.37, p = 2.11 × 10(-8)). This variant lies within a genomic region that includes IL12B and is embedded in an H3K27Ac histone mark. The locus also displays consistent patterns of linkage disequilibrium across African populations and has signals of strong selection in populations from equatorial Africa. Along with prior studies demonstrating that therapy with IL-12 (the cytokine encoded in part by IL12B, associated with longer survival following MTB infection in mice deficient in CD4 T cells), our results suggest that this pathway might be an excellent target for the development of new modalities for treating TB, especially for HIV-positive individuals. Our results also indicate that studying extreme disease resistance in the face of extensive exposure can increase the power to detect associations in complex infectious disease. PMID:26942285

  19. Microdeletions of chromosome 17p13 as a cause of isolated lissencephaly

    SciTech Connect

    Ledbetter, S.A.; Kuwano, Akira; Ledbetter, D.H. ); Dobyns, W.B. )

    1992-01-01

    Lissencephaly (agyria-pachygyria) is a brain malformation manifested by a smooth cerebral surface, resulting from arrest of neuronal migration at 10-14 wk gestation. Type I, or classical, lissencephaly can occur either in association with the Miller-Dieker syndrome (MDS) or as an isolated finding, termed isolated lissencephaly sequence (ILS). About 90% of MDS patients have visible or submicroscopic deletions of 17p13.3. The authors therefore investigated the possibility that some ILS patients have smaller deletions in this chromosomal region. Forty-five ILS patients with gyral abnormalities ranging from complete agyria to mixed agyria/pachygyria and complete pachygyria were studied. RFLP analysis with five polymorphic loci in 17p13.3 was performed on all patients and their parents. Somatic cell hybrids were constructed on three patients, to confirm a deletion or to determine the boundaries of a deletion. These data demonstrate that a locus on 17p13 represents a major genetic etiology for patients with lissencephaly, ranging from complete agyria to pachygyria. In situ hybridization allows rapid and sensitive deletion detection and is the preferred method for diagnostic evaluation of MDA and ILS patients.

  20. CHANDRA OBSERVATIONS OF COMETS 8P/TUTTLE AND 17P/HOLMES DURING SOLAR MINIMUM

    SciTech Connect

    Christian, D. J.; Bodewits, D.; Lisse, C. M.; Dennerl, K.; Wolk, S. J.; Hsieh, H.; Zurbuchen, T. H.; Zhao, L. E-mail: damian.christian@csun.edu E-mail: carey.lisse@jhuapl.edu E-mail: swolk@cfa.harvard.edu E-mail: thomasz@umich.edu

    2010-04-01

    We present results for Chandra X-ray Observatory observations of two comets made during the minimum of solar cycle 24. The two comets, 17P/Holmes (17P) and 8P/Tuttle (8P), were very different in their activity and geometry. 17P was observed, for 30 ks right after its major outburst, on 2007 October 31 (10:07 UT), and comet 8P/Tuttle was observed in 2008 January for 47 ks. During the two Chandra observations, 17P was producing at least 100 times more water than 8P but was 2.2 times further away from the Sun. Also, 17P was at a relatively high solar latitude (+19.{sup 0}1) while 8P was observed at a lower solar latitude (3.{sup 0}4). The X-ray spectrum of 17P is unusually soft with little significant emission at energies above 500 eV. Depending on our choice of background, we derive a 300-1000 eV flux of 0.5-4.5 x 10{sup -13} erg cm{sup -2} s{sup -1}, with over 90% of the emission in the 300-400 eV range. This corresponds to an X-ray luminosity between 0.4 and 3.3 x 10{sup 15} erg s{sup -1}. However, we cannot distinguish between this significant excess emission and possible instrumental effects, such as incomplete charge transfer across the CCD. 17P is the first comet observed at high latitude during solar minimum. Its lack of X-rays in the 400-1000 eV range, in a simple picture, may be attributed to the polar solar wind, which is depleted in highly charged ions. 8P/Tuttle was much brighter, with an average count rate of 0.20 counts s{sup -1} in the 300-1000 eV range. We derive an average X-ray flux in this range of 9.4 x 10{sup -13} erg cm{sup -2} s{sup -1} and an X-ray luminosity for the comet of 1.7 x 10{sup 14} erg s{sup -1}. The light curve showed a dramatic decrease in flux of over 60% between observations on January 1 and 4. When comparing outer regions of the coma to inner regions, its spectra showed a decrease in ratios of C VI/C V, O VIII/O VII, as predicted by recent solar wind charge exchange (SWCX) emission models. There are remarkable differences

  1. Multiphysics Applications of ACE3P

    SciTech Connect

    K.H. Lee, C. Ko, Z. Li, C.-K. Ng, L. Xiao, G. Cheng, H. Wang

    2012-07-01

    The TEM3P module of ACE3P, a parallel finite-element electromagnetic code suite from SLAC, focuses on the multiphysics simulation capabilities, including thermal and mechanical analysis for accelerator applications. In this pa- per, thermal analysis of coupler feedthroughs to supercon- ducting rf (SRF) cavities will be presented. For the realistic simulation, internal boundary condition is implemented to capture RF heating effects on the surface shared by a di- electric and a conductor. The multiphysics simulation with TEM3P matched the measurement within 0.4%.

  2. COMET 17P/HOLMES IN OUTBURST: THE NEAR INFRARED SPECTRUM

    SciTech Connect

    Yang Bin; Jewitt, David; Bus, Schelte J. E-mail: jewitt@ifa.hawaii.edu

    2009-05-15

    Jupiter family comet 17P/Holmes underwent a remarkable outburst on UT 2007 October 24, in which the integrated brightness abruptly increased by about a factor of a million. We obtained near infrared (0.8-4.2 {mu}m) spectra of 17P/Holmes on UT 2007 October 27, 28, and 31, using the 3.0 m NASA Infrared Telescope Facility atop Mauna Kea. Two broad absorption bands were found in the reflectance spectra with centers (at 2 {mu}m and 3 {mu}m, respectively) and overall shapes consistent with the presence of water ice grains in the coma. Synthetic mixing models of these bands suggest an origin in cold ice grains of micron size. Curiously, though, the expected 1.5 {mu}m band of water ice was not detected in our data, an observation for which we have no explanation. Simultaneously, excess thermal emission in the spectra at wavelengths beyond 3.2 {mu}m has a color temperature of 360 {+-} 40 K (corresponding to a superheat factor of {approx}2.0 {+-} 0.2 at 2.45 AU). This is too hot for these grains to be icy. The detection of both water ice spectral features and short-wavelength thermal emission suggests that the coma of 17P/Holmes has two components (hot, refractory dust and cold ice grains) which are not in thermal contact. A similarity to grains ejected into the coma of 9P/Tempel 1 by the Deep Impact spacecraft is noted.

  3. Molecular analyses of 17p11.2 deletions in 62 Smith-Magenis syndrome patients.

    PubMed Central

    Juyal, R. C.; Figuera, L. E.; Hauge, X.; Elsea, S. H.; Lupski, J. R.; Greenberg, F.; Baldini, A.; Patel, P. I.

    1996-01-01

    Smith-Magenis syndrome (SMS) is a clinically recognizable, multiple congenital anomalies/mental retardation syndrome caused by an interstitial deletion involving band p11.2 of chromosome 17. Toward the molecular definition of the interval defining this microdeletion syndrome, 62 unrelated SMS patients in conjunction with 70 available unaffected parents were molecularly analyzed with respect to the presence or absence of 14 loci in the proximal region of the short arm of chromosome 17. A multifaceted approach was used to determine deletion status at the various loci that combined (i) FISH analysis, (ii)PCR and Southern analysis of somatic cell hybrids retaining the deleted chromosome 17 from selected patients, and (iii) genotype determination of patients for whom a parent(s) was available at four microsatellite marker loci and at four loci with associated RFLPs. The relative order of two novel anonymous markers and a new microsatellite marker was determined in 17p11.2. The results confirmed that the proximal deletion breakpoint in the majority of SMS patients is located between markers D17S58 (EW301) and D17S446 (FG1) within the 17p11.1-17p11.2 region. The common distal breakpoint was mapped between markers cCI17-638, which lies distal to D17S71, and cCI17-498, which lies proximal to the Charcot Marie-Tooth disease type 1A locus. The locus D17S258 was found to be deleted in all 62 patients, and probes from this region can be used for diagnosis of the SMS deletion by FISH. Ten patients demonstrated molecularly distinct deletions; of these, two patients had smaller deletions and will enable the definition of the critical interval for SMS. Images Figure 2 PMID:8651284

  4. Association analysis of GABA receptor subunit genes on 5q33 with heroin dependence in a Chinese male population.

    PubMed

    Loh, E W; Tang, N L S; Lee, D T S; Liu, S I; Stadlin, Alfreda

    2007-06-01

    GABAA receptor subunit genes clustered on 5q33 play a role in the development of alcoholism and methamphetamine use disorder without psychosis. The present study explored the possible contribution of the same subunit genes to the development of heroin dependence. Single nucleotide polymorphisms (SNPs) of the GABAA receptor subunits GABRB2, GABRA6, GABRA1, and GABRG2 were examined in 178 male Han Chinese heroin-dependent and 170 male control subjects. A significant difference in allele frequency for the SNP rs211014 in the GABAAgamma2 receptor subunit gene between cases and controls was identified (P = 0.015). A possible mechanism for the involvement of the GABA receptor subunit genes on 5q33 in the development of heroin dependence is discussed. PMID:17440936

  5. A novel 5q11.2 microdeletion in a child with mild developmental delay and dysmorphic features.

    PubMed

    Fontana, Paolo; Tortora, Cristina; Petillo, Roberta; Falco, Mariateresa; Miniero, Martina; De Brasi, Davide; Pisanti, Maria Antonietta

    2016-09-01

    5q11.2 Deletion is a very rare genomic disorder, and its clinical phenotype has not yet been characterized. This report describes a patient with an 8.6 Mb deletion, showing hypotonia, mild developmental delay, short stature, and distinctive dysmorphic features (frontal bossing, square face, deep-set eyes, prominent columella, long philtrum, thin lips). © 2016 Wiley Periodicals, Inc. PMID:27374896

  6. 17p deletions and chromosome 17 copy number correlate strongly with grade and stage in bladder cancer

    SciTech Connect

    Sauter, G.; Matsumura, K.; Kerschmann, R.; Carroll, P.; Waldman, F. ); Moch, H.; Gudat, F.; Mihatsch, M.J. )

    1993-01-01

    The clinical course of bladder cancer is not predicted by histological criteria along. Mutation at p53, usually accompanied by allelic loss on the other chromosome 17p, has been implicated as a prognostic parameter in several tumors, including bladder cancer. The authors therefore examined 153 bladder cancer samples by fluorescence in situ hybridization (FISH) to assess deletions on chromosome 17p. Probes for a pericentromeric region on 17 and a probe for the p53 locus were applied simultaneously. Prevalence of 17p deletion was lower in pTa (4/43), than in pT1 (20/42) or pT2-4 tumors (28/58) (p = 0.0001). There was also a strong correlation between 17p deletions and tumor grade. Average centromere 17 copy number was higher in pT1, than in pTa tumors (p = 0.0001) and correlated also with tumor grade, 17p deletions and p53 immunostaining (CM1). 17p deletions correlated with p53 immunostaining when all cases were considered (p = 0.0005) but not for the subgroup of T2-4 tumors. The findings suggest that p53 mutations as well as 17p deletions are early events in bladder cancer, appearing at the time of early invasion (pT1).

  7. The F17(p,γ)Ne18 resonant cross section

    NASA Astrophysics Data System (ADS)

    Chipps, K. A.; Bardayan, D. W.; Nesaraja, C. D.; Smith, M. S.; Blackmon, J. C.; Chae, K. Y.; Moazen, B. H.; Pittman, S. T.; Greife, U.; Hatarik, R.; Peters, W. A.; Kozub, R. L.; Shriner, J. F., Jr.; Matei, C.; Pain, S. D.

    2009-12-01

    We directly measure the F17(p,γ)Ne18 resonant reaction using a mixed beam of F17 and O17 at the Holifield Radioactive Ion Beam Facility at Oak Ridge National Laboratory (ORNL). The astrophysically important 3+ resonance at ~600 keV above the proton threshold in Ne18 is found to have a partial width Γγ=56±24(stat)±30(sys) meV, in reasonable agreement with the theoretically predicted width. A 2σ upper limit on the direct capture of S(E)⩽65 keV b is determined at an energy of 800 keV. Experimental techniques and astrophysical implications are discussed.

  8. Two interstitial rearrangements (16q deletion and 17p duplication) in a child with MR/MCA

    PubMed Central

    Sanchez-Jimeno, Carolina; Bustamante-Aragonés, Ana; Infantes-Barbero, Fernando; Rodriguez De Alba, Marta; Ramos, Carmen; Trujillo-Tiebas, María Jose; Lorda-Sánchez, Isabel

    2014-01-01

    Key Clinical Meassage Patients with rare deletions in 16q12 and a duplication of 17p, both interstitial and de novo. Only seven cases have been described with these deletions and none of them presented other chromosomal abnormalities. The proband showed a complex phenotype with features found in patients with dup17p11.2 syndrome, deletions in 16q12. PMID:25548634

  9. Comet 17P/Holmes: contrast in activity between before and after the 2007 outburst

    SciTech Connect

    Ishiguro, Masateru; Kim, Yoonyoung; Warjurkar, Dhanraj S.; Ham, Ji-Beom; Kim, Junhan; Usui, Fumihiko; Vaubaillon, Jeremie J.; Ishihara, Daisuke; Hanayama, Hidekazu; Sarugaku, Yuki; Hasegawa, Sunao; Kasuga, Toshihiro; Watanabe, Jun-ichi; Pyo, Jeonghyun; Kuroda, Daisuke; Ootsubo, Takafumi; Sakamoto, Makoto; Narusawa, Shin-ya; Takahashi, Jun; Akisawa, Hiroki

    2013-11-20

    A Jupiter-family comet, 17P/Holmes, underwent outbursts in 1892 and 2007. In particular, the 2007 outburst is known as the greatest outburst over the past century. However, little is known about the activity before the outburst because it was unpredicted. In addition, the time evolution of the nuclear physical status has not been systematically studied. Here, we study the activity of 17P/Holmes before and after the 2007 outburst through optical and mid-infrared observations. We found that the nucleus was highly depleted in its near-surface icy component before the outburst but that it became activated after the 2007 outburst. Assuming a conventional 1 μm sized grain model, we derived a surface fractional active area of 0.58% ± 0.14% before the outburst whereas the area was enlarged by a factor of ∼50 after the 2007 outburst. We also found that large (≥1 mm) particles could be dominant in the dust tail observed around aphelion. Based on the size of the particles, the dust production rate was ≳170 kg s{sup –1} at a heliocentric distance of r{sub h} = 4.1 AU, suggesting that the nucleus was still active around the aphelion passage. The nucleus color was similar to that of the dust particles and average for a Jupiter-family comet but different from that of most Kuiper Belt objects, implying that color may be inherent to icy bodies in the solar system. On the basis of these results, we concluded that more than 76 m of surface material was blown off by the 2007 outburst.

  10. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q).

    PubMed

    Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, András; Mufti, Ghulam J; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik; Muus, Petra; Sanz, Guillermo; Mittelman, Moshe; Bowen, David; Porwit, Anna; Fu, Tommy; Backstrom, Jay; Fenaux, Pierre; MacBeth, Kyle J; Hellström-Lindberg, Eva

    2014-06-01

    Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥ 1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621). PMID:24682512

  11. A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients

    PubMed Central

    Engels, Hartmut; Wohlleber, Eva; Zink, Alexander; Hoyer, Juliane; Ludwig, Kerstin U; Brockschmidt, Felix F; Wieczorek, Dagmar; Moog, Ute; Hellmann-Mersch, Birgit; Weber, Ruthild G; Willatt, Lionel; Kreiß-Nachtsheim, Martina; Firth, Helen V; Rauch, Anita

    2009-01-01

    Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome. PMID:19471318

  12. A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients.

    PubMed

    Engels, Hartmut; Wohlleber, Eva; Zink, Alexander; Hoyer, Juliane; Ludwig, Kerstin U; Brockschmidt, Felix F; Wieczorek, Dagmar; Moog, Ute; Hellmann-Mersch, Birgit; Weber, Ruthild G; Willatt, Lionel; Kreiss-Nachtsheim, Martina; Firth, Helen V; Rauch, Anita

    2009-12-01

    Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome. PMID:19471318

  13. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q)

    PubMed Central

    Saft, Leonie; Karimi, Mohsen; Ghaderi, Mehran; Matolcsy, András; Mufti, Ghulam J.; Kulasekararaj, Austin; Göhring, Gudrun; Giagounidis, Aristoteles; Selleslag, Dominik; Muus, Petra; Sanz, Guillermo; Mittelman, Moshe; Bowen, David; Porwit, Anna; Fu, Tommy; Backstrom, Jay; Fenaux, Pierre; MacBeth, Kyle J.; Hellström-Lindberg, Eva

    2014-01-01

    Del(5q) myelodysplastic syndromes defined by the International Prognostic Scoring System as low- or intermediate-1-risk (lower-risk) are considered to have an indolent course; however, recent data have identified a subgroup of these patients with more aggressive disease and poorer outcomes. Using deep sequencing technology, we previously demonstrated that 18% of patients with lower-risk del(5q) myelodysplastic syndromes carry TP53 mutated subclones rendering them at higher risk of progression. In this study, bone marrow biopsies from 85 patients treated with lenalidomide in the MDS-004 clinical trial were retrospectively assessed for p53 expression by immunohistochemistry in association with outcome. Strong p53 expression in ≥1% of bone marrow progenitor cells, observed in 35% (30 of 85) of patients, was significantly associated with higher acute myeloid leukemia risk (P=0.0006), shorter overall survival (P=0.0175), and a lower cytogenetic response rate (P=0.009), but not with achievement or duration of 26-week transfusion independence response. In a multivariate analysis, p53-positive immunohistochemistry was the strongest independent predictor of transformation to acute myeloid leukemia (P=0.0035). Pyrosequencing analysis of laser-microdissected cells with strong p53 expression confirmed the TP53 mutation, whereas cells with moderate expression predominantly had wild-type p53. This study validates p53 immunohistochemistry as a strong and clinically useful predictive tool in patients with lower-risk del(5q) myelodysplastic syndromes. This study was based on data from the MDS 004 trial (clinicaltrials.gov identifier: NCT00179621). PMID:24682512

  14. Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13

    SciTech Connect

    Francis, M.J.; Nesbit, M.A.; Theodosiou, A.M.

    1995-05-20

    The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, the authors identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, they have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed. 20 refs., 1 fig.

  15. Novel microsatellite repeats (MSRs) and linkage disequilibrium analysis in the SMA region of 5q13.1

    SciTech Connect

    Yaraghi, Z.; Roy, N.; MacKenzie, A.E.

    1994-09-01

    The spinal muscular atrophies (SMA) are characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular atrophy associated with progressive paralysis. The gene involved in SMA has been mapped by linkage analysis to a region of 5q13.1 flanked centromerically by D5S435 and telomerically by D5S557. We are in the process of identifying new microsatellite repeats to further define the genetic map of the SMA region. A contiguous array of YAC clones covering the SMA containing D5S435-D56S112 interval of 5q13.1 was established. From this contig, a 700 kb clone 76C1, which contains the 200 kb CMS-1/CATT-1 critical region, was used to generate a partial Sau3A1 phage library. We have previously shown that 2 CATT-1 subloci are in linkage disequilibrium with type I SMA. The 76C1 subloci are in linkage disequilibrium with type I SMA. The 76C1 phage library has been screened for human MSRs. To date we have identified two novel polymorphic microsatellites and four further candidates are being characterized. Results of linkage disequilibrium studies currently underway will be presented. The identification of a linkage disequilibrium maximum will be helpful in the further narrowing of the SMA region.

  16. TP53 and MDM2 single nucleotide polymorphisms influence survival in non-del(5q) myelodysplastic syndromes.

    PubMed

    McGraw, Kathy L; Cluzeau, Thomas; Sallman, David A; Basiorka, Ashley A; Irvine, Brittany A; Zhang, Ling; Epling-Burnette, P K; Rollison, Dana E; Mallo, Mar; Sokol, Lubomir; Solé, Francesc; Maciejewski, Jaroslaw; List, Alan F

    2015-10-27

    P53 is a key regulator of many cellular processes and is negatively regulated by the human homolog of murine double minute-2 (MDM2) E3 ubiquitin ligase. Single nucleotide polymorphisms (SNPs) of either gene alone, and in combination, are linked to cancer susceptibility, disease progression, and therapy response. We analyzed the interaction of TP53 R72P and MDM2 SNP309 SNPs in relationship to outcome in patients with myelodysplastic syndromes (MDS). Sanger sequencing was performed on DNA isolated from 208 MDS cases. Utilizing a novel functional SNP scoring system ranging from +2 to -2 based on predicted p53 activity, we found statistically significant differences in overall survival (OS) (p = 0.02) and progression-free survival (PFS) (p = 0.02) in non-del(5q) MDS patients with low functional scores. In univariate analysis, only IPSS and the functional SNP score predicted OS and PFS in non-del(5q) patients. In multivariate analysis, the functional SNP score was independent of IPSS for OS and PFS. These data underscore the importance of TP53 R72P and MDM2 SNP309 SNPs in MDS, and provide a novel scoring system independent of IPSS that is predictive for disease outcome. PMID:26416416

  17. Computational and biological analysis of 680 kb of DNA sequence from the human 5q31 cytokine gene cluster region.

    PubMed

    Frazer, K A; Ueda, Y; Zhu, Y; Gifford, V R; Garofalo, M R; Mohandas, N; Martin, C H; Palazzolo, M J; Cheng, J F; Rubin, E M

    1997-05-01

    With the human genome project advancing into what will be a 7- to 10-year DNA sequencing phase, we are presented with the challenge of developing strategies to convert genomic sequence data, as they become available, into biologically meaningful information. We have analyzed 680 kb of noncontiguous DNA sequence from a 1-Mb region of human chromosome 5q31, coupling computational analysis with gene expression studies of tissues isolated from humans as well as from mice containing human YAC transgenes. This genomic interval has been noted previously for containing the cytokine gene cluster and a quantitative trait locus associated with inflammatory diseases. Our analysis identified and verified expression of 16 new genes, as well as 7 previously known genes. Of the total of 23 genes in this region, 78% had similarity matches to sequences in protein databases and 83% had exact expressed sequence tag (EST) database matches. Comparative mapping studies of eight of the new human genes discovered in the 5q31 region revealed that all are located in the syntenic region of mouse chromosome 11q. Our analysis demonstrates an approach for examining human sequence as it is made available from large sequencing programs and has resulted in the discovery of several biomedically important genes, including a cyclin, a transcription factor that is homologous to an oncogene, a protein involved in DNA repair, and several new members of a family of transporter proteins. PMID:9149945

  18. Duplication of the SLIT3 Locus on 5q35.1 Predisposes to Major Depressive Disorder

    PubMed Central

    Glessner, Joseph T.; Wang, Kai; Sleiman, Patrick M. A.; Zhang, Haitao; Kim, Cecilia E.; Flory, James H.; Bradfield, Jonathan P.; Imielinski, Marcin; Frackelton, Edward C.; Qiu, Haijun; Mentch, Frank; Grant, Struan F. A.; Hakonarson, Hakon

    2010-01-01

    Major depressive disorder (MDD) is a common psychiatric and behavioral disorder. To discover novel variants conferring risk to MDD, we conducted a whole-genome scan of copy number variation (CNV), including 1,693 MDD cases and 4,506 controls genotyped on the Perlegen 600K platform. The most significant locus was observed on 5q35.1, harboring the SLIT3 gene (P = 2×10−3). Extending the controls with 30,000 subjects typed on the Illumina 550 k array, we found the CNV to remain exclusive to MDD cases (P = 3.2×10−9). Duplication was observed in 5 unrelated MDD cases encompassing 646 kb with highly similar breakpoints. SLIT3 is integral to repulsive axon guidance based on binding to Roundabout receptors. Duplication of 5q35.1 is a highly penetrant variation accounting for 0.7% of the subset of 647 cases harboring large CNVs, using a threshold of a minimum of 10 SNPs and 100 kb. This study leverages a large dataset of MDD cases and controls for the analysis of CNVs with matched platform and ethnicity. SLIT3 duplication is a novel association which explains a definitive proportion of the largely unknown etiology of MDD. PMID:21152026

  19. Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis

    PubMed Central

    Greipp, Patricia T.; Smoley, Stephanie A.; Viswanatha, David S.; Frederick, Lori S.; Rabe, Kari G.; Sharma, Ruchi G.; Slager, Susan L.; Van Dyke, Daniel L.; Tschumper, Renee C.; Shanafelt, Tait D.; Zent, Clive S.

    2013-01-01

    Summary Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients. PMID:24032430

  20. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    SciTech Connect

    Goliath, R.; Janssens, P.; Beighton, P.

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  1. Mutation of the TP53 gene and allelic imbalance at chromosome 17p13 in ductal carcinoma in situ.

    PubMed Central

    Munn, K. E.; Walker, R. A.; Menasce, L.; Varley, J. M.

    1996-01-01

    A panel of 36 cases of preinvasive breast lesions, including 35 cases of ductal carcinoma in situ (DCIS), has been examined for mutation of TP53, allelic imbalance (AI) on 17p13, and expression of TP53, in a number of cases, has been studied using immunohistochemistry. Areas of DCIS, with or without adjacent invasive or benign cells, have been separately microdissected from paraffin-embedded sections and analysed by PCR for genetic changes to chromosome 17p13. TP53 mutations and AI on 17p have been identified in cases of 'pure' DCIS as well as those with associated invasive carcinoma and, furthermore, have been identified in well-differentiated lesions as well as poorly differentiated ones. Images Figure 1 Figure 2 Figure 4 PMID:8932338

  2. Susceptibility gene for familial acute myeloid leukemia associated with loss of 5q and/or 7q is not localized on the commonly deleted portion of 5q.

    PubMed

    Gao, Q; Horwitz, M; Roulston, D; Hagos, F; Zhao, N; Freireich, E J; Golomb, H M; Olopade, O I

    2000-06-01

    The molecular mechanism for the occurrence of leukemia in multiple members of a family has not been fully elucidated but data support the contribution of highly penetrant mutations in leukemia susceptibility genes. We have investigated the genetic etiology of an unusual three-generation family with apparent autosomal dominant transmission of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) accompanied by somatic loss of the long arm of chromosome 5 and/or loss of heterozygosity (LOH) analysis and fluorescence in situ hybridization (FISH) of leukemia cells have been performed, confirming acquired hemi- and homozygous deletion of the long arm of chromosome 5. However, the chromosome lost in the observed LOH event is from the affected parent, in contradiction to the expectation for a two-hit hypothesis involving a tumor suppressor gene. Furthermore, genetic linkage has been performed at 5q31-33 as well as other loci (21q22 and 16q21-23.2) previously implicated in familial leukemia. In this family, linkage analysis excludes loci at 5q31-33 and 21q22, but localization to 16q21-23.2 cannot be excluded. We observed a maximum multipoint LOD score of 1.19 between marker D16S265 and D16S503 at 16q22 (P = 0.03), suggesting possible linkage to this locus. Considering this family and the previous 16q-linked family together, the linkage of a leukemia susceptibility gene to 16q22 achieved an LOD score of 3.63 at D16S265 with theta = 0. Thus, somatic deletion of the long arm of chromosome 5 appears as a necessary but surprisingly noncausative event for onset of AML and MDS in this family, thereby confirming a multistep etiology in which chromosome 5 plays an important secondary role. PMID:10825001

  3. Genomic instability establishes dependencies on acquired gene regulatory networks: A novel role of p62 in myeloid malignancies with del(5q)

    PubMed Central

    Fang, Jing; Starczynowski, Daniel T

    2015-01-01

    MiR-146a deletion is a driving molecular event in del(5q) myeloid malignancies, which acquire dependency on a nuclear factor kappa B (NF-κB) regulatory network. p62, a neighboring haploid 5q gene, is induced by NF-κB and required to sustain TRAF6-mediated NF-κB activation. Interfering with p62/TRAF6 binding may have a therapeutic benefit in miR-146a–deficient leukemic cells. PMID:27308507

  4. Interleukin 3 gene is located on human chromosome 5 and is deleted in myeloid leukemias with a deletion of 5q

    SciTech Connect

    Le Beau, M.M.; Epstein, N.D.; O'Brien, S.J.; Nienhuis, A.W.; Yang, Y.C.; Clark, S.C.; Rowley, J.D.

    1987-08-01

    The gene IL-3 encodes interleukin 3, a hematopoietic colony-stimulating factor (CSF) that is capable of supporting the proliferation of a broad range of hematopoietic cell types. By using somatic cell hybrids and in situ chromosomal hybridization, the authors localized this gene to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted (del(5q)) in patients with myeloid disorders. By in situ hybridization, IL-3 was found to be deleted in the 5q-chromosome of one patient with refractory anemia who had a del(5)(q15q33.3), of three patients with refractory anemia (two patients) or acute nonlymphocytic leukemia (ANLL) de novo who had a similar distal breakpoint (del(5)(q13q33.3)), and of a fifth patient, with therapy-related ANLL, who had a similar distal breakpoint in band q33(del(5)(q14q33.3)). Southern blot analysis of somatic cell hybrids retaining the normal or the deleted chromosome 5 from two patients with the refractory anemia 5q- syndrome indicated that IL-3 sequences were absent from the hybrids retaining the deleted chromosome 5 but not from hybrids that had a cytologically normal chromosome 5. Thus, a small segment of chromosome 5 contains IL-3, GM-CSF, CSF-1, and FMS. The findings and earlier results indicating that GM-CSF, CSF-1, and FMS were deleted in the 5q- chromosome, suggest that loss of IL-3 or of other CSF genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

  5. Peculiar Near-nucleus Outgassing of Comet 17P/Holmes during its 2007 Outburst

    NASA Astrophysics Data System (ADS)

    Qi, Chunhua; Hogerheijde, Michiel R.; Jewitt, David; Gurwell, Mark A.; Wilner, David J.

    2015-01-01

    We present high angular resolution Submillimeter Array observations of the outbursting Jupiter family comet 17P/Holmes on 2007 October 26-29, achieving a spatial resolution of 2.''5, or ~3000 km at the comet distance. The observations resulted in detections of the rotational lines CO 3-2, HCN 4-3, H13CN 4-3, CS 7-6, H2CO 31, 2-21, 1, H2S 22, 0-21, 1, and multiple CH3OH lines, along with the associated dust continuum at 221 and 349 GHz. The continuum has a spectral index of 2.7 ± 0.3, slightly steeper than blackbody emission from large dust particles. From the imaging data, we identify two components in the molecular emission. One component is characterized by a relatively broad line width (~1 km s-1 FWHM) exhibiting a symmetric outgassing pattern with respect to the nucleus position. The second component has a narrower line width (<0.5 km s-1 FWHM) with the line center redshifted by 0.1-0.2 km s-1 (cometocentric frame), and shows a velocity shift across the nucleus position with the position angle gradually changing from 66° to 30° within the four days of observations. We determine distinctly different CO/HCN ratios for each of the components. For the broad-line component we find CO/HCN < 7, while in the narrow-line component, CO/HCN = 40 ± 5. We hypothesize that the narrow-line component originates from the ice grain halo found in near-nucleus photometry, believed to be created by sublimating recently released ice grains around the nucleus during the outburst. In this interpretation, the high CO/HCN ratio of this component reflects the more pristine volatile composition of nucleus material released in the outburst.

  6. Detection of Remnant Dust Cloud Associated with the 2007 Outburst of 17P/Holmes

    NASA Astrophysics Data System (ADS)

    Ishiguro, Masateru; Sarugaku, Yuki; Kuroda, Daisuke; Hanayama, Hidekazu; Kim, Yoonyoung; Kwon, Yuna G.; Maehara, Hiroyuki; Takahashi, Jun; Terai, Tsuyoshi; Usui, Fumihiko; Vaubaillon, Jeremie J.; Morokuma, Tomoki; Kobayashi, Naoto; Watanabe, Jun-ichi

    2016-01-01

    This article reports a new optical observation of 17P/Holmes one orbital period after the historical outburst event in 2007. We detected not only a common dust tail near the nucleus but also a long narrow structure that extended along the position angle 274.°6 ± 0.°1 beyond the field of view (FOV) of the Kiso Wide Field Camera, i.e., >0.°2 eastward and >2.°0 westward from the nuclear position. The width of the structure decreased westward with increasing distance from the nucleus. We obtained the total cross section of the long extended structure in the FOV, CFOV = (2.3 ± 0.5) × 1010 m2. From the position angle, morphology, and mass, we concluded that the long narrow structure consists of materials ejected during the 2007 outburst. On the basis of the dynamical behavior of dust grains in the solar radiation field, we estimated that the long narrow structure would be composed of 1 mm-1 cm grains having an ejection velocity of >50 m s-1. The velocity was more than one order of magnitude faster than that of millimeter-centimeter grains from typical comets around a heliocentric distance rh of 2.5 AU. We considered that sudden sublimation of a large amount of water-ice (≈1030 mol s-1) would be responsible for the high ejection velocity. We finally estimated a total mass of MTOT = (4-8) × 1011 kg and a total kinetic energy of ETOT = (1-6) × 1015 J for the 2007 outburst ejecta, which are consistent with those of previous studies that were conducted soon after the outburst.

  7. Complex repetitive arrangements of gene sequence in the candidate region of the spinal muscular atrophy gene in 5q13

    SciTech Connect

    Theodosiou, A.M.; Nesbit, A.M.; Daniels, R.J.; Campbell, L.; Francis, M.J.; Christodoulou, Z.; Morrison, K.E.; Davies, K.E. |

    1994-12-01

    Childhood-onset proximal spinal muscular atrophy (SMA) is a heritable neurological disorder, which has been mapped by genetic linkage analysis to chromosome 5q13, in the interval between markers D5S435 and D5S557. Here, we present gene sequences that have been isolated from this interval, several of which show sequence homologies to exons of {beta}-glucuronidase. These gene sequences are repeated several times across the candidate region and are also present on chromosome 5p. The arrangement of these repetitive gene motifs is polymorphic between individuals. The high degree of variability observed may have some influence on the expression of the genes in the region. Since SMA is not inherited as a classical autosomal recessive disease, novel genomic rearrangements arising from aberrant recombination events between the complex repeats may be associated with the phenotype observed.

  8. Detailed deletion mapping in sporadic breast cancer at chromosomal region 17p13 distal to the TP53 gene: association with clinicopathological parameters.

    PubMed

    Seitz, S; Poppe, K; Fischer, J; Nothnagel, A; Estévez-Schwarz, L; Haensch, W; Schlag, P M; Scherneck, S

    2001-07-01

    Chromosome 17p is among the most frequently deleted regions in a variety of human malignancies including breast cancer. This study has further refined the localization of a putative tumour suppressor gene (TSG) at 17p13 distal to the TP53 gene in breast carcinomas. It was found that 73% (37 of 51) of the breast tumours exhibited loss of heterozygosity (LOH) at one or more loci at 17p13. The allelic loss patterns of these tumours suggest the presence of at least seven commonly deleted regions on 17p13. The three most frequently deleted regions were mapped at chromosomal location 17p13.3-17p13.2 between the markers D17S831 and D17S1845 (56% LOH), at 17p13.1 between D17S1810 and D17S1832 (53% LOH), and at 17p13.1 between D17S938 and TP53 (55% LOH). A significant correlation was found between loss at 17p13 and tumour grade, size, proliferative activity, and oestrogen receptor (ER) status. Losses at 17p13 were seen more frequently in large and poorly differentiated tumours with high proliferative activity. These data support and extend previous reports on the presence of a putative TSG(s) at chromosomal region 17p13 distal to the TP53 gene and show that different subsets of LOH are associated with more aggressive tumour behaviour. PMID:11439364

  9. HOPS prevents the disassembly of trans-SNARE complexes by Sec17p/Sec18p during membrane fusion

    PubMed Central

    Xu, Hao; Jun, Youngsoo; Thompson, James; Yates, John; Wickner, William

    2010-01-01

    SNARE-dependent membrane fusion requires the disassembly of cis-SNARE complexes (formed by SNAREs anchored to one membrane) followed by the assembly of trans-SNARE complexes (SNAREs anchored to two apposed membranes). Although SNARE complex disassembly and assembly might be thought to be opposing reactions, the proteins promoting disassembly (Sec17p/Sec18p) and assembly (the HOPS complex) work synergistically to support fusion. We now report that trans-SNARE complexes formed during vacuole fusion are largely associated with Sec17p. Using a reconstituted proteoliposome fusion system, we show that trans-SNARE complex, like cis-SNARE complex, is sensitive to Sec17p/Sec18p mediated disassembly. Strikingly, HOPS inhibits the disassembly of SNARE complexes in the trans-, but not in the cis-, configuration. This selective HOPS preservation of trans-SNARE complexes requires HOPS:SNARE recognition and is lost when the apposed bilayers are dissolved in Triton X-100; it is also observed during fusion of isolated vacuoles. HOPS thus directs the Sec17p/Sec18p chaperone system to maximize functional trans-SNARE complex for membrane fusion, a new role of tethering factors during membrane traffic. PMID:20473271

  10. A new family linked to the RP13 locus for autosomal dominant retinitis pigmentosa on distal 17p.

    PubMed

    Tarttelin, E E; Plant, C; Weissenbach, J; Bird, A C; Bhattacharya, S S; Inglehearn, C F

    1996-06-01

    A form of autosomal dominant retinitis pigmentosa (ADRP) mapping to chromosome 17p has been reported in a single large South African family. We now report a new family with severe early onset ADRP which maps to 17p. Linkage and haplotype analysis in this family places the ADRP locus in the 5 cM interval between markers AFMc024za5 and D17S1845, confirming the data obtained in the South African family. The discovery of a second 17p linked family may imply that this is one of the more common loci for dominant RP. In addition, the confirmation of an RP diagnosis at this locus is of interest since loci for a dominant cone dystrophy and Leber's congenital amaurosis (LCA1) have recently been linked to the same markers. While the cone dystrophy locus may be allelic with RP, our data and that of Goliath et al show that distinct genes are responsible for dominant RP and Leber's congenital amaurosis on chromosome 17p. PMID:8782056

  11. PECULIAR NEAR-NUCLEUS OUTGASSING OF COMET 17P/HOLMES DURING ITS 2007 OUTBURST

    SciTech Connect

    Qi, Chunhua; Gurwell, Mark A.; Wilner, David J.; Hogerheijde, Michiel R.; Jewitt, David

    2015-01-20

    We present high angular resolution Submillimeter Array observations of the outbursting Jupiter family comet 17P/Holmes on 2007 October 26-29, achieving a spatial resolution of 2.''5, or ∼3000 km at the comet distance. The observations resulted in detections of the rotational lines CO 3-2, HCN 4-3, H{sup 13}CN 4-3, CS 7-6, H{sub 2}CO 3{sub 1,} {sub 2}-2{sub 1,} {sub 1}, H{sub 2}S 2{sub 2,} {sub 0}-2{sub 1,} {sub 1}, and multiple CH{sub 3}OH lines, along with the associated dust continuum at 221 and 349 GHz. The continuum has a spectral index of 2.7 ± 0.3, slightly steeper than blackbody emission from large dust particles. From the imaging data, we identify two components in the molecular emission. One component is characterized by a relatively broad line width (∼1 km s{sup –1} FWHM) exhibiting a symmetric outgassing pattern with respect to the nucleus position. The second component has a narrower line width (<0.5 km s{sup –1} FWHM) with the line center redshifted by 0.1-0.2 km s{sup –1} (cometocentric frame), and shows a velocity shift across the nucleus position with the position angle gradually changing from 66° to 30° within the four days of observations. We determine distinctly different CO/HCN ratios for each of the components. For the broad-line component we find CO/HCN < 7, while in the narrow-line component, CO/HCN = 40 ± 5. We hypothesize that the narrow-line component originates from the ice grain halo found in near-nucleus photometry, believed to be created by sublimating recently released ice grains around the nucleus during the outburst. In this interpretation, the high CO/HCN ratio of this component reflects the more pristine volatile composition of nucleus material released in the outburst.

  12. Activation of the mTOR pathway by the amino acid (L)-leucine in the 5q- syndrome and other ribosomopathies.

    PubMed

    Boultwood, Jacqueline; Yip, Bon Ham; Vuppusetty, Chaitanya; Pellagatti, Andrea; Wainscoat, James S

    2013-01-01

    Patients with the 5q- syndrome and Diamond-Blackfan anemia (DBA) suffer from a severe macrocytic anemia. The 5q- syndrome and DBA are disorders of aberrant ribosome biogenesis (ribosomopathies) and haploinsufficiency of the ribosomal protein genes RPS14 and RPS19, respectively, underlies the anemia found in these disorders. Erythroblasts obtained from patients with the 5q- syndrome and DBA show impaired mRNA translation and this defect in translation may represent a potential therapeutic target in these ribosomopathies. There are some indications that the amino acid l-leucine, a translation enhancer, may have some efficacy in this group of disorders. Recent studies have shown that l-leucine treatment of zebrafish and murine models of the 5q- syndrome and DBA results in a marked improvement in the anemia. l-leucine treatment of RPS14-deficient and RPS19-deficient erythroblasts and erythroblasts from patients with the 5q- syndrome has been shown to result in an increase in cell proliferation, erythroid differentiation and mRNA translation in culture. l-leucine has been shown to improve hemoglobin levels and transfusion independence in a patient with DBA. l-leucine activates the mTOR (mammalian target of rapamycin) signaling pathway that controls cell growth and mRNA translation. There is evidence to suggest that the promotion of translation via the mTOR pathway by l-leucine is the mechanism that underlies the enhanced erythroid progenitor cell growth and differentiation observed in animal and cellular models of the 5q- syndrome and DBA treated with this amino acid. These data support the rationale for clinical trials of l-leucine as a therapeutic agent for the 5q- syndrome and DBA. PMID:23031788

  13. Genomic Copy Number Variations in the Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients with del(5q) and/or -7/del(7q).

    PubMed

    Zhang, Rui; Kim, Young-Mi; Wang, Xianfu; Li, Yan; Lu, Xianglan; Sternenberger, Andrea R; Li, Shibo; Lee, Ji-Yun

    2015-01-01

    The most common chromosomal abnormalities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are -5/del(5q) and -7/del(7q). When -5/del(5q) and -7/del(7q) coexist in patients, a poor prognosis is typically associated. Given that -5/del(5q) and/or -7/del(7q) often are accompanied with additional recurrent chromosomal alterations, genetic change(s) on the accompanying chromosome(s) other than chromosomes 5 and 7 may be important factor(s) affecting leukemogenesis and disease prognosis. Using an integrated analysis of karyotype, FISH and array CGH results in this study, we evaluated the smallest region of overlap (SRO) of chromosomes 5 and 7 as well as copy number alterations (CNAs) on the other chromosomes. Moreover, the relationship between the CNAs and del(5q) and -7/del(7q) was investigated by categorizing the cases into three groups based on the abnormalities of chromosomes 5 and 7 [group I: cases only with del(5q), group II: cases only with -7/del(7q) and group III: concurrent del(5q) and del(7q) cases]. The overlapping SRO of chromosome 5 from groups I and III was 5q31.1-33.1 and of chromosome 7 from groups II and III was 7q31.31-q36.1. A total of 318 CNAs were observed; ~ 78.3% of them were identified on chromosomes other than chromosomes 5 and 7, which were defined as 'other CNAs'. Group III was a distinctive group carrying the most high number (HN) CNAs, cryptic CNAs and 'other CNAs'. The loss of TP53 was highly associated with del(5q). The loss of ETV6 was specifically associated with group III. These CNAs or genes may play a secondary role in disease progression and should be further evaluated for their clinical significance and influence on therapeutic approaches in patients with MDS/AML carrying del(5q) and/or -7/del(7q) in large-scale, patient population study. PMID:26392809

  14. Genomic Copy Number Variations in the Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients with del(5q) and/or -7/del(7q)

    PubMed Central

    Zhang, Rui; Kim, Young-Mi; Wang, Xianfu; Li, Yan; Lu, Xianglan; Sternenberger, Andrea R.; Li, Shibo; Lee, Ji-Yun

    2015-01-01

    The most common chromosomal abnormalities in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are -5/del(5q) and -7/del(7q). When -5/del(5q) and -7/del(7q) coexist in patients, a poor prognosis is typically associated. Given that -5/del(5q) and/or -7/del(7q) often are accompanied with additional recurrent chromosomal alterations, genetic change(s) on the accompanying chromosome(s) other than chromosomes 5 and 7 may be important factor(s) affecting leukemogenesis and disease prognosis. Using an integrated analysis of karyotype, FISH and array CGH results in this study, we evaluated the smallest region of overlap (SRO) of chromosomes 5 and 7 as well as copy number alterations (CNAs) on the other chromosomes. Moreover, the relationship between the CNAs and del(5q) and -7/del(7q) was investigated by categorizing the cases into three groups based on the abnormalities of chromosomes 5 and 7 [group I: cases only with del(5q), group II: cases only with -7/del(7q) and group III: concurrent del(5q) and del(7q) cases]. The overlapping SRO of chromosome 5 from groups I and III was 5q31.1-33.1 and of chromosome 7 from groups II and III was 7q31.31-q36.1. A total of 318 CNAs were observed; ~ 78.3% of them were identified on chromosomes other than chromosomes 5 and 7, which were defined as 'other CNAs'. Group III was a distinctive group carrying the most high number (HN) CNAs, cryptic CNAs and 'other CNAs'. The loss of TP53 was highly associated with del(5q). The loss of ETV6 was specifically associated with group III. These CNAs or genes may play a secondary role in disease progression and should be further evaluated for their clinical significance and influence on therapeutic approaches in patients with MDS/AML carrying del(5q) and/or -7/del(7q) in large-scale, patient population study. PMID:26392809

  15. Lenalidomide as a disease-modifying agent in patients with del(5q) myelodysplastic syndromes: linking mechanism of action to clinical outcomes.

    PubMed

    Giagounidis, Aristoteles; Mufti, Ghulam J; Fenaux, Pierre; Germing, Ulrich; List, Alan; MacBeth, Kyle J

    2014-01-01

    Deletion of the long arm of chromosome 5, del(5q), is the most prevalent cytogenetic abnormality in patients with myelodysplastic syndromes (MDS). In isolation, it is traditionally associated with favorable prognosis compared with other subtypes of MDS. However, owing to the inherent heterogeneity of the disease, prognosis for patients with del(5q) MDS is highly variable depending on the presence of factors such as additional chromosomal abnormalities, >5 % blasts in the bone marrow (BM), or transfusion dependence. Over recent years, the immunomodulatory drug lenalidomide has demonstrated remarkable efficacy in patients with del(5q) MDS. Advances in the understanding of the pathogenesis of the disease have suggested that lenalidomide targets aberrant signaling pathways caused by haplosufficiency of specific genes in a commonly deleted region on chromosome 5 (e.g., SPARC, RPS14, Cdc25C, and PP2A). As a result, the agent specifically targets del(5q) clones while also promoting erythropoiesis and repopulation of the bone marrow in normal cells. This review discusses recent developments in the understanding of the mechanism of action of lenalidomide, and how this underlies favorable outcomes in patients with del(5q) MDS. In addition, we discuss how improved understanding of the mechanism of disease will facilitate clinicians' ability to predict/monitor response and identify patients at risk of relapse. PMID:24018623

  16. Important Genes in the Pathogenesis of 5q- Syndrome and Their Connection with Ribosomal Stress and the Innate Immune System Pathway

    PubMed Central

    Fuchs, Ota

    2012-01-01

    Myelodysplastic syndrome (MDS) with interstitial deletion of a segment of the long arm of chromosome 5q [del(5q)] is characterized by bone marrow erythroid hyperplasia, atypical megakaryocytes, thrombocythemia, refractory anemia, and low risk of progression to acute myeloid leukemia (AML) compared with other types of MDS. The long arm of chromosome 5 contains two distinct commonly deleted regions (CDRs). The more distal CDR lies in 5q33.1 and contains 40 protein-coding genes and genes coding microRNAs (miR-143, miR-145). In 5q-syndrome one allele is deleted that accounts for haploinsufficiency of these genes. The mechanism of erythroid failure appears to involve the decreased expression of the ribosomal protein S14 (RPS14) gene and the upregulation of the p53 pathway by ribosomal stress. Friend leukemia virus integration 1 (Fli1) is one of the target genes of miR145. Increased Fli1 expression enables effective megakaryopoiesis in 5q-syndrome. PMID:23213547

  17. Explosion of Comet 17P/Holmes as revealed by the Spitzer Space Telescope

    NASA Astrophysics Data System (ADS)

    Reach, William T.; Vaubaillon, Jeremie; Lisse, Carey M.; Holloway, Mikel; Rho, Jeonghee

    2010-07-01

    An explosion on Comet 17P/Holmes occurred on 2007 October 23, projecting particulate debris of a wide range of sizes into the interplanetary medium. We observed the comet using the mid-Infrared Spectrograph (5-40 μm), on 2007 November 10 and 2008 February 27, and the imaging photometer (24 and 70 μm), on 2008 March 13, on board the Spitzer Space Telescope. The 2007 November 10 spectral mapping revealed spatially diffuse emission with detailed mineralogical features, primarily from small crystalline olivine grains. The 2008 February 27 spectra, and the central core of the 2007 November 10 spectral map, reveal nearly featureless spectra, due to much larger grains that were ejected from the nucleus more slowly. Optical images were obtained on multiple dates spanning 2007 October 27-2008 March 10 at the Holloway Comet Observatory and 1.5-m telescope at Palomar Observatory. The images and spectra can be segmented into three components: (1) a hemispherical shell fully 28' on the sky in 2008 March, due to the fastest (262 m s -1), smallest (2 μm) debris, with a mass 1.7×1012g; (2) a 'blob' or 'pseudonucleus' offset from the true nucleus and subtending some 10' on the sky, due to intermediate speed (93 m s -1) and size (8 μm) particles, with a total mass 2.7×1012g; and (3) a 'core' centered on the nucleus due to slower (9 m s -1), larger (200 μm) ejecta, with a total mass 3.9×1012g. This decomposition of the mid-infrared observations can also explain the temporal evolution of the millimeter-wave flux. The orientation of the leading edge of the ejecta shell and the ejecta 'blob,' relative to the nucleus, do not change as the orientation of the Sun changes; instead, the configuration was imprinted by the orientation of the initial explosion. The distribution and speed of ejecta implies an explosion in a conical pattern directed approximately in the solar direction on the date of explosion. The kinetic energy of the ejecta >10 21 erg is greater than the gravitational

  18. Analysis of complex repeat sequences within the spinal muscular atrophy (SMA) candidate region in 5q13

    SciTech Connect

    Davies, K.E.; Morrison, K.E.; Daniels, R.I.

    1994-09-01

    We previously reported that the 400 kb interval flanked the polymorphic loci D5S435 and D5S557 contains blocks of a chromosome 5 specific repeat. This interval also defines the SMA candidate region by genetic analysis of recombinant families. A YAC contig of 2-3 Mb encompassing this area has been constructed and a 5.5 kb conserved fragment, isolated from a YAC end clone within the above interval, was used to obtain cDNAs from both fetal and adult brain libraries. We describe the identification of cDNAs with stretches of high DNA sequence homology to exons of {beta} glucuronidase on human chromosome 7. The cDNAs map both to the candidate region and to an area of 5p using FISH and deletion hybrid analysis. Hybridization to bacteriophage and cosmid clones from the YACs localizes the {beta} glucuronidase related sequences within the 400 kb region of the YAC contig. The cDNAs show a polymorphic pattern on hybridization to genomic BamH1 fragments in the size range of 10-250 kb. Further analysis using YAC fragmentation vectors is being used to determine how these {beta} glucuronidase related cDNAs are distributed within 5q13. Dinucleotide repeats within the region are being investigated to determine linkage disequilibrium with the disease locus.

  19. Identification of a novel sarcoglycan gene at 5q33 encoding a sarcolemmal 35 kDa glycoprotein.

    PubMed

    Nigro, V; Piluso, G; Belsito, A; Politano, L; Puca, A A; Papparella, S; Rossi, E; Viglietto, G; Esposito, M G; Abbondanza, C; Medici, N; Molinari, A M; Nigro, G; Puca, G A

    1996-08-01

    Mutations in any of the genes encoding the alpha, beta or gamma-sarcoglycan components of dystrophin-associated glycoproteins result in both sporadic and familial cases of either limb-girdle muscular dystrophy or severe childhood autosomal recessive muscular dystrophy. The collective name 'sarcoglycanopathies' has been proposed for these forms. We report the identification of a fourth member of the human sarcoglycan family. We named this novel cDNA delta-sarcoglycan. Its mRNA expression is abundant in striated and smooth muscles, with a main 8 kb transcript, encoding a predicted basic transmembrane glycoprotein of 290 amino acids. Antibodies specifically raised against this protein recognized a single band at 35 kDa on western blots of human and mouse muscle. Immunohistochemical staining revealed a unique sarcolemmal localization. FISH, radiation hybrid and YAC mapping concordantly linked the delta-sarcoglycan gene to 5q33, close to D5S487 and D5S1439. The gene spans at least 100 kb and is composed of eight exons. The identification of a novel sarcoglycan component modifies the current model of the dystrophin-glycoprotein complex. PMID:8842738

  20. Proximal spinal muscular atrophy (SMA) types II and III in the same sibship are not caused by different alleles at the SMA locus on 5q.

    PubMed Central

    Müller, B; Melki, J; Burlet, P; Clerget-Darpoux, F

    1992-01-01

    Proximal spinal muscular atrophy (SMA) is a group of progressive muscular diseases recently mapped to chromosome 5q. SMA is usually classified into types I-III, and there are cases of two types of SMA in the same sibship. Becker and others later proposed that these sibships might be due to the existence of several alleles at the same locus predisposing to the different forms of the disease. In a sample of four sibships in which both SMA type II and SMA type III occur, this hypothesis was clearly rejected for the SMA locus on 5q, by using information on the segregation of linked markers (P less than .001). Thus the difference between SMA type II and SMA type III is not due to different alleles at the SMA locus on 5q. This finding is suggestive of an involvement of other factors, genetic or environmental, in the determination of disease severity in SMA. PMID:1570842

  1. Development profile in a patient with monosomy 10q and Dup(17p) associated with a peripheral neuropathy

    SciTech Connect

    Pellegrino, J.E.; Spinner, N.B.; Zackai, E.H.

    1996-02-02

    We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed to his severe motor development delay. 33 refs., 3 figs., 1 tab.

  2. p53 mutations are associated with 17p allelic loss in grade II and grade III astrocytoma.

    PubMed

    von Deimling, A; Eibl, R H; Ohgaki, H; Louis, D N; von Ammon, K; Petersen, I; Kleihues, P; Chung, R Y; Wiestler, O D; Seizinger, B R

    1992-05-15

    Loss of genetic material on the short arm of chromosome 17 is observed in approximately 40% of human astrocytomas (WHO grades II and III) and in approximately 30% of cases of glioblastoma multiforme (WHO grade IV). Previous studies of glioblastoma multiforme have shown that the p53 gene, located on the short arm of chromosome 17, is frequently mutated in these glioblastomas. To explore whether lower-grade astrocytomas are also associated with corresponding mutations of the p53 gene, we have investigated a series of 22 human astrocytomas of WHO grades II and III both for loss of heterozygosity on chromosome 17p and for p53 mutations. Mutations in the conserved regions of the p53 gene were identified by single strand conformation polymorphism analysis of exons 5, 6, 7, and 8 and were verified by direct DNA sequencing of the polymerase chain reaction products. p53 mutations were observed in 3 of 8 grade II astrocytomas and 4 of 14 grade II astrocytomas. In all 22 tumors, allelic loss of the short arm of chromosome 17 was investigated by restriction fragment length polymorphism analysis. One-half of the grade II astrocytomas (4 of 8) and grade III astrocytomas (7 of 14) exhibited allelic loss on chromosome 17p. Mutations in the p53 gene were exclusively observed in tumors with allelic loss on 17p. Our results show that p53 mutations are not restricted to glioblastoma multiforme and may be important in the tumorigenesis of lower-grade astrocytomas and that p53 mutations in lower-grade astrocytomas are associated with loss of chromosome 17p. These findings are consistent with a recessive mechanism of action of p53 in WHO grade II and III astrocytoma tumorigenesis. PMID:1349850

  3. Myelodysplastic Syndrome with concomitant t(5;21)(q15;q22) and del(5)(q13q33): case report and review of literature.

    PubMed

    Kasi Loknath Kumar, Anup; Weckbaugh, Brandon; Sirridge, Christopher; Woodroof, Janet; Persons, Diane; Kambhampati, Suman

    2016-01-01

    Chromosomal abnormalities lead to the development of hematologic malignancies such as Myelodysplastic Syndrome (MDS). Known chromosomal changes causing MDS include deletion of the long arm of chromosome 5, runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1), and very rarely fusion genes involving RUNX1 at t(5;21)(q15;q22). We present a case of a 71-year-old female with MDS, refractory anemia with excess blasts, type 1, with a combination of two cytogenetic abnormalities, specifically a concomitant translocation between chromosomes 5q15 and 21q22 and deletion of chromosome 5q13q33. Fluorescence in-situ hybridization (FISH) using a probe for RUNX1 (AML1), localized to 21q22, showed three FISH signals for RUNX1, consistent with rearrangement of RUNX1. Therapy was started with Lenalidomide leading to normal blood counts. Most significantly, repeat cytogenetics revealed normal karyotype and resolution of deletion on the long arm of chromosome 5 and a t(5;21). FISH negative for deletion 5q. The results altogether meet criteria for a complete cytogenetic remission (CR). We report a new case of t(5;21)(q15;q22) involving the RUNX1 gene and del(5)(q13q33) in a MDS patient, a combination of chromosomal abnormalities heretofore not reported in the literature. RUNX1 rearrangement is usually associated with an adverse prognosis in AML and MDS. Deletions of 5q are typically associated with poor prognosis in AML, however it is usually associated with a favorable prognosis in MDS. Our patient responded very well to Lenalidomide therapy with achievement of CR. Lenalidomide is approved for treatment of anemia in low and intermediate risk MDS with del (5q), however based on a search of literature it seems that RUNX1 mutations are also more prominent in patients who have responded to Lenalidomide therapy. MDS is a genomically unstable disease. Hence, it is conceivable that our patient started with a 5q minus syndrome and then acquired the

  4. Two patients with duplication of 17p11.2: The reciprocal of the Smith-Magenis syndrome deletion?

    SciTech Connect

    Brown, A. |; Phelan, M.C.; Rogers, R.C.

    1996-05-17

    J.M. and H.G. are two unrelated male patients with developmental delay. Cytogenetic analysis detected a duplication of 17p11.2 in both patients. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-D17S122-tel. Four of the six markers, D17S29, D17S258, D17S71, and D17S445, were duplicated by dosage analysis. Fluorescent in situ hybridization (FISH) analysis of H.G., using cosmids for locus D17S29, confirmed the duplication in 17p11.2. Because the deletion that causes the Smith-Magenis syndrome involves the same region of 17p11.2 as the duplication in these patients, the mechanism may be similar to that proposed for the reciprocal deletion/ duplication event observed in Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) and Charcot-Marie-Tooth Type 1A disease (CMT1A). 30 refs., 3 figs., 1 tab.

  5. Microsatellite analysis of loss of heterozygosity on chromosomes 9q, 11p and 17p in medulloblastomas.

    PubMed

    Albrecht, S; von Deimling, A; Pietsch, T; Giangaspero, F; Brandner, S; Kleihues, P; Wiestler, O D

    1994-02-01

    Medulloblastoma (MB) is a primitive neuroectodermal tumour of the cerebellum whose pathogenesis is poorly understood. Previous studies suggest a role for loci on chromosomes 11p and 17p in the pathogenesis of MB. Evidence for another potential MB locus has recently emerged from studies on Gorlin syndrome (GS), an autosomal dominant syndrome with multiple basal cell carcinomas, epithelial jaw cysts, and skeletal anomalies. Since GS can be associated with MB, we examined sporadic (non-GS) cases of MB for evidence of loss of heterozygosity (LOH) on chromosome 9 where a putative GS locus has been localized to band q31. Nineteen paired blood and MB DNA specimens from 16 patients (11 primary tumours, two primary with recurrent tumours, one primary tumour and cell line, two cell lines) were studied by PCR analysis of microsatellites at D9S55 (9p12), D9S15 (9q13-q21.1), D9S127 (9q21.1-21.3), D9S12 (9q22.3), D9S58 (9q22.3-q31), D9S109 (9q31), D9S53 (9q31), GSN (9q33), D9S60 (9q33-q34), D9S65 (9q33-q34), ASS (9q34), D9S67 (9q34.3), TH (11p15.5), D11S490 (11q23.3), D17S261 (17p11.2-12), D17S520 (17p12), TP53 (17p13.1), D17S5 (17p13.3), D17S515 (17q22-qter), and by RFLP analysis at the WT-1 locus (11p13). Only two tumours had LOH on 9q. One was non-informative at D9S15, D9S65, and GSN but showed LOH at D9S127, D9S12, D9S58, D9S109, D9S53, D9S60, ASS, and D9S67. The other was uninterpretable at D9S65 and non-informative at D9S15, D9S58, D9S53, and D9S67 but exhibited LOH at D9S127, D9S12, D9S109, GSN, D9S60, and ASS. Both these cases were informative at D9S55 without LOH.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8208343

  6. Molecular cloning of the human leukotriene C4 synthase gene and assignment to chromosome 5q35.

    PubMed Central

    Bigby, T. D.; Hodulik, C. R.; Arden, K. C.; Fu, L.

    1996-01-01

    BACKGROUND: Cysteinyl leukotrienes (LT) are mediators involved in inflammatory and allergic disorders LTC4 synthase catalyzes the first committed step in the synthesis of these inflammatory mediators, and its cellular distribution appears to be unique. MATERIALS AND METHODS: A human genomic library was screened by polymerase chain reaction (PCR) with primers that were designed based on the reported cDNA sequence for the LTC4 synthase gene. The gene was identified in one clone by Southern blotting of restriction enzyme digests, subcloning of fragments containing regions of interest, and DNA sequencing of these subclones. The transcription initiation site was determined by primer extension analysis. Chromosome location was determined by fluorescent in situ hybridization and screening of somatic cell hybrids by PCR. RESULTS: The LTC4 synthase gene is approximately 2.5 kb in length, consisting of five exons (136, 100, 71, 82, and 257 bp, respectively) and four introns (1,447, 102, 84, and 230 bp, respectively). Transcription initiation occurs at a single site 78 bp upstream of the coding region. The 5'-flanking region contains neither a TATA nor a CAAT box. The first 1 kb of the 5'-flanking region, however, contains putative DNA binding motifs for SP-1, AP-1, AP-2, ets factors, and CREB/ATF. A STAT binding motif is present in the first intron. The LTC4 synthase gene is located in the distal region of the long arm of chromosome 5 in 5q35. CONCLUSIONS: The LTC4 synthase gene does not contain elements of a typical regulated gene and may therefore contain novel regulatory elements. This gene is also located in a region on chromosome 5 that appears to play a role in allergic and inflammatory disorders, such as asthma. Images FIG. 1 FIG. 5 FIG. 4 FIG. 6 PMID:8898379

  7. De novo apparently balanced reciprocal translocation between 5q11.2 and 17q23 associated with Klippel-Feil anomaly and type A1 brachydactyly

    SciTech Connect

    Fukushima, Yoshimitsu; Ohashi, Hirofumi; Wakui, Keiko

    1995-07-03

    We report on a girl with Klippel-Feil anomaly, type A1 brachydactyly, and minor facial anomalies. She has an apparently balanced de novo reciprocal translocation between 5q11.2 and 17q23. The possible significance of this chromosomal abnormality is discussed. 7 refs., 3 figs.

  8. Normal female carrier and affected male half-sibs with t(X;5)(q13;p15). Location of a gene determining male genital development.

    PubMed

    Callen, D F; Sutherland, G R

    1986-07-01

    A unique family in which half-brothers have a maternally derived t(X;5)(q13;p15) and similar genital malformations is described. This family provides evidence for a gene required for male genital development located at Xq13. PMID:3757297

  9. Delayed globin synthesis leads to excess heme and the macrocytic anemia of Diamond Blackfan anemia and del(5q) myelodysplastic syndrome.

    PubMed

    Yang, Zhantao; Keel, Siobán B; Shimamura, Akiko; Liu, Li; Gerds, Aaron T; Li, Henry Y; Wood, Brent L; Scott, Bart L; Abkowitz, Janis L

    2016-05-11

    Diamond Blackfan anemia (DBA) and myelodysplastic syndrome (MDS) with isolated del(5q) are severe macrocytic anemias; although both are associated with impaired ribosome assembly, why the anemia occurs is not known. We cultured marrow cells from DBA (n = 3) and del(5q) MDS (n = 6) patients and determined how heme (a toxic chemical) and globin (a protein) are coordinated. We show that globin translation initiates slowly, whereas heme synthesis proceeds normally. This results in insufficient globin protein, excess heme and excess reactive oxygen species in early erythroid precursors, and CFU-E (colony-forming unit-erythroid)/proerythroblast cell death. The cells that can more rapidly and effectively export heme or can slow heme synthesis preferentially survive and appropriately mature. Consistent with these observations, treatment with 10 μM succinylacetone, a specific inhibitor of heme synthesis, improved the erythroid cell output of DBA and del(5q) MDS marrow cultures by 68 to 95% (P = 0.03 to 0.05), whereas the erythroid cell output of concurrent control marrow cultures decreased by 4 to 13%. Our studies demonstrate that erythropoiesis fails when heme exceeds globin. Our data further suggest that therapies that decrease heme synthesis (or facilitate heme export) could improve the red blood cell production of persons with DBA, del(5q) MDS, and perhaps other macrocytic anemias. PMID:27169803

  10. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression of Toll-like receptor-TRAF6 signaling.

    PubMed

    Varney, Melinda E; Niederkorn, Madeline; Konno, Hiroyasu; Matsumura, Takayuki; Gohda, Jin; Yoshida, Nobuaki; Akiyama, Taishin; Christie, Susanne; Fang, Jing; Miller, David; Jerez, Andres; Karsan, Aly; Maciejewski, Jaroslaw P; Meetei, Ruhikanta A; Inoue, Jun-ichiro; Starczynowski, Daniel T

    2015-10-19

    TRAF-interacting protein with forkhead-associated domain B (TIFAB) is a haploinsufficient gene in del(5q) myelodysplastic syndrome (MDS). Deletion of Tifab results in progressive bone marrow (BM) and blood defects, including skewed hematopoietic stem/progenitor cell (HSPC) proportions and altered myeloid differentiation. A subset of mice transplanted with Tifab knockout (KO) HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. In competitive transplants, Tifab KO HSPCs are out-competed by wild-type (WT) cells, suggesting a cell-intrinsic defect. Gene expression analysis of Tifab KO HSPCs identified dysregulation of immune-related signatures, and hypersensitivity to TLR4 stimulation. TIFAB forms a complex with TRAF6, a mediator of immune signaling, and reduces TRAF6 protein stability by a lysosome-dependent mechanism. In contrast, TIFAB loss increases TRAF6 protein and the dynamic range of TLR4 signaling, contributing to ineffective hematopoiesis. Moreover, combined deletion of TIFAB and miR-146a, two genes associated with del(5q) MDS/AML, results in a cooperative increase in TRAF6 expression and hematopoietic dysfunction. Re-expression of TIFAB in del(5q) MDS/AML cells results in attenuated TLR4 signaling and reduced viability. These findings underscore the importance of efficient regulation of innate immune/TRAF6 signaling within HSPCs by TIFAB, and its cooperation with miR-146a as it relates to the pathogenesis of hematopoietic malignancies, such as del(5q) MDS/AML. PMID:26458771

  11. 31 CFR 30.5 - Q-5: How does a TARP recipient comply with the requirements under § 30.4 (Q-4) of this part that...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Q-5: How does a TARP recipient comply... recipient? 30.5 Section 30.5 Money and Finance: Treasury Office of the Secretary of the Treasury TARP STANDARDS FOR COMPENSATION AND CORPORATE GOVERNANCE § 30.5 Q-5: How does a TARP recipient comply with...

  12. Molecular characterization of near-complete trisomy 17p syndrome from inverted duplication in association with cryptic deletion of 17pter.

    PubMed

    Park, Chang-Hun; Kim, Hee-Jin; Lee, Seung-Tae; Seo, Jeong Meen; Kim, Sun-Hee

    2014-03-10

    Trisomy of the short arm of chromosome 17 (T17P) is a genomic disorder presenting with growth retardation, motor and mental retardation and constitutional physical anomalies including congenital heart defects. Here we report a case of near-complete T17P of which the genomic dosage aberrations were delineated by chromosomal microarray along with conventional diagnostic modalities. A 9-year-old Korean boy was admitted because of esophageal obstruction. He showed clinical manifestations of T17P, along with atypical features of scoliosis, corpus callosum agenesis, and seizure. Chromosome analyses revealed an inverted duplication of the chromosomal segment between 17p11.2 and 17p13.3. Chromosomal microarray revealed a duplication of the most of the short arm of chromosome 17 (size ~19.09 Mb) along with a cryptic deletion of a small segment of 17p terminal end (17pter) (~261 Kb). This is the first report of molecular characterization of near-complete T17P from inverted duplication in association with 17pter microdeletion. The fine delineation of the extent of genomic aberration by SNP-based microarray could help us better understand the molecular mechanism and genotype-phenotype correlations in T17P syndrome. PMID:24393711

  13. Durable response to lenalidomide in a patient with myelodysplastic syndrome associated with isolated 5q deletion and JAK2 V617F mutation despite discontinuation of treatment

    PubMed Central

    HATZIMICHAEL, ELEFTHERIA; LAGOS, KONSTANTINOS; VASSOU, AMALIA; GOUGOPOULOU, DORA; PAPOUDOU-BAI, ALEXANDRA; BRIASOULIS, EVANGELOS

    2016-01-01

    Loss of a section of the long arm of chromosome 5, as a sole cytogenetic abnormality, characterizes a rare type of myelodysplastic syndrome [del(5q) MDS] and the co-existence of the JAK2 V617F mutation occurs in a small subset of these cases. Patients with isolated del(5q) MDS have a relatively favorable prognosis, with transformation to acute myeloid leukemia occurring in <10%, and their disease responds well to lenalidomide. However the optimal therapeutic approach for patients with del(5q) MDS in coexistence with the JAK2 V617F mutation, which is common to myeloproliferative neoplasms, remains to be elucidated. The present study reports a 77-year-old, transfusion-dependent female patient diagnosed with del(5q) MDS and a concomitant JAK2 V617F mutation. The patient was started on 10 mg lenalidomide daily for 21 days in a 28 day-cycle and within the first month of treatment, the patient became transfusion-independent. The only toxicity observed was grade 3 neutropenia, which was managed with transient treatment discontinuation and dose reduction on restart (5 mg). The patient achieved a complete cytogenetic and molecular response (normal karyotype and undetected JAK2 V617F mutation) within 6 months of treatment. However, 12 months post treatment initiation and while on hematological, cytogenetic and molecular response, the patient was unwilling to continue on treatment and lenalidomide was discontinued. The patient remains in hematological response, which lasts for >5 years despite treatment discontinuation. The present case highlights the coexistence of the JAK2 V617F mutation in del(5q) MDS and suggests that lenalidomide treatment is beneficial and effective for these patients, leading to complete hematological, cytogenetic and molecular response. Hematological response may be sustained for long periods of time, even following the discontinuation of the treatment. PMID:27330758

  14. T-cell/myeloid mixed-phenotype acute leukemia with monocytic differentiation and isolated 17p deletion

    PubMed Central

    Lopes, Germison Silva; Leitão, João Paulo de Vasconcelos; Kaufman, Jacques; Duarte, Fernando Barroso; Matos, Daniel Mazza

    2014-01-01

    Mixed phenotype acute leukemia is a rare subtype of leukemia that probably arises from a hematopoietic pluripotent stem cell. The co-expression of two of myeloid, B- or T-lymphoid antigens is the hallmark of this disease. Herein, the case of a 28-year-old female patient is reported who presented with hemoglobin of 5.8 g/dL, white blood cell count of 138 × 109/L and platelet count of 12 × 109/L. The differential count of peripheral blood revealed 96% of blasts. Moreover, the patient presented with lymphadenopathy, splenomegaly and bone marrow infiltration by monocytoid blasts characterized as 7% positivity by Sudan Black cytochemical staining. Immunophenotyping revealed the involvement of blasts of both T- and monocytic lineages. The cytogenetic analysis showed an isolated 17p deletion. Thus, the diagnosis of T-cell/myeloid mixed phenotype acute leukemia was made with two particular rare features, that is, the monocytic differentiation and the 17p deletion as unique cytogenetic abnormalities. The possibility of concomitant expressions of T-cell and monocytic differentiation antigens in the same blast population is hard to explain using the classical model of hematopoiesis. However, recent studies have suggested that myeloid potential persists even when the lineage branches segregate toward B- and T-cells. The role of an isolated 17p deletion in the pathogenesis of this condition is unclear. At present, the patient is in complete remission after an allogeneic stem cell transplantation procedure. PMID:25031170

  15. A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3.

    PubMed

    Lezirovitz, Karina; Maestrelli, Sylvia Regina Pedrosa; Cotrim, Nelson Henderson; Otto, Paulo A; Pearson, Peter L; Mingroni-Netto, Regina Celia

    2008-07-01

    Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2-q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1-17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected. PMID:18493797

  16. Acute myeloid leukemia with t(10;17)(p13;q12) chromosome translocation: a case report and literature review

    PubMed Central

    Li, Lu; Zhou, Fan; Hou, Jian

    2012-01-01

    More than 50% of adult patients with acute myeloid leukemia (AML) carry chromosome abnormalities, like t(8;21)(q22;q22), t(15;17), t(8;21)inv(16) or t(16;16). t(10;17) translocation was very rare in AML. There are only 10 such cases reported in the literature. Here, we describe a case of acute myeloid leukemia with t(10;17)(p13;q12) chromosome translocation, who had complete remission after one course of chemotherapy. PMID:23226626

  17. Constitutional Haploinsufficiency of Tumor Suppressor Genes in Mentally Retarded Patients With Microdeletions in 17p13.1

    PubMed Central

    Krepischi-Santos, A.C.V.; Rajan, D.; Temple, I.K.; Shrubb, V.; Crolla, J.A.; Huang, S.; Beal, S.; Otto, P.A.; Carter, N.P.; Vianna-Morgante, A.M.; Rosenberg, C.

    2009-01-01

    Chromosome microdeletions or duplications are detected in 10–20% of patients with mental impairment and normal karyotypes. A few cases have been reported of mental impairment with microdeletions comprising tumor suppressor genes. By array-CGH we detected 4 mentally impaired individuals carrying de novo microdeletions sharing an overlapping segment of ∼180 kb in 17p13.1. This segment encompasses 18 genes, including 3 involved in cancer, namely KCTD11/REN, DLG4/PSD95, and GPS2. Furthermore, in 2 of the patients, the deletions also included TP53, the most frequently inactivated gene in human cancers. The 3 tumor suppressor genes KCTD11, DLG4, and GPS2, in addition to the GABARAP gene, have a known or suspected function in neuronal development and are candidates for causing mental impairment in our patients. Among our 4 patients with deletions in 17p13.1, 3 were part of a Brazilian cohort of 300 mentally retarded individuals, suggesting that this segment may be particularly prone to rearrangements and appears to be an important cause (∼1%) of mental retardation. Further, the constitutive deletion of tumor suppressor genes in these patients, particularly TP53, probably confers a significantly increased lifetime risk for cancer and warrants careful oncological surveillance of these patients. Constitutional chromosome deletions containing tumor suppressor genes in patients with mental impairment or congenital abnormalities may represent an important mechanism linking abnormal phenotypes with increased risks of cancer. PMID:19617690

  18. A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13

    SciTech Connect

    Balciuniene, J.; Holmgren, G.; Forsman, K.

    1995-11-20

    Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders. 34 refs., 3 figs., 2 tabs.

  19. Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma

    SciTech Connect

    Zhou, Y.Z.; Slagle, B.L.; Donehower, L.A.; van Tuinen, P.; Ledbetter, D.H.; Butel, J.S.

    1988-11-01

    Hepatitis B virus (HBV) is clearly a factor in the development of hepatocellular carcinoma, but its mechanism of action remains obscure. One possibility is that the HBV integration event alters the expression of a nearby growth-regulatory cellular gene. A 9-kilobase (kb) DNA fragment containing an HBV insert plus flanking cellular sequences was cloned from a hepatoma specimen from Shanghai, People's Republic of China. Restriction mapping of the insert revealed a large inverted repeat structure consisting of both viral sequences (encompassing all of the core and pre-S regions and portions of the X and S genes) and at least 3 kb of unique cellular sequences. The virus-cell junction mapped 11 nucleotides from the DRI region, in a position within the HBV X gene and included in the cohesive overlap region. A probe generated from 1.0 kb of the flanking cellular DNA mapped the viral insert to chromosome 17 in the region designated 17p11.2-17p12, which is near the human proto-oncogene p53. Sequence data from a portion of the flanking cellular DNA revealed a stretch of approximately 70 base pairs that showed highly significant homology with a conserved region of a number of functional mammalian DNA, including the human autonomously replicating sequence 1 (ASRI).

  20. Structural analysis of a hepatitis B virus genome integrated into chromosome 17p of a human hepatocellular carcinoma.

    PubMed Central

    Zhou, Y Z; Slagle, B L; Donehower, L A; vanTuinen, P; Ledbetter, D H; Butel, J S

    1988-01-01

    Hepatitis B virus (HBV) is clearly a factor in the development of hepatocellular carcinoma, but its mechanism of action remains obscure. One possibility is that the HBV integration event alters the expression of a nearby growth-regulatory cellular gene. A 9-kilobase (kb) DNA fragment containing an HBV insert plus flanking cellular sequences was cloned from a hepatoma specimen from Shanghai, People's Republic of China. Restriction mapping of the insert revealed a large inverted repeat structure consisting of both viral sequences (encompassing all of the core and pre-S regions and portions of the X and S genes) and at least 3 kb of unique cellular sequences. The virus-cell junction mapped 11 nucleotides from the DR1 region, in a position within the HBV X gene and included in the cohesive overlap region. A probe generated from 1.0 kb of the flanking cellular DNA mapped the viral insert to chromosome 17 in the region designated 17p11.2-17p12, which is near the human proto-oncogene p53. Sequence data from a portion of the flanking cellular DNA revealed a stretch of approximately 70 base pairs that showed highly significant homology with a conserved region of a number of functional mammalian DNAs, including the human autonomously replicating sequence 1 (ARS1). Images PMID:2845134

  1. Homotypic vacuole fusion requires Sec17p (yeast alpha-SNAP) and Sec18p (yeast NSF).

    PubMed Central

    Haas, A; Wickner, W

    1996-01-01

    In Saccharomyces cerevisiae, vacuoles are inherited by the formation of tubular and vesicular structures from the mother vacuole, the directed projection of these structures into the bud and the homotypic fusion of these vesicles. We have previously exploited a cell-free inheritance assay to show that the fusion step of vacuole inheritance requires cytosol, ATP and the GTPase Ypt7p. Here we demonstrate, using affinity-purified antibodies and purified recombinant proteins, a requirement for Sec17p (yeast alpha-SNAP) and Sec18p (yeast NSF) in homotypic vacuole fusion in vitro. Thus, Sec17p and Sec18p, which are typically involved in heterotypic transport steps, can also be involved in homotypic organelle fusion. We further show that vacuole-to-vacuole fusion is stimulated by certain fatty acyl-coenzyme A compounds in a Sec18p-dependent fashion. Finally, our data suggest the presence of a cytosolic factor which activates vacuole membrane-bound Sec18p. Images PMID:8670830

  2. Monosomy 9p24{r_arrow}pter and trisomy 5q31{r_arrow}qter: Case report and review of two cases

    SciTech Connect

    Schimmenti, L.A.; Steinberger, J.; Mammel, M.C.

    1995-05-22

    Partial deletion of the short arm of chromosome 9 (p24{r_arrow}pter) and partial duplication of the long arm of chromosome 5 (q32{r_arrow}qter) were observed in an abnormal boy who died at age 8 weeks of a complex cyanotic cardiac defect. He also had minor anomalies, sagittal craniosynostosis, triphalangeal thumbs, hypospadias, and a bifid scrotum. Two other infants with similar cytogenetic abnormalities were described previously. These patients had severe congenital heart defect, genitourinary anomalies, broad nasal bridge, low hairline, apparently low-set ears, short neck, and triphalangeal thumbs, in common with our patient. We suggest that combined monosomy 9q23,24{r_arrow}pter and trisomy 5q31,32{r_arrow}qter may constitute a clinically recognizable syndrome. 13 refs., 2 figs., 2 tabs.

  3. Clinical and genetic spectrum of 18 unrelated Korean patients with Sotos syndrome: frequent 5q35 microdeletion and identification of four novel NSD1 mutations.

    PubMed

    Sohn, Young Bae; Lee, Cha Gon; Ko, Jung Min; Yang, Jung-Ah; Yun, Jun-No; Jung, Eun-Jung; Jin, Hyun-Seok; Park, Sang-Jin; Jeong, Seon Yong

    2013-02-01

    Sotos syndrome is an overgrowth syndrome with characteristic facial dysmorphism, variable severity of learning disabilities and macrocephaly with overgrowth. Haploinsufficiency of the nuclear receptor SET domain-containing protein 1 (NSD1) gene located on 5q35 has been implicated as the cause of Sotos syndrome. This study was performed to investigate the mutation spectrum of NSD1 abnormalities and meaningful genotype-phenotype correlations in Korean patients with Sotos syndrome. Eighteen unrelated Korean patients with Sotos syndrome were enrolled for clinical and molecular analyses. Cytogenetic studies were performed to confirm 5q35 microdeletion, and NSD1 sequencing analysis was performed to identify intragenic mutations. NSD1 abnormalities were identified in 15 (83%) patients. Among them, eight patients (53%) had 5q35 microdeletions and the other seven patients (47%) had seven different NSD1 intragenic mutations including four novel mutations. The mutation spectrum of Korean patients with Sotos syndrome was similar to that of previous studies for Japanese patients. Height was significantly shorter and age of walking alone was significantly older in the microdeletion group compared with those in the intragenic mutation group. No significant differences were observed for other clinical characteristics between the microdeletion and intragenic mutation groups. Further studies with a larger number of patients will be necessary to draw conclusive genotype-phenotype correlations. PMID:23190751

  4. The human and mouse receptors of hyaluronan-mediated motility, RHAMM, genes (HMMR) map to human chromosome 5q33.2-qter and mouse chromosome 11

    SciTech Connect

    Spicer, A.P.; McDonald, J.A.; Roller, M.L.; Camper, S.A.

    1995-11-01

    The gene for the receptor for hyaluronan-mediated motility, RHAAM (designated hyaluronan-mediated motility receptor, HMMR (human) and Hmmr (mouse), for mapping purposes), was localized to human chromosome 5q33.2-qter by somatic cell and radiation hybrid analyses. Investigation of two interspecific back-crosses localized the mouse RHAMM (Hmmr) locus 18 cM from the centromere of mouse chromosome 11 within a region of synteny homology with human chromosome 5q23-q35 genes. The map position of the human RHAMM gene places it in a region comparatively rich in disease-associated genes, including those for low-frequency hearing loss, dominant limb-girdle muscular dystrophy, diastrophic dysplasia, Treacher Collins syndrome, and myeloid disorders associated with the 5q-syndrome. The RHAMM gene location and its ability to transform cells when overexpressed implicate RHAMM as a possible candidate gene in the pathogenesis of the recently described t(5;14)(q33-q34;q11) acute lymphoblastic leukemias. 18 refs., 1 fig.

  5. Extended survival and reduced risk of AML progression in erythroid-responsive lenalidomide-treated patients with lower-risk del(5q) MDS

    PubMed Central

    List, A F; Bennett, J M; Sekeres, M A; Skikne, B; Fu, T; Shammo, J M; Nimer, S D; Knight, R D; Giagounidis, A

    2014-01-01

    Lenalidomide is the approved treatment for patients with red blood cell (RBC) transfusion-dependent lower-risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)). We report the long-term outcomes (median follow-up 3.2 years) in patients treated with lenalidomide in the MDS-003 trial. RBC transfusion independence (TI) ⩾8 weeks was achieved in 97 of 148 treated patients (65.5%), with a median response duration of 2.2 years. Partial or complete cytogenetic response was achieved by 63 of 88 evaluable patients (71.6%). Median overall survival (OS) was longer in patients achieving RBC-TI ⩾8 weeks (4.3 vs 2.0 years in non-responders; P<0.0001) or cytogenetic response (4.9 vs 3.1 years in non-responders; P=0.010). Time to acute myeloid leukemia (AML) progression was longer in patients achieving RBC-TI ⩾8 weeks or any cytogenetic response versus non-responders (P=0.001 and P=0.0002, respectively). In a landmark multivariate analysis, RBC-TI ⩾8 weeks was associated with prolonged OS (P<0.001) and a trend toward reduced relative risk of AML progression (P=0.080). Among these lower-risk MDS patients with del(5q), lenalidomide was associated with prolonged RBC-TI and cytogenetic responses, which were linked to improved OS and reduced risk of AML progression. PMID:24150217

  6. Clinical utility of a DNA probe to 17p11.2 in screening of patients with a peripheral neuropathy

    SciTech Connect

    Blancato, J.; Precht, K.; Meck, J.

    1994-09-01

    We assessed the usefulness of in situ hybridization with a DNA probe to the area of chromosome 17 at p11.2 as a diagnostic tool for screening for Charcot Marte Tooth 1A (CMT 1A). In situ hybridization with a probe to 17p11.2 was performed on fixed lymphocytes from the following groups of individuals: (1) normal controls; (2) patients evoking a strong clinical suspicion of CMT 1A; and (3) 3 families with an apparent autosomal dominant peripheral neuropathy of unknown diagnoses. Group 2 patients had evidence of demyelination as defined by nerve conduction of less that 50% of the normal mean or terminal latency greater than 50% of the normal mean in conduction studies. Analysis of interphase cells hybridized with a cosmid DNA probe to 17p11.2 requires inclusion of a normal control with each trial and masked observer. Due to the size of the target DNA and the nature of the centromeric heterochromatin, the scoring of this probe is more subjective than centromere probes. For example, if the two 17 chromosomes are decondensed as in interphase, two tandem signals may be visualized as one. Results from duplication positive patients demonstrate a large proportion of cells with two closely aligned, but separate, signals with an additional single signal. Normal results demonstrate a majority of cells with two separate signals representing both normal homologues. None of the 3 families with questionable diagnosis revealed a duplication at the region, reinforcing our belief that a clinical diagnosis is the most discriminating tool available for diagnosis of CMT 1A. We concur with Boylan that molecular analysis for CMT 1A is useful for establishing a diagnosis of CMT 1A, but is not a primary differential diagnostic test. The yield in screening patients without physiologic evidence of demyelination is likely to be low. We further find that the use of in situ hybridization is a simple method of performing the duplication analysis.

  7. Deletion 17p11.2 (Smith-Magenis syndrome) is relatively common among patients having mental retardation and myopia

    SciTech Connect

    Finucane, B.; Jaeger, E.R.; Freitag, S.K.

    1994-09-01

    We recently reported the finding of moderate to severe myopia in 6 of 10 patients with Smith-Magenis syndrome (SMS). To investigate the prevalence of SMS among mentally retarded people having myopia, we surveyed a cohort of patients residing at a facility for individuals with mental retardation (MR). Of 547 institutionalized individuals with MR, 72 (13.2%) had moderate to high myopia defined as a visual acuity of minus 3 diopters or more. It should be noted that our institution does not specifically select for people with visual impairment; rather, the facility serves people with a primary diagnosis of MR. Sixty-five of 72 (90.3%) myopic individuals identified were available for cytogenetic analysis. Seventeen (26.2%) of these patients had trisomy 21. Down syndrome (DS) is well known to be associated with eye abnormalities, including myopia. Of 48 individuals with moderate to high myopia not having DS, 5 (10.4%) were shown to have deletions of 17p11.2. This is a high prevalence considering the relative rarity of SMS. By contrast, in a randomized sample of 48 patients without significant myopia at the same facility, we found no individuals with deletion 17p11.2. We conclude that the diagnosis of SMS should be considered in any non-Down syndrome individual having MR and myopia, and that ophthalmologists serving people with MR should be made aware of this deletion syndrome. Furthermore, our results suggest that significant numbers of people having SMS could be identified through selective institutional screening of patients having a combination of MR and moderate to severe myopia.

  8. On Ramsey (P3, P6)-minimal graphs

    NASA Astrophysics Data System (ADS)

    Rahmadani, Desi; Baskoro, Edy Tri; Assiyatun, Hilda

    2016-02-01

    Finding all Ramsey (G, H)-minimal graphs for a certain pair of graphs G and H is an interesting and difficult problem. Even though, it is just for small graphs G and H. In this paper, we determine some Ramsey (P3, P6)-minimal graphs of small order. We also characterize all such Ramsey minimal graphs of order 6 by using their degree sequences. We prove that Ramsey (P3, P6)-minimal graphs have diameter at least two. We construct an infinite class of trees [6] which provides Ramsey (P3, P6)-minimal graphs.

  9. Obtaining P3P Privacy Policies for Composite Services

    PubMed Central

    Sun, Yi; Huang, Zhiqiu; Ke, Changbo

    2014-01-01

    With the development of web services technology, web services have changed from single to composite services. Privacy protection in composite services is becoming an important issue. P3P (platform for privacy preferences) is a privacy policy language which was designed for single web services. It enables service providers to express how they will deal with the privacy information of service consumers. In order to solve the problem that P3P cannot be applied to composite services directly, we propose a method to obtain P3P privacy policies for composite services. In this method, we present the definitions of Purpose, Recipient, and Retention elements as well as Optional and Required attributes for P3P policies of composite services. We also provide an instantiation to illustrate the feasibility of the method. PMID:25126609

  10. Obtaining P3P privacy policies for composite services.

    PubMed

    Sun, Yi; Huang, Zhiqiu; Ke, Changbo

    2014-01-01

    With the development of web services technology, web services have changed from single to composite services. Privacy protection in composite services is becoming an important issue. P3P (platform for privacy preferences) is a privacy policy language which was designed for single web services. It enables service providers to express how they will deal with the privacy information of service consumers. In order to solve the problem that P3P cannot be applied to composite services directly, we propose a method to obtain P3P privacy policies for composite services. In this method, we present the definitions of Purpose, Recipient, and Retention elements as well as Optional and Required attributes for P3P policies of composite services. We also provide an instantiation to illustrate the feasibility of the method. PMID:25126609

  11. Auger decay of 3p-ionized krypton

    SciTech Connect

    Jonauskas, V.; Kucas, S.; Karazija, R.

    2011-11-15

    A theoretical study of Auger cascades during the decay of 3p{sub 1/2} and 3p{sub 3/2} vacancies in krypton has been performed by level-by-level calculations using a wide configuration interaction basis. Auger spectra for all steps of the cascades are presented and are compared with the existing experimental data. Good agreement of our results with the branching ratios of ions measured by a coincidence technique is obtained.

  12. Miller-Dieker syndrome due to maternal cryptic translocation t(10;17)(q26.3;p13.3)

    SciTech Connect

    Masuno, Mitsuo; Imaizumi, Kiyoshi; Nakamura, Mihoko; Kuroki, Yoshikazu

    1995-12-04

    We report on a 3-month-old girl with Miller-Dieker syndrome resulting from a maternal full-cryptic translocation t(10;17)(q26.3;p13.3) detectable only by using fluorescence in situ hybridization (FISH). Parental studies using FISH are crucial for genetic counselling in cases of Miller-Dieker syndrome with submicroscopic deletion at 17p13.3. In a family with a parental cryptic translocation and high recurrence risk, prenatal diagnosis using FISH is feasible. 15 refs., 3 figs.

  13. Chromosome 17p13.2 transfer reverts transformation phenotypes and Fas-mediated apoptosis in breast epithelial cells.

    PubMed

    Lareef, Mohamed H; Tahin, Quivo; Song, Joon; Russo, Irma H; Mihaila, Dana; Slater, Carolyn M; Balsara, Binaifer; Testa, Joseph R; Broccoli, Dominique; Grobelny, Jennifer V; Mor, Gil; Cuthbert, Andrew; Russo, Jose

    2004-04-01

    Transformation of the human breast epithelial cells (HBEC) MCF-10F with the carcinogen benz(a)pyrene (BP) into BP1-E cells resulted in the loss of the chromosome 17 p13.2 locus (D17S796 marker) and formation of colonies in agar-methocel (colony efficiency (CE)), loss of ductulogenic capacity in collagen matrix, and resistance to anti-Fas monoclonal antibody (Mab)-induced apoptosis. For testing the role of that specific region of chromosome 17 in the expression of transformation phenotypes, we transferred chromosome 17 from mouse fibroblast donors to BP1-E cells. Chromosome 11 was used as negative control. After G418 selection, nine clones each were randomly selected from BP1-E-11neo and BP1-E-17neo hybrids, respectively, and tested for the presence of the donor chromosomes by fluorescent in situ hybridization and polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analyses. Sensitivity to Fas Mab-induced apoptosis and evaluation of transformation phenotype expression were tested in MCF-10F, BP1-E, and nine BP1-E-11neo and BP1-E-17neo clones each. Six BP1-E-17neo clones exhibited a reversion of transformation phenotypes and a dose dependent sensitivity to Fas Mab-induced apoptosis, behaving similarly to MCF-10F cells. All BP1-E-11neo, and three BP1-E-17neo cell clones, like BP1-E cells, retained a high CE, loss of ductulogenic capacity, and were resistant to all Fas Mab doses tested. Genomic analysis revealed that those six BP1-E-17neo clones that were Fas-sensitive and reverted their transformed phenotypes had retained the 17p13.2 (D17S796 marker) region, whereas it was absent in all resistant clones, indicating that the expression of transformation phenotypes and the sensitivity of the cells to Fas-mediated apoptosis were under the control of genes located in this region. PMID:15057875

  14. Lenalidomide with or without erythropoietin in transfusion-dependent erythropoiesis-stimulating agent-refractory lower-risk MDS without 5q deletion.

    PubMed

    Toma, A; Kosmider, O; Chevret, S; Delaunay, J; Stamatoullas, A; Rose, C; Beyne-Rauzy, O; Banos, A; Guerci-Bresler, A; Wickenhauser, S; Caillot, D; Laribi, K; De Renzis, B; Bordessoule, D; Gardin, C; Slama, B; Sanhes, L; Gruson, B; Cony-Makhoul, P; Chouffi, B; Salanoubat, C; Benramdane, R; Legros, L; Wattel, E; Tertian, G; Bouabdallah, K; Guilhot, F; Taksin, A L; Cheze, S; Maloum, K; Nimuboma, S; Soussain, C; Isnard, F; Gyan, E; Petit, R; Lejeune, J; Sardnal, V; Renneville, A; Preudhomme, C; Fontenay, M; Fenaux, P; Dreyfus, F

    2016-04-01

    After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA. PMID:26500139

  15. Theoretical investigation of the electronic and optical properties of pseudocubic Si3P4, Ge3P4 and Sn3P4

    NASA Astrophysics Data System (ADS)

    Xu, Ming; Wang, Songyou; Yin, Gang; Chen, Liangyao; Jia, Yu

    2006-01-01

    Group-IV phosphides are relatively unknown materials as compared to the Group-IV carbide. In this work, we detailed the first principles calculations of the electronic and optical properties of the pseudocubic M3 P4 (M=Si, Ge, Sn) using the density function theory (DFT). Results are in good agreement with those previous works. Furthermore, the optical constants, such as the dielectric function, energy loss function and effective number of valence electrons are calculated and presented in the study.

  16. Chromosome 3p alterations in pancreatic endocrine neoplasia

    PubMed Central

    Amato, Eliana; Barbi, Stefano; Malpeli, Giorgio; Bersani, Samantha; Pelosi, Giuseppe; Capelli, Paola

    2010-01-01

    Pancreatic endocrine tumors (PET) are rare neoplasms classified as functioning (F-PET) or non-functioning (NF-PET) according to the presence of a clinical syndrome due to hormonal hypersecretion. PETs show variable degrees of clinical aggressiveness and loss of chromosome 3p has been suggested to be associated with an advanced stage of disease. We assessed chromosome 3p copy number in 113 primary PETs and 32 metastases by fluorescence in situ hybridization (FISH) using tissue microarrays. The series included 56 well-differentiated endocrine tumors (WDET), 62 well-differentiated endocrine carcinomas (WDEC), and 6 poorly differentiated endocrine carcinomas (PDEC). Chromosome 3p alterations were found in 23/113 (20%) primary tumors, with losses being predominant over gains (14% vs. 6%). Loss of 3p was found in 5/55 (9%) WDET, 11/52 (21%) WDEC, and never in PDEC. Gains of 3p were detected in 4/55 (7%) WDET, no WDEC, but notably in 3/6 (50%) PDEC (OR 23.6; P = 0.003). Metastases were more frequently monosomic for 3p compared to primary tumors (OR 3.6; P = 0.005). Monosomy was significantly associated with larger tumor size, more advanced tumor stage, and metastasis. No association was found with survival. Chromosome 3p copy number alterations are frequent events in advanced stage PET, with gains prevailing in PDEC while losses are more frequent in WDEC, supporting the view that a specific pattern of alterations are involved in these diverse disease subtypes. PMID:20981439

  17. Clinical and cytogenetic features of a Potocki-Lupski syndrome with the shortest 0.25Mb microduplication in 17p11.2 including RAI1.

    PubMed

    Lee, Cha Gon; Park, Sang-Jin; Yim, Shin-Young; Sohn, Young Bae

    2013-08-01

    Potocki-Lupski syndrome (PTLS [MIM 610883]) is a recently recognized microduplication syndrome associated with 17p11.2. It is characterized by mild facial dysmorphic features, hypermetropia, infantile hypotonia, failure to thrive, mental retardation, autistic spectrum disorders, behavioral abnormalities, sleep apnea, and cardiovascular anomalies. In several studies, the critical PTLS region was deduced to be 1.3Mb in length, and included RAI1 and 17 other genes. We report a 3-year-old Korean boy with the smallest duplication in 17p11.2 and a milder phenotype. He had no family history of neurologic disease or developmental delay and no history of seizure, autistic features, or behavior problems. He showed subtle facial dysmorphic features (dolichocephaly and a mildly asymmetric smile) and flat feet. All laboratory tests were normal and he had no evidence of internal organ anomalies. He was found to have mild intellectual disabilities (full scale IQ 65 on K-WPPSI) and language developmental delay (age of 2.2year-old on PRESS). Array comparative genomic hybridization (CGH) showed about a 0.25Mb microduplication on chromosome 17p11.2 containing four Refseq (NCBI reference sequence) genes, including RAI1 [arr 17p11.2(17,575,978-17,824,623)×3]. When compared with previously reported cases, the milder phenotype of our patient may be associated with the smallest duplication in 17p11.2, 0.25Mb in length. PMID:23078968

  18. [17p13.3 duplication as a cause of psychomotor developmental delay in an infant - a further case of a new syndrome].

    PubMed

    Przybylska-Kruszewska, Amanda; Kutkowska-Kaźmierczak, Anna; Krzywdzińska, Amanda; Smyk, Marta; Nowakowska, Beata; Gryglicka, Halina; Obersztyn, Ewa; Hozyasz, Kamil K

    2016-04-01

    17p13.3 duplication is a rare and heterogeneous genetic syndrome. Microdeletions of this region are responsible for the symptoms of Miller-Dieker syndrome. We present a case of 17p13.3 duplication consisting of about 730kb in a patient with psychomotor developmental delay, concerning eye-hand coordination, posture, locomotion and speech. Among other symptoms, we found excessive physical development in relation to age, hypotonia, dysmorphic facial features (high and prominent forehead, low-set ears, hypertelorism, short nose, small upturned nose, narrow lips and pointed chin) and discrete changes in the CNS - enhanced frontal horns of the lateral ventricles and quite narrow corpus callosum. These symptoms overlap with phenotype of previously described patients with 17p13.3 duplication. The aberration has been identified by array comparative genomic hybridization (aCGH) and confirmed by fluorescence in situ hybridization (FISH). This publication presents a detailed, comparative characteristic of clinical fetures expression in discussed patient with 17p13.3 duplication and patients previously described in medical literature. Further cases with different variants of 17p13.3 duplication may contribute to characterise the specific genotypephenotype correlation. PMID:27137828

  19. Large Excess of Heavy Nitrogen in Both Hydrogen Cyanide and Cyanogen from Comet 17P/Holmes

    NASA Astrophysics Data System (ADS)

    Bockelée-Morvan, D.; Biver, N.; Jehin, E.; Cochran, A. L.; Wiesemeyer, H.; Manfroid, J.; Hutsemékers, D.; Arpigny, C.; Boissier, J.; Cochran, W.; Colom, P.; Crovisier, J.; Milutinovic, N.; Moreno, R.; Prochaska, J. X.; Ramirez, I.; Schulz, R.; Zucconi, J.-M.

    2008-05-01

    From millimeter and optical observations of the Jupiter-family comet 17P/Holmes performed soon after its huge outburst of 2007 October 24, we derive 14N/15N = 139 ± 26 in HCN and 14N/15N = 165 ± 40 in CN, establishing that HCN has the same nonterrestrial isotopic composition as CN. The same conclusion is obtained for the long-period comet C/1995 O1 (Hale-Bopp) after a reanalysis of previously published measurements. These results are compatible with HCN being the prime parent of CN in cometary atmospheres. The15N excess relative to the Earth's atmospheric value indicates that N-bearing volatiles in the solar nebula underwent important N isotopic fractionation at some stage of solar system formation. HCN molecules never isotopically equilibrated with the main nitrogen reservoir in the solar nebula before being incorporated in Oort Cloud and Kuiper Belt comets. The 12C/13C ratios in HCN and CN are measured to be consistent with the terrestrial value.

  20. Size-tunable, hexagonal plate-like Cu3P and Janus-like Cu-Cu3P nanocrystals.

    PubMed

    De Trizio, Luca; Figuerola, Albert; Manna, Liberato; Genovese, Alessandro; George, Chandramohan; Brescia, Rosaria; Saghi, Zineb; Simonutti, Roberto; Van Huis, Marijn; Falqui, Andrea

    2012-01-24

    We describe two synthesis approaches to colloidal Cu(3)P nanocrystals using trioctylphosphine (TOP) as phosphorus precursor. One approach is based on the homogeneous nucleation of small Cu(3)P nanocrystals with hexagonal plate-like morphology and with sizes that can be tuned from 5 to 50 nm depending on the reaction time. In the other approach, metallic Cu nanocrystals are nucleated first and then they are progressively phosphorized to Cu(3)P. In this case, intermediate Janus-like dimeric nanoparticles can be isolated, which are made of two domains of different materials, Cu and Cu(3)P, sharing a flat epitaxial interface. The Janus-like nanoparticles can be transformed back to single-crystalline copper particles if they are annealed at high temperature under high vacuum conditions, which makes them an interesting source of phosphorus. The features of the Cu-Cu(3)P Janus-like nanoparticles are compared with those of the striped microstructure discovered more than two decades ago in the rapidly quenched Cu-Cu(3)P eutectic of the Cu-P alloy, suggesting that other alloy/eutectic systems that display similar behavior might give origin to nanostructures with flat, epitaxial interface between domains of two diverse materials. Finally, the electrochemical properties of the copper phosphide plates are studied, and they are found to be capable of undergoing lithiation/delithiation through a displacement reaction, while the Janus-like Cu-Cu(3)P particles do not display an electrochemical behavior that would make them suitable for applications in batteries. PMID:22136519

  1. Au Nanowire-Striped Cu3P Platelet Photoelectrocatalysts.

    PubMed

    Dutta, Anirban; Samantara, Aneeya K; Adhikari, Samrat Das; Jena, Bikash Kumar; Pradhan, Narayan

    2016-03-17

    A stripy pattern of continuous epitaxial growth of thin Au nanowires on plasmonic Cu3P platelets is reported. The obtained Au-Cu3P heterostructures retain their wide area interfacial heterojunction, which is typically not observed in metal-semiconductor heterostructures. This is performed by phosphine-mediated in situ reduction of Au ions on specific facets of Cu3P platelets. The intriguing stripy movements of nanowires are regulated by strong surface binding ligands. Because this is a dual plasmon heterostructure with wide visible absorption window, these are further explored as a photoelectrocatalyst for efficient hole transfer and sensing of an important biomolecule, nicotinamide adenine dinucleotide (NADH). The observed anodic photocurrent was 30 times higher in the presence of NADH, and this proves that the heterostructured material is an ideal photosenser and an efficient catalyst for solar energy conversion. PMID:26938025

  2. NR2F1 Deletion in a Patient with a de novo Paracentric Inversion, inv(5)(q15q33.2), and Syndromic Deafness

    PubMed Central

    Brown, Kerry K.; Alkuraya, Fowzan S.; Matos, Michael; Robertson, Richard L.; Kimonis, Virginia E.; Morton, Cynthia C.

    2009-01-01

    In an effort to discover genes important for human development, we have ascertained patients with congenital anomalies and cytogenetically balanced chromosomal rearrangements. Herein, we report a four year-old girl with profound deafness, a history of feeding difficulties, dysmorphism, strabismus, developmental delay, and an apparently balanced de novo paracentric chromosome 5 inversion, inv(5)(q15q33.2). Molecular cytogenetic analysis of the inversion revealed the presence of microdeletions of approximately 400-500 kb at or near both breakpoints. The 5q15 microdeletion completely removes the nuclear receptor NR2F1 (COUP-TFI) from the inverted chromosome 5. We propose haploinsufficiency of NR2F1 to be the cause of the patient's deafness and many of the other associated anomalies based on striking similarity with the Nr2f1 null mouse. Additionally, this study further highlights the need for high resolution analysis of clinical samples with chromosomal rearrangements as associated deletions may be primarily responsible for the clinical features of these patients. PMID:19353646

  3. Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3.

    PubMed

    Wang, Meilin; Li, Zhiqiang; Chu, Haiyan; Lv, Qiang; Ye, Dingwei; Ding, Qiang; Xu, Chuanliang; Guo, Jianming; Du, Mulong; Chen, Jianhua; Song, Zhijian; Yin, Changjun; Qin, Chao; Gu, Chengyuan; Zhu, Yao; Xia, Guowei; Liu, Fang; Zhang, Zhengsheng; Yuan, Lin; Fu, Guangbo; Hu, Zhibin; Tong, Na; Shen, Jiawei; Liu, Ke; Sun, Jielin; Sun, Yinghao; Li, Jue; Li, Xingwang; Shen, Hongbing; Xu, Jianfeng; Shi, Yongyong; Zhang, Zhengdong

    2016-06-01

    Genome-wide association studies (GWAS) of bladder cancer have identified a number of susceptibility loci in European populations but have yet to uncover the genetic determinants underlying bladder cancer incidence among other ethnicities. Therefore, we performed the first GWAS in a Chinese cohort comprising 3,406 cases of bladder cancer and 4,645 controls. We identified a new susceptibility locus for bladder cancer at 5q12.3, located in the intron of CWC27 (rs2042329), that was significantly associated with disease risk (OR = 1.40; P = 4.61 × 10(-11)). However, rs2042329 was not associated with bladder cancer risk in patients of European descent. The rs2042329 risk allele was also related to significantly increased expression levels of CWC27 mRNA and protein in bladder cancer tissues from Chinese patients. Additional functional analyses suggested that CWC27 played an oncogenic role in bladder cancer by inducing cell proliferation and suppressing apoptosis. In conclusion, the identification of a risk-associated locus at 5q12.3 provides new insights into the inherited susceptibility to bladder cancer in Chinese populations and may help to identify high-risk individuals. Cancer Res; 76(11); 3277-84. ©2016 AACR. PMID:27206850

  4. 5q14.3 deletion neurocutaneous syndrome: Contiguous gene syndrome caused by simultaneous deletion of RASA1 and MEF2C: A progressive disease.

    PubMed

    Ilari, Rita; Agosta, Guillermo; Bacino, Carlos

    2016-03-01

    We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder. PMID:26774077

  5. Identification of a Potential Regulatory Variant for Colorectal Cancer Risk Mapping to Chromosome 5q31.1: A Post-GWAS Study

    PubMed Central

    Ke, Juntao; Lou, Jiao; Chen, Xueqin; Li, Jiaoyuan; Liu, Cheng; Gong, Yajie; Yang, Yang; Zhu, Ying; Zhang, Yi; Gong, Jing

    2015-01-01

    Large-scale genome-wide association studies (GWAS) have established chromosome 5q31.1 as a susceptibility locus for colorectal cancer (CRC), which was still lack of causal genetic variants. We searched potentially regulatory single nucleotide polymorphisms (SNPs) in the overlap region between linkage disequilibrium (LD) block of 5q31.1 and regulatory elements predicted by histone modifications, then tested their association with CRC via a case-control study. Among three candidate common variants, we found rs17716310 conferred significantly (heterozygous model: OR = 1.273, 95% confidence interval (95%CI) = 1.016–1.595, P = 0.036) and marginally (dominant model: OR = 1.238, 95%CI = 1.000–1.532, P = 0.050) increase risk for CRC in a Chinese population including 695 cases and 709 controls. This variation was suggested to be regulatory altering the activity of enhancer that control PITX1 expression. Using epigenetic information such as chromatin immunoprecipitation-sequencing (ChIP-seq) data might help researchers to interpret the results of GWAS and locate causal variants for diseases in post-GWAS era. PMID:26381143

  6. A physical map of 15 loci on human chromosome 5q23-q33 by two-color fluorescence in situ hybridization

    SciTech Connect

    Saltman, D.L.; Dolganov, G.M. ); Warrington, J.A.; Wasmuth, J.J. ); Lovett, M. )

    1993-06-01

    The q23-q33 region of human chromosome 5 encodes a large number of growth factors, growth factor receptors, and hormone/neurotransmitter receptors. This is also the general region into which several disease genes have been mapped, including diastrophic dysplasia, Treacher Collins syndrome, hereditary startle disease, the myeloid disorders that are associated with the 5q-syndrome, autosomal-dominant forms of hereditary deafness, and limb girdle muscular dystrophy. The authors have developed a framework physical map of this region using cosmid clones isolated from the Los Alamos arrayed chromosome 5-specific library. Entry points into this library included 14 probes to genes within this interval and one anonymous polymorphic marker locus. A physical map has been constructed using fluorescence in situ hybridization of these cosmids on metaphase and interphase chromosomes, and this is in good agreement with the radiation hybrid map of the region. The derived order of loci across the region is cen-IL4-IL5-IRF1-IL3-IL9-EGR1-CD14-FGFA-GRL-D5S207-ADRB2-SPARC-RPS14-CSF1R-ADRA1, and the total distance spanned by these loci is approximately 15 Mb. The framework map, genomic clones, and contig expansion within 5q23-q33 should provide valuable resources for the eventual isolation of the clinically relevant loci that reside in this region. 31 refs., 3 figs., 2 tabs.

  7. Narrowing the position of the Treacher Collins syndrome locus to a small interval between three new microsatellite markers at 5q32-33. 1

    SciTech Connect

    Dixon, M.J.; Dixon, J. ); Houseal, T.; Klinger, K.; Landes, G.M. ); Bhatt, M.; Ward, D.C. )

    1993-05-01

    Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCOF1 locus has been localized to chromosome 5q32-33.2. In the present study the authors have used the combined techniques of genetic linkage analysis and fluorescence in situ hybridization (FISH) to more accurately define the TCOF1 critical region. Cosmids IG90 and SPARC, which map to distal 5q, encompass two and one hypervariable microsatellite markers, respectively. The heterozygosity values of these three markers range from .72 to .81. Twenty-two unrelated TCOF1 families have been analyzed for linkage to these markers. There is strong evidence demonstrating linkage to all three markers, the strongest support for positive linkage being provided by haplotyping those markers at the locus encompassed by the cosmid IG90 (Z[sub max]= 19.65; 0 = .010). FISH to metaphase chromosomes and interphase nuclei established that IG90 lies centromeric to SPARC. This information combined with the data generated by genetic linkage analysis demonstrated that the TCOF1 locus is closely flanked proximally by IG90 and distally by SPARC. 30 refs., 2 figs., 4 tabs.

  8. Vrp1p-Las17p interaction is critical for actin patch polarization but is not essential for growth or fluid phase endocytosis in S. cerevisiae.

    PubMed

    Wong, Ming Hwa; Meng, Lei; Rajmohan, Rajamuthiah; Yu, Shangjuan; Thanabalu, Thirumaran

    2010-12-01

    Vrp1p (yeast WIP) forms a protein complex with Las17p (yeast WASP), however the physiological significance of the interaction has not been fully characterized. Vrp1p residues, (788)MPKPR(792) are essential for Vrp1p-Las17p interaction. While C-Vrp1p(364-817) complements all the defects of the vrp1Δ strain, C-Vrp1p(364-817)(5A) ((788)AAAAA(792)) does not complement any of the defects, due to its inability to localize to cortical patches. Targeting C-Vrp1p(364-817)(5A) to membranes using CAAX motif (C-Vrp1p(364-817)(5A)-CAAX) rescued the growth and endocytosis defect but not the actin patch polarization defect of vrp1Δ. Vrp1p can localize to cortical patches, either by binding to Las17p through LBD (Las17 Binding Domain, Vrp1p(760-817)) or independent of Las17p through residues in N-Vrp1p(1-364). Unlike Vrp1p, Vrp1p(5A) localizes poorly to cortical patches and complements all the defects of vrp1Δ strain except actin patch polarization at elevated temperature. N-Vrp1p(1-364) complements all the defects of vrp1Δ strain except the actin patch polarization defect while N-Vrp1p(1-364)-LBD fusion protein complements all the defects. Thus our results show that while both Vrp1p and Las17p are essential for many cellular processes, the two proteins do not necessarily have to bind to each other to carry out these cellular functions. However, Las17p-Vrp1p interaction is essential for actin patch polarization at elevated temperature. PMID:20816901

  9. Monitoring Observations of the Jupiter-Family Comet 17P/Holmes during its 2014 Perihelion Passage

    NASA Astrophysics Data System (ADS)

    Kwon, Yuna Grace; Ishiguro, Masateru; Hanayama, Hidekazu; Kuroda, Daisuke; Honda, Satoshi; Takahashi, Jun; Kim, Yoonyoung; Lee, Myung Gyoon; Choi, Young-Jun; Kim, Myung-Jin; Vaubaillon, Jeremie J.; Miyaji, Takeshi; Yanagisawa, Kenshi; Yoshida, Michitoshi; Ohta, Kouji; Kawai, Nobuyuki; Fukushima, Hideo; Watanabe, Jun-ichi

    2016-02-01

    We performed a monitoring observation of a Jupiter-family comet, 17P/Holmes, during its 2014 perihelion passage to investigate its secular change in activity. The comet has drawn the attention of astronomers since its historic outburst in 2007, and this occasion was its first perihelion passage since then. We analyzed the obtained data using an aperture photometry package and derived the {Af}ρ parameter, a proxy for the dust-production rate. We found that {Af}ρ showed asymmetric properties with respect to the perihelion passage: it increased moderately from 100 cm at the heliocentric distance of rh = 2.6-3.1 AU to a maximal value of 185 cm at rh = 2.2 AU (near the perihelion) during the inbound orbit, while dropping rapidly to 35 cm at rh = 3.2 AU during the outbound orbit. We applied a model for characterizing dust-production rates as a function of rh and found that the fractional active area of the cometary nucleus had dropped from 20%-40% in 2008-2011 (around the aphelion) to 0.1%-0.3% in 2014-2015 (around the perihelion). This result suggests that a dust mantle would have developed rapidly in only one orbital revolution around the Sun. Although a minor eruption was observed on UT 2015 January 26 at rh = 3.0 AU, the areas excavated by the 2007 outburst would be covered with a layer of dust (≲10 cm depth) which would be enough to insulate the subsurface ice and to keep the nucleus in a state of low activity.

  10. Genomic losses at 5q13.2 and 8p23.1 in dysplastic hepatocytes are common events in hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    ZHAO, ZHANG; CHEN, GUANG-YONG; LONG, JIANG; LI, HAI; HUANG, JIAN

    2015-01-01

    Chromosomal loci with genomic imbalances are frequently identified in hepatocellular carcinoma (HCC). Greater than two-thirds of hepatitis B virus (HBV)-related HCCs originate from liver cirrhosis following a duration of up to two decades. However, it is unclear whether these genomic imbalances occur and accumulate in dysplastic hepatocytes of the cirrhotic liver during the progression from regenerated nodules to preneoplastic lesions, including dysplastic nodules (DN). In the present study, high-grade DNs (HGDNs) of HBV-related liver cirrhosis were screened to identify loci with genomic imbalances, and the frequency of the identified loci in a group of HCCs was analyzed in order to determine whether there may be a genetic link between liver cirrhosis and HCC. Genomic DNA was extracted from six HGDNs of two cases of HBV-related liver cirrhosis and subjected to array comparative genomic hybridization (CGH) analysis with a NimbleGen 720K microarray. Loci with the most frequently observed genomic imbalances in DNs were further analyzed in 83 cases of HCC by differential polymerase chain reaction (PCR) and quantitative PCR. The array CGH analysis revealed that the majority of genomic imbalances in the HGDNs were genomic losses of small segments, with loss of heterozygosity (LOH) at 5q13.2 and 8p23.1 identified most frequently. Of the 83 HCC cases, 30 (36.1%) cases were identified with LOH at 5q13.2, where known tumor-associated genes are located, including general transcription factor IIH subunit 2 (GTF2H2), baculoviral IAP repeat-containing protein 1 (BIRC1) and occludin (OCLN). LOH frequency at 8p23.1 in HCC was 61.29% (D8S1130) and 68.4% (D8S503) respectively, similar to the results obtained in previous studies. In conclusion, the results of the present study provided evidence that genomic losses at 5q13.2 and 8p23.1 identified in dysplastic hepatocytes of the cirrhotic liver are common events in HCC. HCC-associated chromosomal abnormalities may occur and accumulate

  11. L-Leucine improves the anaemia in models of Diamond Blackfan anaemia and the 5q- syndrome in a TP53-independent way.

    PubMed

    Narla, Anupama; Payne, Elspeth M; Abayasekara, Nirmalee; Hurst, Slater N; Raiser, David M; Look, A Thomas; Berliner, Nancy; Ebert, Benjamin L; Khanna-Gupta, Arati

    2014-11-01

    Haploinsufficiency of ribosomal proteins (RPs) and upregulation of the tumour suppressor TP53 have been shown to be the common basis for the anaemia observed in Diamond Blackfan anaemia and 5q- myelodysplastic syndrome. We previously demonstrated that treatment with L-Leucine resulted in a marked improvement in anaemia in disease models. To determine if the L-Leucine effect was Tp53-dependent, we used antisense MOs to rps19 and rps14 in zebrafish; expression of tp53 and its downstream target cdkn1a remained elevated following L-leucine treatment. We confirmed this observation in human CD34+ cells. L-Leucine thus alleviates anaemia in RP-deficient cells in a TP53-independent manner. PMID:25098371

  12. Interferometric mapping of the 3.3-mm continuum emission of comet 17P/Holmes after its 2007 outburst

    NASA Astrophysics Data System (ADS)

    Boissier, J.; Bockelée-Morvan, D.; Biver, N.; Crovisier, J.; Lellouch, E.; Moreno, R.; Zakharov, V.

    2012-06-01

    Context. Comet 17P/Holmes underwent a dramatic outburst in October 2007, caused by the sudden fragmentation of its nucleus and the production of a large quantity of grains scattering sunlight. Aims: We report on 90 GHz continuum observations carried out with the IRAM Plateau de Bure interferometer on 27.1 and 28.2 October 2007 UT, i.e., 4-5 days after the outburst. These observations probed the thermal radiation of large dust particles, and therefore provide the best constraints on the mass in the ejecta debris. Methods: The thermal emission of the debris was modelled and coupled to a time-dependent description of their expansion after the outburst. The analysis was performed in the Fourier plane. Visibilities were computed for the two observing dates and compared to the data to measure their velocity and mass. Optical data and 250-GHz continuum measurements published in the literature were used to further constrain the dust kinematics and size distribution. Results: Two distinct dust components in terms of kinematic properties are identified in the data. The large-velocity component, with typical velocities V0 of 50-100 m s-1 for 1 mm particles, displays a steep size distribution with a size index estimated to q = -3.7 (±0.1), assuming a minimum grain size of 0.1 μm. It corresponds to the fast expanding shell observed in optical images. The slowly-moving "core" component (V0 = 7-9 m s-1) detected near the nucleus has a size index |q| < 3.4 and contains a higher proportion of large particles than the shell. The dust mass in the core is in the range 0.1-1 that of the shell. Using optical constants pertaining to porous grains (50% porosity) made of astronomical silicates mixed with water ice (48% in mass), the total dust mass Mdust injected by the outburst is estimated to 4-14 × 1011 kg, corresponding to 3-9% the nucleus mass. Based on observations carried out with the IRAM Plateau de Bure Interferometer. IRAM is supported by INSU/CNRS (France), MPG (Germany) and

  13. THE LONG-TERM DECAY IN PRODUCTION RATES FOLLOWING THE EXTREME OUTBURST OF COMET 17P/HOLMES

    SciTech Connect

    Schleicher, David G.

    2009-10-15

    Numerous sets of narrowband filter photometry were obtained of Comet 17P/Holmes from Lowell Observatory during the interval of 2007 November 1 to 2008 March 5. Observations began 8 days following its extreme outburst, at which time the derived water production rate, based on OH measurements, was 5 x 10{sup 29} molecule s{sup -1} and the derived proxy of dust production, A({theta})f{rho}, was about 5 x 10{sup 5} cm. Relative production rates for the other gas species, CN, C{sub 2}, C{sub 3}, and NH, are consistent with 'typical' composition (based on our update to the classifications by A'Hearn et al.). An exponential decay in the logarithm of measured production rates as a function of time was observed for all species, with each species dropping by factors of about 200-500 after 125 days. All gas species exhibited clear trends with aperture size, and these trends are consistent with larger apertures having a greater proportion of older material that was released when production rates were higher. Much larger aperture trends were measured for the dust, most likely because the dust grains have smaller outflow velocities and longer lifetimes than the gas species; therefore, a greater proportion of older, i.e., higher production dust is contained within a given aperture. By extrapolating to a sufficiently small aperture size, we derive near-instantaneous water and dust production rates throughout the interval of observation, and also estimate values immediately following the outburst. The finite lifetime of the gas species requires that much higher ice vaporization rates were taking place throughout the observation interval than occurred prior to the outburst, likely due to the continued release of icy grains from the nucleus. The relatively small aperture trends for the gas species also imply that the bulk of fresh, excess volatiles are confined to the nucleus and near-nucleus regime, rather than being associated with the outburst ejecta cloud. A minimum of about 0

  14. Increased support for linkage of a novel locus on chromosome 5q13 for essential hypertension in the British Genetics of Hypertension Study.

    PubMed

    Munroe, Patricia B; Wallace, Chris; Xue, Ming-Zhan; Marçano, Ana Carolina B; Dobson, Richard J; Onipinla, Abiodun K; Burke, Beverley; Gungadoo, Johannie; Newhouse, Stephen J; Pembroke, Janine; Brown, Morris; Dominiczak, Anna F; Samani, Nilesh J; Lathrop, Mark; Connell, John; Webster, John; Clayton, David; Farrall, Martin; Mein, Charles A; Caulfield, Mark

    2006-07-01

    Human hypertension arises from a combination of genetic factors and lifestyle influences. With cardiovascular disease set to become the number 1 cause of death worldwide, it is important to understand the etiologic mechanisms for hypertension, because these might provide new routes to improved treatment. The British Genetics of Hypertension Study has recently published a primary genome screen that identified 4 chromosomal regions of interest. We have now genotyped additional markers to confirm the most promising regions for follow-up studies. Thirty-four additional microsatellites were genotyped in our severely hypertensive affected sibling pair resource (now 1635 families with 2142 affected sibling pairs), leading to a substantial increase in information content in the regions of interest. We found increased support for linkage of chromosome 5q13 to human hypertension (multipoint logarithm of odds=2.50) with 3 adjacent markers yielding single point logarithm of odds scores of 3.22, 2.84, and 2.51. The placement of additional markers on 2q, 6q, and 9q diminished support for linkage in these regions. However, the addition of new data and families identified novel regions of interest on chromosomes 1q and 11q. The 3 positive markers in the chromosome 5 region were also genotyped in 712 distinct parent-offspring trios with the same severe phenotype to replicate linkage and association. Borderline support for replication was found (P=0.07). We found increased evidence for linkage and borderline-significant evidence for association for a hypertension susceptibility locus on chromosome 5q13 that is worthy of detailed fine mapping and assessment of candidate genes. PMID:16754790

  15. Genetic and physical mapping of the Treacher Collins syndrome locus with respect to loci in the chromosome 5q3 region

    SciTech Connect

    Jabs, E.W.; Li, Xiang; Coss, C.; Taylor, E. ); Lovett, M. ); Yamaoka, L.H.; Speer, M.C. ); Cadle, R.; Hall, B. ); Brown, K. )

    1993-10-01

    Treacher Collins syndrome is an autosomal dominant, craniofacial developmental disorder, and its locus (TCOF1) has been mapped to chromosome 5q3. To refine the location of the gene within this region, linkage analysis was performed among the TCOF1 locus and 12 loci (IL9, FGFA, GRL, D5S207, D5S210, D5S376, CSF1R, SPARC, D5S119, D5S209, D5S527, FGFR4) in 13 Treacher Collins syndrome families. The highest maximum lod score was obtained between loci TCOF1 and D5S210 (Z = 10.52; [theta] = 0.02 [+-] 0.07). The best order, IL9-GRL-D5S207/D5S210-CSF1R-SPARC-D5S119, and genetic distances among these loci were determined in the 40 CEPH families by multipoint linkage analysis. YAC clones were used to establish the order of loci, centromere-5[prime]GRL3[prime]-D5S207-D5S210-D5S376-CSF1R-SPARC-D5S119-telomere. By combining known physical mapping data with ours, the order of chromosome 5q3 markers is centomere-IL9-FGFA-5[prime]GRL3[prime]-D5s207-D5S210-D5S376-CSF1R-SPARC-D5S119-D5S209-FGFR4-telomere. Based on this order, haplotype analysis suggests that the TCOF1 locus resides distal CSF1R and proximal to SPARC within a region less than 1 Mb in size. 29 refs., 2 figs., 2 tabs.

  16. Molecular Analysis of the Retinoic Acid Induced 1 Gene (RAI1) in Patients with Suspected Smith-Magenis Syndrome without the 17p11.2 Deletion

    PubMed Central

    Vilboux, Thierry; Ciccone, Carla; Blancato, Jan K.; Cox, Gerald F.; Deshpande, Charu; Introne, Wendy J.; Gahl, William A.; Smith, Ann C. M.; Huizing, Marjan

    2011-01-01

    Smith-Magenis syndrome (SMS) is a complex neurobehavioral disorder characterized by multiple congenital anomalies. The syndrome is primarily ascribed to a ∼3.7 Mb de novo deletion on chromosome 17p11.2. Haploinsufficiency of multiple genes likely underlies the complex clinical phenotype. RAI1 (Retinoic Acid Induced 1) is recognized as a major gene involved in the SMS phenotype. Extensive genetic and clinical analyses of 36 patients with SMS-like features, but without the 17p11.2 microdeletion, yielded 10 patients with RAI1 variants, including 4 with de novo deleterious mutations, and 6 with novel missense variants, 5 of which were familial. Haplotype analysis showed two major RAI1 haplotypes in our primarily Caucasian cohort; the novel RAI1 variants did not occur in a preferred haplotype. RNA analysis revealed that RAI1 mRNA expression was significantly decreased in cells of patients with the common 17p11.2 deletion, as well as in those with de novo RAI1 variants. Expression levels varied in patients with familial RAI1 variants and in non-17p11.2 deleted patients without identified RAI1 defects. No correlation between SNP haplotype and RAI1 expression was found. Two clinical features, ocular abnormalities and polyembolokoilomania (object insertion), were significantly correlated with decreased RAI1 expression. While not significantly correlated, the presence of hearing loss, seizures, hoarse voice, childhood onset of obesity and specific behavioral aspects and the absence of immunologic abnormalities and cardiovascular or renal structural anomalies, appeared to be specific for the de novo RAI1 subgroup. Recognition of the combination of these features will assist in referral for RAI1 analysis of patients with SMS-like features without detectable microdeletion of 17p11.2. Moreover, RAI1 expression emerged as a genetic target for development of therapeutic interventions for SMS. PMID:21857958

  17. Assignment of CSF-1 to 5q33. 1: evidence for clustering of genes regulating hematopoiesis and for their involvement in the deletion of the long arm of chromosome 5 in myeloid disorders

    SciTech Connect

    Pettenati, M.J.; Le Beau, M.M.; Lemons, R.S.; Shima, E.A.; Kawasaki, E.S.; Larson, R.A.; Sherr, C.J.; Diaz, M.O.; Rowley, J.D.

    1987-05-01

    The CSF-1 gene encodes a hematopoietic colony-stimulating factor (CSF) that promotes growth, differentiation, and survival of mononuclear phagocytes. By using somatic cell hybrids and in situ hybridization, the authors localized this gene to human chromosome 5 at bands q31 to q35, a chromosomal region that is frequently deleted (del(5q)) in patients with myeloid disorders. By in situ hybridization, the CSF-1 gene was found to be deleted in the 5q- chromosome of a patient with refractory anemia who had a del(5) (q15q33.3) and in that of a second patient with acute nonlymphocytic leukemia de novo who had a similar distal breakpoint (del(5)(q13q33.3)). The gene was present in the deleted chromosome of a third patient, with therapy-related acute nonlymphocytic leukemia, who had a more proximal breakpoint in band q33 (del(5)(q22q33.1)). Hybridization of the CSF-1 probe to metaphase cells of a fourth patient, with acute nonlymphocytic leukemia de novo, who had a rearrangement of chromosomes 5 and 21 resulted in labeling of the breakpoint junctions of both rearranged chromosomes; this suggested that CSF-1 is located at 5q33.1. Thus, a small segment of chromosome 5 contains GM-CSF (the gene encoding the granulocyte-macrophage CSF), CSF-1, and FMS, which encodes the CSF-1 receptor, in that order from the centromere; this cluster of genes may be involved in the altered hematopoiesis associated with a deletion of 5q.

  18. Persistent photoconductivity in high resistive Zn3P2

    NASA Astrophysics Data System (ADS)

    Sierański, K.; Szatkowski, J.; Pawlikowski, J. M.

    2014-02-01

    Resistivity and photoconductivity of p-type Zn3P2 polycrystals grown by closed tube vapour transport method have been investigated. Persistent photoconductivity (PPC) has been observed at temperatures T < 200 K. At 77 K, the photoconduction persists for over 103 s after termination of the light. The PPC buildup and decay kinetics have been measured at 77 K and analyzed in the frame of large lattice-relaxed deep levels. We have determined the spectral dependence for the optical cross section and obtain an optical ionization energy of 0.83 eV.

  19. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

    PubMed Central

    Glubb, Dylan M.; Maranian, Mel J.; Michailidou, Kyriaki; Pooley, Karen A.; Meyer, Kerstin B.; Kar, Siddhartha; Carlebur, Saskia; O’Reilly, Martin; Betts, Joshua A.; Hillman, Kristine M.; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K.; Broeks, Annegien; Hogervorst, Frans B.; van der Schoot, C. Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A.; Ruebner, Matthias; Ekici, Arif B.; Beckmann, Matthias W.; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D.P.; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K.; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V.; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Wu, Anna H.; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O.; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M. Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Van Asperen, Christi J.; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J.; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W.M.; Collée, J. Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W.R.; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E.; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M. Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Brown, Melissa A.; Ponder, Bruce A.J.; Chenevix-Trench, Georgia; Thompson, Deborah J.; Edwards, Stacey L.; Easton, Douglas F.; Dunning, Alison M.; French, Juliet D.

    2015-01-01

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER+: odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21–1.27, ptrend = 5.7 × 10−44) and estrogen-receptor-negative (ER−: OR = 1.10, 95% CI = 1.05–1.15, ptrend = 3.0 × 10−4) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10−5]) and five variants composing iCHAV3 (lead rs11949391; ER+: OR = 0.90, 95% CI = 0.87–0.93, pcond = 1.4 × 10−4). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID:25529635

  20. Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.

    PubMed

    Glubb, Dylan M; Maranian, Mel J; Michailidou, Kyriaki; Pooley, Karen A; Meyer, Kerstin B; Kar, Siddhartha; Carlebur, Saskia; O'Reilly, Martin; Betts, Joshua A; Hillman, Kristine M; Kaufmann, Susanne; Beesley, Jonathan; Canisius, Sander; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Hogervorst, Frans B; van der Schoot, C Ellen; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Fasching, Peter A; Ruebner, Matthias; Ekici, Arif B; Beckmann, Matthias W; Peto, Julian; dos-Santos-Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Pharoah, Paul D P; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Yang, Rongxi; Surowy, Harald; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Arias Perez, Jose Ignacio; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Meindl, Alfons; Schmutzler, Rita K; Brauch, Hiltrud; Ko, Yon-Dschun; Brüning, Thomas; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tanaka, Hideo; Dörk, Thilo; Bogdanova, Natalia V; Helbig, Sonja; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; Lambrechts, Diether; Zhao, Hui; Weltens, Caroline; van Limbergen, Erik; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Seibold, Petra; Radice, Paolo; Peterlongo, Paolo; Barile, Monica; Capra, Fabio; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Teo, Soo Hwang; Yip, Cheng Har; See, Mee-Hoong; Cornes, Belinda; Cheng, Ching-Yu; Ikram, M Kamran; Kristensen, Vessela; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; García-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Klevebring, Daniel; Darabi, Hatef; Eriksson, Mikael; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Hall, Per; Li, Jingmei; Humphreys, Keith; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Shah, Mitul; Ghoussaini, Maya; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Tang, Anthony; Hamann, Ute; Torres, Diana; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Hou, Ming-Feng; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Brown, Melissa A; Ponder, Bruce A J; Chenevix-Trench, Georgia; Thompson, Deborah J; Edwards, Stacey L; Easton, Douglas F; Dunning, Alison M; French, Juliet D

    2015-01-01

    Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival. PMID:25529635

  1. The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

    SciTech Connect

    Kimura, Toshiyuki; Arakawa, Yoshiki; Inazawa, Johji

    1997-03-31

    Smith-Magenis syndrome (SAIS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to l7p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISH ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS. 27 refs., 2 figs.

  2. The yeast ubiquitin protease, Ubp3p, promotes protein stability.

    PubMed Central

    Brew, Christine T; Huffaker, Tim C

    2002-01-01

    Stu1p is a microtubule-associated protein required for spindle assembly. In this article we show that the temperature-sensitive stu1-5 allele is synthetically lethal in combination with ubp3, gim1-gim5, and kem1 mutations. The primary focus of this article is on the stu1-5 ubp3 interaction. Ubp3 is a deubiquitination enzyme and a member of a large family of cysteine proteases that cleave ubiquitin moieties from protein substrates. UBP3 is the only one of 16 UBP genes in yeast whose loss is synthetically lethal with stu1-5. Stu1p levels in stu1-5 cells are several-fold lower than the levels in wild-type cells and the stu1-5 temperature sensitivity can be rescued by additional copies of stu1-5. These results indicate that the primary effect of the stu1-5 mutation is to make the protein less stable. The levels of Stu1p are even lower in ubp3Delta stu1-5 cells, suggesting that Ubp3p plays a role in promoting protein stability. We also found that ubp3Delta produces growth defects in combination with mutations in other genes that decrease protein stability. Overall, these data support the idea that Ubp3p has a general role in the reversal of protein ubiquitination. PMID:12454057

  3. Products of the Benzene + O(3P) Reaction

    SciTech Connect

    Taatjes, Craig A.; Osborn, David L.; Selby, Talitha M.; Meloni, Giovanni; Trevitt, Adam J.; Epifanovsky, Evgeny; Krylov, Anna I.; Sirjean, Baptiste; Dames, Enoch; Wang, Hai

    2009-12-21

    The gas-phase reaction of benzene with O(3P) is of considerable interest for modeling of aromatic oxidation, and also because there exist fundamental questions concerning the prominence of intersystem crossing in the reaction. While its overall rate constant has been studied extensively, there are still significant uncertainties in the product distribution. The reaction proceeds mainly through the addition of the O atom to benzene, forming an initial triplet diradical adduct, which can either dissociate to form the phenoxy radical and H atom, or undergo intersystem crossing onto a singlet surface, followed by a multiplicity of internal isomerizations, leading to several possible reaction products. In this work, we examined the product branching ratios of the reaction between benzene and O(3P) over the temperature range of 300 to 1000 K and pressure range of 1 to 10 Torr. The reactions were initiated by pulsed-laser photolysis of NO2 in the presence of benzene and helium buffer in a slow-flow reactor, and reaction products were identified by using the multiplexed chemical kinetics photoionization mass spectrometer operating at the Advanced Light Source (ALS) of Lawrence Berkeley National Laboratory. Phenol and phenoxy radical were detected and quantified. Cyclopentadiene and cyclopentadienyl radical were directly identified for the first time. Finally, ab initio calculations and master equation/RRKM modeling were used to reproduce the experimental branching ratios, yielding pressure-dependent rate expressions for the reaction channels, including phenoxy + H, phenol, cyclopentadiene + CO, which are proposed for kinetic modeling of benzene oxidation.

  4. Photoinduced Kondo effect in CeZn3P3

    NASA Astrophysics Data System (ADS)

    Kitagawa, J.; Kitajima, D.; Shimokawa, K.; Takaki, H.

    2016-01-01

    The Kondo effect, which originates from the screening of a localized magnetic moment by a spin-spin interaction, is widely observed in nonartificial magnetic materials, artificial quantum dots, and carbon nanotubes. In devices based on quantum dots or carbon nanotubes that target quantum information applications, the Kondo effect can be tuned by a gate voltage, a magnetic field, or light. However, the manipulation of the Kondo effect in nonartificial materials has not been thoroughly studied; in particular, the artificial creation of the Kondo effect remains unexplored. Per this subject study, however, a route for the optical creation of the Kondo effect in the nonartificial material p -type semiconductor CeZn3P3 is presented. The Kondo effect emerges under visible-light illumination of the material by a continuous-wave laser diode and is ultimately revealed by photoinduced electrical resistivity, which clearly exhibits a logarithmic temperature dependency. By contrast, a La-based compound (LaZn3P3 ) displays only normal metallic behavior under similar illumination. The photoinduced Kondo effect, which occurs at higher temperatures when compared with the Kondo effect in artificial systems, provides a potential range of operation for not only quantum information/computation devices but also for operation of magneto-optic devices, thereby expanding the range of device applications based on the Kondo effect.

  5. Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems

    PubMed Central

    2012-01-01

    Background Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication. Methods We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization. Results We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted. Conclusions We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications. PMID:23035971

  6. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa

    SciTech Connect

    Kojis, T.L.; Heinzmann, C.; Ngo, J.T.

    1996-02-01

    In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families. 39 refs., 4 figs., 3 tabs.

  7. Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa.

    PubMed Central

    Kojis, T. L.; Heinzmann, C.; Flodman, P.; Ngo, J. T.; Sparkes, R. S.; Spence, M. A.; Bateman, J. B.; Heckenlively, J. R.

    1996-01-01

    In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families. PMID:8571961

  8. Dosage Changes of a Segment at 17p13.1 Lead to Intellectual Disability and Microcephaly as a Result of Complex Genetic Interaction of Multiple Genes

    PubMed Central

    Carvalho, Claudia M.B.; Vasanth, Shivakumar; Shinawi, Marwan; Russell, Chad; Ramocki, Melissa B.; Brown, Chester W.; Graakjaer, Jesper; Skytte, Anne-Bine; Vianna-Morgante, Angela M.; Krepischi, Ana C.V.; Patel, Gayle S.; Immken, LaDonna; Aleck, Kyrieckos; Lim, Cynthia; Cheung, Sau Wai; Rosenberg, Carla; Katsanis, Nicholas; Lupski, James R.

    2014-01-01

    The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO. PMID:25439725

  9. Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3 medulloblastoma tumor suppressor locus.

    PubMed

    Smith, J S; Tachibana, I; Allen, C; Chiappa, S A; Lee, H K; McIver, B; Jenkins, R B; Raffel, C

    1999-07-01

    Allelic loss of 17p13.3 is observed in approximately 40% of medulloblastomas, suggesting the presence of a tumor suppressor gene in this region. Deletion mapping has defined a region of common loss flanking the telomeric marker D17S34, and a recent report delineated a 9-kb homozygous deletion within the D17S34 locus in one such tumor. Using cDNA selection, we have identified a transcript spanning this deletion, designated (HSA)RPH3AL (rabphillin-3A-like), based on its 77% overall amino acid identity with a recently cloned rat gene, (RNO)Rph3al (originally termed Noc2), a gene putatively involved in regulated endocrine exocytosis through its interactions with the cytoskeleton. We determined the exon-intron boundaries of RPH3AL and screened the coding region for mutations by direct sequencing in DNA extracted from 33 tumor samples with allelic loss of 17p13, including 10 medulloblastoma, 14 follicular thyroid cancer (FTC), and 9 ovarian cancer specimens. No mutations were identified. Thus, despite its location in a homozygously deleted 17p13.3 locus, it is unlikely that RPH3AL is a gene involved in the oncogenesis of medulloblastoma, FTC, or ovarian cancer. PMID:10395805

  10. A new 17p13.3 microduplication including the PAFAH1B1 and YWHAE genes resulting from an unbalanced X;17 translocation.

    PubMed

    Hyon, Capucine; Marlin, Sandrine; Chantot-Bastaraud, Sandra; Mabboux, Philippe; Beaujard, Marie-Paule; Al Ageeli, Essam; Vazquez, Marie-Paule; Picard, Arnaud; Siffroi, Jean-Pierre; Portnoï, Marie-France

    2011-01-01

    Submicroscopic duplications of the genomic interval deleted in Miller-Dieker syndrome (MDS) were recently identified by array-based comparative genomic hybridization (a-CGH) studies, describing new genomic disorders in the MDS locus. These rearrangements of varying size, from 59-88 kb to 4 Mb, were non-recurrent, and appear to result from diverse molecular mechanisms. Only five patients had overlapping 17p13.3 duplications including the entire MDS critical region. We describe here a 13-year-old girl with a novel microduplication of the MDS critical region, involving the PAFAH1B1 and YWHAE genes. She presented with moderate psychomotor retardation, speech delay, behavioral problems, and bilateral cleft lip and palate, a previously unreported manifestation. Initially diagnosed as having an apparently simple terminal Xq26 deletion on standard cytogenetic analysis, she was found to have an associated terminal 4.2 Mb 17p13.3 submicroscopic duplication, identified by subtelomere FISH analysis, further characterized by high-resolution array CGH, resulting from an unbalanced X;17 translocation. Phenotypic comparison with the 5 other patients previously described, revealed common phenotypic features, such as hypotonia, mild to moderate developmental delay/mental retardation, speech abnormalities, behavioral problems, recurrent infections, relatively increase of body weight, discrete facial dysmorphism including downslanting palpebral fissures, broad midface, pointed chin, contributing to further delineate this new 17p13.3 microduplication syndrome. PMID:21195811

  11. Physical mapping of chromosome 17p13.3 in the region of a putative tumor suppressor gene important in medulloblastoma

    SciTech Connect

    McDonald, J.D.; Daneshvar, L.; Willert, J.R.

    1994-09-01

    Deletion mapping of a medulloblastoma tumor panel revealed loss of distal chromosome 17p13.3 sequences in tumors from 14 of 32 patients (44%). Of the 14 tumors showing loss of heterozygosity by restriction fragment length polymorphism analysis, 14 of 14 (100%) displayed loss of the telomeric marker p144-D6 (D17S34), while a probe for the ABR gene on 17p13.3 was lost in 7 of 8 (88%) informative cases. Using pulsed-field gel electrophoresis, we localized the polymorphic marker (VNTR-A) of the ABR gene locus to within 220 kb of the p144-D6 locus. A cosmid contig constructed in this region was used to demonstrate by fluorescence in situ hybridization that the ABR gene is oriented transcriptionally 5{prime} to 3{prime} toward the telomere. This report provides new physical mapping data for the ABR gene, which has not been previously shown to be deleted in medulloblastoma. These results provide further evidence for the existence of a second tumor suppressor gene distinct from p53 on distal chromosome 17p. 12 refs., 3 figs.

  12. Detection of classical 17p11.2 deletions, an atypical deletion and RAI1 alterations in patients with features suggestive of Smith–Magenis syndrome

    PubMed Central

    Vieira, Gustavo H; Rodriguez, Jayson D; Carmona-Mora, Paulina; Cao, Lei; Gamba, Bruno F; Carvalho, Daniel R; de Rezende Duarte, Andréa; Santos, Suely R; de Souza, Deise H; DuPont, Barbara R; Walz, Katherina; Moretti-Ferreira, Danilo; Srivastava, Anand K

    2012-01-01

    Smith–Magenis syndrome (SMS) is a complex disorder whose clinical features include mild to severe intellectual disability with speech delay, growth failure, brachycephaly, flat midface, short broad hands, and behavioral problems. SMS is typically caused by a large deletion on 17p11.2 that encompasses multiple genes including the retinoic acid induced 1, RAI1, gene or a mutation in the RAI1 gene. Here we have evaluated 30 patients with suspected SMS and identified SMS-associated classical 17p11.2 deletions in six patients, an atypical deletion of ∼139 kb that partially deletes the RAI1 gene in one patient, and RAI1 gene nonsynonymous alterations of unknown significance in two unrelated patients. The RAI1 mutant proteins showed no significant alterations in molecular weight, subcellular localization and transcriptional activity. Clinical features of patients with or without 17p11.2 deletions and mutations involving the RAI1 gene were compared to identify phenotypes that may be useful in diagnosing patients with SMS. PMID:21897445

  13. Methods of Reprogramming to Induced Pluripotent Stem Cell Associated with Chromosomal Integrity and Delineation of a Chromosome 5q Candidate Region for Growth Advantage.

    PubMed

    Sobol, Maria; Raykova, Doroteya; Cavelier, Lucia; Khalfallah, Ayda; Schuster, Jens; Dahl, Niklas

    2015-09-01

    Induced pluripotent stem cells (iPSCs) have brought great promises for disease modeling and cell-based therapies. One concern related to the use of reprogrammed somatic cells is the loss of genomic integrity and chromosome stability, a hallmark for cancer and many other human disorders. We investigated 16 human iPSC lines reprogrammed by nonintegrative Sendai virus (SeV) and another 16 iPSC lines generated by integrative lentivirus for genetic changes. At early passages we detected cytogenetic rearrangements in 44% (7/16) of iPSC lines generated by lentiviral integration whereas the corresponding figure was 6% (1/16) using SeV-based delivery. The rearrangements were numerical and/or structural with chromosomes 5 and 12 as the most frequently involved chromosomes. Three iPSC lines with chromosome 5 aberrations were derived from one and the same donor. We present in this study the aberrant karyotypes including a duplication of chromosome 5q13q33 that restricts a candidate region for growth advantage. Our results suggest that the use of integrative lentivirus confers a higher risk for cytogenetic abnormalities at early passages when compared to SeV-based reprogramming. In combination, our findings expand the knowledge on acquired cytogenetic aberrations in iPSC after reprogramming and during culture. PMID:25867454

  14. Reactions of atomic oxygen /O(3P)/ with polymer films

    NASA Technical Reports Server (NTRS)

    Golub, Morton A.

    1992-01-01

    The reactions of polymer films with oxygen atoms are reviewed focusing on laboratory tests on polybutadienes with different amount of 1,4 or 1,2 double bonds and their polyalkenamer homologues, polyimide (Kapton), and a series of polyolefines with increasing fluorine content. It is found that etch rates increase with decrease in -CH=CH- unsaturation, starting with 1,4 -polybutadiene and reaching the maximum rate with polyethylene or ethylene-propylene rubber. IN polybutadienes with both 1,4 and 1,2 double bonds, the rate of O(3P)-induced etching is lower the higher the 1,2 content. The reactions are confined to the polymer surface.

  15. Lenalidomide for the Treatment of Low- or Intermediate-1-Risk Myelodysplastic Syndromes Associated with Deletion 5q Cytogenetic Abnormality: An Evidence Review of the NICE Submission from Celgene.

    PubMed

    Blommestein, Hedwig M; Armstrong, Nigel; Ryder, Steve; Deshpande, Sohan; Worthy, Gill; Noake, Caro; Riemsma, Rob; Kleijnen, Jos; Severens, Johan L; Al, Maiwenn J

    2016-01-01

    The National Institute for Health and Care Excellence (NICE) invited the manufacturer of lenalidomide (Celgene) to submit evidence of the clinical and cost effectiveness of the drug for treating adults with myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic abnormality, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and the NICE's subsequent decisions. The ERG reviewed the evidence for clinical and cost effectiveness of the technology, as submitted by the manufacturer to the NICE. The ERG searched for relevant additional evidence and validated the manufacturer's decision analytic model to examine the robustness of the cost-effectiveness results. Clinical effectiveness was obtained from a three-arm, European, randomized, phase III trial among red blood cell (RBC) transfusion-dependent patients with low-/intermediate-1-risk del5q31 MDS. The primary endpoint was RBC independence for ≥26 weeks, and was reached by a higher proportion of patients in the lenalidomide 10 and 5 mg groups compared with placebo (56.1 and 42.6 vs 5.9 %, respectively; both p < 0.001). The option of dose adjustments after 16 weeks due to dose-limiting toxicities or lack of response made long-term effectiveness estimates unreliable, e.g. overall survival (OS). The de novo model of the manufacturer included a Markov state-transition cost-utility model implemented in Microsoft Excel. The base-case incremental cost-effectiveness ratio (ICER) of the manufacturer was £56,965. The ERG assessment indicated that the modeling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. In response to the appraisal documentation, the company revised the economic model

  16. Physical map, marker order, and YAC contig of an 11 cM region of 5q31 involved in myeloid leukemia and limb girdle muscular dystrophy

    SciTech Connect

    Horrigan, S.K.; Ramesar, R.S.; Yamaoka, L.H.

    1994-09-01

    Chromosome band 5q31 contains a large number of disease genes including those for limb girdle muscular dystrophy 1 (LGM1), an autosomal dominant form of hereditary deafness, corneal dystrophies, as well as a putative tumor suppressor gene involved in myelodysplastic syndrome/acute myeloid leukemia. To facilitate the identification of these genes, we prepared a YAC contig spanning the region from IL9 to D5S434. This was done with reference to a composite map consisting of markers which had been ordered physically by FISH, which was integrated with CEPH and CHLC markers that had been ordered genetically. These markers were used to screen the CEPH megaYAC library, and also to extract YACs from the CEPH-genethon physical map data base. YAC overlaps were used to confirm marker order and localize additional markers to the region. This YAC contig spans approximately 11 cM and contains 24 polymorphic microsatellite markers, 12 non-polymorphic STS markers and 6 known genes (including IL9, CDC25, EGR1, CD14, FGF1, GRL). A total of 51 YACs were isolated using these markers. YAC overlaps were identified by STS content and Alu-PCR hybridization. Thirty nine YACs fall within the minimum deleted region involved in acute myeloid leukemia (IL9 to D5S166 interval); these YACs were further used to order 10 microsatellite and 8 STS markers that had been regionally localized. This map and the new markers will be used to facilitate the search for candidate genes for the myeloid leukemia tumor suppressor and for LGM1.

  17. A Narrow and Highly Significant Linkage Signal for Severe Bipolar Disorder in the Chromosome 5q33 Region in Latin American Pedigrees

    PubMed Central

    Jasinska, A.J.; Service, S.; Jawaheer, D.; DeYoung, J.; Levinson, M.; Zhang, Z.; Kremeyer, B.; Muller, H.; Aldana, I.; Garcia, J.; Restrepo, G.; Lopez, C.; Palacio, C.; Duque, C.; Parra, M.; Vega, J.; Ortiz, D.; Bedoya, G.; Mathews, C.; Davanzo, P.; Fournier, E.; Bejarano, J.; Ramirez, M.; Ortiz, C. Araya; Araya, X.; Molina, J.; Sabatti, C.; Reus, V.; Ospina, J.; Macaya, G.; Ruiz-Linares, A.; Freimer, N.B.

    2016-01-01

    We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees. PMID:19319892

  18. A transcription map of the regions surrounding the CSF1R locus on human chromosome 5q31: Candidate genes for diastrophic dysplasia

    SciTech Connect

    Clines, G.; Lovett, M.

    1994-09-01

    Diastrophic dysplasia (DTD) is an autosomal recessive disorder of unknown pathogenesis that is characterized by abnormal skeletal and cartilage growth. Phenotypic characteristics of the disorder include short stature, scoliosis, and deformation of the first metacarpal. The diastrophic dysplasia gene has been localized to chromosome 5q31-33, within {approximately}60 kb of the colony stimulating factor 1 receptor gene (CSF1R). We have used direct cDNA selection to build a transcription map across {approximately}250 kb surrounding and including the CSF1R locus. cDNA pools from human placenta, activated T cells, cerebellum, Hela cells, fetal brain, chondrocytes, chondrosarcomas and osteosarcomas were multiplexed in these selections. After two rounds of selection, an analysis revealed that {approximately}70% of the selected cDNAs were contained within the contig. DNA sequencing and cosmid mapping data from a collection of 310 clones revealed the presence of three new genes in this region that show no appreciable homologies on sequence database searches, as well as cDNA clones from the CSF1R and the PDGFRB loci (another of the known genes in the region). An additional cDNA was found with 100% homology to the gene encoding human ribosomal protein L7 (RPL7). This cDNA comprised {approximately}25% of all selected clones. However, further analysis of the genomic contig revealed the presence of an RPL7 processed pseudogene in very close proximity to the CSF1R and PDGFRB genes. The selection of processed pseudogenes is one previously anticipated artifact of selection metholodolgies, but has not been previously observed. Mutational analysis of the three new genes is underway in diastrophic dysplasia families, as is derivation of full length cDNA clones and the expansion of this detailed transcription map into a larger genomic contig.

  19. A 1.5-Mb deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Pandolfo, M. |; Pareyson, D.; Sghirlanzoni, A.; Di Donato, S.; Roa, B.B.; Abbas, N.E.; Lupski, J.R.

    1995-01-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies. A 1.5-Mb deletion in chromosome 17p11.2-p12 has been associated with HNPP. Duplication of the same 1.5-Mb region is known to be associated with Charcot-Marie-Tooth disease type 1 (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity (NCV). The CMT1A duplication and HNPP deletion appear to be the reciprocal products of a recombination event involving a repeat element (CMT1A-REP) that flanks the 1.5-Mb region involved in the duplication/deletion. Patients from nine unrelated Italian families who were diagnosed with HNPP on the basis of clinical, electrophysiological, and histological evaluations were analyzed by molecular methods for DNA deletion on chromosome 17p. In all nine families, Southern analysis using a CMT1A-REP probe detected a reduced hybridization signal of a 6.0-kb EcoRI fragment mapping within the distal CMT1A-REP, indicating deletion of one copy of CMT1A-REP in these HNPP patients. Families were also typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125, and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, providing an independent indication for deletion. Furthermore, pulsed-field gel electrophoresis analysis of SacII-digested genomic DNA detected junction fragments specific to the 1.5-Mb HNPP deletion in seven of nine Italian families included in this study. These findings suggest that a 1.5-Mb deletion on 17p11.2-p12 is the most common mutation associated with HNPP. 51 refs., 5 figs., 1 tab.

  20. microRNA fingerprinting of CLL patients with chromosome 17p deletion identify a miR-21 score that stratifies early survival

    PubMed Central

    Rossi, Simona; Shimizu, Masayoshi; Barbarotto, Elisa; Nicoloso, Milena S.; Dimitri, Federica; Sampath, Deepa; Fabbri, Muller; Lerner, Susan; Barron, Lynn L.; Rassenti, Laura Z.; Jiang, Li; Xiao, Lianchun; Hu, Jianhua; Secchiero, Paola; Zauli, Giorgio; Volinia, Stefano; Negrini, Massimo; Wierda, William; Kipps, Thomas J.; Plunkett, William; Coombes, Kevin R.; Abruzzo, Lynne V.

    2010-01-01

    Aberrant expression of microRNAs (miRNAs) has been associated with clinical outcome in patients with chronic lymphocytic leukemia (CLL). To identify a powerful and easily assessable miRNA bio-marker of prognosis and survival, we performed quantitative reverse-transcription polymerase chain reaction (qRT-PCR) profiling in 104 CLL patients with a well-defined chromosome 17p status, and we validated our findings with miRNA microarray data from an independent cohort of 80 patients. We found that miR-15a, miR-21, miR-34a, miR-155, and miR-181b were differentially expressed between CLLs with chromosome 17p deletion and CLLs with normal 17p and normal karyotype, and that miR-181b was down-regulated in therapy-refractory cases. miR-21 expression levels were significantly higher in patients with poor prognosis and predicted overall survival (OS), and miR-181b expression levels significantly predicted treatment-free survival. We developed a 21FK score (miR-21 qRT-PCR, fluorescence in situ hybridization, Karyotype) to stratify patients according to OS and found that patients with a low score had a significantly longer OS time. When we evaluated the relative power of the 21FK score with the most used prognostic factors, the score was the most significant in both CLL cohorts. We conclude that the 21FK score represents a useful tool for distinguishing between good-prognosis and poor-prognosis CLL patients. PMID:20393129

  1. Verprolin function in endocytosis and actin organization. Roles of the Las17p (yeast WASP)-binding domain and a novel C-terminal actin-binding domain.

    PubMed

    Thanabalu, Thirumaran; Rajmohan, Rajamuthiah; Meng, Lei; Ren, Gang; Vajjhala, Parimala R; Munn, Alan L

    2007-08-01

    Vrp1p (verprolin, End5p) is the yeast ortholog of human Wiskott-Aldrich syndrome protein (WASP)-interacting protein (WIP). Vrp1p localizes to the cortical actin cytoskeleton, is necessary for its polarization to sites of growth and is also essential for endocytosis. At elevated temperature, Vrp1p becomes essential for growth. A C-terminal Vrp1p fragment (C-Vrp1p) retains the ability to localize to the cortical actin cytoskeleton and function in actin-cytoskeleton polarization, endocytosis and growth. Here, we demonstrate that two submodules in C-Vrp1p are required for actin-cytoskeleton polarization: a novel C-terminal actin-binding submodule (CABS) that contains a novel G-actin-binding domain, which we call a verprolin homology 2 C-terminal (VH2-C) domain; and a second submodule comprising the Las17p-binding domain (LBD) that binds Las17p (yeast WASP). The LBD localizes C-Vrp1p to membranes and the cortical actin cytoskeleton. Intriguingly, the LBD is sufficient to restore endocytosis and growth at elevated temperature to Vrp1p-deficient cells. The CABS also restores these functions, but only if modified by a lipid anchor to provide membrane association. Our findings highlight the role of Las17p binding for Vrp1p membrane association, suggest general membrane association may be more important than specific targeting to the cortical actin cytoskeleton for Vrp1p function in endocytosis and cell growth, and suggest that Vrp1p binding to individual effectors may alter their physiological activity. PMID:17635585

  2. IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

    PubMed Central

    2012-01-01

    Background Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed. Methods Overall survival and time to treatment in 620 untreated CLL patients were analyzed retrospectively to evaluate the multivariate independence and predictive power of mutational status of immunoglobulin heavy chain variable gene segments (IGHV), high-risk chromosomal aberration such as 17p or 11q deletions, CD38 and ZAP-70 expression, age, gender, Binet stage, β2-microglobulin levels, absolute lymphocyte count and number of lymph node regions. Results IGHV mutational status and 17p deletion were the sole biological variables with independent prognostic relevance in a multivariate model for overall survival, which included easily measurable clinical parameters (Binet staging, β2-microglobulin levels) and demographics (age and gender). Analysis of time to treatment in Binet A patients below 70 years of age showed that IGHV was the most important predictor. A novel 6-variable clinical-biological prognostic index was developed and internally validated, which assigned 3 points for Binet C stage, 2 points/each for Binet B stage and for age > 65 years, 1 point/each for male gender, high β2-microglobulin levels, presence of an unmutated IGHV gene status or 17p deletion. Patients were classified at low-risk (score = 0-1; 21%), intermediate-risk (score 2-5; 63% of cases), high-risk (score 6-9; 16% of cases). Projected 5-year overall survival was 98%, 90% and 58% in low-, intermediate- and high-risk groups, respectively. A nomogram for individual patient survival estimation was also proposed. Conclusions Data indicate that IGHV mutational status and 17p deletion may be integrated with clinical

  3. The Putative Exchange Factor Gef3p Interacts with Rho3p GTPase and the Septin Ring during Cytokinesis in Fission Yeast*

    PubMed Central

    Muñoz, Sofía; Manjón, Elvira; Sánchez, Yolanda

    2014-01-01

    The small GTP-binding proteins of the Rho family and its regulatory proteins play a central role in cytokinetic actomyosin ring assembly and cytokinesis. Here we show that the fission yeast guanine nucleotide exchange factor Gef3p interacts with Rho3p at the division site. Gef3p contains a putative DH homology domain and a BAR/IMD-like domain. The protein localized to the division site late in mitosis, where it formed a ring that did not constrict with actomyosin ring (cytokinetic actomyosin ring) invagination; instead, it split into a double ring that resembled the septin ring. Gef3p co-localized with septins and Mid2p and required septins and Mid2p for its localization. Gef3p interacts physically with the GTP-bound form of Rho3p. Although Gef3p is not essential for cell separation, the simultaneous disruption of gef3+ and Rho3p-interacting proteins, such as Sec8p, an exocyst component, Apm1p, a subunit of the clathrin adaptor complex or For3p, an actin-polymerizing protein, yielded cells with strong defects in septation and polarity respectively. Our results suggest that interactions between septins and Rho-GEFs provide a new targeting mechanism for GTPases in cytokinesis, in this case probably contributing to Rho3p function in vesicle tethering and vesicle trafficking in the later steps of cell separation. PMID:24947517

  4. Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

    PubMed Central

    Ikram, M. Arfan; Wang, Jie Jin; Klein, Ronald; Klein, Barbara E. K.; Breteler, Monique M. B.; Cheung, Ning; Liew, Gerald; Mitchell, Paul; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert; de Jong, Paulus T. V. M.; van Duijn, Cornelia M.; Kao, Linda; Cheng, Ching-Yu; Smith, Albert Vernon; Glazer, Nicole L.; Lumley, Thomas; McKnight, Barbara; Psaty, Bruce M.; Jonasson, Fridbert; Eiriksdottir, Gudny; Aspelund, Thor; Harris, Tamara B.; Launer, Lenore J.; Taylor, Kent D.; Li, Xiaohui; Iyengar, Sudha K.; Xi, Quansheng; Sivakumaran, Theru A.; Mackey, David A.; MacGregor, Stuart; Martin, Nicholas G.; Young, Terri L.; Bis, Josh C.; Wiggins, Kerri L.; Heckbert, Susan R.; Hammond, Christopher J.; Andrew, Toby; Fahy, Samantha; Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.; Islam, F. M. Amirul; Rotter, Jerome I.; McAuley, Annie K.; Boerwinkle, Eric; Tai, E. Shyong; Gudnason, Vilmundur; Siscovick, David S.; Vingerling, Johannes R.; Wong, Tien Y.

    2010-01-01

    There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10−8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%–3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10−25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10−16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10−13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10−16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease. PMID

  5. Association between rs2431697 T allele on 5q33.3 and systemic lupus erythematosus: case-control study and meta-analysis.

    PubMed

    Tang, Zhao-Ming; Wang, Ping; Chang, Pan-Pan; Hasahya, Tony; Xing, Hui; Wang, Jin-Ping; Hu, Li-Hua

    2015-11-01

    rs2431697 is located on 5q33.3, between pituitary tumor-transforming gene 1 and miR-146a. Several studies have estimated the association between rs2431697 and systemic lupus erythematosus risk. However, the results were inconsistent. A case-control study was carried out to explore the association between rs2431697 and systemic lupus erythematosus risk in a central Chinese population. Meta-analyses combining present with previous studies were conducted to further explore the association. Our case-control study included 322 cases and 353 controls. rs2431697 T allele was associated with increased risk of systemic lupus erythematosus (odds ratios (ORs) = 1.461, 95% confidence intervals (CI) 1.091-1.957, P = 0.011). The association was stronger between T allele and the risk of anti-double-stranded DNA (dsDNA)-positive systemic lupus erythematosus (OR = 2.510, 95% CI 1.545-4.077, P < 0.001). The meta-analyses included 8648 systemic lupus erythematosus patients and 10947 controls. rs2431697 T allele had an overall OR of 1.262 (95% CI 1.205-1.323, P < 0.001) under fixed-effects model. After stratified by ethnicity, I (2) reduced from 24.3 to 0 %. T allele had an OR of 1.213 (95% CI 1.145-1.284, P < 0.001) in European descendant and 1.365 (95% CI 1.259-1.480, P < 0.001) in Asian under fixed-effects model. Data on women were also extracted, and T allele had an OR of 1.337 (95% CI 1.162-1.539, P < 0.001) under random-effects model. The pooled ORs were not influenced by each study in sensitivity analyses. There were no publication biases observed in these analyses. The results from our case-control study and the meta-analyses indicate that rs2431697 T allele significantly associates with the increased risk of systemic lupus erythematosus. PMID:26251230

  6. Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms.

    PubMed

    Wang, Ke-Sheng; Liu, Xuefeng; Zhang, Qunyuan; Wu, Long-Yang; Zeng, Min

    2012-04-01

    Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10(-4). The first best signal was rs770182 (p = 3.65 × 10(-6)) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10(-4) (p = 7.15 × 10(-6), 2.79 × 10(-5) and 4.93 × 10(-5), respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10(-4) in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10(-4) and 9.48 × 10(-5), respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10(-2)) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS. PMID:22072270

  7. Apparent mosaicism for del(17)(p11.2) ruled out by fluorescence in situ hybridization in a Smith-Magenis syndrome patient

    SciTech Connect

    Juyal, R.C.; Shaffer, L.G.; Lupski, J.R.; Greenberg, F.; Baldini, A.; Patel, P.I.

    1995-11-20

    Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome typically associated with a deletion of band p11.2 of human chromosome 17. Finucane et al. reported a 14-year-old boy with mild physical and behavior manifestations of SMS. No evidence for deletion was initially evident in 20 peripheral blood lymphocytes examined at 850 band level of resolution. Examination of metaphase chromosomes of skin fibroblasts showed a deletion of 17p11.2 in 25/25 cells examined which was consistent with the patient`s clinical manifestations of SMS. Subsequent examination of 25 cells from peripheral blood cultures indicated that 11% of cells harbored a deletion at 17p11.2, thus suggesting a mosaicism for the deletion. A third study of 20 peripheral blood lymphocytes examined at 550-850 band length resolution in a different laboratory, indicated that 13 cells had no apparent deletion, 4 cells had an apparent deletion and 3 cells were questionable. 7 refs.

  8. Genetic homogeneity in Sjoegren-Larsson syndrome: Linkage to chromosome 17p in families of different non-Swedish ethnic origins

    SciTech Connect

    Rogers, G.R.; Lee, M.; Compton, J.G.

    1995-11-01

    Sjoegren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Three United States families, three Egyptian families, and one Israeli Arab family were investigated for linkage of the SLS gene to a region of chromosome 17. Pairwise and multipoint linkage analysis with nine markers mapped the SLS gene to the same region of the genome as that reported in Swedish SLS pedigrees. Examination of recombinants by haplotype analysis showed that the gene lies in the region containing the markers D17S953, D17S805, D17S689, and D17S842. D17S805 is pericentromeric on 17p. Patients in two consanguineous Egyptian families were homozygous at the nine marker loci tested, and another patient from a third family was homozygous for eight of the nine, suggesting that within each of these families the region of chromosome 17 carrying the SLS gene is identical by descent. Linkage of the SLS gene to chromosome 17p in families of Arabic, mixed European, Native American, and Swedish descent provides evidence for a single SLS locus and should prove useful for diagnosis and carrier detection in worldwide cases. 25 refs., 4 figs., 1 tab.

  9. First Direct Measurement of the O17(p,γ)F18 Reaction Cross Section at Gamow Energies for Classical Novae

    NASA Astrophysics Data System (ADS)

    Scott, D. A.; Caciolli, A.; Di Leva, A.; Formicola, A.; Aliotta, M.; Anders, M.; Bemmerer, D.; Broggini, C.; Campeggio, M.; Corvisiero, P.; Elekes, Z.; Fülöp, Zs.; Gervino, G.; Guglielmetti, A.; Gustavino, C.; Gyürky, Gy.; Imbriani, G.; Junker, M.; Laubenstein, M.; Menegazzo, R.; Marta, M.; Napolitani, E.; Prati, P.; Rigato, V.; Roca, V.; Somorjai, E.; Salvo, C.; Straniero, O.; Strieder, F.; Szücs, T.; Terrasi, F.; Trezzi, D.

    2012-11-01

    Classical novae are important contributors to the abundances of key isotopes, such as the radioactive F18, whose observation by satellite missions could provide constraints on nucleosynthesis models in novae. The O17(p,γ)F18 reaction plays a critical role in the synthesis of both oxygen and fluorine isotopes, but its reaction rate is not well determined because of the lack of experimental data at energies relevant to novae explosions. In this study, the reaction cross section has been measured directly for the first time in a wide energy range Ec.m.≃200-370keV appropriate to hydrogen burning in classical novae. In addition, the Ec.m.=183keV resonance strength, ωγ=1.67±0.12μeV, has been measured with the highest precision to date. The uncertainty on the O17(p,γ)F18 reaction rate has been reduced by a factor of 4, thus leading to firmer constraints on accurate models of novae nucleosynthesis.

  10. Serum expression levels of microRNA-382-3p, −598-3p, −1246 and −184 in breast cancer patients

    PubMed Central

    FU, LUN; LI, ZHAOYUN; ZHU, JIE; WANG, PAN; FAN, GUANGMIN; DAI, YUECHU; ZHENG, ZHIBAO; LIU, YANG

    2016-01-01

    The purpose of the present study was to investigate the serum levels of microRNA (miRNA/miR)-382-3p, −598-3p, −1246 and −184 in breast cancer patients and to assess their feasibility as biomarkers for breast cancer screening. Serum samples were obtained from 100 breast cancer patients and 40 age-matched healthy control subjects in Taizhou Central Hospital (Taizhou, Zhejiang, China) between January 2013 and September 2014. The serum expression levels of miR-382-3p, −598-3p, −1246 and −184 were determined by stem-loop reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were drawn to evaluate the sensitivity and specificity of the serum miRNA expression levels for the screening of breast cancer. miR-382-3p and −1246 were significantly upregulated in the serum of the breast cancer patients, while miR-598-3p and −184 were significantly downregulated. The sensitivity and specificity to detect breast cancer were as follows: miR-382-3p, 52.0 and 92.5%; miR-598-3p, 95.0 and 85.0%; miR-1246, 93.0 and 75.0%; and miR-184, 87.5 and 71.0%, respectively. The expression levels of the four serum miRNAs were not correlated with the patients' clinical stage. In summary, miR-382-3p, −598-3p, −1246 and −184 are all involved in the development of breast cancer, and are promising biomarkers for breast cancer detection. PMID:27347136

  11. A Case of Concurrent Miller-Dieker Syndrome (17p13.3 Deletion) and 22q11.2 Deletion Syndrome.

    PubMed

    Atwal, Paldeep S; Macmurdo, C

    2015-12-01

    Features of Miller-Dieker syndrome (MDS, 17p13.3 deletion syndrome, LIS1-associated lissencephaly) include classic lissencephaly, microcephaly, cardiac malformations, growth restriction, and characteristic facial changes. Individuals with 22q11.2 deletion syndrome (DiGeorge syndrome or velocardiofacial syndrome) are known to have congenital cardiac malformations (in particular conotruncal defects), palatal abnormalities (especially velopharyngeal insufficiency), hypocalcemia, immune deficiency, learning disabilities, and characteristic facial features. This case report describes phenotypic characteristics of a patient with extremely rare instance of having both MDS and 22q11.2 deletion syndrome that is unique in the medical literature. Prognosis in this concurrent phenotype is poor with our patient suffering from several malformations seen in both conditions and expiring in the neonatal period. PMID:27617133

  12. Superior verbal ability and nonverbal learning disability in a child with a novel 17p12p13.1 deletion.

    PubMed

    Steele, D L; Chisholm, A K; McGhie, J D R; Gardner, R J M; Scheffer, I E; Slater, H R; Dawson, G

    2005-04-01

    We report the case of a 10-year-old girl with the karyotype 46,XX,del(17)(p12p13.1) who presented a remarkable incongruence in higher cerebral functioning. Certain language skills were very superior, with reading and spelling at a 17-19 year-old level of proficiency. Nonverbal skills, however, were mostly below average, executive functioning and socialization were impaired, and a diagnosis of "nonverbal learning disability" is applied. We speculate that the genes deleted include one or some which code for certain specific categories of neural substrate that subserve aspects of visual processing and higher functioning, but that no "language loci" have been deleted. The particular neuropsychological profile that we describe may assist diagnosis of this chromosomal deletion. PMID:15717294

  13. Microdeletion on 17p11.2 in a Smith-Magenis syndrome patient with mental retardation and congenital heart defect: first report from China.

    PubMed

    Huang, C; Yang, Y-F; Zhang, H; Xie, L; Chen, J-L; Wang, J; Tan, Z-P; Luo, H

    2012-01-01

    Smith-Magenis syndrome (SMS) is a rare syndrome with multiple congenital malformations, including development and mental retardation, behavioral problems and a distinct facial appearance. SMS is caused by haploinsufficiency of RAI1 (deletion or mutation of RAI1). We describe an eight-year-old female Chinese patient with multiple malformations, congenital heart defect, mental retardation, and behavioral problems (self hugging, sleeping disturbance). High-resolution genome wide single nucleotide polymorphism array revealed a 3.7-Mb deletion in chromosome region 17p11.2. This chromosome region contains RAI1, a critical gene involved in SMS. To the best of our knowledge, this is the first report of an SMS patient in mainland China. PMID:22911601

  14. MEF2C haploinsufficiency caused by either microdeletion of the 5q14.3 region or mutation is responsible for severe mental retardation with stereotypic movements, epilepsy and/or cerebral malformations

    PubMed Central

    Le Meur, Nathalie; Holder-Espinasse, Muriel; Jaillard, Sylvie; Goldenberg, Alice; Joriot, Sylvie; Amati-Bonneau, Patrizia; Guichet, Agnès; Barth, Magalie; Charollais, Aude; Journel, Hubert; Auvin, Stéphane; Boucher, Cécile; Kerckaert, Jean-Pierre; David, Véronique; Manouvrier-Hanu, Sylvie; Saugier-Veber, Pascale; Frébourg, Thierry; Dubourg, Christèle; Andrieux, Joris; Bonneau, Dominique

    2010-01-01

    Over the last few years, array-CGH has remarkably improved the ability to detect cryptic unbalanced rearrangements in patients presenting with syndromic mental retardation. Using whole genome oligonucleotide array-CGH, we detected 5q14.3 microdeletions ranging from 216 kb to 8.8 Mb in 5 unrelated patients showing phenotypic similarities, namely severe mental retardation with absent speech, hypotonia and stereotypic movements. Most of the patients presented also with facial dysmorphic features, epilepsy and/or cerebral malformations. The minimal common deleted region of these 5q14 microdeletions encompassed only MEF2C, known to act in brain as a neurogenesis effector which regulates excitatory synapse number. In a patient presenting a similar phenotype, we subsequently identified a MEF2C nonsense mutation. Taken together, these results strongly suggest that haploinsufficiency of MEF2C is responsible for severe mental retardation with stereotypic movements, seizures and/or cerebral malformations. PMID:19592390

  15. Refined mapping of the G[sub M2] activator protein (GM2A) locus to 5q31. 3-q33. 1, distal to the spinal muscular atrophy locus

    SciTech Connect

    Heng, H.H.Q.; Xie, B.; Shi, X.M.; Tsui, L.C.; Mahuran, D.J. )

    1993-11-01

    The G[sub M2] activator locus (GM2A) had previously been considered as a candidate gene for some forms of spinal muscular atrophy (SMA; mapped to 5q11.2-q13.3). It was eliminated as a possible candidate because PCR-based mapping failed to localize the gene to chromosome 5, as was previously reported using an ELISA-based methodology. However, the authors demonstrated that the PCR primers used preferentially amplified a processed pseudogene (GM2AP) that was mapped to chromosome 3 and that GM2A was located on chromosome 5. In this report, they reconsider the candidacy of GM2A by refining its localization on chromosome 5 using fluorescence in situ hybridization. They localize GM2A to 5q31.3-q33.1; thus, it is not a candidate gene for SMA. 11 refs., 2 figs.

  16. Bortezomib-based induction improves progression-free survival of myeloma patients harboring 17p deletion and/or t(4;14) and overcomes their adverse prognosis.

    PubMed

    El-Ghammaz, Amro M S; Abdelwahed, Essam

    2016-08-01

    Providing a risk-adapted treatment strategy has been a key goal in the ongoing research efforts aimed at providing treatment tailored to the individual genetic make-up. Eighty myeloma patients have been tested for presence of 17p deletion and/or t(4;14) by fluorescent in situ hybridization (FISH). Based on FISH results, they have been categorized into patients lacking them (standard risk) and those harboring them (high risk). Patients in each category were randomly assigned 1:1 to induction treatment by either vincristine, adriamycin and dexamethasone (VAD), or bortezomib and dexamethasone (VD) followed by autologous stem cell transplantation and thalidomide maintenance and were followed up for 32 months. 32.5 % of patients were high risk. Following induction, there were significantly higher rates of at least very good partial response achievement in VD arms in standard- and high-risk patients. Regarding complete response achievement, there were insignificant differences between VAD and VD arms in standard and high-risk patients. After a median follow-up of 17.5 months, there was insignificant difference in overall survival (OS) between VAD and VD arms in standard and high-risk patients. There was superior progression-free survival (PFS) in VD arms in standard- and high-risk patients. Among patients who received VD, those belonging to standard and high-risk groups had similar PFS. In conclusion, bortezomib-based induction is superior to non-bortezomib-based one in patients harboring 17p deletion and/or t(4;14) in terms of improving PFS but not OS. Also, it reduces progression risk in patients harboring these high risk cytogenetics. PMID:27184486

  17. Lip cancer and pre-cancerous lesions harbor TP53 mutations, exhibit allelic loss at 9p, 9q, and 17p, but no BRAFV600E mutations.

    PubMed

    Correa, Gefter Thiago Batista; Bernardes, Vanessa Fátima; de Sousa, Silvia Ferreira; Diniz, Marina Gonçalves; Salles, José Maria Porcaro; Souza, Renan Pedra; De-Paula, Alfredo Maurício Batista; Gomez, Ricardo Santiago; Gomes, Carolina Cavalieri

    2015-11-01

    Molecular mechanisms of lip squamous cell carcinoma (LSCC) and actinic cheilitis (AC) are unclear. We aimed at assessing loss of heterozygosity (LOH) and TP53 and BRAF V600E mutations in these lesions. Formalin-fixed paraffin-embedded (FFPE) samples of 17 LSCC and 16 AC were included, with additional 5 fresh LSCC genotyped for TP53 mutations. LOH was assessed by six polymorphic markers located at 9p22, 9q22, and 17p13 and correlated with cell proliferation (Ki-67) and P53 immunostaining. Direct sequencing of TP53 exons 2-11 (fresh samples), and exons 5-9 (FFPE samples) was carried out. BRAF V600E mutation was genotyped in eight LSCC. LOH occurred in at least one marker in 15/17 LSCC and in 9/16 AC. The marker exhibiting the highest frequency of allelic loss (FAL) in LSCC was D9S157 (8/12 informative cases) and D9S287 in AC (4/11 informative cases). Cell proliferation was not correlated with LOH or with the FAL and no correlation between P53 IHC and 17p LOH was observed. We found TP53 missense mutations in both lesions and nonsense in LSCC, including CC>TT transition, which is a marker of UV damage. BRAF V600E mutation was not detected. LOH and TP53 mutations detected in LSCC and AC may be associated with tumorigenesis, whereas BRAF V600E mutation does not seem to significantly contribute to LSCC pathogenesis. PMID:26084614

  18. A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53-Independent and p53-Dependent Mechanism of Erythroid Failure.

    PubMed

    Ear, Jason; Hsueh, Jessica; Nguyen, Melinda; Zhang, QingHua; Sung, Victoria; Chopra, Rajesh; Sakamoto, Kathleen M; Lin, Shuo

    2016-05-20

    5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q-deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP-011, L-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype. PMID:27216296

  19. Regulation of the formin for3p by cdc42p and bud6p.

    PubMed

    Martin, Sophie G; Rincón, Sergio A; Basu, Roshni; Pérez, Pilar; Chang, Fred

    2007-10-01

    Formins are conserved actin nucleators responsible for the assembly of diverse actin structures. Many formins are controlled through an autoinhibitory mechanism involving the interaction of a C-terminal DAD sequence with an N-terminal DID sequence. Here, we show that the fission yeast formin for3p, which mediates actin cable assembly and polarized cell growth, is regulated by a similar autoinhibitory mechanism in vivo. Multiple sites govern for3p localization to cell tips. The localization and activity of for3p are inhibited by an intramolecular interaction of divergent DAD and DID-like sequences. A for3p DAD mutant expressed at endogenous levels produces more robust actin cables, which appear to have normal organization and dynamics. We identify cdc42p as the primary Rho GTPase involved in actin cable assembly and for3p regulation. Both cdc42p, which binds at the N terminus of for3p, and bud6p, which binds near the C-terminal DAD-like sequence, are needed for for3p localization and full activity, but a mutation in the for3p DAD restores for3p localization and other phenotypes of cdc42 and bud6 mutants. In particular, the for3p DAD mutation suppresses the bipolar growth (NETO) defect of bud6Delta cells. These findings suggest that cdc42p and bud6p activate for3p by relieving autoinhibition. PMID:17699595

  20. An Efficient Bifunctional Decadentate Ligand 3p-C-DEPA for Targeted Alpha Radioimmunotherapy Applications

    PubMed Central

    Song, Hyun A; Kang, Chi Soo; Baidoo, Kwamena E.; Milenic, Diane E.; Chen, Yunwei; Dai, Anzhi; Brechbiel, M. W.; Chong, Hyun-Soon

    2011-01-01

    A new bifunctional ligand 3p-C-DEPA was synthesized and evaluated for use in targeted alpha radioimmunotherapy. 3p-C-DEPA was efficiently prepared via regiospecific ring opening of an aziridinium ion and conjugated with trastuzumab. The 3p-C-DEPA-trastuzumab conjugate was extremely rapid in binding 205/6Bi, and the corresponding 205/6Bi-3p-C-DEPA-trastuzumab complex was stable in human serum. Biodistribution studies were performed to evaluate in vivo stability and tumor targeting of 205/6Bi-3p-C-DEPA-trastuzumab conjugate in tumor bearing athymic mice. 205/6Bi-3p-C-DEPA-trastuzumab conjugate displayed excellent in vivo stability and targeting as evidenced by low organ uptake and high tumor uptake. The results of the in vitro and in vivo studies indicate that 3p-C-DEPA is a promising chelator for radioimmunotherapy of 212Bi and 213Bi. PMID:21604692

  1. Laser-spectroscopy measurement of the fine-structure splitting 2 3P1-2 3P2 of 4He

    NASA Astrophysics Data System (ADS)

    Feng, G.-P.; Zheng, X.; Sun, Y. R.; Hu, S.-M.

    2015-03-01

    Laser spectroscopy has been performed on a beam of neutral 4He atoms. By using transverse laser cooling and focusing, we are able to prepare a bright beam of atoms in the metastable state 2 3S1 deflected from the original effusive atomic beam. The initial state preparation is completed with optical pumping on the 2 3P1←2 3S1 transition at the wavelength of 1083 nm, followed by laser spectroscopy on the 2 3P1 ,2←2 3S1 transitions. The 2 3P1-2 3P2 fine-structure splitting is determined to be 2 291 177.69 ±0.36 kHz . The quantum interference effect is included in data extraction. This is the most precise laser spectroscopy measurement of the interval. Our result is in agreement with both the latest QED-based calculation and the most precise measurement conducted with microwave spectroscopy.

  2. Proximal chromosome 3p harbors a DNA segment frequently deleted in small cell lung cancer

    SciTech Connect

    Todd, S.; Drabkin, H.A.; Gemmill, R.M.

    1994-09-01

    Several lines of evidence suggest that potential tumor suppressor genes involved in small cell lung cancer (SCLC) reside at three separate locations on human chromosome 3p including 3p25, 3p21.3 and 3p14-cen. The most proximal region (3p14-cen) was first identified by a homozygous deletion of 7-10 Mb found in a SCLC cell line U2020. Daly et al. (1991) reported allele loss in a tumor sample from the 3p14-cen region in an SCLC tumor sample which retained heterozygosity distally and this same segment has been implicated in both sporadic and familial kidney cancer. Other evidence suggests that deletion of this proximal region may be an early event in SCLC development. Our analysis of 31 SCLC cell lines with 26 microsatellite repeat DNA markers (most of which fall into the region 3p14-cen) indicates that the majority of SCLC samples lose an entire copy of 3p. However, from those cell lines which retain distal heterozygosity, there is evidence for potential regions of loss in 3p13 and 3p14. Analysis of matched pairs of normal/tumor samples from SCLC patients has confirmed nearly complete loss of 3p in most cases and has provided further evidence of loss in the region 3p14-cen. All samples that retain heterozygosity at the distal markers are being analyzed with the complete set of 3p markers in order to refine the location of any potential tumor suppressor gene(s). This information along with the DNA contig physical map we have constructed of this portion of the chromosome should allow rapid isolation of potential tumor suppressor loci involved in SCLC and possibly other forms of cancer.

  3. A balanced t(5;17) (p15;q22-23) in chondroblastoma: frequency of the re-arrangement and analysis of the candidate genes

    PubMed Central

    2009-01-01

    Background Chondroblastoma is a benign cartilaginous tumour of bone that predominantly affects the epiphysis of long bones in young males. No recurrent chromosomal re-arrangements have so far been observed. Methods: We identified an index case with a balanced translocation by Combined Binary Ratio-Fluorescent in situ Hybridisation (COBRA-FISH) karyotyping followed by breakpoint FISH mapping and array-Comparative Genomic Hybridisation (aCGH). Candidate region re-arrangement and candidate gene expression were subsequently investigated by interphase FISH and immunohistochemistry in another 14 cases. Results A balanced t(5;17)(p15;q22-23) was identified. In the index case, interphase FISH showed that the translocation was present only in mononucleated cells and was absent in the characteristic multinucleated giant cells. The t(5;17) translocation was not observed in the other cases studied. The breakpoint in 5p15 occurred close to the steroid reductase 5α1 (SRD5A1) gene. Expression of the protein was found in all cases tested. Similar expression was found for the sex steroid signalling-related molecules oestrogen receptor alpha and aromatase, while androgen receptors were only found in isolated cells in a few cases. The breakpoint in 17q22-23 was upstream of the carbonic anhydrase × (CA10) gene region and possibly involved gene-regulatory elements, which was indicated by the lack of CA10 protein expression in the index case. All other cases showed variable levels of CA10 expression, with low expression in three cases. Conclusion We report a novel t(5;17)(p15;q22-23) translocation in chondroblastoma without involvement of any of the two chromosomal regions in other cases studied. Our results indicate that the characteristic multinucleated giant cells in chondroblastoma do not have the same clonal origin as the mononuclear population, as they do not harbour the same translocation. We therefore hypothesise that they might be either reactive or originate from a distinct

  4. A child with split-hand/foot associated with tibial hemimelia (SHFLD syndrome) and thrombocytopenia maps to chromosome region 17p13.3.

    PubMed

    Al Kaissi, Ali; Ganger, Rudolf; Rötzer, Katharina M; Klaushofer, Klaus; Grill, Franz

    2014-09-01

    We describe a-2-year-old boy who presented with a neonatal history of thrombocytopenia associated with a constellation of limb malformations mimicking split hand/foot malformation with long bone deficiency (SHFLD) syndrome. Limb malformations consisted of unilateral monodactyly with radial aplasia, unilateral split foot and bilateral club foot. Tibial aplasia of one limb and tibial hypoplasia of the other limb were notable. Partial agenesis of the sacrum was additional skeletal malformation. Craniofacial features included dense thick scalp hair, narrow frontal area, thick eye-brows, deep-set eyes, depressed nasal bridge, and small overhanging nasal tip, full-cheeks, and large ears. Array-CGH showed duplication of the short arm of chromosome 17p13.3 in the boy and his father, respectively. The father was free from any skeletal abnormalities, though he shares similar craniofacial dysmorphic features like his son. In addition, a paternal sib (uncle of the proband) manifested a phenotype similar to that of the proband. To the best of our knowledge the overall phenotypic and genotypic characterizations were consistent but not completely compatible with the traditional type of TAR syndrome or with SHFLD syndrome. We report on what might be a novel variant of SHFLD associated with transient thrombocytopenia, dysmorphic facial features, and a constellation of bone malformations. PMID:24838992

  5. Recurrent translocation t(10;17)(p15;q21) in minimally differentiated acute myeloid leukemia results in ZMYND11/MBTD1 fusion.

    PubMed

    de Rooij, Jasmijn D E; van den Heuvel-Eibrink, Marry M; Kollen, Wouter J W; Sonneveld, Edwin; Kaspers, Gertjan J L; Beverloo, H Berna; Fornerod, Maarten; Pieters, Rob; Zwaan, C Michel

    2016-03-01

    Pediatric acute myeloid leukemia (AML) is a heterogeneous disease, characterized by different collaborating karyotypic and molecular abnormalities, which are used in risk group stratification. In ∼20% of the pediatric AML cases a specific genetic aberration is still unknown. Minimally differentiated myeloid leukemia or FAB-type M0 is a rare morphological subtype of AML. The translocation t(10;17)(p15;q21) is described to be recurrent in minimally differentiated AML, but the involved genes and location of the breakpoints have so far not been identified. In this study, we show that this translocation results in an in-frame translocation fusing exon 12 of the tumor suppressor gene ZMYND11 to exon 3 of the chromatin protein MBTD1, encoding a protein of 1,054 amino acids, while the reciprocal fusion product is predicted to lack a productive start codon. Gene expression profiling of the leukemic cells showed high HOXA expression. ZMYND11, also known as BS69, is a tumor suppressor that specifically recognizes H3K36me3, which is linked to aberrant HOXA expression in leukemogenesis. Aberrant expression of the genes involved in this fusion may thus contribute to the HOXA-phenotype observed with gene expression profiling. PMID:26608508

  6. THE SEARCH FOR THE DIFFUSE INTERSTELLAR BANDS AND OTHER MOLECULES IN COMETS 17P (HOLMES) AND C/2007 W1 (BOATTINI)

    SciTech Connect

    O'Malia, K. K. J.; Snow, T. P.; Thorburn, J. A.; Hammergren, M.; Dembicky, J.; Hobbs, L. M.; York, D. G.

    2010-01-01

    We present the search for both diffuse interstellar bands (DIBs) and molecules in Comet 17P (Holmes) and Comet C/2007 W1 (Boattini) occultation observations. Absorption spectra were taken during stellar occultations by Comet Holmes of 31 and beta Persei, and the occultation of BD+22 216 by Comet Boattini. While no signature of the comets was detected, we present upper limits for some common cometary molecules such as C{sub 2}, C{sub 3}, CH, CN and for the most common DIBs. We did not detect either comet in absorption, most likely because of the large distance between the line of sight to the star and the nucleus of the comet. Interstellar sight lines with comparable reddening to what was measured in Comet Holmes have DIB equivalent widths between 5 and 50 mA. However, future observations with closer approaches to a background star have great potential for spatially mapping molecule distributions in comets, and in discovering DIBs, if they are present, in comets. Future observations could detect DIBs and molecules if they are done: (1) less than approx10{sup 4}-10{sup 3} km from the nucleus (2) with a signal to noise in the background star of approx300 and (3) with a resolving power of at least 38,000.

  7. Soft-tissue aneurysmal bone cyst with translocation t(17;17)(p13;q21) corresponding to COL1A1 and USP6 loci.

    PubMed

    Jacquot, Cyril; Szymanska, Jadwiga; Nemana, Lakshmi J; Steinbach, Lynne S; Horvai, Andrew E

    2015-11-01

    We present the case of a 46-year-old woman with no significant past medical history who developed left mid-thigh pain and fullness. Imaging demonstrated a mineralized soft-tissue mass, which increased in size during a year of monitoring, but retained a circumscribed appearance. The mass was located in the medial soft tissues of the thigh, separate from the bone on imaging studies, and this finding was confirmed during excision. The mass showed gross and microscopic features of an aneurysmal bone cyst. This diagnosis was supported by cytogenetic analysis revealing a t(17;17)(p13;q21) translocation corresponding to the USP6 and COL1A1 loci. Soft-tissue aneurysmal bone cyst is a rare entity, with fewer than 25 reports in the literature. Limited cytogenetic information about these tumors is available. To our knowledge, the USP6 and COL1A1 rearrangement has only previously been described in a pediatric soft-tissue aneurysmal bone cyst. We also discuss the differential diagnosis of ossifying soft-tissue lesions. PMID:26142538

  8. Subaru/COMICS Mid-Infrared Observation of the Near-Nucleus Region of Comet 17P/Holmes at the Early Phase of an Outburst

    NASA Astrophysics Data System (ADS)

    Watanabe, Jun-Ichi; Honda, Mitsuhiko; Ishiguro, Masateru; Ootsubo, Takafumi; Sarugaku, Yuki; Kadono, Toshihiko; Sakon, Itsuki; Fuse, Tetsuharu; Takato, Naruhisa; Furusho, Reiko

    2009-08-01

    Mid-infrared 8--25μm imaging and spectroscopic observations of the comet 17P/Holmes in the early phase of its outburst in brightness were performed on 2007 October 25--28UT using the Cooled Mid-Infrared Camera and Spectrometer (COMICS) on the 8.2-m Subaru Telescope. We detected an isolated dust cloud that moved toward the south-west direction from the nucleus. The 11.2μm peak of a crystalline silicate feature onto a broad amorphous silicate feature was also detected both in the central condensation of the nucleus and an isolated dust cloud. The color temperature of the isolated dust cloud was estimated to be ˜200K, which is slightly higher than the black-body temperature. Our analysis of the motion indicates that the isolated cloud moved anti-sunward. We propose several possibilities for the motion of the cloud: fluffy dust particles in the isolated cloud started to depart from the nucleus due to radiation pressure almost as soon as the main outburst occurred, or dust particles moved by some other anti-sunward forces, such as a rocket effect and photophoresis when the surrounding dust coma became optically thin. The origin and the nature of the isolated dust cloud are discussed in this paper.

  9. Canavan disease: Genomic organization and localization of human ASPA to 17p13-ter and conservation of the ASPA gene during evolution

    SciTech Connect

    Kaul, R.; Balamurugan, K.; Gao, G.P.; Matalon, R. )

    1994-05-15

    Canavan disease, or spongy degeneration of the brain, is a severe leukodystrophy caused by the deficiency of aspartoacylase (ASPA). Recently, a missense mutation was identified in human ASPA coding sequence from patients with Canavan disease. The human ASPA gene has been cloned and found to span 29 kb of the genome. Human aspartoacylase is coded by six exons intervened by five introns. The exons vary from 94 (exon III) to 514 (exon VI) bases. The exon/intron splice junction sites follow the gt/ag consensus sequence rule. Southern blot analysis of genomic DNA from human/mouse somatic cell hybrid cell lines localized ASPA to human chromosome 17. The human ASPA locus was further mapped in the 17p13-ter region by fluorescence in situ hybridization. The bovine aspa gene has also been cloned, and its exon/intron organization is identical to that of the human gene. The 500-base sequence upstream of the initiator ATG codon in the human gene and that in the bovine gene are 77% identical. Human ASPA coding sequences cross-hybridize with genomic DNA from yeast, chicken, rabbit, cow, dog, mouse, rat, and monkey. The specificity of cross-species hybridization of coding sequences suggests that aspartoacylase has been conserved during evolution. It should now be possible to identify mutations in the noncoding genomic sequences that lead to Canavan disease and to study the regulation of ASPA. 45 refs., 4 figs., 1 tab.

  10. A 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region in 17p11.2-p12

    SciTech Connect

    Murakami, Tatsufumi; Lupski, J.R.

    1996-05-15

    Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a 1.5-Mb tandem duplication in chromosome 17p11.2-p12, and hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a 1.5-Mb deletion at this locus. Both diseases appear to result from an altered copy number of the peripheral myelin protein-22 gene, PMP22, which maps within the critical region. To identify additional genes and characterize chromosomal elements, a 1.5-Mb cosmid contig of the CMT1A duplication/HNPP deletion critical region was assembled using a yeast artificial chromosome (YAC)-based isolation and binning strategy. Whole YAC probes were used for screening a high-density arrayed chromosome 17-specific cosmid library. Selected cosmids were spotted on dot blots and assigned to bins defined by YACs. This binning of cosmids facilitated the subsequent fingerprint analysis. The 1.5-Mb region was covered by 137 cosmids with a minimum overlap set of 52 cosmids assigned to 17 bins and 9 contigs. 20 refs., 2 figs.

  11. Review of Disrupted Sleep Patterns in Smith-Magenis Syndrome and Normal Melatonin Secretion in a Patient with an Atypical Interstitial 17p11.2 Deletion

    PubMed Central

    Boudreau, Eilis A.; Johnson, Kyle P.; Jackman, Angela R.; Blancato, Jan; Huizing, Marjan; Bendavid, Claude; Jones, MaryPat; Chandrasekharappa, Settara C.; Lewy, Alfred J.; Smith, Ann C. M.; Magenis, R. Ellen

    2009-01-01

    Smith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body’s signal for nighttime darkness. Published reports of 24-hour melatonin secretion patterns in two independent SMS cohorts (US & France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion (∼6Mb; cen<->TNFRSFproteinB) of chromosome band (17)(p11.1p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern. PMID:19530184

  12. Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation

    PubMed Central

    Li, Defang; Liu, Jin; Guo, Baosheng; Liang, Chao; Dang, Lei; Lu, Cheng; He, Xiaojuan; Cheung, Hilda Yeuk-Siu; Xu, Liang; Lu, Changwei; He, Bing; Liu, Biao; Shaikh, Atik Badshah; Li, Fangfei; Wang, Luyao; Yang, Zhijun; Au, Doris Wai-Ting; Peng, Songlin; Zhang, Zongkang; Zhang, Bao-Ting; Pan, Xiaohua; Qian, Airong; Shang, Peng; Xiao, Lianbo; Jiang, Baohong; Wong, Chris Kong-Chu; Xu, Jiake; Bian, Zhaoxiang; Liang, Zicai; Guo, De-an; Zhu, Hailong; Tan, Weihong; Lu, Aiping; Zhang, Ge

    2016-01-01

    Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. However, whether miRNAs mediate osteoclast-directed osteoblastic bone formation is mostly unknown. Here, we show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214-3p and reduced bone formation that is rescued by osteoclast-targeted antagomir-214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214-3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo. Moreover, osteoclast-targeted miR-214-3p inhibition promotes bone formation in ageing OVX mice. Collectively, our results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation. PMID:26947250

  13. The direct measurement of the 3 3P0-3 3P1 fine-structure interval and the gJ-factor of atomic silicon by laser magnetic resonance

    NASA Technical Reports Server (NTRS)

    Evenson, K. M.; Beltran-Lopez, V.; Ley-Koo, E.; Inguscio, M.

    1984-01-01

    The J - 1 fine structure interval and the g-factor of the 3P1 state have been determined with high precision in the present laser magnetic resonance measurements of the ground 3p2 3P multiplet of atomic Si. Delta-E(3P1-3P0) = 2,311,755.6(7) MHz, and gJ(3P1) = 1.500830(70). Single-configuration calculations of gJ for 3P1 and 3P2 yield a value for the latter which, at 1.501095, is noted to differ by an unexpectedly large margin from the experimental value.

  14. A firefly inspired one-pot chemiluminescence system using n-propylphosphonic anhydride (T3P).

    PubMed

    Kato, Dai-ichiro; Shirakawa, Daiki; Polz, Robin; Maenaka, Mika; Takeo, Masahiro; Negoro, Seiji; Niwa, Kazuki

    2014-12-01

    A simple reaction procedure for chemiluminescence of firefly luciferin (D-luc) using n-propylphosphonic anhydride (T3P) is reported. A luminescent photon is produced as a result of one-pot reaction, only requiring mixing with the substrate carboxylic acid and T3P in the presence of a mild organic base. PMID:25350893

  15. Surfactant-assisted synthesis and electrochemical performances of Cu{sub 3}P dendrites

    SciTech Connect

    Liu, Shuling; Li, Shu; Wang, Jingping; Shi, Qiangqiang; Li, Miaomiao

    2012-11-15

    Highlights: ► Dendrite-like Cu{sub 3}P microstructures have been synthesized by a low-temperature method. ► The surfactant SDS was used as template. ► The as-obtained Cu{sub 3}P dendrites exhibit a high first discharge capacity. -- Abstract: Well-defined Cu{sub 3}P hierarchical dendrites were successfully synthesized by a facile and effective surfactant-assisted hydrothermal approach. X-ray powder diffraction (XRD) and scanning electron microscopy (SEM) indicated that the as-obtained Cu{sub 3}P had a well-crystallized hexagonal phase and consisted of a wealth of Cu{sub 3}P dendritic microstructures. A surfactant-assisted growth accompanied by the Ostwald ripening process was proposed for the formation. As anode materials for lithium ion batteries, the electrochemical property of the Cu{sub 3}P dendrites was also examined. The results showed that the initial discharge capacity of the Cu{sub 3}P dendrites exceeded 1300 mA h/g and it still kept at 291 mA h/g after 20 cycles, which might be related to the size of Cu{sub 3}P particles and their assembly structure.

  16. The duplication 17p13.3 phenotype: analysis of 21 families delineates developmental, behavioral and brain abnormalities, and rare variant phenotypes.

    PubMed

    Curry, Cynthia J; Rosenfeld, Jill A; Grant, Erica; Gripp, Karen W; Anderson, Carol; Aylsworth, Arthur S; Saad, Taha Ben; Chizhikov, Victor V; Dybose, Giedre; Fagerberg, Christina; Falco, Michelle; Fels, Christina; Fichera, Marco; Graakjaer, Jesper; Greco, Donatella; Hair, Jennifer; Hopkins, Elizabeth; Huggins, Marlene; Ladda, Roger; Li, Chumei; Moeschler, John; Nowaczyk, Malgorzata J M; Ozmore, Jillian R; Reitano, Santina; Romano, Corrado; Roos, Laura; Schnur, Rhonda E; Sell, Susan; Suwannarat, Pim; Svaneby, Dea; Szybowska, Marta; Tarnopolsky, Mark; Tervo, Raymond; Tsai, Anne Chun-Hui; Tucker, Megan; Vallee, Stephanie; Wheeler, Ferrin C; Zand, Dina J; Barkovich, A James; Aradhya, Swaroop; Shaffer, Lisa G; Dobyns, William B

    2013-08-01

    Chromosome 17p13.3 is a gene rich region that when deleted is associated with the well-known Miller-Dieker syndrome. A recently described duplication syndrome involving this region has been associated with intellectual impairment, autism and occasional brain MRI abnormalities. We report 34 additional patients from 21 families to further delineate the clinical, neurological, behavioral, and brain imaging findings. We found a highly diverse phenotype with inter- and intrafamilial variability, especially in cognitive development. The most specific phenotype occurred in individuals with large duplications that include both the YWHAE and LIS1 genes. These patients had a relatively distinct facial phenotype and frequent structural brain abnormalities involving the corpus callosum, cerebellar vermis, and cranial base. Autism spectrum disorders were seen in a third of duplication probands, most commonly in those with duplications of YWHAE and flanking genes such as CRK. The typical neurobehavioral phenotype was usually seen in those with the larger duplications. We did not confirm the association of early overgrowth with involvement of YWHAE and CRK, or growth failure with duplications of LIS1. Older patients were often overweight. Three variant phenotypes included cleft lip/palate (CLP), split hand/foot with long bone deficiency (SHFLD), and a connective tissue phenotype resembling Marfan syndrome. The duplications in patients with clefts appear to disrupt ABR, while the SHFLD phenotype was associated with duplication of BHLHA9 as noted in two recent reports. The connective tissue phenotype did not have a convincing critical region. Our experience with this large cohort expands knowledge of this diverse duplication syndrome. PMID:23813913

  17. A Constitutional Translocation t(1;17)(p36.2;q11.2) in a Neuroblastoma Patient Disrupts the Human NBPF1 and ACCN1 Genes

    PubMed Central

    Staes, Katrien; Vandesompele, Jo; Laureys, Geneviève; De Smet, Els; Berx, Geert; Speleman, Frank; van Roy, Frans

    2008-01-01

    The human 1p36 region is deleted in many different types of tumors, and so it probably harbors one or more tumor suppressor genes. In a Belgian neuroblastoma patient, a constitutional balanced translocation t(1;17)(p36.2;q11.2) may have led to the development of the tumor by disrupting or activating a gene. Here, we report the cloning of both translocation breakpoints and the identification of a novel gene that is disrupted by this translocation. This gene, named NBPF1 for Neuroblastoma BreakPoint Family member 1, belongs to a recently described gene family encoding highly similar proteins, the functions of which are unknown. The translocation truncates NBPF1 and gives rise to two chimeric transcripts of NBPF1 sequences fused to sequences derived from chromosome 17. On chromosome 17, the translocation disrupts one of the isoforms of ACCN1, a potential glioma tumor suppressor gene. Expression of the NBPF family in neuroblastoma cell lines is highly variable, but it is decreased in cell lines that have a deletion of chromosome 1p. More importantly, expression profiling of the NBPF1 gene showed that its expression is significantly lower in cell lines with heterozygous NBPF1 loss than in cell lines with a normal 1p chromosome. Meta-analysis of the expression of NBPF and ACCN1 in neuroblastoma tumors indicates a role for the NBPF genes and for ACCN1 in tumor aggressiveness. Additionally, DLD1 cells with inducible NBPF1 expression showed a marked decrease of clonal growth in a soft agar assay. The disruption of both NBPF1 and ACCN1 genes in this neuroblastoma patient indicates that these genes might suppress development of neuroblastoma and possibly other tumor types. PMID:18493581

  18. Microporosity, the wetted layer and the role of CO and CO2 driving the activity of comets 29P/Schwassmann-Wachmann and 17P/Holmes

    NASA Astrophysics Data System (ADS)

    Miles, R.

    2013-09-01

    In a previous paper [1], it was shown that melting of cometary ices will occur in the near-surface of some cometary nuclei where the escape of volatiles is restricted by a microporous matrix held together by surface tension forces: the so-called 'wetted layer'. In this paper, two distinct melting regimes are discussed, namely; (a) an 'hydrophobic' regime at heliocentric distances, rh of ~4-10 AU, where the melting of hydrocarbons and especially ethane (C2H6) ice is likely to dominate, and (b) at rh of ~1.5-4.0 AU, where oxygenated, 'hydrophilic' species are more likely to exist in the liquid phase. Literature data show that the thermophysical properties of carbon monoxide (CO) favour solution of this gas in light hydrocarbons, in particular in liquid methane (CH4) and liquid propane (C3H8) near to their melting point (85-90 K). Consequently, CO must also dissolve in liquid C2H6 at very low ambient pressures (<10 Pa). Similarly, carbon dioxide (CO2) has an affinity to dissolve in methanol (CH3OH) and CH3OH-H2O mixtures at low temperatures and pressures, and especially when approaching freezing point. Thermal gradients within the near-surface generated by the diurnal rotation of the nucleus will concentrate gas solutes in both hydrophobic and hydrophilic environments. Temperature rise and a rapid loss in ambient pressure can result in supersaturation and an explosive release of gas leading to an associated cometary outburst. Thermal cycling can also result in the gradual migration of volatile ices from deep within a microporous nucleus. New observations of comets 29P and 17P, including new observational evidence of the anomalously slow rotation rates of their nuclei, support these hypotheses.

  19. A case of 3p deletion syndrome associated with cerebellar hemangioblastoma.

    PubMed

    Suzuki-Muromoto, Sato; Hino-Fukuyo, Naomi; Haginoya, Kazuhiro; Kikuchi, Atsuo; Sato, Hiroki; Sato, Yuko; Nakayama, Tojo; Kubota, Yuki; Kakisaka, Yosuke; Uematsu, Mitsugu; Kumabe, Toshihiro; Md, Shigeo Kure

    2016-02-01

    We described clinical course of a 24-year-old woman with 3p deletion syndrome associated with cerebellar hemangioblastoma at the age of 16 years old. She presented dysmorphic facial features, growth retardation and severe psychomotor retardation associated with 3p deletion syndrome. We identified de novo 3p deletion encompassing p25 by using array-based comparative genomic hybridization, where causative gene of von Hippel-Lindau (VHL) disease located. Surgical therapy for cerebellar hemangioblastoma was performed, and histological examination was consistent in cerebellar hemangioblastoma. She showed no other tumors associated VHL disease till 24 years old. This is the first case report of a patient with 3p deletion syndrome whose cerebellar hemangioblastoma may be associated with VHL disease. Repeat imaging studies were recommended for the patients with 3p deletion syndrome. PMID:26365017

  20. Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression.

    PubMed

    Zweier, Markus; Gregor, Anne; Zweier, Christiane; Engels, Hartmut; Sticht, Heinrich; Wohlleber, Eva; Bijlsma, Emilia K; Holder, Susan E; Zenker, Martin; Rossier, Eva; Grasshoff, Ute; Johnson, Diana S; Robertson, Lisa; Firth, Helen V; Ekici, Arif B; Reis, André; Rauch, Anita

    2010-06-01

    The etiology of mental retardation remains elusive in the majority of cases. Microdeletions within chromosomal bands 5q14.3q15 were recently identified as a recurrent cause of severe mental retardation, epilepsy, muscular hypotonia, and variable minor anomalies. By molecular karyotyping we identified two novel 2.4- and 1.5-Mb microdeletions of this region in patients with a similar phenotype. Both deletions contained the MEF2C gene, which is located proximally to the previously defined smallest region of overlap. Nevertheless, due to its known role in neurogenesis, we considered MEF2C as a phenocritical candidate gene for the 5q14.3q15 microdeletion phenotype. We therefore performed mutational analysis in 362 patients with severe mental retardation and found two truncating and two missense de novo mutations in MEF2C, establishing defects in this transcription factor as a novel relatively frequent autosomal dominant cause of severe mental retardation accounting for as much as 1.1% of patients. In these patients we found diminished MECP2 and CDKL5 expression in vivo, and transcriptional reporter assays indicated that MEF2C mutations diminish synergistic transactivation of E-box promoters including that of MECP2 and CDKL5. We therefore conclude that the phenotypic overlap of patients with MEF2C mutations and atypical Rett syndrome is due to the involvement of a common pathway. PMID:20513142

  1. Ge 3P 6Si 2O 25: A cage structure closely related to the intersecting tunnel structure KMo 3P 6Si 2O 25

    NASA Astrophysics Data System (ADS)

    Leclaire, A.; Raveau, B.

    1988-08-01

    A germanosilicophosphate Ge 3P 6Si 2O 25 has been isolated. Its structure was solved from a single-crystal study in the space group P overline31c . Its cell parameters are a = b = 7.994(1) Å, c = 16.513(2) Å, Z = 2. The refinement by full-matrix least-squares calculations leads to R = 0.043 with 686 independent reflections. The structure of this oxide is built up from corner-sharing PO 4 and SiO 4 tetrahedra and GeO 6 octahedra. One observes a feature common to several silicophosphates: the presence of the structural unit P 6Si 2O 25 built up from a disilicate group sharing its corners with six PO 4 tetrahedra. The structural relationships between this oxide and the silicophosphates AMo 3P 6Si 2O 25 and Si 3P 6Si 2O 25 (or Ge 3P 6 Ge 2O 25) are described.

  2. Electronic and rovibrational quantum chemical analysis of C3P-: the next interstellar anion?

    NASA Astrophysics Data System (ADS)

    Fortenberry, Ryan C.; Lukemire, Joseph A.

    2015-11-01

    C3P- is analogous to the known interstellar anion C3N- with phosphorus replacing nitrogen in a simple step down the periodic table. In this work, it is shown that C3P- is likely to possess a dipole-bound excited state. It has been hypothesized and observationally supported that dipole-bound excited states are an avenue through which anions could be formed in the interstellar medium. Additionally, C3P- has a valence excited state that may lead to further stabilization of this molecule, and C3P- has a larger dipole moment than neutral C3P (˜6 D versus ˜4 D). As such, C3P- is probably a more detectable astromolecule than even its corresponding neutral radical. Highly accurate quantum chemical quartic force fields are also applied to C3P- and its singly 13C substituted isotopologues in order to provide structures, vibrational frequencies, and spectroscopic constants that may aid in its detection.

  3. Definition of a tumor suppressor locus within human chromosome 3p21-p22.

    PubMed Central

    Killary, A M; Wolf, M E; Giambernardi, T A; Naylor, S L

    1992-01-01

    Cytogenetic abnormalities and high-frequency allele losses involving the short arm of human chromosome 3 have been identified in a variety of histologically different neoplasms. These findings suggest that a tumor-suppressor gene or genes may be located in the region of 3p14-p25, although there has been no definitive functional proof for the involvement of a particular region of 3p. We report a rapid genetic assay system that has allowed functional analysis of defined regions of 3p in the suppression of tumorigenicity in vivo. Interspecific microcell hybrids containing fragments of chromosome 3p were constructed and screened for tumorigenicity in athymic nude mice. Hybrid clones were obtained that showed a dramatic tumor suppression and contained a 2-megabase fragment of human chromosomal material encompassing the region 3p21 near the interface with 3p22. With these hybrid clones, we have defined a genetic locus at 3p21-p22 intimately involved in tumor suppression. Images PMID:1438292

  4. The copper-iron connection in biology: Structure of the metallo-oxidase Fet3p

    SciTech Connect

    Taylor, A. B.; Stoj, C. S.; Ziegler, L.; Kosman, D. J.; Hart, P. J.

    2005-10-17

    Fet3p is a multicopper-containing glycoprotein localized to the yeast plasma membrane that catalyzes the oxidation of Fe(II) to Fe(III). This ferrous iron oxidation is coupled to the reduction of O2 to H2O and is termed the ferroxidase reaction. Fet3p-produced Fe(III) is transferred to the permease Ftr1p for import into the cytosol. The posttranslational insertion of four copper ions into Fet3p is essential for its activity, thus linking copper and iron homeostasis. The mammalian ferroxidases ceruloplasmin and hephaestin are homologs of Fet3p. Loss of the Fe(II) oxidation catalyzed by these proteins results in a spectrum of pathological states, including death. Here, we present the structure of the Fet3p extracellular ferroxidase domain and compare it with that of human ceruloplasmin and other multicopper oxidases that are devoid of ferroxidase activity. The Fet3p structure delineates features that underlie the unique reactivity of this and homologous multicopper oxidases that support the essential trafficking of iron in diverse eukaryotic organisms. The findings are correlated with biochemical and physiological data to cross-validate the elements of Fet3p that define it as both a ferroxidase and cuprous oxidase.

  5. Molecular and cytogenetic characterization of a de novo partial trisomy 3p case with review

    SciTech Connect

    Conte, R.A.; Pitter, J.; Verma, R.S.

    1994-09-01

    A one-year-old male infant was found to have a de novo unbalanced translocation resulting in partial trisomy for 3p, i.e. 46,XY,der(7)t(3;7)(p24.2;p22). Major clinical features included: dysmorphic ears, decreased muscle tone and episodes of seizures associated with fever. GTG- and QFQ-banding revealed additional material suggestive of chromosome 3p that was translocated to the terminal 7p. The FISH technique with two-color specific DNA probes for whole chromosomes 3 and 7 verified this finding. Other probands with the same amount of trisomic 3p2 segments as the present case had additional clinical abnormalities. Previously, identification of this so-called trisomy 3p2 syndrome was invariably based on the analysis of GTG-banded metaphase chromosomes. A review of 37 earlier cases revealed that the clinical manifestations varied with the amount of 3p2 material in the trisomic state, demonstrating increased anomalies with increased 3p2 sub-band trisomy. Phenotype to genotype correlation is best understood under conditions that can achieve respective characterization with a high degree of certainty. Presently, the FISH technique fulfills this requirement and the employment of loci probes that span 3p, when available, will ultimately increase the characterization resolution to the gene level.

  6. miR-17-3p Exacerbates Oxidative Damage in Human Retinal Pigment Epithelial Cells

    PubMed Central

    Tian, Bo; Maidana, Daniel E.; Dib, Bernard; Miller, John B.; Bouzika, Peggy; Miller, Joan W.; Vavvas, Demetrios G.; Lin, Haijiang

    2016-01-01

    Oxidative stress has been shown to contribute to the development of age-related macular degeneration (AMD). MicroRNAs (miRNA) are small non-coding RNA molecules that function in RNA silencing and post-transcriptional regulation of gene expression. We showed miR-17-3p to be elevated in macular RPE cells from AMD patients and in ARPE-19 cells under oxidative stress. Transfection of miR-17-3p mimic in ARPE-19 induced cell death and exacerbated oxidative lethality that was alleviated by miR-17-3p inhibitor. The expression of antioxidant enzymes manganese superoxide dismutase (MnSOD) and thioredoxin reductase-2 (TrxR2) were suppressed by miR-17-3p mimic and reversed by miR-17-3p inhibitor. These results suggest miR-17-3p aggravates oxidative damage-induced cell death in human RPE cells, while miR-17-3p inhibitor acts as a potential protector against oxidative stress by regulating the expression of antioxidant enzymes. PMID:27505139

  7. Progress on the Multiphysics Capabilities of the Parallel Electromagnetic ACE3P Simulation Suite

    SciTech Connect

    Kononenko, Oleksiy

    2015-03-26

    ACE3P is a 3D parallel simulation suite that is being developed at SLAC National Accelerator Laboratory. Effectively utilizing supercomputer resources, ACE3P has become a key tool for the coupled electromagnetic, thermal and mechanical research and design of particle accelerators. Based on the existing finite-element infrastructure, a massively parallel eigensolver is developed for modal analysis of mechanical structures. It complements a set of the multiphysics tools in ACE3P and, in particular, can be used for the comprehensive study of microphonics in accelerating cavities ensuring the operational reliability of a particle accelerator.

  8. Thermal Analysis of SRF Cavity Couplers Using Parallel Multiphysics Tool TEM3P

    SciTech Connect

    Akcelik, V; Lee, L.-Q.; Li, Z.; Ng, C.-K.; Ko, K.; Cheng, G.; Rimmer, R.; Wang, H.; /Jefferson Lab

    2009-05-20

    SLAC has developed a multi-physics simulation code TEM3P for simulating integrated effects of electromagnetic, thermal and structural loads. TEM3P shares the same software infrastructure with SLAC's parallel finite element electromagnetic codes, thus enabling all physics simulations within a single framework. The finite-element approach allows high-fidelity, high-accuracy simulations and the parallel implementation facilitates large-scale computation with fast turnaround times. In this paper, TEM3P is used to analyze thermal loading at coupler end of the JLAB SRF cavity.

  9. Thermal Analysis of SRF Cavity Couplers Using Parallel Multiphysics Tool TEM3P

    SciTech Connect

    Akcelik, V, Lee, L.-Q., Li, Z., Ng, C.-K., Ko, K.,Cheng, G., Rimmer, R., Wang, H.

    2009-05-01

    SLAC has developed a multi-physics simulation code TEM3P for simulating integrated effects of electromagnetic, thermal and structural loads. TEM3P shares the same software infrastructure with SLAC’s paralell finite element electromagnetic codes, thus enabling all physics simulations within a single framework. The finite-element approach allows high fidelity, high-accuracy simulations and the parallel implementation facilitates large-scale computation with fast turnaround times. In this paper, TEM3P is used to analyze thermal loading at coupler end of the JLAB SRF cavity.

  10. Congenital hypothyroidism in association with chromosome 3p25.3-pter deletion.

    PubMed

    Malhotra, Atul; Bergman, Phil; Brown, Justin; Mc Gillivray, George

    2011-01-01

    This report describes a case of a neonate presenting with many of the typical phenotypic characteristics of chromosome 3p deletion including hypertelorism, flat nasal bridge, flat philtrum, thin lips and low-set ears. The hands and feet showed post axial polydactyly, single palmar creases and rocker bottom feet. A karyotype confirmed chromosome 3p25.3-pter deletion with normal parental karyotypes. A high TSH was noted on newborn screening and congenital hypothyroidism was confirmed on thyroid function tests. Thyroid nuclear imaging was suggestive of dyshormonogenesis. This is the first reported case of congenital hypothyroidism in an infant with chromosome 3p deletion. PMID:22145477

  11. Elevation of Circulating miR-210-3p in High-Altitude Hypoxic Environment

    PubMed Central

    Yan, Yan; Wang, Cheng; Zhou, Wanqing; Shi, Yonghui; Guo, Pengtao; Liu, Yuxiu; Wang, Junjun; Zhang, Chen-Yu; Zhang, Chunni

    2016-01-01

    Background: The induction of miR-210-3p, a master hypoxamir, is a consistent feature of the hypoxic response in both normal and malignant cells. However, whether miR-210-3p acts as a circulating factor in response to a hypoxic environment remains unknown. The current study aimed to examine the effect of a high-altitude hypoxic environment on circulating miR-210-3p. Methods: We examined and compared the levels of miR-210-3p using TaqMan-based qRT-PCR in both peripheral blood cells and plasma from 84 ethnic Chinese Tibetans residing at 3560 m, 46 newly arrived migrant Han Chinese (Tibet Han) and 82 Han Chinese residing at 8.9 m (Nanjing Han). Furthermore, we analyzed the correlations of miR-210-3p with hematological indices. Results: The relative concentrations of miR-210-3p to internal reference U6 in blood cells were significantly higher in the Tibet Han group (1.01 ± 0.11, P < 0.001) and in the Tibetan group (1.17 ± 0.09, P < 0.001) than in the Nanjing Han group (0.51 ± 0.04). The absolute concentrations of plasma miR-210-3p were also markedly elevated in the Tibet Han group (503.54 ± 42.95 fmol/L, P = 0.004) and in the Tibetan group (557.78 ± 39.84 fmol/L, P < 0.001) compared to the Nanjing Han group (358.39 ± 16.16 fmol/L). However, in both blood cells and plasma, miR-210-3p levels were not significantly different between the Tibet Han group and the Tibetan group (P = 0.280, P = 0.620, respectively). Plasma miR-210-3p concentrations were positively correlated with miR-210-3p levels in blood cells (r = 0.192, P = 0.005). Furthermore, miR-210-3p levels in both blood cells and plasma showed strong positive correlations with red blood cell counts and hemoglobin and hematocrit values. Conclusion: These data demonstrated, for the first time, that miR-210-3p might act as a circulating factor in response to hypoxic environments and could be associated with human adaptation to life at high altitudes. PMID:27014085

  12. Characterization of Potocki-Lupski Syndrome (dup(17)(p11.2p11.2)) and Delineation of a Dosage-Sensitive Critical Interval That Can Convey an Autism Phenotype

    PubMed Central

    Potocki, Lorraine; Bi, Weimin; Treadwell-Deering, Diane; Carvalho, Claudia M. B.; Eifert, Anna; Friedman, Ellen M.; Glaze, Daniel; Krull, Kevin; Lee, Jennifer A.; Lewis, Richard Alan; Mendoza-Londono, Roberto; Robbins-Furman, Patricia; Shaw, Chad; Shi, Xin; Weissenberger, George; Withers, Marjorie; Yatsenko, Svetlana A.; Zackai, Elaine H.; Stankiewicz, Pawel; Lupski, James R.

    2007-01-01

    The duplication 17p11.2 syndrome, associated with dup(17)(p11.2p11.2), is a recently recognized syndrome of multiple congenital anomalies and mental retardation and is the first predicted reciprocal microduplication syndrome described—the homologous recombination reciprocal of the Smith-Magenis syndrome (SMS) microdeletion (del(17)(p11.2p11.2)). We previously described seven subjects with dup(17)(p11.2p11.2) and noted their relatively mild phenotype compared with that of individuals with SMS. Here, we molecularly analyzed 28 additional patients, using multiple independent assays, and also report the phenotypic characteristics obtained from extensive multidisciplinary clinical study of a subset of these patients. Whereas the majority of subjects (22 of 35) harbor the homologous recombination reciprocal product of the common SMS microdeletion (∼3.7 Mb), 13 subjects (∼37%) have nonrecurrent duplications ranging in size from 1.3 to 15.2 Mb. Molecular studies suggest potential mechanistic differences between nonrecurrent duplications and nonrecurrent genomic deletions. Clinical features observed in patients with the common dup(17)(p11.2p11.2) are distinct from those seen with SMS and include infantile hypotonia, failure to thrive, mental retardation, autistic features, sleep apnea, and structural cardiovascular anomalies. We narrow the critical region to a 1.3-Mb genomic interval that contains the dosage-sensitive RAI1 gene. Our results refine the critical region for Potocki-Lupski syndrome, provide information to assist in clinical diagnosis and management, and lend further support for the concept that genomic architecture incites genomic instability. PMID:17357070

  13. Effects of partial anion substitution on the thermoelectric properties of silver(I) chalcogenide halides in the system Ag{sub 5}Q{sub 2}X with Q=Te, Se and S and X=Br and Cl

    SciTech Connect

    Eckstein, Nadine; Nilges, Tom; Decourt, Rodolphe; Bobet, Jean-Louis; Chevalier, Bernard

    2011-04-15

    A selection of mixed conducting silver chalcogenide halides of the general formula Ag{sub 5}Q{sub 2}X with Q=sulfur, selenium and tellurium and X=chlorine and bromine has been investigated due to their thermoelectric properties. Recently, the ternary counterpart Ag{sub 5}Te{sub 2}Cl showed a defined d{sup 10}-d{sup 10} interaction in the disordered cation substructure at elevated temperatures where Ag{sub 5}Te{sub 2}Cl is present in its high temperature {alpha}-phase. A significant drop of the thermal diffusivity has been observed during the {beta}-{alpha} phase transition reducing the values from 0.12 close to 0.08 mm{sup 2} s{sup -1}. At the same transition the thermopower reacts on the increasing silver mobility and jumps towards less negative values. Thermal conductivities, thermopower and thermal diffusivity of selected compounds with various grades of anion substitution in Ag{sub 5}Q{sub 2}X were determined around the silver-order/disorder {beta}-{alpha} phase transition. A formation of attractive interactions could be observed for selenium substituted phases while no effect was detected for bromide and sulfide samples. Depending on the grade and type of substitution the thermopower changes significantly at and after the {beta}-{alpha} phase transition. Thermal conductivities are low reaching values around 0.2-0.3 W m{sup -1} K{sup -1} at 299 K. Partial anion exchange can substantially tune the thermoelectric properties in Ag{sub 5}Q{sub 2}X phases. -- Graphical abstract: A structure section of the {alpha}-Ag{sub 5}Te{sub 2}Cl structure type and the thermopower evolution of Ag{sub 5}Te{sub 2}Cl{sub 0.4}Br{sub 0.6} undergoing a silver ion order/disorder phase transition. Display Omitted Research highlights: > We report on thermoelectric properties of silver(I) chalcogenide halides. > We examine thermopower, thermal diffusivity and thermal behavior. > Silver mobility, phase transitions and order/disorder phenomena are discussed. > Partial anion exchange can

  14. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 EPH families using 15 polymorphic loci in the region 5q11. 2-q13. 3

    SciTech Connect

    Wirth, B.; Pick, E.; Leutner, A.; Dadze, A.; Voosen, B.; Piechaczek-Wappenschmidt, B.; Rudnik-Schoeneborn, S.; Schoenling, J.; Zerres, K. ); Knapp, M. )

    1994-03-01

    The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q.13.3 in 1990. Here, the authors present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q.13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z[sub max] = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557. The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene. They localized a recently described polymorphic marker, D5S351, close to the SMA. Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, they developed a new reverse primer for the nearest centromeric locus D5S435, a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5s507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q.13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507-D5S6-D5S125-D5S680-D5S435-SMA-D5S557-D5S35 -15[prime]MAP1B-3[prime]MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable. 25 refs., 4 figs., 5 tabs.

  15. J/ψ Decay in the C3P0 Model

    NASA Astrophysics Data System (ADS)

    de Quadros, J. N.; Hadjimichef, D.

    2012-01-01

    The Fock-Tani representation, is a field theoretic formalism to treat problems involving both composite particles and their constituents. The application of the Fock-Tani transformation to a pair creation Hamiltonian produces the characteristic expansion in powers of the wave function. In lowest order of this expansion, we obtain the model known in the literature: the 3P0 model. In higher orders, the Corrected 3P0 model (C3P0) is obtained by introducing the bound state kernel. In this work, we use the C3P0 model to calculate the J/ψ decay rates in the following channels: ρ π, ω η, ω η‧, K*+ K-, K{* 0} \\bar {K}0, ϕ η, ϕ η‧. We consider that the J/ψ is a mixture given by c1[u\\bar {u}+d\\bar {d}]+c_2 s\\bar {s}+c3 c\\bar {c}.

  16. miR-483-3p regulates hyperglycaemia-induced cardiomyocyte apoptosis in transgenic mice.

    PubMed

    Qiao, Yu; Zhao, Yanli; Liu, Yan; Ma, Ning; Wang, Chuxuan; Zou, Jiaqi; Liu, Zhiyan; Zhou, Zhongqiu; Han, Dong; He, Jun; Sun, Qian; Liu, Yicong; Xu, Changqing; Du, Zhimin; Huang, Hui

    2016-09-01

    Diabetic cardiomyopathy represents severe heart complications, and is the leading cause of morbidity and mortality among patients with diabetes. Although a few microRNAs (miRNAs) have been implicated in diabetes-related complications, a functional association between miRNAs and cardiac dysfunction in diabetic cardiomyopathy remains to be demonstrated. Our results show that miR-483-3p is upregulated in streptozotocin-induced diabetic mice, and cultured cardiomyocytes mimicking hyperglycemia. Overexpressing miR-483-3p in transgenic mice with diabetes mellitus (DM) exacerbated cardiomyocyte apoptosis by transcriptionally repressing insulin growth factor 1 (IGF1). Therefore, we have uncovered a novel signaling pathway, involving miR-483-3p-IGF1, that promotes myocardial cell apoptosis under high blood-glucose condition. Further, our study indicates that miR-483-3p could be a potential therapeutic target for managing diabetes-associated heart complications. PMID:27346130

  17. Kinetics of the Reaction of O((sup 3)P) with CF3NO

    NASA Technical Reports Server (NTRS)

    Thorn, R. P.; Nicovich, J. M.; Cronkhite, J. M.; Wine, P. H.

    1997-01-01

    A laser flash photolysis-resonance fluorescence technique has been employed to study the kinetics of the reaction of O((sup 3)P) with CF3NO (k(2)) as a function of temperature. Our results are described by the Arrhenius expression k(2)(T) = (4.54 +/- 0.70) x 10(exp -l2)exp[(-560 +/- 46)/T] cu cm/molecule.s (243 K is less than or equal to T is less than or equal to 424 K); errors are 2 sigma and represent precision only. The O((sup 3)P) + CF3NO reaction is sufficiently rapid that CF3NO cannot be employed as a selective quencher for O2(alpha(1) Delta-g) in laboratory systems where O((sup 3)P) and O2(alpha 1 Delta g) coexist, and where O((sup 3)P) kinetics are being investigated.

  18. Investigation of Structural and Electronic Properties of Zn3P2: Theory and Experiment

    NASA Astrophysics Data System (ADS)

    Kaur, M.; Kabra, K.; Kumar, R.; Sharma, B. K.; Sharma, G.

    2016-03-01

    This paper deals with the structural and electronic properties of the compound Zn3P2. Equilibrium structural properties have been calculated by fitting the energy-volume data to standard equation of state. The theoretical as well as experimental spherically averaged Compton profiles are also determined. The experiment is performed using a 5 Ci 241Am gamma-rays Compton spectrometer, allowing 59.54 keV gamma rays to get scattered by the polycrystalline sample and the corresponding theoretical profiles are obtained from linear combination of atomic orbital method within density functional theory framework. Anisotropy curves using three different directions [100], [110] and [111] are obtained for the compound and an ionic model is also proposed, which supports the transfer of 2.0 electrons from Zn to P atom. At last, equal-valence-electron-density profiles for Zn3P2 and Cd3P2 are presented, confirming more ionic characters in Zn3P2.

  19. Investigation of Structural and Electronic Properties of Zn3P2: Theory and Experiment

    NASA Astrophysics Data System (ADS)

    Kaur, M.; Kabra, K.; Kumar, R.; Sharma, B. K.; Sharma, G.

    2016-06-01

    This paper deals with the structural and electronic properties of the compound Zn3P2. Equilibrium structural properties have been calculated by fitting the energy-volume data to standard equation of state. The theoretical as well as experimental spherically averaged Compton profiles are also determined. The experiment is performed using a 5 Ci 241Am gamma-rays Compton spectrometer, allowing 59.54 keV gamma rays to get scattered by the polycrystalline sample and the corresponding theoretical profiles are obtained from linear combination of atomic orbital method within density functional theory framework. Anisotropy curves using three different directions [100], [110] and [111] are obtained for the compound and an ionic model is also proposed, which supports the transfer of 2.0 electrons from Zn to P atom. At last, equal-valence-electron-density profiles for Zn3P2 and Cd3P2 are presented, confirming more ionic characters in Zn3P2.

  20. Determination of diffusion, reflection and deexcitation coefficients of metastable excited Ne(3P2) atom

    NASA Astrophysics Data System (ADS)

    Suzuki, S.; Itoh, H.

    2016-05-01

    The diffusion coefficient of the metastable excited Ne(3P2) atom in neon, the reflection coefficient of Ne(3P2) at the surface of an electrode and the rate coefficient of Ne(3P2) for collisional quenching by Ne(1S0) were determined from the gas pressure dependence of the effective lifetime of Ne(3P2). The effective lifetime of Ne(3P2) was measured from the transient current after turning off the Ultraviolet (UV) light in a Townsend discharge. The observed transient current waveform was analysed by solving the diffusion equation for the metastable excited Ne(3P2) atom using the third kind of boundary condition. The rate coefficient of Ne(3P2) for collisional quenching by Ne(1S0) and the reflection coefficient were determined by a nonspectroscopic method for the first time in neon to the best of our knowledge and were (3.2  ±  0.4)  ×  10‑16 cm3 s‑1 and 0.10  ±  0.04, respectively. The obtained diffusion coefficient at 1 Torr was 177  ±  17 cm2 s‑1, which is consistent with the value reported by Dixon and Grant. Moreover, the present results are compared with the results of Phelps and were found to be in good agreement. We also discuss the deexcitation rate of Ne(3P2) at pressures of up to 60 Torr in comparison with previously reported values.

  1. MPI spectroscopy in the region of the 3p Rydberg state of some cycloketones

    NASA Astrophysics Data System (ADS)

    Kosmidis, C.; Boulakis, G.; Bolovinos, A.; Tsekeris, P.; Brint, P.

    1992-03-01

    The two-photon resonance three photon ionization spectra of cyclopentanone, cyclohexanone and cycloheptanone in the region of the 3p Rydberg state have been recorded, analysed and compared with the one-photon absorption spectra. A new 3p origin is identified for cyclopentanone. The absence from the MPI spectra of a sharp spectral feature that is observed in the absorption spectra is discussed. Photochemical generation of acetaldehyde is observed at high laser intensities and possible mechanisms for this are considered.

  2. miR-1207-3p Is a Novel Prognostic Biomarker of Prostate Cancer.

    PubMed

    Das, Dibash K; Osborne, Joseph R; Lin, Hui-Yi; Park, Jong Y; Ogunwobi, Olorunseun O

    2016-06-01

    MicroRNAs (miRNAs) have been found to be dysregulated in prostate cancer (PCa). In this study, we investigated if miR-1207-3p is capable of distinguishing between indolent and aggressive PCa and if it contributes to explaining the disproportionate aggressiveness of PCa in men of African ancestry (moAA). A total of 404 patients with primary adenocarcinoma of the prostate were recruited between 1988 and 2003 at the Moffitt Cancer Center, Tampa, FL, USA. Patient clinicopathological features and demographic characteristics such as race were identified. RNA samples from 404 postprostatectomy prostate tumor tissue samples were analyzed by real-time quantitative reverse transcription polymerase chain reaction for the mRNA expression of miR-1207-3p. miR-1207-3p expression in PCa that resulted in overall death or PCa-specific death is significantly higher than in PCa cases that did not. The same positive correlation holds true for other clinical characteristics such as biochemical recurrence, Gleason score, clinical stage, and prostate-specific antigen level. Furthermore, miR-1207-3p expression was significantly less in moAA in comparison to Caucasian men. We also evaluated whether miR-1207-3p is associated with clinical outcomes adjusted for age at diagnosis and tumor stage in the modeling. Using competing risk regression, the PCa patients with a high miR-1207-3p expression (≥6 vs 3) had a high risk to develop PCa recurrence (hazard rate = 2.5, P < .001) adjusting for age at diagnosis and tumor stage. In conclusion, miR-1207-3p is a promising novel prognostic biomarker for PCa. Furthermore, miR-1207-3p may also be important in explaining the disproportionate aggressiveness of PCa in moAA. PMID:27267842

  3. A novel DNA binding motif for yeast zinc cluster proteins: the Leu3p and Pdr3p transcriptional activators recognize everted repeats.

    PubMed Central

    Hellauer, K; Rochon, M H; Turcotte, B

    1996-01-01

    The Gal4, Put3, and Ppr1 yeast zinc cluster proteins bind as homodimers to DNA sequences composed of palindromic CGG triplets. Spacing between the triplets specifies the target site for a given zinc cluster protein. In addition, Hap1p, another zinc cluster protein, also recognizes CGG triplets but only when oriented as a direct repeat. Unexpectedly, our results show that Leu3p, another member of this family, also recognizes CGG triplets but oriented in opposite directions and spaced by 4 nucleotides (an everted repeat or inverted palindrome: CCG-N4-CGG). This constitutes a novel DNA motif for zinc cluster proteins. Moreover, the presence of this motif was shown to be essential for in vivo activation by Leu3p of a minimal reporter containing one copy of a target site for this activator. We also provide evidence that another member of this family, Pdr3p, binds to an everted repeat spaced by 0 nucleotides (CCGCGG). Thus, our results show that three CGG motifs are used by members of the zinc cluster family: palindromes, direct repeats, and everted repeats. PMID:8887639

  4. Laser gain on 3p-3d and 3s-3p transitions and X-ray line ratios for the nitrogen isoelectronic sequence

    NASA Technical Reports Server (NTRS)

    Feldman, U.; Seely, J. F.; Bhatia, A. K.

    1989-01-01

    Results are presented on calculations of the 72 levels belonging to the 2s(2)2p(3), 2s2p(4), 2p(5), 2s(2)2p(2)3s, 2s(2)2p(2)3p, and 2s(2)2p(2)3d configurations of the N I isoelectronic sequence for the ions Ar XII, Ti XVI, Fe XX, Zn XXIV, and Kr XXX, for electron densities up to 10 to the 24th/cu cm. It was found that large population inversions and gain occur between levels in the 2s(2)2p(2)3p configuration and levels in the 2s(2)2p(2)3d configuration that cannot decay to the ground configuration by an electric dipole transition. For increasing electron densities, the intensities of the X-ray transitions from the 2s(2)2p(2)3p configuration to the ground configuration decrease relative to the transitions from the 2s(2)2p(2)3s and 2s(2)2p(2)3d configurations to the ground configuration. The density dependence of these X-ray line ratios is presented.

  5. MicroRNA-139-3p indicates a poor prognosis of colon cancer

    PubMed Central

    Liu, Xiaojing; Duan, Bensong; Dong, Yuanyuan; He, Chengzhi; Zhou, Hongmei; Sheng, Haihui; Gao, Hengjun; Zhang, Xizhi

    2014-01-01

    MicroRNAs (miRNAs) play an important role in the regulation of gene expression and are involved in almost biological procession. Recently, miR-139-5p has been reported to be downregulated in some types of cancer, and inhibits cancer cell invasion and metastasis. However, there are few reports on the role of miR-139-3p in cancer. In this study, we examined the expression level of miR-139-3p in 63 pairs of colon cancer and adjacent paracancerous tissues using quantitative reverse transcription PCR. The levels of miR-139-3p in colon cancer tissues were significantly lower than those in adjacent noncancerous tissues. There was an inverse correlation between the level of miR-139-3p and patient’s age. Lower level of miR-139-3p was significantly associated with poor overall survival, especially in patients with TNM stages I and II. In conclusion, miR-139-3p has potential as a prognostic biomarker for colon cancer. Further prospective studies are required to validate this result. PMID:25550849

  6. miR-193a-3p is a potential tumor suppressor in malignant pleural mesothelioma

    PubMed Central

    Cheng, Yuen Yee; Hanh, Jacky; Weiss, Jocelyn; Mugridge, Nancy; Wright, Casey M.; Linton, Anthony; Kao, Steven C.; Edelman, J. James B.; Vallely, Michael P.; McCaughan, Brian C.; Cooper, Wendy; Klebe, Sonja; Lin, Ruby C.Y.; Brahmbhatt, Himanshu; MacDiarmid, Jennifer; van Zandwijk, Nico; Reid, Glen

    2015-01-01

    Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated with increased apoptosis. In conclusion, miR-193a-3p appears to have importance in the biology of MPM and may represent a target for therapeutic intervention. PMID:26125439

  7. Protective role of miR-23b-3p in kainic acid-induced seizure.

    PubMed

    Zhan, Lianbo; Yao, Yi; Fu, Huajun; Li, Zhenghui; Wang, Fengpeng; Zhang, Xiaobin; He, Wencan; Zheng, Weihong; Zhang, Yunwu; Zheng, Honghua

    2016-07-01

    Dysregulation of microRNAs has been proposed to contribute toward epilepsy. The miRNA miR-23b-3p has been found to protect against neuronal apoptosis and the production of reactive oxygen species. In this study, we assessed the potential role of miR-23b-3p in the kainic acid (KA)-induced seizure model. We found that miR-23b-3p levels were significantly decreased in the brain cortex of mice and in cultured mouse primary neurons treated with KA. Importantly, supplement of miR-23b-3p agomir by an intacerebroventricular injection alleviated seizure behaviors and abnormal cortical electroencephalogram recordings in KA-treated mice. Together, these results indicate that miR-23b-3p plays a crucial role in suppressing seizure formation in experimental models of epilepsy and that miR-23b-3p supplement may be a potential anabolic strategy for ameliorating seizure. PMID:27232518

  8. Optical, transport and magnetic properties of new compound CeCd3P3

    NASA Astrophysics Data System (ADS)

    Higuchi, Shohei; Noshima, Yuki; Shirakawa, Naoki; Tsubota, Masami; Kitagawa, Jiro

    2016-05-01

    We have found that CeCd3P3 crystallizes into a hexagonal ScAl3C3-type structure. The optical, transport and magnetic properties of CeCd3P3 were investigated by measuring the diffuse reflectance, electrical resistivity and magnetization. CeCd3P3 is a semiconductor with a fundamental band gap of approximately 0.75 eV. The 4f electrons of Ce3+ ions are well localized but do not show long-range order down to 0.48 K, presumably due to the geometrical frustration of Ce atoms. The magnetic ordering temperature is possibly lower than that of isostructural CeZn3P3 (0.75 K). Because several f-electron compounds with the ScAl3C3-type structure are quantum spin systems, CeCd3P3 may be a candidate for quantum spin liquid. On the other hand, the relatively large band gap compared to approximately 0.4 eV in CeZn3P3, would not be in accordance with the observation of the photoinduced Kondo effect, providing a potentially new range of applications for devices based on the Kondo effect.

  9. Multiplex FISH telomere integrity assay identifies an unbalanced cryptic translocation der(5)t(3;5)(q27;p15.3) in a family with three mentally retarded individuals.

    PubMed

    Granzow, M; Popp, S; Keller, M; Holtgreve-Grez, H; Brough, M; Schoell, B; Rauterberg-Ruland, I; Hager, H D; Tariverdian, G; Jauch, A

    2000-07-01

    Cryptic rearrangements involving the terminal regions of chromosomes are suspected to be the cause of idiopathic mental retardation in a significant number of cases. This finding highlights the necessity of a primary screening test for such chromosome aberrations. Here we present a multiplex fluorescence in situ hybridization telomere integrity assay which allows the detection of submicroscopic aberrations in the telomeric regions of all chromosomes. This novel approach identified an unbalanced cryptic translocation der(5)t(3;5)(q27;p15.3) in a family with three cases of unexplained mental retardation and dysmorphic features. The symptoms of the patients represent neither the classical dup(3q)- nor cri du chat syndrome, although all affected individuals demonstrate several features of both syndromes. The identification of two balanced translocation carriers emphasizes the significance of the telomere integrity assay for genetic counseling and prenatal diagnosis. PMID:10982035

  10. Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation.

    PubMed

    Deprez, Liesbet; Claes, Lieve R F; Claeys, Kristl G; Audenaert, Dominique; Van Dyck, Tine; Goossens, Dirk; Van Paesschen, Wim; Del-Favero, Jurgen; Van Broeckhoven, Christine; De Jonghe, Peter

    2006-01-01

    Febrile seizures (FS) represent the most common seizure disorder in childhood and contribution of a genetic predisposition has been clearly proven. In some families FS is associated with a wide variety of afebrile seizures. Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with a spectrum of phenotypes including FS, atypical febrile seizures (FS+) and afebrile generalized and partial seizures. Mutations in the genes SCN1B, SCN1A and GABRG2 were identified in GEFS+ families. GEFS+ is genetically heterogeneous and mutations in these three genes were detected in only a minority of the families. We performed a 10 cM density genome-wide scan in a multigenerational family with febrile seizures and epilepsy and obtained a maximal multipoint LOD score of 3.12 with markers on chromosome 5q14.3-q23.1. Fine mapping and segregation analysis defined a genetic interval of approximately 33 cM between D5S2103 and D5S1975. This candidate region overlapped with a previously reported locus for febrile seizures (FEB4) in the Japanese population, in which MASS1 was proposed as disease gene. Mutation analysis of the exons and exon-intron boundaries of MASS1 in our family did not reveal a disease causing mutation. Our linkage data confirm for the first time that a locus on chromosome 5q14-q23 plays a role in idiopathic epilepsies. However, our mutation data is negative and do not support a role for MASS1 suggesting that another gene within or near the FEB4 locus might exist. PMID:16273391

  11. Increased miR-132-3p expression is associated with chronic neuropathic pain.

    PubMed

    Leinders, M; Üçeyler, N; Pritchard, R A; Sommer, C; Sorkin, L S

    2016-09-01

    Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain. PMID:27349406

  12. Molecular architecture of a Leu3p-DNA complex in solution: a biochemical approach.

    PubMed Central

    Remboutsika, E; Kohlhaw, G B

    1994-01-01

    The Leu3 protein (Leu3p) of Saccharomyces cerevisiae is a pleiotropic transregulator that can function both as an activator and as a repressor of transcription. It binds to upstream promoter elements (UASLEU) with the consensus sequence 5'-GCCGGNNCCGGC-3'. The DNA-binding motif of Leu3p belongs to the family of Zn(II)2-Cys6 clusters. The motif is located between amino acid residues 37 and 67 of the 886-residue protein. In this study, we used a recombinant peptide consisting of residues 17 to 147 to explore the interaction between Leu3p and its cognate DNA. We found that the Leu3p(17-147) peptide is a monomer in the absence of UASLEU but assumes a dimeric structure when the DNA is present. Results of protein-DNA cross-linking and methylation and ethylation interference footprinting experiments show that the Leu3p(17-147) dimer interacts symmetrically with two contact triplets separated by 6 bp and suggest that the peptide approaches its target DNA in such a way that each subunit is positioned closer to one DNA strand than to the other. The binding of Leu3p is strongly affected by the spacing between the contact triplets of the UASLEU and by the type of triplet. Binding occurs when the triplets are 6 bp apart (normal spacing) but fails to occur when the triplets are 0, 5, or 8 bp apart. Weak binding occurs when the triplets are 7 bp apart. Binding does not occur when the UASLEU triplets (GCC....GGC) are replaced with triplets found in the UAS elements for Gal4p, Put3p, and Ppr1p (CGG....CCG). The apparent Kd for the normal Leu3p(17-147)-UASLEU complex is about 3 nM. A mutant form of Leu3p(17-147) in which the histidine at position 50 has been replaced with cysteine binds UASLEU with significantly greater affinity (apparent Kd of about 0.7 nM), even though the interaction between the mutant peptide and target DNA appears to be unchanged. Interestingly, repression of basal-level transcription, which is a hallmark property of the wild-type Leu3p(17-147) peptide, is

  13. Comparisons of phosphorus ligation properties in P(CH2NR)3P.

    PubMed

    Thirupathi, Natesan; Stricklen, Phillip M; Liu, Xiaodong; Oshel, Reed; Guzei, Ilia; Ellern, Arkady; Verkade, John G

    2007-10-29

    Bicyclic P(CH2NMe)3P was synthesized, and its reactions with MnO2, elemental sulfur, p-toluenesulfonyl azide, BH3.THF, and W(CO)5(THF) were shown to furnish a variety of products in which the PC3 and/or the PN3 phosphorus are oxidized/coordinated. In contrast, reactions of the previously known P(CH2NPh)3P with Mo(0) and Ru(II) precursors were shown to afford products in which only the PC3 phosphorus is coordinated. The contrast in reactivity of P(CH2NR)3P (R = Me, Ph) with the aforementioned reagents is discussed in terms of steric and electronic factors. The new compounds are characterized by analytical and spectroscopic (IR, 1H, 31P, and 13C NMR) methods. The results of crystal and molecular structure X-ray analyses of the previously known compounds P(CH2O)3P and P(CH2NPh)3P and 6 of the 14 new compounds obtained in this investigation are presented. Salient features of these structures and the analysis of the Tolman cone angles calculated from their structural parameters are discussed in terms of the effects of constraint in the bicyclic moieties. Evidence is presented for greater M-P sigma bonding effects on coordination of the PC3 phosphorus of P(CH2NR)3P (R = Me, Ph) than are present in PMe3 analogues of group 6B metal carbonyls. From 1JBP data on the BH3 adducts of P(CH2NMe)3P, it is suggested that the free bases MeC(CH2NMe)3P < P(CH2NMe)3P < (Me2N)3P < P(MeNCH2CH2)3N increase in Lewis basicity at the PN3 phosphorus in the order shown. Substantial differences in 31P chemical shifts in the bicyclic compounds discussed herein relative to their acyclic analogues do not seem to be associated with the relatively small bond angle changes that occur around either the PN3 or the PC3 trivalent phosphorus atoms. PMID:17892282

  14. Transduction of Recombinant M3-p53-R12 Protein Enhances Human Leukemia Cell Apoptosis

    PubMed Central

    Lu, Tsung Chi; Zhao, Guan- Hao; Chen, Yao Yun; Chien, Chia-Ying; Huang, Chi-Hung; Lin, Kwang Hui; Chen, Shen Liang

    2016-01-01

    Tumor suppressor protein p53 plays important roles in initiating cell cycle arrest and promoting tumor cell apoptosis. Previous studies have shown that p53 is either mutated or defective in approximately 50% of human cancers; therefore restoring normal p53 activity in cancer cells might be an effective anticancer therapeutic approach. Herein, we designed a chimeric p53 protein flanked with the MyoD N-terminal transcriptional activation domain (amino acids 1-62, called M3) and a poly-arginine (R12) cell penetrating signal in its N-and C-termini respectively. This chimeric protein, M3-p53-R12, can be expressed in E. coli and purified using immobilized metal ion chromatography followed by serial refolding dialysis. The purified M3-p53-R12 protein retains DNA-binding activity and gains of cell penetrating ability. Using MTT assay, we demonstrated that M3-p53-R12 inhibited the growth of K562, Jurkat as well as HL-60 leukemia cells carrying mutant p53 genes. Results from FACS analysis also demonstrated that transduction of M3-p53-R12 protein induced cell cycle arrest of these leukemia cells. Of special note, M3-p53-R12 has no apoptotic effect on normal mesenchymal stem cells (MSC) and leukocytes, highlighting its differential effects on normal and tumor cells. To sum up, our results reveal that purified recombinant M3-p53-R12 protein has functions of suppressing the leukemia cell lines' proliferation and launching cell apoptosis, suggesting the feasibility of using M3-p53-R12 protein as an anticancer drug. In the future we will test whether this chimeric protein can preferentially trigger the death of malignant cancer cells without affecting normal cells in animals carrying endogenous or xenographic tumors. PMID:27390612

  15. Whole genome sequencing reveals genetic heterogeneity of G3P[8] rotaviruses circulating in Italy.

    PubMed

    Medici, Maria Cristina; Tummolo, Fabio; Martella, Vito; Arcangeletti, Maria Cristina; De Conto, Flora; Chezzi, Carlo; Magrì, Alessandro; Fehér, Enikő; Marton, Szilvia; Calderaro, Adriana; Bányai, Krisztián

    2016-06-01

    After a sporadic detection in 1990s, G3P[8] rotaviruses emerged as a predominant genotype during recent years in many areas worldwide, including parts of Italy. The present study describes the molecular epidemiology and evolution of G3P[8] rotaviruses detected in Italian children with gastroenteritis during two survey periods (2004-2005 and 2008-2013). Whole genome of selected G3P[8] strains was determined and antigenic differences between these strains and rotavirus vaccine strains were analyzed. Among 819 (271 in 2004-2005 and 548 in 2008-2013) rotaviruses genotyped during the survey periods, the number of G3P[8] rotavirus markedly varied over the years (0/83 in 2004, 30/188 in 2005 and 0/96 in 2008, 6/88 in 2009, 4/97 in 2010, 0/83 in 2011, 9/82 in 2012, 56/102 cases in 2013). The genotypes of the 11 gene segments of 15 selected strains were assigned to G3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1; thus all strains belonged to the Wa genogroup. Phylogenetic analysis of the Italian G3P[8] strains showed a peculiar picture of segregation with a 2012 lineage for VP1-VP3, NSP1, NSP2, NSP4 and NSP5 genes and a 2013 lineage for VP6, NSP1 and NSP3 genes, with a 1.3-20.2% nucleotide difference from the oldest Italian G3P[8] strains. The genetic variability of the Italian G3P[8] observed in comparison with sequences of rotaviruses available in GenBank suggested a process of selection acting on a global scale, rather than the emergence of local strains, as several lineages were already circulating globally. Compared with the vaccine strains, the Italian G3P[8] rotaviruses segregated in different lineages (5-5.3% and 7.2-11.4% nucleotide differences in the VP7 and VP4, respectively) with some mismatches in the putative neutralizing epitopes of VP7 and VP4 antigens. The accumulation of point mutations and amino acid differences between vaccine strains and currently circulating rotaviruses might generate, over the years, vaccine-resistant variants. PMID:26980605

  16. Puf3p induces translational repression of genes linked to oxidative stress

    PubMed Central

    Rowe, William; Kershaw, Christopher J.; Castelli, Lydia M.; Costello, Joseph L.; Ashe, Mark P.; Grant, Christopher M.; Sims, Paul F. G.; Pavitt, Graham D.; Hubbard, Simon J.

    2014-01-01

    In response to stress, the translation of many mRNAs in yeast can change in a fashion discordant with the general repression of translation. Here, we use machine learning to mine the properties of these mRNAs to determine specific translation control signals. We find a strong association between transcripts acutely translationally repressed under oxidative stress and those associated with the RNA-binding protein Puf3p, a known regulator of cellular mRNAs encoding proteins targeted to mitochondria. Under oxidative stress, a PUF3 deleted strain exhibits more robust growth than wild-type cells and the shift in translation from polysomes to monosomes is attenuated, suggesting puf3Δ cells perceive less stress. In agreement, the ratio of reduced:oxidized glutathione, a major antioxidant and indicator of cellular redox state, is increased in unstressed puf3Δ cells but remains lower under stress. In untreated conditions, Puf3p migrates with polysomes rather than ribosome-free fractions, but this is lost under stress. Finally, reverse transcriptase-polymerase chain reaction (RT-PCR) of Puf3p targets following affinity purification shows Puf3p-mRNA associations are maintained or increased under oxidative stress. Collectively, these results point to Puf3p acting as a translational repressor in a manner exceeding the global translational response, possibly by temporarily limiting synthesis of new mitochondrial proteins as cells adapt to the stress. PMID:24163252

  17. miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

    PubMed Central

    De Cecco, Loris; Dugo, Matteo; Cassinelli, Giuliana; Pilotti, Silvana; Degl'Innocenti, Debora; Lanzi, Cinzia; Casalini, Patrizia; Pierotti, Marco A.; Greco, Angela; Borrello, Maria Grazia

    2014-01-01

    Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC. PMID:24810336

  18. A case of partial trisomy 3p syndrome with rare clinical manifestations

    PubMed Central

    Han, Dong Hoon; Lee, Woo In; Bae, Chong Woo

    2012-01-01

    Partial trisomy 3p results from either unbalanced translocation or de novo duplication. Common clinical features consist of dysmorphic facial features, congenital heart defects, psychomotor and mental retardation, abnormal muscle tone, and hypoplastic genitalia. In this paper, we report a case of partial trisomy 3p with rare clinical manifestations. A full-term, female newborn was transferred to our clinic. She had cleft lip-plate, dysgenesis of the corpus callosum, patent ductus arteriosus, pulmonary hypertension, and severe right-sided hydronephrosis, associated with ureteropelvic junction obstruction. Cytogenetic investigation revealed partial trisomy 3p; 46,XX,der(4)t(3;4) (p21.1;p16). The karyotype of her father showed a balanced translocation, t(3;4)(p21.1;p16). Therefore, the size of duplication can be an important factor. PMID:22474466

  19. Magnetic trapping of Yb in the metastable {sup 3}P{sub 2} state

    SciTech Connect

    Pandey, Kanhaiya; Rathod, K. D.; Pal, Sambit Bikas; Natarajan, Vasant

    2010-03-15

    We report magnetic trapping of Yb in the excited {sup 3}P{sub 2} state. This state, with a lifetime of 15 s, could play an important role in studies ranging from optical clocks and quantum computation to the search for a permanent electric dipole moment. Yb atoms are first cooled and trapped in the ground state in a 399-nm magneto-optic trap. The cold atoms are then pumped into the excited state by driving the {sup 1}S{sub 0{yields}}{sup 3}P{sub 1{yields}}{sup 3}S{sub 1} transition. Atoms in the {sup 3}P{sub 2} state are magnetically trapped in a spherical quadrupole field with an axial gradient of 110 G/cm. We trap up to 10{sup 6} atoms with a lifetime of 1.5 s.

  20. Effects of Magnetic Field and Rotation on 3P2 Superfluidity in Neutron Stars

    NASA Astrophysics Data System (ADS)

    Masuda, Kota; Nitta, Muneto

    2014-09-01

    It is believed that an anisotropic 3P2 superfluid state is realized in the core of neutron stars. Historically, a lot of works (Anderson et al. (1961), Hoffberg et al. (1970) and Tamagaki (1970)) discussed the properties of 3P2 superfluid state. Ginzburg-Landau (GL) equation was derived by Fujita, Tsuneto (1972) and Richardson (1972). After that, Mermin (1974) solved the problem of minimizing GL free energy density for d-wave pairing and showed what ground states are realized. By using these results, Sauls and Serene (1978) concluded that the unitary phase is realized in BCS limit, and Sauls et al. (1982) showed 3P2 vortices have a spontaneous magnetization. In this presentation, we firstly introduce GL equation and show some analogy to that of spin2-BEC. In BCS limit, degenerate ground states are parameterized by one parameter. We show effects of gradient terms, magnetic field and rotation on ground states and half-quantized 3P2 vortices are the most stable states under certain conditions. Next, by using an anisotropic GL equation, we discuss a spontaneous magnetization caused by half-quantized 3P2 vortices and compare results with that of integer vortices. Finally, we comment on possible effects of 3P2 superfluid state on neutron star observables. It is believed that an anisotropic 3P2 superfluid state is realized in the core of neutron stars. Historically, a lot of works (Anderson et al. (1961), Hoffberg et al. (1970) and Tamagaki (1970)) discussed the properties of 3P2 superfluid state. Ginzburg-Landau (GL) equation was derived by Fujita, Tsuneto (1972) and Richardson (1972). After that, Mermin (1974) solved the problem of minimizing GL free energy density for d-wave pairing and showed what ground states are realized. By using these results, Sauls and Serene (1978) concluded that the unitary phase is realized in BCS limit, and Sauls et al. (1982) showed 3P2 vortices have a spontaneous magnetization. In this presentation, we firstly introduce GL equation and

  1. Activation energies for addition of O/3P/ to simple olefins.

    NASA Technical Reports Server (NTRS)

    Demore, W. B.

    1972-01-01

    Description of relative rate measurements for the addition of O(3P) to C2H4, C2F4, C3H6, and C4H8-1 in liquid argon at 87.5 K. The data strongly indicate that the activation energies for the addition of O(3P) to the double bonds of propylene and butene-1 are identical, probably to within 0.1 kcal/mole. It is very doubtful that differences in pre-exponential factors or other factors such as solvent effects, could invalidate this conclusion. A similar argument holds for the C2H4 and C2F4 reactions. Furthermore, the experiments suggest that the activation energy for addition of O(3P) to the double bond of butene-1 is about 0.1 kcal/mole.

  2. Quantitative determination of the O({sup 3}P) density via visible cavity-enhanced spectroscopy

    SciTech Connect

    Gupta, Manish; Owano, Thomas; Baer, Douglas; O'Keefe, Anthony

    2006-12-11

    A simple method has been developed to quantitatively measure the ground state oxygen atom, O({sup 3}P), density. The technique exploits cavity-enhanced spectroscopy to probe the relatively weak O({sup 1}D)(leftarrow)O({sup 3}P{sub 1}) transition near 636 nm. O({sup 3}P{sub 1}) densities of approximately 3.4x10{sup 14} at./cm{sup 3} were measured in an inductively coupled plasma produced within a high-finesse optical cavity, and a minimum detectable atom state density of 1.3x10{sup 12} at./cm{sup 3} was determined. The absorption profile yielded a translational temperature of 453 K. The technique can be readily extended to other atomic species.

  3. Influence of Optical Properties on the Spin Polarization of Cu3P Photoelectrons

    NASA Astrophysics Data System (ADS)

    Chassé, A.; Niebergall, L.

    We have investigated the influence of optical properties of Cu(001) on the spin polarization in Cu3p photoelectron diffraction patterns. The refraction and absorption of light have been taken into account in the calculation of the dipole transition matrix element. Therefore, a general polarization vector of light is defined within a macroscopic theory of electromagnetic fields. Results are shown and discussed for Cu3p photoelectrons excited by linearly or circularly polarized light, respectively. It is shown that the optical behavior of crystals may cause a symmetry breaking in the angular dependence of the photoelectron intensity. Besides, there are strong quantitative changes in the related spin polarization of Cu3p photoelectrons.

  4. Determination of the lifetime of the Mercury 6/3/P-1 state

    NASA Technical Reports Server (NTRS)

    Halstead, J. A.; Reeves, R. R.

    1982-01-01

    A pulsed tunable dye laser was used for a high resolution experimental study of mercury fluorescence from the 6(3)P-1 state. The output of the dye laser was frequency doubled into the 253.7 nm region using a potassium pentaborate crystal. Exponential decays were separately observed for each of the five individual components of the hyperfine structure and the effects of the trapping of resonance radiation on the observed lifetime of the 6(3)P-1 state of mercury were investigated for each resolvable component. Within experimental error, the natural radiative lifetime of the 6(3)P-1 state was found to be independent of the hyperfine component irradiated and a value of 122 + or 2 nsec was obtained, consistent with results found by other methods.

  5. Molecular characterization of bovine group A rotavirus G3P[3] strains.

    PubMed

    Ghosh, S; Varghese, V; Samajdar, S; Sinha, M; Kobayashi, N; Naik, T N

    2007-01-01

    During a surveillance study, four of 130 group A rotavirus strains, detected from diarrheic calves in Eastern India, exhibited G3P[3] specificities. Molecular characterization of VP7 and VP8(*) genes of one such strain [named as RUBV3 (RU: ruminant and BV: bovine)] revealed genetic relatedness to a G3P[3] simian strain, RRV, and RRV-related caprine strain GRV. Strain RUBV3 had VP6, NSP4 and NSP5 genes of bovine origin. Therefore, the present study provides evidence for multiple reassortment events involving ruminant and simian strains and, to our knowledge, is the first report of detection of bovine group A rotavirus strains with G3P[3] specificities. PMID:17577612

  6. Experimental and theoretical study of 3p photoionization and subsequent Auger decay in atomic chromium

    NASA Astrophysics Data System (ADS)

    Keskinen, J.; Huttula, S.-M.; Mäkinen, A.; Patanen, M.; Huttula, M.

    2015-12-01

    3p photoionization and subsequent low kinetic energy Coster-Kronig and super Coster-Kronig Auger decay have been studied in atomic chromium. The binding energies, line widths, and relative intensities for the transitions seen in the synchrotron radiation excited 3p photoelectron spectrum are determined. The high resolution M2,3 M4,5 M4,5 and M2,3 M4,5 N1 Auger electron spectra following the electron impact excited 3p ionization are presented and the kinetic energies, relative intensities, and identifications are given for the main lines. The experimental findings are compared with the theoretical predictions obtained from Hartree-Fock and multiconfiguration Dirac-Fock approaches.

  7. BOREAS Level-3p Landsat TM Imagery: Geocoded and Scaled At-sensor Radiance

    NASA Technical Reports Server (NTRS)

    Nickeson, Jaime; Knapp, David; Newcomer, Jeffrey A.; Hall, Forrest G. (Editor); Cihlar, Josef

    2000-01-01

    For BOReal Ecosystem-Atmosphere Study (BOREAS), the level-3p Landsat Thematic Mapper (TM) data were used to supplement the level-3s Landsat TM products. Along with the other remotely sensed images, the Landsat TM images were collected in order to provide spatially extensive information over the primary study areas. This information includes radiant energy, detailed land cover, and biophysical parameter maps such as Fraction of Photosynthetically Active Radiation (FPAR) and Leaf Area Index (LAI). Although very similar to the level-3s Landsat TM products, the level-3p images were processed with ground control information, which improved the accuracy of the geographic coordinates provided. Geographically, the level-3p images cover the BOREAS Northern Study Area (NSA) and Southern Study Area (SSA). Temporally, the four images cover the period of 20-Aug-1988 to 07-Jun-1994. Except for the 07-Jun-1994 image, which contains seven bands, the other three contain only three bands.

  8. Angle-resolved photoemission extended fine structure of the Ni 3p, Cu 3s, and Cu 3p core levels of the respective clean (111) surfaces

    SciTech Connect

    Huff, W.R. |; Chen, Y.; Kellar, S.A.; Moler, E.J. |; Hussain, Z.; Huang, Z.Q.; Zheng, Y.; Shirley, D.A.

    1997-07-01

    We report a non-s initial-state angle-resolved photoemission extended fine-structure (ARPEFS) study of clean surfaces for the purpose of further understanding the technique. The surface structure sensitivity of ARPEFS applied to clean surfaces and to arbitrary initial states is studied using normal photoemission data taken from the Ni 3p core levels of a Ni(111) single crystal and the Cu 3s and the Cu 3p core levels of a Cu(111) single crystal. The Fourier transforms of these clean surface data are dominated by backscattering. Unlike the s initial-state data, the p initial-state data show a peak in the Fourier transform corresponding to in-plane scattering from the six nearest neighbors to the emitter. Evidence was seen for single-scattering events from the same plane as the emitters and double-scattering events. Using a recently developed, multiple-scattering calculation program, ARPEFS data from clean surfaces and from p initial states can be modeled to high precision. Although there are many layers of emitters when measuring photoemission from a clean surface, test calculations show that the ARPEFS signal is dominated by photoemission from atoms in the first two crystal layers. Thus ARPEFS applied to clean surfaces is sensitive to surface reconstruction. The best-fit calculation for clean Ni(111) indicates an expansion of the first two layers. {copyright} {ital 1997} {ital The American Physical Society}

  9. Excitation of the 3p states in electron-sodium scattering at intermediate energies

    SciTech Connect

    Kamali, M. Z. M.; Wong, B. R.; Chin, J. H.; Ratnavelu, K.

    2014-03-05

    A coupled-channel-optical method (CCOM), to investigate the excitation of the 3p states for e{sup −}-Na scattering at intermediate energies, is reported. Nine atomic states( Na(3s), Na(3p), Na(4s), Na(3d), Na(4p), Na(5s), Na(4d), Na(5p), Na(5d) ) together with three optical potentials are used in this work. The inelastic differential cross sections (DCS) as well as the reduced Stokes parameters are compared with latest theoretical data and experimental measurements.

  10. Chromosome 3p microsatellite allelotyping in neuroblastoma: a report on the technical hurdles.

    PubMed

    Hoebeeck, Jasmien; De Wilde, Bram; Michels, Evi; Combaret, Valérie; Yigit, Nurten; De Smet, Els; Van Roy, Nadine; Stanbridge, Eric; Ru, Ning; Laureys, Geneviève; De Paepe, Anne; Speleman, Frank; Vandesompele, Jo

    2009-10-01

    Pinpointing critical regions of recurrent loss may help localize tumor suppressor genes. To determine the regions of loss on chromosome 3p in neuroblastoma, we performed loss of heterozygosity analysis using 16 microsatellite markers in a series of 65 primary tumors and 29 neuroblastoma cell lines. In this study, we report the results and discuss the technical hurdles that we encountered during data generation and interpretation that are of relevance for current studies or tests employing microsatellites. To provide functional support for the implication of 3p tumor suppressor genes in this childhood malignancy, we performed a microcell-mediated chromosome 3 transfer in neuroblastoma cells. PMID:19544108

  11. On the mechanism of populating 3p levels of neon under pumping by a hard ioniser

    SciTech Connect

    Khasenov, M U

    2011-03-31

    The effect of quenching additives on the luminescence properties of helium - neon mixtures under pumping by {alpha} particles emitted from {sup 210}Po atoms is considered. It is concluded that, under excitation by a heavy charged particle, the population of the 3p'[1/2]{sub 0} level of neon is not related to the dissociative recombination of molecular ions. It is suggested that the most likely channels for populating the 3p level are the excitation transfer from metastable helium atoms to neon atoms and direct excitation of neon by nuclear particles and secondary electrons. (lasers and active media)

  12. MicroRNA-142-3p Negatively Regulates Canonical Wnt Signaling Pathway

    PubMed Central

    Hu, Tanyu; Phiwpan, Krung; Guo, Jitao; Zhang, Wei; Guo, Jie; Zhang, Zhongmei; Zou, Mangge; Zhang, Xuejie; Zhang, Jianhua

    2016-01-01

    Wnt/β-catenin signaling pathway plays essential roles in mammalian development and tissue homeostasis. MicroRNAs (miRNAs) are a class of regulators involved in modulating this pathway. In this study, we screened miRNAs regulating Wnt/β-catenin signaling by using a TopFlash based luciferase reporter. Surprisingly, we found that miR-142 inhibited Wnt/β-catenin signaling, which was inconsistent with a recent study showing that miR-142-3p targeted Adenomatous Polyposis Coli (APC) to upregulate Wnt/β-catenin signaling. Due to the discordance, we elaborated experiments by using extensive mutagenesis, which demonstrated that the stem-loop structure was important for miR-142 to efficiently suppress Wnt/β-catenin signaling. Moreover, the inhibitory effect of miR-142 relies on miR-142-3p rather than miR-142-5p. Further, we found that miR-142-3p directly modulated translation of Ctnnb1 mRNA (encoding β-catenin) through binding to its 3’ untranslated region (3’ UTR). Finally, miR-142 was able to repress cell cycle progression by inhibiting active Wnt/β-catenin signaling. Thus, our findings highlight the inhibitory role of miR-142-3p in Wnt/β-catenin signaling, which help to understand the complex regulation of Wnt/β-catenin signaling. PMID:27348426

  13. The 3P0-VERSUS 3S1-MODELS for Quark-Antiquark Annihilation

    NASA Astrophysics Data System (ADS)

    Green, A. M.; Niskanen, J. A.

    A comparison is made between the 3S1- and 3P0-models for quark-antiquark annihilation or creation. Even though the former appears, at first sight, to be superior for Nbar {N} annihilation into two mesons, it is argued from their effects in meson decays that this conclusion is premature.

  14. Toward a 3-P Model of Workplace Learning: A Literature Review

    ERIC Educational Resources Information Center

    Tynjala, Paivi

    2013-01-01

    The interest in research focusing on learning taking place at work, through work and for work has considerably increased over the past two decades. The purpose of the paper is to review and structure this wide and diverse research field. A tentative holistic model--the 3-P model of workplace learning--is presented, in relation to which the…

  15. miR-200a-3p regulates TLR1 expression in bacterial challenged miiuy croaker.

    PubMed

    Wang, Yanjin; Xu, Guoliang; Han, Jingjing; Xu, Tianjun

    2016-10-01

    MicroRNAs (miRNAs) are highly conserved, small non-coding RNAs which post-transcriptionally regulate various biological processes by repressing mRNA translation or degradating mRNA. It has been demonstrated that miRNAs play crucial roles in regulating the immune system. In this study, we explored the potential roles of miR-200a-3p in regulating TLR signaling pathway in miiuy croaker. Bioinformatics analysis showed that miiuy croaker TLR1 (mmiTLR1) was a putative target of miR-200a-3p. Negative expression profiles in spleen of Vibrio anguillarum challenged miiuy croaker and in lipopolysaccharide (LPS) stimulated miiuy croaker leukocytes further validated the prediction. Luciferase reporter assays showed that the dual-luciferase reporter fused to the 3'UTR of wild type mmiTLR1 cotransfected with miR-200a-3p mimics exhibited a reduction in luciferase activity compared with the controls. All of the present data provide direct evidence that miR-200a-3p is involved in TLR1 expression modulation in miiuy croaker, which will offer a basis for better understanding of miRNA regulation in fish TLR signaling pathways. PMID:27288848

  16. Selective removal of either metastable species from a mixed 3P 0,2 rare-gas metastable beam

    NASA Technical Reports Server (NTRS)

    Dunning, F. B.; Cook, T. B.; West, W. P.; Stebbings, R. F.

    1975-01-01

    A tunable CW laser has been used to selectively remove either of the two metastable species, 3P 0,2, which are initially present in a neon metastable beam. The method is applicable to other rare gases and provides the opportunity for separate investigation of effects due to atoms in either the 3P 0 or 3P 2 state.

  17. Transition probabilities for the 3s2 3p(2P0)-3s3p2(4P) intersystem lines of Si II

    NASA Technical Reports Server (NTRS)

    Calamai, Anthony G.; Smith, Peter L.; Bergeson, S. D.

    1993-01-01

    Intensity ratios of lines of the spin-changing 'intersystem' multiplet of S II (4P yields 2P0) at 234 nm have been used to determine electron densities and temperatures in a variety of astrophysical environments. However, the accuracy of these diagnostic calculations have been limited by uncertainties associated with the available atomic data. We report the first laboratory measurement, using an ion-trapping technique, of the radiative lifetimes of the three metastable levels of the 3s3p2 4P term of Si II. Our results are 104 +/- 16, 406 +/- 33, and 811 +/- 77 micro-s for lifetimes of the J = 1/2, 5/2, and 3/2 levels, respectively. A-values were derived from our lifetimes by use of measured branching fractions. Our A-values, which differ from calculated values by 30 percent or more, should give better agreement between modeled and observed Si II line ratios.

  18. Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces cerevisiae.

    PubMed Central

    Kshirsagar, Meenakshi; Parker, Roy

    2004-01-01

    The major pathway of mRNA decay in yeast initiates with deadenylation, followed by mRNA decapping and 5'-3' exonuclease digestion. An in silico approach was used to identify new proteins involved in the mRNA decay pathway. One such protein, Edc3p, was identified as a conserved protein of unknown function having extensive two-hybrid interactions with several proteins involved in mRNA decapping and 5'-3' degradation including Dcp1p, Dcp2p, Dhh1p, Lsm1p, and the 5'-3' exonuclease, Xrn1p. We show that Edc3p can stimulate mRNA decapping of both unstable and stable mRNAs in yeast when the decapping enzyme is compromised by temperature-sensitive alleles of either the DCP1 or the DCP2 genes. In these cases, deletion of EDC3 caused a synergistic mRNA-decapping defect at the permissive temperatures. The edc3Delta had no effect when combined with the lsm1Delta, dhh1Delta, or pat1Delta mutations, which appear to affect an early step in the decapping pathway. This suggests that Edc3p specifically affects the function of the decapping enzyme per se. Consistent with a functional role in decapping, GFP-tagged Edc3p localizes to cytoplasmic foci involved in mRNA decapping referred to as P-bodies. These results identify Edc3p as a new protein involved in the decapping reaction. PMID:15020463

  19. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1.

    PubMed

    Cai, Qiuyin; Zhang, Ben; Sung, Hyuna; Low, Siew-Kee; Kweon, Sun-Seog; Lu, Wei; Shi, Jiajun; Long, Jirong; Wen, Wanqing; Choi, Ji-Yeob; Noh, Dong-Young; Shen, Chen-Yang; Matsuo, Keitaro; Teo, Soo-Hwang; Kim, Mi Kyung; Khoo, Ui Soon; Iwasaki, Motoki; Hartman, Mikael; Takahashi, Atsushi; Ashikawa, Kyota; Matsuda, Koichi; Shin, Min-Ho; Park, Min Ho; Zheng, Ying; Xiang, Yong-Bing; Ji, Bu-Tian; Park, Sue K; Wu, Pei-Ei; Hsiung, Chia-Ni; Ito, Hidemi; Kasuga, Yoshio; Kang, Peter; Mariapun, Shivaani; Ahn, Sei Hyun; Kang, Han Sung; Chan, Kelvin Y K; Man, Ellen P S; Iwata, Hiroji; Tsugane, Shoichiro; Miao, Hui; Liao, Jiemin; Nakamura, Yusuke; Kubo, Michiaki; Delahanty, Ryan J; Zhang, Yanfeng; Li, Bingshan; Li, Chun; Gao, Yu-Tang; Shu, Xiao-Ou; Kang, Daehee; Zheng, Wei

    2014-08-01

    In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified 3 genetic loci newly associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene; P=8.82×10(-9)), rs10474352 at 5q14.3 (near the ARRDC3 gene; P=1.67×10(-9)) and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene; P=4.25×10(-8)). We replicated these associations in 16,003 cases and 41,335 controls of European ancestry (P=0.030, 0.004 and 0.010, respectively). Data from the ENCODE Project suggest that variants rs4951011 and rs10474352 might be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. PMID:25038754

  20. Mapping of the {beta}{sub 2} subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABA{sub A} receptor isoform

    SciTech Connect

    Russek, S.J.; Farb, D.H. |

    1994-10-01

    The {gamma}-aminobutyric acid receptor (GABA{sub A}R) is a multisubunit Cl{sup -} channel that mediates most fast inhibitory synaptic transmission in the central nervous system. Molecular evolution has given rise to many genetic variants of GABA{sub A}R subunits, including {alpha}{sub 1-6}, {beta}{sub 1-4}, {gamma}{sub 1-4}, {sigma}, and {rho}{sub 1-2}, suggesting that an enormous number of combinations of subunits are possible. Here we report that the {beta}{sub 2} gene is located on chromosome 5q34-q35, defining a cluster comprising {alpha}{sub 1}, {beta}{sub 2}, and {gamma}{sub 2} genes that together code for the most abundant GABA{sub A}R isoform. The fact that intron position is conserved in the {beta}{sub 1-3} genes, taken together with the observation that chromosomes 4 and 15 also contain distinct {alpha}-{beta}-{gamma} gene clusters, strongly suggests that an ancestral {alpha}-{beta}-{gamma} cluster was duplicated and translocated to at least two different chromosomes. This organization of GABA{sub A}R gene clusters may have been preserved as linkage provides a mechanism for facilitating coordinate gene expression. 34 refs., 5 figs., 1 tab.

  1. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1

    PubMed Central

    Cai, Qiuyin; Zhang, Ben; Sung, Hyuna; Low, Siew-Kee; Kweon, Sun-Seog; Lu, Wei; Shi, Jiajun; Long, Jirong; Wen, Wanqing; Choi, Ji-Yeob; Noh, Dong-Young; Shen, Chen-Yang; Matsuo, Keitaro; Teo, Soo-Hwang; Kim, Mi Kyung; Khoo, Ui Soon; Iwasaki, Motoki; Hartman, Mikael; Takahashi, Atsushi; Ashikawa, Kyota; Matsuda, Koichi; Shin, Min-Ho; Park, Min Ho; Zheng, Ying; Xiang, Yong-Bing; Ji, Bu-Tian; Park, Sue K.; Wu, Pei-Ei; Hsiung, Chia-Ni; Ito, Hidemi; Kasuga, Yoshio; Kang, Peter; Mariapun, Shivaani; Ahn, Sei Hyun; Kang, Han Sung; Chan, Kelvin Y. K.; Man, Ellen P. S.; Iwata, Hiroji; Tsugane, Shoichiro; Miao, Hui; Liao, Jiemin; Nakamura, Yusuke; Kubo, Michiaki; Delahanty, Ryan J.; Zhang, Yanfeng; Li, Bingshan; Li, Chun; Gao, Yu-Tang; Shu, Xiao-Ou; Kang, Daehee; Zheng, Wei

    2014-01-01

    In a three-stage genome-wide association study among East Asian women including 22,780 cases and 24,181 controls, we identified three novel genetic loci associated with breast cancer risk, including rs4951011 at 1q32.1 (in intron 2 of the ZC3H11A gene, P = 8.82 × 10−9), rs10474352 at 5q14.3 (near the ARRDC3 gene, P = 1.67 × 10−9), and rs2290203 at 15q26.1 (in intron 14 of the PRC1 gene, P = 4.25 × 10−8). These associations were replicated in European-ancestry populations including 16,003 cases and 41,335 controls (P = 0.030, 0.004, and 0.010, respectively). Data from the ENCODE project suggest that variants rs4951011 and rs10474352 may be located in an enhancer region and transcription factor binding sites, respectively. This study provides additional insights into the genetics and biology of breast cancer. PMID:25038754

  2. Assignment of the human pro-melanin-concentrating hormone gene (PMCH) to chromosome 12q23-q24 and two variant genes (PMCHL1 and PMCHL2) to chromosome 5p14 and 5q12-q13

    SciTech Connect

    Pedeutour, F. ); Szpirer, C. ); Nahon, J.L. )

    1994-01-01

    Melanin-concentrating hormone (MCH) is a peptide that has been isolated from salmon pituitary and rat hypothalamus. In mammals, pro-MCH (PMCH) encodes two putative peptides, named NEI and NGE, in addition to MCH. Those peptides are expressed predominantly in hypothalamus and display a broad array of functions in rat brain. The authors have previously mapped the PMCH locus on human chromosome 12q and rat chromosome 7. Genomic cloning has revealed the existence of two distinct MCH genes in human: one authentic and one variant. In this report, they describe Southern blotting analysis with DNA from a panel of somatic cell hybrids and demonstrate that the authentic human MCH (hMCH) gene is located as expected on chromosome 12, while the variant form of hMCH gene is located on chromosome 5. Direct chromosomal assignment of the authentic and variant hMCH genes was obtained by using fluorescence in situ hybridization on metaphase chromosomes. A strong signal was observed in 12q23-q24 with the authentic HMCH genomic DNA probe. Surprisingly, two signals were conspicuously found in 5p14 and 5q12-q13 with different variant hMCH genomic DNA probes. These loci were designated PMCHL1 and PMCHL2. Evidence of physiological and pathological data in rodents together with locus linkage analyses in human suggests that hMCH authentic and variant genes may be involved in human brain disorders. 44 refs., 3 figs., 1 tab.

  3. Photoelectric characteristics of CH3NH3PbI3/p-Si heterojunction

    NASA Astrophysics Data System (ADS)

    Yamei, Wu; Ruixia, Yang; Hanmin, Tian; Shuai, Chen

    2016-05-01

    Organic–inorganic hybrid perovskite CH3NH3PbI3 film is prepared on p-type silicon substrate using the one-step solution method to form a CH3NH3PbI3/p-Si heterojunction. The film morphology and structure are characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The photoelectric properties of the CH3NH3PbI3/p-Si heterojunction are studied by testing the current–voltage (I–V) with and without illumination and capacitance–voltage (C–V) characteristics. It turns out from the I–V curve without illumination that the CH3NH3PbI3/p-Si heterojunction has a rectifier feature with the rectification ratio over 70 at the bias of ±5 V. Also, there appears a photoelectric conversion phenomenon on this heterojunction with a short circuit current (Isc) of 0.16 μA and an open circuit voltage (Voc) of about 10 mV The high frequency C–V characteristic of the Ag/CH3NH3PbI3/p-Si heterojunction turns out to be similar to that of the metal–insulator–semiconductor (MIS) structure, and a parallel translation of the C–V curve along the forward voltage axis is found. This parallel translation means the existence of defects at the CH3NH3PbI3/p-Si interface and positive fixed charges in the CH3NH3PbI3 layer. The defects at the interface of the CH3NH3PbI3/p-Si heterojunction result in the dramatic decline of the Voc. Besides, the C–V test of CH3NH3PbI3 film shows a non-linear dielectric property and the dielectric value is about 4.64 as calculated. Project supported by the Hebei Province Natural Science Foundation of China (No. F2014202184) and the Tianjin Natural Science Foundation of China (No. 15JCZDJC37800).

  4. MiR-625-3p promotes cell migration and invasion via inhibition of SCAI in colorectal carcinoma cells.

    PubMed

    Zheng, Hailun; Ma, Renqiang; Wang, Qizhi; Zhang, Pei; Li, Dapeng; Wang, Qiangwu; Wang, Jianchao; Li, Huabin; Liu, Hao; Wang, Zhiwei

    2015-09-29

    MicroRNAs (miRNAs) play a critical role in controlling tumor invasion and metastasis via regulating the expression of a variety of targets, which act as oncogenes or tumor suppressor genes. Abnormally expressed miR-625-3p has been observed in several types of human cancers. However, the molecular mechanisms of miR-625-3p-mediated tumorigenesis are largely elusive. Therefore, the aim of this study was to evaluate the biological function and molecular insight on miR-625-3p-induced oncogenesis in colorectal carcinoma (CRC). The effects of miR-625-3p in cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. In addition, the expression of miR-625-3p and its targets was detected in five human CRC cell lines. In the present study, we found that overexpression of miR-625-3p promoted migration and invasion in SW480 cells, whereas downregulation of miR-625-3p inhibited cell motility in SW620 cells. More importantly, we observed potential binding sites for miR-625-3p in the 3'-untranslated region of suppressor of cancer cell invasion (SCAI). Notably, we identified that overexpression of miR-625-3p inhibited the expression of SCAI, while depletion of miR-625-3p increased SCAI level, suggesting that SCAI could be a target of miR-625-3p. Additionally, we revealed that miR-625-3p exerts its oncogenic functions through regulation of SCAI/E-cadherin/MMP-9 pathways. Our findings indicate the pivotal role of miR-625-3p in invasion that warrants further exploration whether targeting miR-625-3p could be a promising approach for the treatment of CRC. PMID:26314959

  5. MiR-625-3p promotes cell migration and invasion via inhibition of SCAI in colorectal carcinoma cells

    PubMed Central

    Wang, Qizhi; Zhang, Pei; Li, Dapeng; Wang, Qiangwu; Wang, Jianchao; Li, Huabin; Liu, Hao; Wang, Zhiwei

    2015-01-01

    MicroRNAs (miRNAs) play a critical role in controlling tumor invasion and metastasis via regulating the expression of a variety of targets, which act as oncogenes or tumor suppressor genes. Abnormally expressed miR-625-3p has been observed in several types of human cancers. However, the molecular mechanisms of miR-625-3p-mediated tumorigenesis are largely elusive. Therefore, the aim of this study was to evaluate the biological function and molecular insight on miR-625-3p-induced oncogenesis in colorectal carcinoma (CRC). The effects of miR-625-3p in cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. In addition, the expression of miR-625-3p and its targets was detected in five human CRC cell lines. In the present study, we found that overexpression of miR-625-3p promoted migration and invasion in SW480 cells, whereas downregulation of miR-625-3p inhibited cell motility in SW620 cells. More importantly, we observed potential binding sites for miR-625-3p in the 3′-untranslated region of suppressor of cancer cell invasion (SCAI). Notably, we identified that overexpression of miR-625-3p inhibited the expression of SCAI, while depletion of miR-625-3p increased SCAI level, suggesting that SCAI could be a target of miR-625-3p. Additionally, we revealed that miR-625-3p exerts its oncogenic functions through regulation of SCAI/E-cadherin/MMP-9 pathways. Our findings indicate the pivotal role of miR-625-3p in invasion that warrants further exploration whether targeting miR-625-3p could be a promising approach for the treatment of CRC. PMID:26314959

  6. Circulating microRNA 132-3p and 324-3p Profiles in Patients after Acute Aneurysmal Subarachnoid Hemorrhage

    PubMed Central

    Su, Xian Wei; Chan, Anna Ho Yin; Lu, Gang; Lin, Marie; Sze, Johnny; Zhou, Jing Ye; Poon, Wai Sang; Liu, Qiang; Zheng, Vera Zhi Yuan; Wong, George Kwok Chu

    2015-01-01

    Background Aneurysmal subarachnoid hemorrhage (SAH) is a highly morbid and fatal condition with high rate of cognitive impairment and negative impact in quality of life among survivors. Delayed cerebral infarction (DCI) is one the major factors for these negative outcomes. In this study we compared the circulating microRNA profiles of SAH patients and healthy individuals, and the circulating microRNA profiles of SAH patients with and without DCI. Methods Peripheral blood samples on Day 7 after the onset of SAH were subjected to microarray analysis with Affymetrix miRNA 3.0 array and quantitative PCR analysis. SAH patients with (N = 20) and without DCI (N = 20) and Healthy controls (N = 20) were included for analyses. Results We demonstrated that 99 miRNAs were found to be dysregulated in the SAH patient group with DCI. 81 miRNAs were upregulated and 18 were downregulated. Findings from KEGG pathway analysis showed that miRNAs and target genes for axon guidance and TGF-beta signaling were involved, implying that the resulted differential miRNA expression pattern reflect the results of SAH instead of etiology of the disease. miR-132-3p and miR-324-3p showed distinctive upregulations in qPCR [miR-132: 9.5 fold (95%CI: 2.3 to 16.7) in DCI group and 3.4 fold (95%CI: 1.0 to 5.8) in Non-DCI group; miR-324: 4924 fold (95%CI: 2620 to 7228) in DCI group and 4545 fold (95%CI: 2408 to 6683) in non-DCI group]. However, there were no significant differences in fold changes between SAH patients with and without DCI [fold change ratios (mean+/-SD): 2.7+/-4.2 and 1.1+/-1.1 for miRNA-132 and miRNA-324]. Conclusion Our study demonstrated that as compared to healthy control, miR-132 and miR-324 showed a upregulation in both SAH DCI and Non-DCI groups. However, the differences between the SAH DCI and non-DCI groups were not statistically significant. PMID:26675167

  7. Gamma-ray irradiation induced bulk photochromism in WO3-P2O5 glass

    NASA Astrophysics Data System (ADS)

    Shen, Wei; Baccaro, Stefania; Cemmi, Alessia; Xu, Xiaoqing; Chen, Guorong

    2015-11-01

    In the present work, photochromism of WO3-P2O5 glass under gamma-ray irradiation was reported. As-prepared glass samples with different WO3 content are all optically transparent in the visible wavelength range thanks to the addition of a small amount of oxidizing couple Sb2O3-NaNO3. The photochromic properties are identified by transmission spectra of the glasses before and after irradiation. The results show that the irradiation induced darkening results from the reduction of W6+ to W5+ or W4+. The existence of WO6 clusters in glasses of high WO3 content is proved by XPS, which is the main reason for the obvious photochromic effects. The WO3-P2O5 glass is a promising candidate in gamma-ray sensitive detector.

  8. Impurity scattering effect in Pd-doped superconductor SrPt3P

    NASA Astrophysics Data System (ADS)

    Hu, Kang-Kang; Gao, Bo; Ji, Qiu-Cheng; Ma, Yong-Hui; Zhang, Hui; Mu, Gang; Huang, Fu-Qiang; Cai, Chuan-Bing; Xie, Xiao-Ming

    2016-08-01

    We present a systematic study of the impurity scattering effect induced by Pd dopants in the superconductor SrPt3P. Using a solid-state reaction method, we fabricated the Pd-doped superconductor Sr(Pt1- x Pd x )3P.We found that the residual resistivity ρ 0 increases quickly with Pd doping, whereas the residual resistance ratio (RRR) displays a dramatic reduction. In addition, both the nonlinear field-dependent behavior of the Hall resistivity ρ xy and the strong temperature dependence of the Hall coefficient R H at low temperature are suppressed by Pd doping. All the experimental results can be explained by an increase in scattering by impurities induced by doping. Our results suggest that the Pt position is very crucial to the carrier conduction in the present system.

  9. Redox mechanism in the binary transition metal phosphide Cu3P

    NASA Astrophysics Data System (ADS)

    Mauvernay, B.; Doublet, M.-L.; Monconduit, L.

    2006-05-01

    The electrochemical behaviour of the binary transition metal phosphide Cu3P towards lithium is investigated through galvano- and potentiostatic measurements. Obtained through high-temperature synthesis, this system shows a better volumetric capacity than graphite and a good capacity retention. In situ X-ray diffraction and first-principles electronic structure calculations are combined with the electrochemical results to show that the complete insertion of 3Li+ in the Cu3P electrode proceeds with the formation of three intermediate phases of lithium composition LixCu(3-x)P (x=1,2,3). The extra capacity previously observed in discharge is now clearly assigned to lithium insertion into the CuP2 impurity and to SEI reactions.

  10. Synthesis and characterization of Zn 3P 2/ZnS core/shell nanowires

    NASA Astrophysics Data System (ADS)

    Sun, T.; Wu, P. C.; Guo, Z. D.; Dai, Y.; Meng, H.; Fang, X. L.; Shi, Z. J.; Dai, L.; Qin, G. G.

    2011-05-01

    Fully-surrounded Zn3P2/ZnS core/shell nanowires (NWs) were synthesized for the first time via a two-step method: a catalyst free chemical vapor deposition followed by a low-pressure vulcanization process. Field emission scanning electron microscopy, high-resolution transmission electron microscopy, and high-angle angular dark field scanning transmission electron microscopy were used to characterize the morphologies, crystal structure, and element composition of the core/shell NWs. The band structure analysis demonstrates that the Zn3P2/ZnS core-shell NW type-II heterostructures have bright potential in photovoltaic nanodevice applications. The core/shell NW growth method used here can be extended to other material system.

  11. Electron impact excitation of the 3s3p 1P1 state in magnesium

    NASA Astrophysics Data System (ADS)

    Predojević, Branko

    2006-12-01

    Differential cross sections (DCSs) for electron-impact excitation of the 3s3p 1P1 resonance state of magnesium have been measured at 10, 15, 20, 40, 60, 80 and 100 eV incident electron energies (Eo). Scattered-electron intensities were measured over wide range of scattering angles from 2° to 150°. The absolute DCS scale for the 1P1 state was determined through normalizations of its relative DCSs to optical oscillator strength using forward scattering function method, except at Eo ⩽ 15 eV where the excitation function of the 3s3p 1P1 state experimentally obtained by Leep and Gallagher (1976 Phys. Rev. A 13 148) was utilized for normalization. These absolute DCSs were extrapolated to 0° and 180° and numerically integrated to yield integral, momentum transfer and viscosity cross sections. Our results are compared with available experimental and theoretical data.

  12. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    PubMed

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  13. Molecular analysis of two patients with a duplicated 17p11.2 indicates that this entity may be the reciprocal of the deletion seen in Smith-Magenis syndrome

    SciTech Connect

    Brown, A.; Schwartz, C.; Rogers, R.C.

    1994-09-01

    J.M. and H.G. are two unrelated patients that presented at an early age with developmental delay and failure to thrive. Clinical features specific to J.M. include unusual facies, global developmental delay, and clinodactyly of the fifth toe. A cytogenetic analysis of H.G. was performed on amniocytes obtained due to a low MSAFP conducted as part of a routine screening. In both J.M. and H.G., a duplication of chromosome 17p11.2 was discovered. The extent of the duplicated region was determined using single copy DNA probes: cen-D17S58-D17S29-D17S258-D17S71-D17S445-tel. All of the markers were found to be duplicated by dosage analysis except for D17S58. FISH analysis of H.G., using the Smith-Magenis diagnostic probe obtained from ONCOR, also detected a duplication in 17p11.2. The chromosome containing the duplication could be the result of unequal crossing over due to a misalignment of the two chromosomes during meiosis I. It has been shown that the markers deleted in Smith-Magenis syndrome (SMS) patients are the same as those markers duplicated in J.M. and H.G. Therefore, the chromosomal duplication in 17p11.2 observed in these two patients could be the reciprocal of the chromosomal deletion seen in Smith-Magenis syndrome patients. Interestingly, a similar reciprocal duplication/deletion event is observed for CMT1A and HNPP (hereditary neuropathy with liability to pressure palsies) just distal to the SMS region.

  14. Whole-arm translocation of der(5;17)(p10;q10) with concurrent TP53 mutations in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS): A unique molecular-cytogenetic subgroup.

    PubMed

    Hong, Ming; Hao, Suyang; Patel, Keyur P; Kantarjian, Hagop M; Garcia-Manero, Guillermo; Yin, C Cameron; Medeiros, L Jeffrey; Lin, Pei; Lu, Xinyan

    2016-05-01

    Der(5;17)(p10;q10) is a recurrent but rare aberration reported in myeloid neoplasms (MNs). We report 48 such patients including 19 acute myeloid leukemia (AML) and 29 myelodysplastic syndrome (MDS), to characterize their clinicopathological features. There were 29 men and 19 women, with a median age of 61 years (range, 18-80). 62.5% patients had therapy-related diseases (t-MNs), 70.8% had multilineage dysplasia and 83.3% showed complex karyotypes. In 39 patients tested, FLT3, NPM1, CEBPA, KIT were all wild type and NRAS, KRAS, IDH1, APC, TET2 mutations were detected in single case(s) respectively. TP53 mutations were identified in 8 of 10 cases (80%) tested. Median disease-free survival (DFS) and overall survival (OS) were 3 and 10 months, respectively and did not differ between AML or MDS cases, or between de novo versus therapy-related cases, or between the groups with or without complex karyotypes. In 19 patients who achieved complete remission after chemotherapy, and in 9 patients who underwent stem cell transplantation, the OS was better (14 and 17.5 months, P = 0.0128 and P = 0.0086, respectively). The der(5;17)(p10;q10) represents a unique molecular-cytogenetic subgroup in t-MNs and, associated with complex karyotypes. TP53 inactivation, resulting from 17p deletion coupled with TP53 mutation, likely contributes to the poor clinical outcome of these patients. PMID:27134073

  15. Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells

    PubMed Central

    Zent, Clive S.; Taylor, Ronald P.; Lindorfer, Margaret A.; Beum, Paul V.; LaPlant, Betsy; Wu, Wenting; Call, Timothy G.; Bowen, Deborah A.; Conte, Michael J.; Frederick, Lori A.; Link, Brian K.; Blackwell, Sue E.; Veeramani, Suresh; Baig, Nisar A.; Viswanatha, David S.; Weiner, George J.; Witzig, Thomas E.

    2014-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  16. The Participative Design of an Endoscopy Facility using Lean 3P.

    PubMed

    Smith, Iain

    2016-01-01

    In the UK, bowel cancer is the second largest cancer killer. Diagnosing people earlier can save lives but demand for endoscopies is increasing and this can put pressure on waiting times. To address this challenge, an endoscopy unit in North East England decided to improve their facilities to increase capacity and create environments that improve the experience of users. This presented a significant opportunity for step change improvement but also a problem in terms of creating designs that meet user requirements whilst addressing structural or space constraints. The Lean design process known as '3P' (standing for the production preparation process) was utilised as a participative design strategy to engage stakeholders in the design of the new department. This involved a time-out workshop (or 3P event) in which Lean and participative design tools were utilised to create an innovative design based on 'point of delivery' (POD) principles. The team created a design that demonstrated an increase in treatment room capacity by 25% and bed capacity by 70% whilst reducing travel distance for patients by 25.8% and staff by 27.1%. This was achieved with an increase in available space of only 13%. The Lean 3P method provided a structured approach for corporate and clinical staff to work together with patient representatives as cross-functional teams. This participative approach facilitated communication and learning between stakeholders about care processes and personal preferences. Lean 3P therefore appears to be a promising approach to improving the healthcare facilities design process to meet user requirements. PMID:27493744

  17. [Chronic insomnia: treatment methods based on the current "3P" model of insomnia].

    PubMed

    Poluektov, M G; Pchelina, P V

    2015-01-01

    Authors consider one of the popular models of the pathogenesis of chronic insomnia--"3P" model. It explains the origin and course of insomnia on the basis of interaction of three factors: predisposing, precipitating and perpetuating. The role of each group of factors and its connection to the cerebral hyperarousal state is discussed. Different variants of cognitive-behavioral therapy and pharmacological treatment of chronic insomnia are described. PMID:26978509

  18. Omega3P: A Parallel Finite-Element Eigenmode Analysis Code for Accelerator Cavities

    SciTech Connect

    Lee, Lie-Quan; Li, Zenghai; Ng, Cho; Ko, Kwok; /SLAC

    2009-03-04

    Omega3P is a parallel eigenmode calculation code for accelerator cavities in frequency domain analysis using finite-element methods. In this report, we will present detailed finite-element formulations and resulting eigenvalue problems for lossless cavities, cavities with lossy materials, cavities with imperfectly conducting surfaces, and cavities with waveguide coupling. We will discuss the parallel algorithms for solving those eigenvalue problems and demonstrate modeling of accelerator cavities through different examples.

  19. WIPI proteins: essential PtdIns3P effectors at the nascent autophagosome.

    PubMed

    Proikas-Cezanne, Tassula; Takacs, Zsuzsanna; Dönnes, Pierre; Kohlbacher, Oliver

    2015-01-15

    Autophagy is a pivotal cytoprotective process that secures cellular homeostasis, fulfills essential roles in development, immunity and defence against pathogens, and determines the lifespan of eukaryotic organisms. However, autophagy also crucially contributes to the development of age-related human pathologies, including cancer and neurodegeneration. Macroautophagy (hereafter referred to as autophagy) clears the cytoplasm by stochastic or specific cargo recognition and destruction, and is initiated and executed by autophagy related (ATG) proteins functioning in dynamical hierarchies to form autophagosomes. Autophagosomes sequester cytoplasmic cargo material, including proteins, lipids and organelles, and acquire acidic hydrolases from the lysosomal compartment for cargo degradation. Prerequisite and essential for autophagosome formation is the production of phosphatidylinositol 3-phosphate (PtdIns3P) by phosphatidylinositol 3-kinase class III (PI3KC3, also known as PIK3C3) in complex with beclin 1, p150 (also known as PIK3R4; Vps15 in yeast) and ATG14L. Members of the human WD-repeat protein interacting with phosphoinositides (WIPI) family play an important role in recognizing and decoding the PtdIns3P signal at the nascent autophagosome, and hence function as autophagy-specific PtdIns3P-binding effectors, similar to their ancestral yeast Atg18 homolog. The PtdIns3P effector function of human WIPI proteins appears to be compromised in cancer and neurodegeneration, and WIPI genes and proteins might present novel targets for rational therapies. Here, we summarize the current knowledge on the roles of the four human WIPI proteins, WIPI1-4, in autophagy. This article is part of a Focus on Autophagosome biogenesis. For further reading, please see related articles: 'ERES: sites for autophagosome biogenesis and maturation?' by Jana Sanchez-Wandelmer et al. (J. Cell Sci. 128, 185-192) and 'Membrane dynamics in autophagosome biogenesis' by Sven R. Carlsson and Anne

  20. Defect-related transitions in Zn3P2 studied by means of photovoltaic effect spectroscopy

    NASA Astrophysics Data System (ADS)

    Mirowska, N.; Misiewicz, J.

    1992-11-01

    Transitions at energies of 1.31 eV and 1.41 eV have been observed in Zn3P2 at room temperature (T=295 K) by using surface photovoltage (SPV) spectroscopy. Results obtained from absorption and photoconductivity measurements are also discussed here. The polarity of the PSV signal has been analysed. Two acceptor levels were found to be at 0.29 eV and 0.19 eV above the valence band.

  1. The Participative Design of an Endoscopy Facility using Lean 3P

    PubMed Central

    Smith, Iain

    2016-01-01

    In the UK, bowel cancer is the second largest cancer killer. Diagnosing people earlier can save lives but demand for endoscopies is increasing and this can put pressure on waiting times. To address this challenge, an endoscopy unit in North East England decided to improve their facilities to increase capacity and create environments that improve the experience of users. This presented a significant opportunity for step change improvement but also a problem in terms of creating designs that meet user requirements whilst addressing structural or space constraints. The Lean design process known as ‘3P' (standing for the production preparation process) was utilised as a participative design strategy to engage stakeholders in the design of the new department. This involved a time-out workshop (or 3P event) in which Lean and participative design tools were utilised to create an innovative design based on ‘point of delivery' (POD) principles. The team created a design that demonstrated an increase in treatment room capacity by 25% and bed capacity by 70% whilst reducing travel distance for patients by 25.8% and staff by 27.1%. This was achieved with an increase in available space of only 13%. The Lean 3P method provided a structured approach for corporate and clinical staff to work together with patient representatives as cross-functional teams. This participative approach facilitated communication and learning between stakeholders about care processes and personal preferences. Lean 3P therefore appears to be a promising approach to improving the healthcare facilities design process to meet user requirements. PMID:27493744

  2. Hydrogen atom migration in the oxidation of aldehydes - O(3P) + H2CO

    NASA Technical Reports Server (NTRS)

    Dupuis, M.; Lester, W. A., Jr.

    1984-01-01

    An ab initio study of hydrogen atom migration in methylenebis(oxy)H2CO2(3B2) to form triplet formic acid HCOOH (3A1) is reported. From HF, MCHF, and CI calculated energy barriers, the activation energy is estimated to be no less than 30 kcal/mol. It is concluded that the hydrogen migration channel is not accessible in recent room temperature experiments on the O(3P) + H2CO reaction.

  3. Ca3P2 and other topological semimetals with line nodes and drumhead surface states

    NASA Astrophysics Data System (ADS)

    Chan, Y.-H.; Chiu, Ching-Kai; Chou, M. Y.; Schnyder, Andreas P.

    2016-05-01

    As opposed to ordinary metals, whose Fermi surfaces are two dimensional, topological (semi)metals can exhibit protected one-dimensional Fermi lines or zero-dimensional Fermi points, which arise due to an intricate interplay between symmetry and topology of the electronic wave functions. Here, we study how reflection symmetry, time-reversal symmetry, SU(2) spin-rotation symmetry, and inversion symmetry lead to the topological protection of line nodes in three-dimensional semimetals. We obtain the crystalline invariants that guarantee the stability of the line nodes in the bulk and show that a quantized Berry phase leads to the appearance of protected surfaces states, which take the shape of a drumhead. By deriving a relation between the crystalline invariants and the Berry phase, we establish a direct connection between the stability of the line nodes and the drumhead surface states. Furthermore, we show that the dispersion minimum of the drumhead state leads to a Van Hove singularity in the surface density of states, which can serve as an experimental fingerprint of the topological surface state. As a representative example of a topological semimetal, we consider Ca3P2 , which has a line of Dirac nodes near the Fermi energy. The topological properties of Ca3P2 are discussed in terms of a low-energy effective theory and a tight-binding model, derived from ab initio DFT calculations. Our microscopic model for Ca3P2 shows that the drumhead surface states have a rather weak dispersion, which implies that correlation effects are enhanced at the surface of Ca3P2 .

  4. Temperature dependence and mechanism of the reaction between O(3P) and chlorine dioxide

    NASA Technical Reports Server (NTRS)

    Colussi, A. J.; Sander, S. P.; Fiedl, R. R.

    1992-01-01

    Second-order rate constants for the decay of O(3P) in excess chlorine dioxide, k(II), were measured as a function of total pressure (20-600 Torr argon) and temperature (248-312 K), using flash photolysis-atomic resonance fluorescence. Results indicate that k(II) is pressure dependent with a value, K(b), that is nonzero at zero pressure, and both the third-order rate constant and k(b) have negative temperature dependences.

  5. Ypq3p-dependent histidine uptake by the vacuolar membrane vesicles of Saccharomyces cerevisiae.

    PubMed

    Manabe, Kunio; Kawano-Kawada, Miyuki; Ikeda, Koichi; Sekito, Takayuki; Kakinuma, Yoshimi

    2016-06-01

    The vacuolar membrane proteins Ypq1p, Ypq2p, and Ypq3p of Saccharomyces cerevisiae are known as the members of the PQ-loop protein family. We found that the ATP-dependent uptake activities of arginine and histidine by the vacuolar membrane vesicles were decreased by ypq2Δ and ypq3Δ mutations, respectively. YPQ1 and AVT1, which are involved in the vacuolar uptake of lysine/arginine and histidine, respectively, were deleted in addition to ypq2Δ and ypq3Δ. The vacuolar membrane vesicles isolated from the resulting quadruple deletion mutant ypq1Δypq2Δypq3Δavt1Δ completely lost the uptake activity of basic amino acids, and that of histidine, but not lysine and arginine, was evidently enhanced by overexpressing YPQ3 in the mutant. These results suggest that Ypq3p is specifically involved in the vacuolar uptake of histidine in S. cerevisiae. The cellular level of Ypq3p-HA(3) was enhanced by depletion of histidine from culture medium, suggesting that it is regulated by the substrate. PMID:26928127

  6. Pulsed laser photolysis study of the reaction between O(3P) and HO2

    NASA Technical Reports Server (NTRS)

    Ravishankara, A. R.; Wine, P. H.; Nicovich, J. M.

    1983-01-01

    It is pointed out that bimolecular reactions involving two free radicals are of great interest because both reactants have unpaired electrons and hence could interact at distances longer than those typical of radical-molecule encounters. A method based on laser photolysis is being developed to produce selectively free radicals in the homogeneous gas phase. This is to be done in such a way as to isolate the reaction of interest and subsequently follow the course of the reaction using spectroscopic techniques. The present investigation is concerned with a study in which the rate coefficient for the reaction of O(3P) with HO2, has been measured at N2 pressures ranging from 10 to 500 torr, taking into account the reaction O(3P)+HO2 yields OH-O2. In the described study, O(3P) and HO2 were produced by cophotolysis of O3 and H2O2 in N2 at 248.5 nm using a KrF excimer laser.

  7. Preparation of Polyimide/MWCNT Nanocomposites via Solid State Shearing Pulverization (S3P) Processing.

    PubMed

    Liu, Ruojin; Zhao, Fenghua; Zhang, Huanhuan; Yu, Xiaoyan; Ding, Huili; Naito, Kimiyoshi; Qu, Xiongwei; Zhang, Qingxin

    2015-05-01

    Polyimide/multiwall carbon nanotube (PI/MWCNT) nanocomposite films with homogeneous MWCNTs dispersion were prepared via a solid state shearing pulverization (S3P) approach. Polyimide precursor, viz., poly(amic acid) (PAA), was synthesized from 4,4'-oxydianiline (ODA) and pyromellitic dianhydride (PMDA). Then, 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BTDA) was mixed with the PAA powder and acid functionalized MWCNTs (acid-MWCNTs) by solid state shearing pulverization (S3P) approach. Finally, PI/MWCNT nanocomposite films were prepared by thermal imidization at elevated temperatures. Using such an approach not only the MWCNTs are well-dispersed but also the mechanical and thermal properties of PI are improved. The tensile strength of PI was enhanced by 74% and the elongation at break decreased to 10.35% with 5.0 wt% acid- MWCNT loading. And the glass transition temperature of PI was increased to 341 degrees C from 303 degrees C because of the strong interfacial bonding between PI and acid-MWCNTs. The solid state shearing pulverization (S3P) approach developed in this study provides a novel method to prepare various polymer composites with desired particle dispersion. PMID:26505005

  8. Crystal structure of the Saccharomyces cerevisiae monoglyceride lipase Yju3p.

    PubMed

    Aschauer, Philipp; Rengachari, Srinivasan; Lichtenegger, Joerg; Schittmayer, Matthias; Das, Krishna Mohan Padmanabha; Mayer, Nicole; Breinbauer, Rolf; Birner-Gruenberger, Ruth; Gruber, Christian C; Zimmermann, Robert; Gruber, Karl; Oberer, Monika

    2016-05-01

    Monoglyceride lipases (MGLs) are a group of α/β-hydrolases that catalyze the hydrolysis of monoglycerides (MGs) into free fatty acids and glycerol. This reaction serves different physiological functions, namely in the last step of phospholipid and triglyceride degradation, in mammalian endocannabinoid and arachidonic acid metabolism, and in detoxification processes in microbes. Previous crystal structures of MGLs from humans and bacteria revealed conformational plasticity in the cap region of this protein and gave insight into substrate binding. In this study, we present the structure of a MGL from Saccharomyces cerevisiae called Yju3p in its free form and in complex with a covalently bound substrate analog mimicking the tetrahedral intermediate of MG hydrolysis. These structures reveal a high conservation of the overall shape of the MGL cap region and also provide evidence for conformational changes in the cap of Yju3p. The complex structure reveals that, despite the high structural similarity, Yju3p seems to have an additional opening to the substrate binding pocket at a different position compared to human and bacterial MGL. Substrate specificities towards MGs with saturated and unsaturated alkyl chains of different lengths were tested and revealed highest activity towards MG containing a C18:1 fatty acid. PMID:26869448

  9. miR-342-3p affects hepatocellular carcinoma cell proliferation via regulating NF-κB pathway

    SciTech Connect

    Zhao, Liang; Zhang, Yubao

    2015-02-13

    Recent research indicates that non-coding microRNAs (miRNAs) help regulate basic cellular processes in many types of cancer cells. We hypothesized that overexpression of miR-342-3p might affect proliferation of hepatocellular carcinoma (HCC) cells. After confirming overexpression of miR-342-3p with qRT-PCR, MTT assay showed that HCC cell proliferation was significantly inhibited by miR-342-3p, and that it significantly decreased BrdU-positive cell proliferation by nearly sixfold. Searching for targets using three algorithms we found that miR-342-3p is related to the NF-κB pathway and luciferase assay found that IKK-γ, TAB2 and TAB3 are miR-342-3p target genes. Results of western blot on extracted nuclear proteins of HepG2 and HCT-116 cells showed that miR-342-3p reduced and miR-342-3p-in increased p65 nuclear levels and qRT-PCR found that NF-κB pathway downstream genes were downregulated by miR-342-3p and upregulated by miR-342-3p-in, confirming that miR-342 targets NF-κB pathway. Overexpression of Ikk-γ, TAB2 and TAB3 partially rescued HCC cells proliferation inhibited by miR-342-3p. Using the GSE54751 database we evaluated expression from 10 HCC samples, which strongly suggested downregulation of miR-342-3p and we also found inverse expression between miR-342-3p and its targets IKK-γ, TAB2 and TAB3 from 71 HCC samples. Our results show that miR-342-3p has a significant role in HCC cell proliferation and is suitable for investigation of therapeutic targets. - Highlights: • MiR-342-3p suppresses hepatocellular carcinoma cell proliferation. • MiR-342-3p targets IKK-γ, TAB2 and TAB3 genes. • MiR-342-3p downregulates NF-kB signaling pathway. • MiR-342-3p is downregulated in clinical hepatocellular carcinoma samples. • The expression of miR-342-3p and its target gene is inversely related.

  10. Staphylococcus aureus adherence to Candida albicans hyphae is mediated by the hyphal adhesin Als3p

    PubMed Central

    Peters, Brian M.; Ovchinnikova, Ekaterina S.; Krom, Bastiaan P.; Schlecht, Lisa Marie; Zhou, Han; Hoyer, Lois L.; Busscher, Henk J.; van der Mei, Henny C.; Jabra-Rizk, Mary Ann

    2012-01-01

    The bacterium Staphylococcus (St.) aureus and the opportunistic fungus Candida albicans are currently among the leading nosocomial pathogens, often co-infecting critically ill patients, with high morbidity and mortality. Previous investigations have demonstrated preferential adherence of St. aureus to C. albicans hyphae during mixed biofilm growth. In this study, we aimed to characterize the mechanism behind this observed interaction. C. albicans adhesin-deficient mutant strains were screened by microscopy to identify the specific receptor on C. albicans hyphae recognized by St. aureus. Furthermore, an immunoassay was developed to validate and quantify staphylococcal binding to fungal biofilms. The findings from these experiments implicated the C. albicans adhesin agglutinin-like sequence 3 (Als3p) in playing a major role in the adherence process. This association was quantitatively established using atomic force microscopy, in which the adhesion force between single cells of the two species was significantly reduced for a C. albicans mutant strain lacking als3. Confocal microscopy further confirmed these observations, as St. aureus overlaid with a purified recombinant Als3 N-terminal domain fragment (rAls3p) exhibited robust binding. Importantly, a strain of Saccharomyces cerevisiae heterologously expressing Als3p was utilized to further confirm this adhesin as a receptor for St. aureus. Although the parental strain does not bind bacteria, expression of Als3p on the cell surface conferred upon the yeast the ability to strongly bind St. aureus. To elucidate the implications of these in vitro findings in a clinically relevant setting, an ex vivo murine model of co-infection was designed using murine tongue explants. Fluorescent microscopic images revealed extensive hyphal penetration of the epithelium typical of C. albicans mucosal infection. Interestingly, St. aureus bacterial cells were only seen within the epithelial tissue when associated with the invasive

  11. A Whole-Genome Scan and Fine-Mapping Linkage Study of Auditory-Visual Synesthesia Reveals Evidence of Linkage to Chromosomes 2q24, 5q33, 6p12, and 12p12

    PubMed Central

    Asher, Julian E.; Lamb, Janine A.; Brocklebank, Denise; Cazier, Jean-Baptiste; Maestrini, Elena; Addis, Laura; Sen, Mallika; Baron-Cohen, Simon; Monaco, Anthony P.

    2009-01-01

    Synesthesia, a neurological condition affecting between 0.05%–1% of the population, is characterized by anomalous sensory perception and associated alterations in cognitive function due to interference from synesthetic percepts. A stimulus in one sensory modality triggers an automatic, consistent response in either another modality or a different aspect of the same modality. Familiality studies show evidence of a strong genetic predisposition; whereas initial pedigree analyses supported a single-gene X-linked dominant mode of inheritance with a skewed F:M ratio and a notable absence of male-to-male transmission, subsequent analyses in larger samples indicated that the mode of inheritance was likely to be more complex. Here, we report the results of a whole-genome linkage scan for auditory-visual synesthesia with 410 microsatellite markers at 9.05 cM density in 43 multiplex families (n = 196) with potential candidate regions fine-mapped at 5 cM density. Using NPL and HLOD analysis, we identified four candidate regions. Significant linkage at the genome-wide level was detected to chromosome 2q24 (HLOD = 3.025, empirical genome-wide p = 0.047). Suggestive linkage was found to chromosomes 5q33, 6p12, and 12p12. No support was found for linkage to the X chromosome; furthermore, we have identified two confirmed cases of male-to-male transmission of synesthesia. Our results demonstrate that auditory-visual synesthesia is likely to be an oligogenic disorder subject to multiple modes of inheritance and locus heterogeneity. This study comprises a significant step toward identifying the genetic substrates underlying synesthesia, with important implications for our understanding of the role of genes in human cognition and perception. PMID:19200526

  12. Autophagy inhibition of hsa-miR-19a-3p/19b-3p by targeting TGF-β R II during TGF-β1-induced fibrogenesis in human cardiac fibroblasts

    PubMed Central

    Zou, Meijuan; Wang, Fang; Gao, Rui; Wu, Jingjing; Ou, Yingwei; Chen, Xuguan; Wang, Tongshan; Zhou, Xin; Zhu, Wei; Li, Ping; Qi, Lian-Wen; Jiang, Ting; Wang, Weiwei; Li, Chunyu; Chen, Jun; He, Qifang; Chen, Yan

    2016-01-01

    Transforming growth factor-β1 (TGF-β1) plays an important role on fibrogenesis in heart disease. MicroRNAs have exhibited as crucial regulators of cardiac homeostasis and remodeling in various heart diseases. MiR-19a-3p/19b-3p expresses with low levels in the plasma of heart failure patients. The purpose of our study is to determine the role of MiR-19a-3p/19b-3p in regulating autophagy-mediated fibrosis of human cardiac fibroblasts. We elucidate our hypothesis in clinical samples and human cardiac fibroblasts (HCF) to provide valuable basic information. TGF-β1 promotes collagen I α2 and fibronectin synthesis in HCF and that is paralleled by autophagic activation in these cells. Pharmacological inhibition of autophagy by 3-methyladenine decreases the fibrotic response, while autophagy induction of rapamycin increases the response. BECN1 knockdown and Atg5 over-expression either inhibits or enhances the fibrotic effect of TGF-β1 in experimental HCF. Furthermore, miR-19a-3p/19b-3p mimics inhibit epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) prodution and invasion of HCF. Functional studies suggest that miR-19a-3p/19b-3p inhibits autophagy of HCF through targeting TGF-β R II mRNA. Moreover, enhancement of autophagy rescues inhibition effect of miR-19a-3p/19b-3p on Smad 2 and Akt phosphorylation through TGF-β R II signaling. Our study uncovers a novel mechanism that miR-19a-3p/19b-3p inhibits autophagy-mediated fibrogenesis by targeting TGF-β R II. PMID:27098600

  13. Identification of miR-508-3p and miR-509-3p that are associated with cell invasion and migration and involved in the apoptosis of renal cell carcinoma

    SciTech Connect

    Zhai, Qingna; Zhou, Liang; Zhao, Chunjuan; Wan, Jun; Yu, Zhendong; Guo, Xin; Qin, Jie; Chen, Jing; Lu, Ruijing

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer Previous method was the second-generation sequencing technology. Black-Right-Pointing-Pointer miR-508-3p and miR-509-3p were significantly down-regulated in RCC tissues. Black-Right-Pointing-Pointer They can inhibit cell proliferation and migration and promote cell apoptosis. Black-Right-Pointing-Pointer The expression of miR-508-3p was significantly decreased in RCC patients plasma. Black-Right-Pointing-Pointer miR-508-3p may be a novel diagnostic marker of RCC. -- Abstract: MicroRNAs (miRNAs) have emerged as powerful regulators of multiple processes linked to human cancer, including cell apoptosis, proliferation and migration, suggesting that the regulation of miRNA function could play a critical role in cancer progression. Recent studies have found that human serum/plasma contains stably expressed miRNAs. If they prove indicative of disease states, miRNAs measured from peripheral blood samples may be a source for routine clinical detection of cancer. Our studies showed that both miR-508-3p and miR-509-3p were down-regulated in renal cancer tissues. The level of miR-508-3p but not miR-509-3p in renal cell carcinoma (RCC) patient plasma demonstrated significant differences from that in control plasma. In addition, the overexpression of miR-508-3p and miR-509-3p suppressed the proliferation of RCC cells (786-0), induced cell apoptosis and inhibited cell migration in vitro. Our data demonstrated that miR-508-3p and miR-509-3p played an important role as tumor suppressor genes during tumor formation and that they may serve as novel diagnostic markers for RCC.

  14. Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13).

    PubMed

    Panagopoulos, Ioannis; Gorunova, Ludmila; Davidson, Ben; Heim, Sverre

    2015-02-28

    Multicystic mesothelioma is a rare disease of unknown etiology and pathogenesis. Nothing has been known about the cytogenetic and molecular genetic features of these tumors. Here we present the first cytogenetically analyzed multicystic mesothelioma with the karyotype 46,XX,t(7;17)(p13;q23),t(8;11)(q23;p13). RNA-sequencing showed that the t(7;17)(p13;q23) generated a chimeric TNS3-MAP3K3 gene, which codes for a chimeric protein kinase, as well as the reciprocal MAP3K3-TNS3 in which the region of TNS3 coding for the SH2_Tensin_like region and the tensin phosphotyrosine-binding domain is under the control of the MAP3K3 promoter. The other translocation, t(8;11)(q23;p13), generated a chimeric ZFPM2-ELF5 gene which codes for a chimeric transcription factor in which the first 40 amino acids of ELF5 are replaced by the first 100 amino acids of ZFPM2. RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcripts. The finding of acquired clonal chromosome abnormalities in cells cultured from the lesion and the presence of the TNS3-MAP3K3 chimeric protein kinase and the ZFPM2-ELF5 chimeric transcription factor confirm the neoplastic nature of multicystic mesothelioma. PMID:25484136

  15. Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p

    PubMed Central

    Paskulin, Diego Davila; Giacomazzi, Juliana; Achatz, Maria Isabel; Costa, Sandra; Reis, Rui Manoel; Hainaut, Pierre; dos Santos, Sidney Emanuel Batista; Ashton-Prolla, Patricia

    2015-01-01

    Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72–84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil. PMID:26618902

  16. Detection of leucine-independent DNA site occupancy of the yeast Leu3p transcriptional activator in vivo.

    PubMed Central

    Kirkpatrick, C R; Schimmel, P

    1995-01-01

    The product of the Saccharomyces cerevisiae LEU3 gene, Leu3p, is a transcriptional activator which regulates leucine biosynthesis in response to intracellular levels of leucine through the biosynthetic intermediate alpha-isopropylmalate. We devised a novel assay to examine the DNA site occupancy of Leu3p under different growth conditions, using a reporter gene with internal Leu3p-binding sites. Expression of the reporter is inhibited by binding of nuclear Leu3p to these sites; inhibition is dependent on the presence of the sites in the reporter, on the integrity of the Leu3p DNA-binding domain, and, surprisingly, on the presence of a transcriptional activation domain in the inhibiting protein. By this assay, Leu3p was found to occupy its binding site under all conditions tested, including high and low levels of leucine and in the presence and absence of alpha-isopropylmalate. The localization of Leu3p to the nucleus was confirmed by immunofluorescence staining of cells expressing epitope-tagged Leu3p derivatives. We conclude that Leu3p regulates transcription in vivo without changing its intracellular localization and DNA site occupancy. PMID:7623798

  17. Mmu-miR-126a-3p plays a role in murine embryo implantation by regulating Itga11.

    PubMed

    Li, Zhengyu; Jia, Jia; Gou, Jinhai; Tong, Aiping; Liu, Xinyu; Zhao, Xia; Yi, Tao

    2015-09-01

    miR-126a-3p has been found to be specifically up-regulated in the process of murine embryo implantation. This study aimed to further clarify the role of miR-126a-3p in embryo implantation. The expression of miR-126a-3p in implantation sites was significantly higher than that in interimplantation sites (P = 0.009). Its expression dynamics in a series of models, including pseudopregnancy, delayed implantation and artificial decidualization, suggested that the induction of miR-126a-3p is dependent on hormonal signalling and decidualization of the endometrium. Bioinformatic analysis predicted and luciferase activity assay confirmed that Itga11, a member of the integrin family, was a target gene of miR-126a-3p. miR-126a-3p bound to the 3' untranslated region of Itga11 and regulated Itga11 by inhibiting mRNA translation and affecting mRNA stability. Transwell assay showed that miR-126a-3p promoted cell migratory and invasive capacity in vitro. Loss of function of miR-126a-3p significantly reduced the number of implantation sites in vivo (P = 0.013). Collectively, miR-126a-3p may play a major role in embryo implantation by regulating Itga11, possibly through impairing cell migratory and invasive capacity. These findings should contribute to a better understanding of the miRNA-based mechanism of embryo implantation. PMID:26194885

  18. MiR-142-3p is a RANKL-dependent inducer of cell death in osteoclasts

    PubMed Central

    Fordham, Jezrom B.; Guilfoyle, Katherine; Naqvi, Afsar Raza; Nares, Salvador

    2016-01-01

    MicroRNA are small, non-coding, single-stranded RNAs that are estimated to regulate ~60% of the human genome. MiRNA profiling of monocyte-to-osteoclast differentiation identified miR-142-3p as a miRNA that is significantly, differentially expressed throughout osteoclastogenesis. Enforced expression of miR-142-3p via transient transfection with miR-142-3p mimic inhibited cell-to-cell contact and fusion, decreased protein kinase C alpha expression, and ultimately reduced cell viability. miR-142-3p was also identified as significantly differentially expressed during monocyte-to-macrophage differentiation and overexpression of miR-142-3p prevented their conversion to osteoclasts. Furthermore, the inhibitory effect of miR-142-3p on osteoclastogenesis extended to the conversion of a third osteoclast precursor cell type- dendritic cells. These results demonstrate miR-142-3p to be a negative regulator of osteoclastogenesis from the 3 main precursor cell types: monocytes, macrophages and dendritic cells. Importantly, decreased survival was dependent upon both miR-142-3p expression and RANK-signaling, with no harmful effects detected in the absence of this combination. As such, miR-142-3p represents a novel target for the selective removal of osteoclasts by targeting of osteoclastogenic pathways. PMID:27113904

  19. MicroRNA-223-3p suppresses leukemia inhibitory factor expression and pinopodes formation during embryo implantation in mice

    PubMed Central

    Dong, Xiyuan; Sui, Cong; Huang, Kai; Wang, Lan; Hu, Dan; Xiong, Ting; Wang, Rui; Zhang, Hanwang

    2016-01-01

    MicroRNA (miRNA) regulates gene expression in a post-transcriptional manner, which hybridizes the target mRNAs with complementary sequence and subsequently leads to translation repression or mRNA degradation. Online sequence alignment showed that there is a putative binding site of miR-223-3p on the 3’UTR of LIF, which is considered to be an important marker of endometrial receptivity. Thus, we hypothesized that miR-223-3p may affect embryo implantation by suppressing LIF expression. In this study, we found that miR-223-3p and LIF protein was inversely expressed in the endometrium of mice during implantation window. Then we proved that miR-223-3p directly binds to LIF 3’UTR with luciferase reporter assay and supresses the expression of LIF. To investigate whether miR-233-3p affects embryo implantation, miR-223-3p agonist was injected into the uteri of pregnant mice. The results demonstrated the suppressing effect of miR-223-3p on embryo implantation. Furthermore, over-expression of miR-223-3p was found to compromise pinopodes formation in the endometrium of mice. Taken all together, our findings revealed that miR-223-3p suppresses pinopodes formation and LIF protein expression, which may lead to diminished embryo implantation. PMID:27158401

  20. MicroRNA-409-3p inhibits osteosarcoma cell migration and invasion by targeting catenin-δ1.

    PubMed

    Wu, Shifeng; Du, Xinjie; Wu, Manwu; Du, Hechun; Shi, Xiaoliang; Zhang, Tao

    2016-06-10

    Osteosarcoma is the most common primary bone cancer which is associated with early metastatic potential and poor prognosis. However, the molecular mechanisms underlying osteosarcoma progression are not well characterized. Here, we investigated the role of miR-409-3p in osteosarcoma metastasis. Osteosarcoma tissue showed decreased expression of miR-409-3p compared to adjacent non-tumorous tissue. The expression level of miR-409-3p was negatively correlated with osteosarcoma metastasis. Overexpression of miR-409-3p in osteosarcoma cells (U2OS) inhibited cell migration and invasion. Bioinformatics analysis showed that catenin-δ1 (CTNND1, p120-catenin) is a direct target of miR-409-3p. Overexpression of miR-409-3p repressed the expression of catenin-δ1 in U2OS cells at both mRNA and protein levels. Meanwhile, miR-409-3p repressed the activity of luciferase reporter containing the 3'-untranslated region (3'UTR) of CTNND1 gene. Furthermore, expression of catenin-δ1 rescued the inhibitory effect of miR-409-3p on cell migration and invasion. Altogether, these results indicated that miR-409-3p targets catenin-δ1 to repress osteosarcoma metastasis. PMID:26992637

  1. Studies of Yb ^1S0 -- ^3P0 clock transitions

    NASA Astrophysics Data System (ADS)

    Hong, Tao

    2005-05-01

    We are exploring two quite different methods for observing the ultra-sharp 6s^2 ^1S0 -- 6s6p ^3P0 optical interval in atomic Yb, which is considered a primary candidate for future optical frequency standards [1].In the first method, we observe the 578 nm single photon transition allowed in the odd isotopes through internal hyperfine coupling of the nuclear spin.† We shine a 578 nm laser beam on cold Yb atoms held in a magneto-optical trap (MOT), and detect a decrease in MOT fluorescence when the laser is resonant with the clock transition.† Our second approach is to use the even Yb isotopes, connecting the ^1S0 and ^3P0 states† by† a multi- photon transition [2]. Sharp electromagnetically induced transparency and absorption (EITA) resonance features appear when the photon frequencies combine to equal† the ^1S0 -- ^3P0 clock interval.† We will describe our initial studies of† 2 and 3 photon resonances in Yb, including Doppler-free 3 photon EITA. [1]S. G.† Porsev, A. Derevianko, E. N. Fortson, Phys. Rev. A 69, 021403(R)† (2004); H. Katori, in Proc. 6th Symposium Frequency Standards and Metrology, edited by P. Gill (World Scienti.c, Singapore, 2002), pp. 323-330 [2]Tao Hong, Claire Cramer, Warren Nagourney, E. N. Fortson, physics/0409051 and to be published in Phys. Rev. Lett.; Robin Santra, Ennio Arimondo, Tetsuya Ido, Crhis H. Greene, Jun Ye, physics/0411197

  2. Structural stability and electronic properties of small gold clusters induced by 3p electron atoms

    NASA Astrophysics Data System (ADS)

    Zhang, Meng; Yang, Su-Bin; Feng, Xiao-Juan; Zhao, Li-Xia; Zhang, Hong-Yu; Luo, You-Hua

    2013-01-01

    The geometries and electronic properties of gold clusters doped with atoms containing 3 p valence electrons (MAu n ; M = Al, Si, P, S, Cl; n = 2-8) have been systematically investigated using density functional theory (DFT) at the PBE/LANL2DZ level. A number of low-energy isomers are identified for neutral MAu n clusters. It is found that doping with different 3 p impurity atoms can drastically influence the geometrical structures, relative stabilities, electronic properties, and growth-pattern behaviors of gold clusters, which is very different from the case of 3 d transition-metal impurity doped Au n clusters. Partially filled 3 p electron impurities can stabilize Au clusters. In particular, SiAu4 cluster with T d symmetry have been found to have highly stable geometries and electronic structures with binding energies of 2.43 eV per atom (0.96 eV higher than pristine Au5 clusters), large HOMO-LUMO gaps (2.17 eV), and vertical ionization potentials of 8.68 eV. Using scalar relativistic molecular dynamics at T = 300 K, we show that the T d symmetry structure of SiAu4 is stable. The frontier molecular orbitals (HOMO and LUMO) and the partial densities of states (PDOS) show that strong hybridization occurs between the atomic orbitals of Si and Au atoms, resulting in strong Si-Au bonding. In addition, the vertical ionization potential, the vertical electron affinity, and charge transfers of MAu n clusters have also been analyzed. Our results are in good agreement with available experimental data.

  3. Fine mapping of the chromosome 3p susceptibility locus in inflammatory bowel disease

    PubMed Central

    Hampe, J; Lynch, N; Daniels, S; Bridger, S; Macpherson, A; Stokkers, P; Forbes, A; Lennard-Jones, J; Mathew, C; Curran, M; Schreiber, S

    2001-01-01

    BACKGROUND AND AIMS—Genetic predisposition for inflammatory bowel disease (IBD) has been demonstrated by epidemiological and genetic linkage studies. Genetic linkage of IBD to chromosome 3 has been observed previously. A high density analysis of chromosome 3p was performed to confirm prior linkages and elucidate potential genetic associations.
METHODS—Forty three microsatellite markers on chromosome 3 were genotyped in 353 affected sibling pairs of North European Caucasian extraction (average marker density 2 cM in the linkage interval). Marker order was defined by genetic and radiation hybrid techniques.
RESULTS—The maximum single point logarithm of odds (LOD) score was observed for Crohn's disease at D3S3591. Peak multipoint LOD scores of 1.65 and 1.40 for the IBD phenotype were observed near D3S1304 (distal 3p) and near D3S1283 in the linkage region previously reported. Crohn's disease contributed predominantly to the linkage. The transmission disequilibrium test showed significant evidence of association (p=0.009) between allele 4 of D3S1076 and the IBD phenotype (51 transmitted v 28 non-transmitted). Two known polymorphisms in the CCR2 and CCR5 genes were analysed, neither of which showed significant association with IBD. Additional haplotype associations were observed in the vicinity of D3S1076.
CONCLUSIONS—This study provides confirmatory linkage evidence for an IBD susceptibility locus on chromosome 3p and suggests that CCR2 and CCR5 are unlikely to be major susceptibility loci for IBD. The association findings in this region warrant further investigation.


Keywords: inflammatory bowel disease; fine mapping; chromosome 3 PMID:11156639

  4. Precision measurement of the (3 p-1 s) X-ray transition in muonic hydrogen

    NASA Astrophysics Data System (ADS)

    Gotta, D.; Covita, D. S.; Anagnostopoulos, D. F.; Fuhrmann, H.; Gorke, H.; Gruber, A.; Hirtl, A.; Ishiwatari, T.; Indelicato, P.; Le Bigot, E.-O.; Nekipelov, M.; Pomerantsev, V.; Popov, M.; dos Santos, J. M. F.; Schmid, Ph.; Simons, L. M.; Trassinelli, M.; Veloso, J. F. C. A.; Zmeskal, J.

    2014-01-01

    The (3 p — 1 s) X-ray transition to the muonic hydrogen ground state was measured with a highresolution crystal spectrometer. The assumption of a statistical population of the hyperfine levels of the muonic hydrogen ground state was directly confirmed by the experiment and measured values for the hyperfine splitting can be reported. The measurement supplements studies on line broadening effects induced by Coulomb de-excitation hindering the direct extraction of the pion-nucleon scattering lengths from pionic hydrogen and deuterium X-ray lines.

  5. Oligonucleotide n3'-->p5' phosphoramidates and thio-phoshoramidates as potential therapeutic agents.

    PubMed

    Gryaznov, Sergei M

    2010-03-01

    Nucleic acids analogues, i.e., oligonucleotide N3'-->P5' phosphoramidates and N3'-->P5' thio-phosphoramidates, containing 3'-amino-3'-deoxy nucleosides with various 2'-substituents were synthesized and extensively studied. These compounds resist nuclease hydrolysis and form stable duplexes with complementary native phosphodiester DNA and, particularly, RNA strands. An increase in duplexes' melting temperature, DeltaT(m), relative to their phosphodiester counterparts, reaches 2.2-4.0 degrees per modified nucleoside. 2'-OH- (RNA-like), 2'-O-Me-, and 2'-ribo-F-nucleoside substitutions result in the highest degree of duplex stabilization. Moreover, under close to physiological salt and pH conditions, the 2'-deoxy- and 2'-fluoro-phosphoramidate compounds form extremely stable triple-stranded complexes with either single- or double-stranded phosphodiester DNA oligonucleotides. Melting temperature, T(m), of these triplexes exceeds T(m) values for the isosequential phosphodiester counterparts by up to 35 degrees . 2'-Deoxy-N3'-->P5' phosphoramidates adopt RNA-like C3'-endo or N-type nucleoside sugar-ring conformations and hence can be used as stable RNA mimetics. Duplexes formed by 2'-deoxy phosphoramidates with complementary RNA strands are not substrates for RNase H-mediated cleavage in vitro. Oligonucleotide phosphoramidates and especially thio-phosphoramidates conjugated with lipid groups are cell-permeable and demonstrate high biological target specific activity in vitro. In vivo, these compounds show good bioavailability and efficient biodistribution to all major organs, while exerting acceptable toxicity at therapeutically relevant doses. Short oligonucleotide N3'-->P5' thio-phosphoramidate conjugated to 5'-palmitoyl group, designated as GRN163L (Imetelstat), was recently introduced as a potent human telomerase inhibitor. GRN163L is not an antisense agent; it is a direct competitive inhibitor of human telomerase, which directly binds to the active site of the enzyme

  6. Reactions of Ar2+ (3P) ions with some neutrals at 30 K

    NASA Astrophysics Data System (ADS)

    Dupeyrat, G.; Marquette, J. B.; Rowe, B. R.; Rebrion, C.

    1991-01-01

    Measurements of reaction rate coefficients of Ar2+ (3P) with Ar, He, H2, O2 and CO2 at 30 K are reported. They have been performed using the Cinétique de Réaction en Encoulement Supersonique Uniforme apparatus with a newly designed Mach five argon nozzle which is briefly described. All the data remain close to previous selected-ion flow tube determinations at room temperature (D. Smith, D. Grief and N.G. Adams, Int. J. Mass Spectrom, Ion Phys., 30 (1979) 271). The present results are also compared to existing theoretical calculations.

  7. Scaling of collisionally pumped 3s-3p lasers in the neon isoelectronic sequence

    NASA Technical Reports Server (NTRS)

    Feldman, U.; Seely, J. F.; Bhatia, A. K.

    1984-01-01

    Atomic-number scaling in the 3p-3s population-inversion and plasma parameters of neonlike ions of Si, Ar, Ti, Fe, Ge, and Kr is investigated theoretically. The population levels are calculated; the Z-scaling relationships are defined; the results are presented in tables and graphs; and the implications for the laser gain are explored. Laser gain in excess of 1/cm are predicted for all ions except Si V, with a peak of 30/cm for Fe XVII at electron density 10 to the 21st/cu cm.

  8. High current Cu3P liquid metal ion source using a novel extractor configuration

    NASA Astrophysics Data System (ADS)

    Higuchi-Rusli, R. H.; Corelli, J. C.

    1987-12-01

    It has been found that by utilizing a sharp needle for the extractor electrode in close proximity to the source tip wetted with Cu3P liquid alloy, a large increase (factor ˜300) in ion current is observed in comparison to standard liquid metal ion sources (LMIS's). In standard previously used LMIS's the extractor electrode was a flat plane with a circular hole centered on the source needle tip. This new high current source has important applications in focused and broad ion beam deposition systems.

  9. Persistent photoconductivity in high resistive Zn{sub 3}P{sub 2}

    SciTech Connect

    Sierański, K.; Szatkowski, J. Pawlikowski, J. M.

    2014-02-28

    Resistivity and photoconductivity of p-type Zn{sub 3}P{sub 2} polycrystals grown by closed tube vapour transport method have been investigated. Persistent photoconductivity (PPC) has been observed at temperatures T < 200 K. At 77 K, the photoconduction persists for over 10{sup 3} s after termination of the light. The PPC buildup and decay kinetics have been measured at 77 K and analyzed in the frame of large lattice-relaxed deep levels. We have determined the spectral dependence for the optical cross section and obtain an optical ionization energy of 0.83 eV.

  10. Quantum chaos in ultracold collisions between Yb(1S0) and Yb(3P2)

    NASA Astrophysics Data System (ADS)

    Green, Dermot G.; Vaillant, Christophe L.; Frye, Matthew D.; Morita, Masato; Hutson, Jeremy M.

    2016-02-01

    We calculate and analyze Feshbach resonance spectra for ultracold Yb (1S0) +Yb (3P2) collisions as a function of an interatomic potential scaling factor λ and external magnetic field. We show that, at zero field, the resonances are distributed randomly in λ , but that signatures of quantum chaos emerge as a field is applied. The random zero-field distribution arises from superposition of structured spectra associated with individual total angular momenta. In addition, we show that the resonances with respect to magnetic field in the experimentally accessible range of 400 to 2000 G are chaotically distributed, with strong level repulsion that is characteristic of quantum chaos.

  11. MicroRNA-409-3p regulates cell invasion and metastasis by targeting ZEB1 in breast cancer.

    PubMed

    Ma, Zhenhai; Li, Yang; Xu, Jingchao; Ren, Qiaozhen; Yao, Jihong; Tian, Xiaofeng

    2016-05-01

    MicroRNA-409-3p (miR-409-3p) is an miRNA expressed by embryonic stem cells, and our previous study demonstrated depressed miR-409-3p expression in human breast cancer (BC) cell lines; however, its role and function in BC metastasis are still unknown. The purpose of this study was to examine the expression levels of miR-409-3p in human BC and its role in the metastasis of BC. We analyzed the status of miR-409-3p expression in BC tissues by quantitative real-time polymerase chain reaction (PCR) and its relationship to the clinicopathologic features of patients with BC. To study the role of miR-409-3p in BC metastasis, the invasion ability of BC cells was detected by transwell invasion assays and wound healing assays. WST-1 assays and colony formation assays were used to investigate cell proliferation. Luciferase reporter assays were used to verify that miR-409-3p targeted zinc-finger E-box-binding homeobox 1 (ZEB1). Western blot analyses and transwell assays were carried out to assess ZEB1 expression and its role in BC cell metastasis. The expression of miR-409-3p was lower in tumor tissues than in noncancerous breast tissues. We verified that miR-409-3p levels were downregulated and significantly correlated with poor outcomes in patients with BC. Overexpression of miR-409-3p inhibited cellular proliferation and suppressed cellular migration and invasion in vitro and in vivo. Dual-luciferase reporter assays showed that miR-409-3p binds the 3'-untranslated region (3'-UTR) of ZEB1, suggesting that ZEB1 is a direct target of miR-409-3p. Western blot analysis confirmed that overexpression of miR-409-3p reduced ZEB1 protein levels. These data demonstrate that miR-409-3p plays an important role in regulating the metastasis of BC, which is involved in the post-transcriptional repression of ZEB1. Our results indicate that miR-409-3p can regulate the invasion and metastasis process of BC by targeting ZEB1 and may serve as a new prognostic marker and therapeutic target for

  12. Effects of microRNA‑338‑3p on morphine‑induced apoptosis and its underlying mechanisms.

    PubMed

    Weng, Hong-Liang; Wang, Ming-Jing

    2016-09-01

    The aim of the present study was to investigate the effects of microRNA-338-3p (miR-338-3p) on morphine (MP)-induced apoptosis, and its underlying mechanisms. Freshly‑isolated mouse peritoneal macrophages were cultured in vitro and treated with MP following transfection with miR‑338‑3p mimic, inhibitor or controls. miR‑338‑3p expression levels increased significantly following MP treatment (P<0.01). This increase was enhanced following transfection with miR‑338‑3p mimic (P<0.05) and abrogated following transfection with miR‑338‑3p inhibitor (P<0.05). The apoptotic rate increased significantly in groups treated with MP (P<0.05); however, this increase was abrogated by transfection with miR‑338‑3p inhibitor (P<0.05). Bioinformatics software predicted that sex determining region Y‑box 4 (SOX4) was the target gene of miR‑338‑3p and this was verified using a dual‑luciferase reporter gene system. SOX4 mRNA and protein expression levels decreased significantly following MP treatment (P<0.05); however, this decrease was abrogated following transfection with miR‑338‑3p inhibitor (P<0.05). Caspase‑3 protein expression levels increased markedly following MP treatment (P<0.05); however, this increase was inhibited by transfection with miR‑338‑3p inhibitor (P<0.05). Therefore, decreased expression of miR‑338‑3p may suppress MP‑induced apoptosis, potentially via the upregulation of SOX4 expression and the caspase‑3‑dependent apoptotic signaling pathway. PMID:27432229

  13. MicroRNA-338-3p suppresses metastasis of lung cancer cells by targeting the EMT regulator Sox4

    PubMed Central

    Li, Yang; Chen, Peirui; Zu, Lingling; Liu, Bin; Wang, Min; Zhou, Qinghua

    2016-01-01

    Metastasis remains the leading cause of the majority of cancer-related mortality. MicroRNAs (miRNAs) have frequently emerged as tumor metastatic regulator by acting on multiple signaling pathways. In the present study, we demonstrated that miR-338-3p was significantly downregulated in highly metastatic NSCLC cell lines and clinical metastatic tissues. Then, we found that introduction of miR-338-3p significantly suppressed the migration and invasion of lung cancer cells both in vitro and in vivo, suggesting that miR-338-3p may be a novel tumor suppressor. Further studies indicated that the EMT-related transcription factor Sox4 was one direct target gene of miR-338-3p, evidenced by the direct binding of miR-338-3p with the 3’untranslated region (3’UTR) of Sox4. Furthermore, miR-338-3p could decrease the expression of Sox4 both at mRNA and protein levels. Notably, the EMT marker E-cadherin or vimentin, a downstream regulator of Sox4, was also down-regulated or up-regulated upon miR-338-3p treatment. Additionally, over-expressing or silencing Sox4 could elevate or inhibit the migration and invasion of lung cancer cells, parallel to the effect of miR-338-3p on the lung cancer cells. Meanwhile, knockdown of Sox4 reversed the enhanced migration and invasion mediated by miR-338-3p. These results indicated that miR-338-3p suppressed the migration and invasion of NSCLC cells through targeting Sox4 involving in the EMT process. Thus, our finding provides new insight into the mechanism of NSCLC progression. Therapeutically, miR-338-3p may serve as a potential target in the treatment of human lung cancer. PMID:27186391

  14. MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a.

    PubMed

    Zhao, Yuanyuan; Wang, Pengchao; Meng, Jinzhu; Ji, Yuankai; Xu, Dongmei; Chen, Tianzhi; Fan, Ruiwen; Yu, Xiuju; Yao, Jianbo; Dong, Changsheng

    2015-01-01

    MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a-3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post-transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced β-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression. PMID:26006230

  15. MicroRNA-27a-3p Inhibits Melanogenesis in Mouse Skin Melanocytes by Targeting Wnt3a

    PubMed Central

    Zhao, Yuanyuan; Wang, Pengchao; Meng, Jinzhu; Ji, Yuankai; Xu, Dongmei; Chen, Tianzhi; Fan, Ruiwen; Yu, Xiuju; Yao, Jianbo; Dong, Changsheng

    2015-01-01

    MicroRNAs (miRNAs) play an essential role in the regulation of almost all the biological processes, including melanogenesis. MiR-27a-3p is nearly six times higher in white alpaca skin compared to brown skin, which indicates that miR-27a-3p may be a candidate regulator for melanogenesis. Wnt3a plays an important role in promoting melanoblasts to differentiate into melanocytes and melanogenesis. To confirm the function of miR-27a-3p to melanogenesis in mammals, miR-27a-3p mimic, inhibitor and their negative control were transfected into mouse melanocytes. As a result, miR-27a-3p inhibits melanogenesis by repressing Wnt3a at post-transcriptional level. A significant decrease in Wnt3a luciferase activity was observed in 293T cells co-transfected with the matched luciferase reporter vector and pre-miR-27a. Furthermore, the presence of exogenous miR-27a-3p significantly decreased Wnt3a protein expression rather than mRNA and reduced β-catenin mRNA levels in melanocytes. The over-expression of miR-27a-3p significantly increased the melanin content of melanocytes. However, miR-27a-3p inhibitor performs an opposite effect on melanogenesis. Wnt3a is one target of miR-27a-3p. MiR-27a-3p could inhibit Wnt3a protein amount by post-transcriptional regulation and melanogenesis in mouse melanocytes. Previous studies reported that Wnt3a promoted melanogenensis in mouse melanocytes. Thus, miR-27-3p inhibits melanogenesis by repressing Wnt3a protein expression. PMID:26006230

  16. A New Case of an Extremely Rare 3p21.31 Interstitial Deletion.

    PubMed

    Lovrecic, Luca; Bertok, Sara; Žerjav Tanšek, Mojca

    2016-05-01

    Interstitial 3p21.31 deletions have been very rarely reported. We describe a 7-year-old boy with global developmental delay, specific facial characteristics, hydronephrosis, and hypothyreosis with a de novo deletion of 3p21.31, encompassing 29 OMIM genes. Despite the wide use of microarrays, no similar case has been reported in the literature so far. Five overlapping cases are deposited in the DECIPHER database, 2 of which have significant overlapping chromosomal aberrations. They both share some phenotypic characteristics with our case, e.g. developmental delay, intellectual disability and facial dysmorphism (arched eyebrows, hypertelorism, low-set ears, and a large nose tip). In addition, loss-of-function mutations in the SETD2 gene (OMIM 612778) of the deleted region have been described in 3 patients, presenting with some similar clinical features, namely overgrowth, intellectual disability, speech delay, hypotonia, autism, and epilepsy. Therefore, SETD2 may explain part of the phenotype in our case. We focused on 3 other genes in the deleted region, based on their known functions, namely CSPG5 (OMIM 606775), PTH1R (OMIM 168468) and SMARCC1 (OMIM 601732), and assessed their potentially important role in describing the patient's phenotype. Additional cases with haploinsufficiency of this region are needed to elucidate further genotype-phenotype correlations. PMID:27385966

  17. A Mixed-Valent Molybdenum Monophosphate with a Layer Structure: KMo 3P 2O 14

    NASA Astrophysics Data System (ADS)

    Guesdon, A.; Borel, M. M.; Leclaire, A.; Grandin, A.; Raveau, B.

    1994-03-01

    A new mixed-valent molybdenum monophosphate with a layer structure KMo 3P 2O 14 has been isolated. It crystallizes in the space group P2 1/ m with a = 8.599(2) Å, b = 6.392(2) Å, c = 10.602(1) Å, and β = 111.65(2)°. The layers [Mo 3P 2O 14] ∞ are parallel to (100) and consist of [MoPO 8] ∞ chains running along limitb→ , in which one MoO 6 octahedron alternates with one PO 4 tetrahedron. In fact, four [MoPO 8] ∞ chains share the corners of their polyhedra and the edges of their octahedra, forming [Mo 4P 4O 24] ∞ columns which are linked through MoO 5 bipyramids along limitc→. The K + ions interleaved between these layers are surrounded by eight oxygens, forming bicapped trigonal prisms KO 8. Besides the unusual trigonal bipyramids MoO 5, this structure is also characterized by a tendency to the localization of the electrons, since one octahedral site is occupied by Mo(V), whereas the other octahedral site and the trigonal bipyramid are occupied by Mo(VI). The similarity of this structure with pure octahedral layer structures suggests the possibility of generating various derivatives, and of ion exchange properties.

  18. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

    PubMed Central

    Ahmed, Shahana; Thomas, Gilles; Ghoussaini, Maya; Healey, Catherine S; Humphreys, Manjeet K; Platte, Radka; Morrison, Jonathan; Maranian, Melanie; Pooley, Karen A; Luben, Robert; Eccles, Diana; Evans, D Gareth; Fletcher, Olivia; Johnson, Nichola; Silva, Isabel dos Santos; Peto, Julian; Stratton, Michael R; Rahman, Nazneen; Jacobs, Kevin; Prentice, Ross; Anderson, Garnet L; Rajkovic, Aleksandar; Curb, J David; Ziegler, Regina G; Berg, Christine D; Buys, Saundra S; McCarty, Catherine A; Feigelson, Heather Spencer; Calle, Eugenia E; Thun, Michael J; Diver, W Ryan; Bojesen, Stig; Nordestgaard, Børge G; Flyger, Henrik; Dörk, Thilo; Schürmann, Peter; Hillemanns, Peter; Karstens, Johann H; Bogdanova, Natalia V; Antonenkova, Natalia N; Zalutsky, Iosif V; Bermisheva, Marina; Fedorova, Sardana; Khusnutdinova, Elza; Kang, Daehee; Yoo, Keun-Young; Noh, Dong Young; Ahn, Sei-Hyun; Devilee, Peter; van Asperen, Christi J; Tollenaar, R A E M; Seynaeve, Caroline; Garcia-Closas, Montserrat; Lissowska, Jolanta; Brinton, Louise; Peplonska, Beata; Nevanlinna, Heli; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Hopper, John L; Southey, Melissa C; Smith, Letitia; Spurdle, Amanda B; Schmidt, Marjanka K; Broeks, Annegien; van Hien, Richard R; Cornelissen, Sten; Milne, Roger L; Ribas, Gloria; González-Neira, Anna; Benitez, Javier; Schmutzler, Rita K; Burwinkel, Barbara; Bartram, Claus R; Meindl, Alfons; Brauch, Hiltrud; Justenhoven, Christina; Hamann, Ute; Chang-Claude, Jenny; Hein, Rebecca; Wang-Gohrke, Shan; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; English, Dallas R; Hankinson, Susan E; Cox, David G; Kraft, Peter; Vatten, Lars J; Hveem, Kristian; Kumle, Merethe; Sigurdson, Alice; Doody, Michele; Bhatti, Parveen; Alexander, Bruce H; Hooning, Maartje J; van den Ouweland, Ans M W; Oldenburg, Rogier A; Schutte, Mieke; Hall, Per; Czene, Kamila; Liu, Jianjun; Li, Yuqing; Cox, Angela; Elliott, Graeme; Brock, Ian; Reed, Malcolm W R; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Giu-Cheng; Chen, Shou-Tung; Anton-Culver, Hoda; Ziogas, Argyrios; Andrulis, Irene L; Knight, Julia A; kConFab; Beesley, Jonathan; Goode, Ellen L; Couch, Fergus; Chenevix-Trench, Georgia; Hoover, Robert N; Ponder, Bruce A J; Hunter, David J; Pharoah, Paul D P; Dunning, Alison M; Chanock, Stephen J; Easton, Douglas F

    2009-01-01

    Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10−23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10−8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q. PMID:19330027

  19. Hyperfine Quenching of the 2s2p 3P0 State of Berylliumlike Ions

    SciTech Connect

    Cheng, K T; Chen, M H; Johnson, W R

    2008-03-13

    The hyperfine-induced 2s2p {sup 3}P{sub 0}-2s{sup 2} {sup 1}S{sub 0} transition rate for Be-like {sup 47}Ti{sup 18+} was recently measured in a storage-ring experiment by Schippers et al. [Phys. Rev. Lett. 98, 033001 (2007)]. The measured value of 0.56(3) s{sup -1} is almost 60% larger than the theoretical value of 0.356 s{sup -1} from a multiconfiguration Dirac-Fock calculation by Marques et al. [Phys. Rev. A 47, 929 (1993)]. In this work, we use a large-scale relativistic configuration-interaction method to calculate these hyperfine-induced rates for ions with Z = 6-92. Coherent hyperfine-quenching effects between the 2s2p {sup 1,3}P{sub 1} states are included in a perturbative as well as a radiation damping approach. Contrary to the claims of Marques et al., contributions from the {sup 1}P{sub 1} state are substantial and lead to a hyperfine-induced rate of 0.67 s{sup -1}, in better agreement with, though larger than, the measured value.

  20. Polypeptide binding specificities of Saccharomyces cerevisiae oligosaccharyltransferase accessory proteins Ost3p and Ost6p.

    PubMed

    Jamaluddin, M Fairuz B; Bailey, Ulla-Maja; Tan, Nikki Y J; Stark, Anthony P; Schulz, Benjamin L

    2011-05-01

    Asparagine-linked glycosylation is a common and vital co- and post-translocational modification of diverse secretory and membrane proteins in eukaryotes that is catalyzed by the multiprotein complex oligosaccharyltransferase (OTase). Two isoforms of OTase are present in Saccharomyces cerevisiae, defined by the presence of either of the homologous proteins Ost3p or Ost6p, which possess different protein substrate specificities at the level of individual glycosylation sites. Here we present in vitro characterization of the polypeptide binding activity of these two subunits of the yeast enzyme, and show that the peptide-binding grooves in these proteins can transiently bind stretches of polypeptide with amino acid characteristics complementary to the characteristics of the grooves. We show that Ost6p, which has a peptide-binding groove with a strongly hydrophobic base lined by neutral and basic residues, binds peptides enriched in hydrophobic and acidic amino acids. Further, by introducing basic residues in place of the wild type neutral residues lining the peptide-binding groove of Ost3p, we engineer binding of a hydrophobic and acidic peptide. Our data supports a model of Ost3/6p function in which they transiently bind stretches of nascent polypeptide substrate to inhibit protein folding, thereby increasing glycosylation efficiency at nearby asparagine residues. PMID:21384453

  1. Polypeptide binding specificities of Saccharomyces cerevisiae oligosaccharyltransferase accessory proteins Ost3p and Ost6p

    PubMed Central

    Jamaluddin, M Fairuz B; Bailey, Ulla-Maja; Tan, Nikki YJ; Stark, Anthony P; Schulz, Benjamin L

    2011-01-01

    Asparagine-linked glycosylation is a common and vital co- and post-translocational modification of diverse secretory and membrane proteins in eukaryotes that is catalyzed by the multiprotein complex oligosaccharyltransferase (OTase). Two isoforms of OTase are present in Saccharomyces cerevisiae, defined by the presence of either of the homologous proteins Ost3p or Ost6p, which possess different protein substrate specificities at the level of individual glycosylation sites. Here we present in vitro characterization of the polypeptide binding activity of these two subunits of the yeast enzyme, and show that the peptide-binding grooves in these proteins can transiently bind stretches of polypeptide with amino acid characteristics complementary to the characteristics of the grooves. We show that Ost6p, which has a peptide-binding groove with a strongly hydrophobic base lined by neutral and basic residues, binds peptides enriched in hydrophobic and acidic amino acids. Further, by introducing basic residues in place of the wild type neutral residues lining the peptide-binding groove of Ost3p, we engineer binding of a hydrophobic and acidic peptide. Our data supports a model of Ost3/6p function in which they transiently bind stretches of nascent polypeptide substrate to inhibit protein folding, thereby increasing glycosylation efficiency at nearby asparagine residues. PMID:21384453

  2. miR-185-3p regulates nasopharyngeal carcinoma radioresistance by targeting WNT2B in vitro

    PubMed Central

    Li, Guo; Wang, Yunyun; Liu, Yong; Su, Zhongwu; Liu, Chao; Ren, Shuling; Deng, Tengbo; Huang, Donghai; Tian, Yongquan; Qiu, Yuanzheng

    2014-01-01

    Aberrant microRNA (miRNA) expression contributes to a series of malignant cancer behaviors, including radioresistance. Our previous study showed differential expression of miR-185-3p in post-radiation nasopharyngeal carcinoma (NPC) cells. To investigate the role of miR-185-3p in NPC radioresistance, CNE-2 and 5-8F cells were transfected with miR-185-3p mimic and miR-185-3p inhibitor, respectively. CCK-8 assay and colony formation experiment confirmed that the expression of miR-185-3p affected the radioresistance of NPC cells. A negative correlation between miR-185-3p and WNT2B expression was observed in NPC cells and tissues. Luciferase reporter assays confirmed that miR-185-3p directly targeted the coding region of WNT2B. Furthermore, we found radioresistance decreased in WNT2B-silenced NPC cells. Activation of the WNT2B/β-catenin pathway was accompanied by epithelial–mesenchymal transition biomarker changes in NPC. We concluded that miR-185-3p contributed to the radioresistance of NPC via modulation of WNT2B expression in vitro. PMID:25297925

  3. A comparative study of Li8NaV3(P2O7)3(PO4)2 and Li9V3(P2O7)3(PO4)2: Synthesis, structure and electrochemical properties

    NASA Astrophysics Data System (ADS)

    Kuang, Quan; Zhao, Yanming; Dong, Youzhong; Fan, Qinghua; Lin, Xinghao; Liu, Xudong

    2016-02-01

    The energy-density improvement for cathode materials by using the method of occupying the Li site with the lowest formation enthalpy was first presented, and successfully applied to Li9V3(P2O7)3(PO4)2. Herein, the synthesis, structure and electrochemical properties (including both Li extraction and intercalation) of mixed alkali-ion phosphate Li8NaV3(P2O7)3(PO4)2 were comprehensively studied, and compared with its isologue Li9V3(P2O7)3(PO4)2. Both Li8NaV3(P2O7)3(PO4)2 and Li9V3(P2O7)3(PO4)2 were synthesized via an original two-step method for the first time. The sintering temperature of Li8NaV3(P2O7)3(PO4)2 (650 °C) was much lower than that of Li9V3(P2O7)3(PO4)2 (750 °C). The Rietveld structure refinement indicated that Na ions occupied the Li1(2b) site of Li9V3(P2O7)3(PO4)2 as expected, and Li8NaV3(P2O7)3(PO4)2 showed a single charge plateau at 4.4 V vs. Li in the 1st cycle. However, the Na ions migrated from Li1(2b) site after the initial cycle, and the charge plateau at 3.7 V vs. Li reappeared. On the other hand, both Li9V3(P2O7)3(PO4)2 and Li8NaV3(P2O7)3(PO4)2 can deliver a high reversible capacity (∼200 mAh g-1), and reveal excellent cycle and rate performance in 3.0-0.05 V vs. Li. The gentle structure changes along with abundant Li intercalation into the bulks suggested that Li9V3(P2O7)3(PO4)2 and Li8NaV3(P2O7)3(PO4)2 were also promising anode materials for Li-ion batteries.

  4. Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas

    PubMed Central

    Yim, Rita Lh; Wong, Kwan Yeung; Kwong, Yok Lam; Loong, Florence; Leung, Chung Ying; Chu, Raymond; Lam, William Wai Lung; Hui, Pak Kwan; Lai, Raymond; Chim, Chor Sang

    2014-01-01

    Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma (NHL). In cancers, tumor suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling of representative EBV-negative MCL cell lines before and after demethylation treatment, miR-155-3p was found significantly restored. Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-aza-2′-deoxycytidine treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties. By luciferase assay, lymphotoxin-beta (LT-β) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p = 0.024), and LT-β upregulation (p = 0.043). Collectively, miR-155-3p is a potential tumor suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-β, which is an upstream activator of the non-canonical NF-kB signaling, miR-155-3p methylation is potentially important in lymphomagenesis. PMID:25211095

  5. Unified interpretation of Hund's first and second rules for 2p and 3p atoms.

    PubMed

    Oyamada, Takayuki; Hongo, Kenta; Kawazoe, Yoshiyuki; Yasuhara, Hiroshi

    2010-10-28

    A unified interpretation of Hund's first and second rules for 2p (C, N, O) and 3p (Si, P, S) atoms is given by Hartree-Fock (HF) and multiconfiguration Hartree-Fock (MCHF) methods. Both methods exactly satisfy the virial theorem, in principle, which enables one to analyze individual components of the total energy E(=T+V(en)+V(ee)), where T, V(en), and V(ee) are the kinetic, the electron-nucleus attraction, and the electron-electron repulsion energies, respectively. The correct interpretation for each of the two rules can only be achieved under the condition of the virial theorem 2T+V=0 by investigating how V(en) and V(ee) interplay to attain the lower total potential energy V(=V(en)+V(ee)). The stabilization of the more stable states for all the 2p and 3p atoms is ascribed to a greater V(en) that is caused by contraction of the valence orbitals accompanied with slight expansion of the core orbitals. The contraction of the valence orbitals for the two rules is a consequence of reducing the Hartree screening of the nucleus at short interelectronic distances. The reduced screening in the first rule is due to a greater amount of Fermi hole contributions in the state with the highest total spin-angular momentum S. The reduced screening in the second rule is due to the fact that two valence electrons are more likely to be on opposite sides of the nucleus in the state with the highest total orbital-angular momentum L. For each of the two rules, the inclusion of correlation does not qualitatively change the HF interpretation, but HF overestimates the energy difference ∣ΔE∣ between two levels being compared. The magnitude of the correlation energy is significantly larger for the lower L states than for the higher L states since two valence electrons in the lower L states are less likely to be on opposite sides of the nucleus. The MCHF evaluation of ∣ΔE∣ is in excellent agreement with experiment. The present HF and MCHF calculations demonstrate the above statements

  6. Unified interpretation of Hund's first and second rules for 2p and 3p atoms

    NASA Astrophysics Data System (ADS)

    Oyamada, Takayuki; Hongo, Kenta; Kawazoe, Yoshiyuki; Yasuhara, Hiroshi

    2010-10-01

    A unified interpretation of Hund's first and second rules for 2p (C, N, O) and 3p (Si, P, S) atoms is given by Hartree-Fock (HF) and multiconfiguration Hartree-Fock (MCHF) methods. Both methods exactly satisfy the virial theorem, in principle, which enables one to analyze individual components of the total energy E(=T +Ven+Vee), where T, Ven, and Vee are the kinetic, the electron-nucleus attraction, and the electron-electron repulsion energies, respectively. The correct interpretation for each of the two rules can only be achieved under the condition of the virial theorem 2T+V=0 by investigating how Ven and Vee interplay to attain the lower total potential energy V(=Ven+Vee). The stabilization of the more stable states for all the 2p and 3p atoms is ascribed to a greater Ven that is caused by contraction of the valence orbitals accompanied with slight expansion of the core orbitals. The contraction of the valence orbitals for the two rules is a consequence of reducing the Hartree screening of the nucleus at short interelectronic distances. The reduced screening in the first rule is due to a greater amount of Fermi hole contributions in the state with the highest total spin-angular momentum S. The reduced screening in the second rule is due to the fact that two valence electrons are more likely to be on opposite sides of the nucleus in the state with the highest total orbital-angular momentum L. For each of the two rules, the inclusion of correlation does not qualitatively change the HF interpretation, but HF overestimates the energy difference |ΔE | between two levels being compared. The magnitude of the correlation energy is significantly larger for the lower L states than for the higher L states since two valence electrons in the lower L states are less likely to be on opposite sides of the nucleus. The MCHF evaluation of |ΔE| is in excellent agreement with experiment. The present HF and MCHF calculations demonstrate the above statements that were originally

  7. De novo t(12;17)(p13.3;q21.3) translocation with a breakpoint near the 5' end of the HOXB gene cluster in a patient with developmental delay and skeletal malformations.

    PubMed

    Yue, Ying; Farcas, Ruxandra; Thiel, Gundula; Bommer, Christiane; Grossmann, Bärbel; Galetzka, Danuta; Kelbova, Christina; Küpferling, Peter; Daser, Angelika; Zechner, Ulrich; Haaf, Thomas

    2007-05-01

    A boy with severe mental retardation, funnel chest, bell-shaped thorax, and hexadactyly of both feet was found to have a balanced de novo t(12;17)(p13.3;q21.3) translocation. FISH with BAC clones and long-range PCR products assessed in the human genome sequence localized the breakpoint on chromosome 17q21.3 to a 21-kb segment that lies <30 kb upstream of the HOXB gene cluster and immediately adjacent to the 3' end of the TTLL6 gene. The breakpoint on chromosome 12 occurred within telomeric hexamer repeats and, therefore, is not likely to affect gene function directly. We propose that juxtaposition of the HOXB cluster to a repetitive DNA domain and/or separation from required cis-regulatory elements gave rise to a position effect. PMID:17327879

  8. Functional Expression and Characterization of Schizosaccharomyces pombe Avt3p as a Vacuolar Amino Acid Exporter in Saccharomyces cerevisiae

    PubMed Central

    Chardwiriyapreecha, Soracom; Manabe, Kunio; Iwaki, Tomoko; Kawano-Kawada, Miyuki; Sekito, Takayuki; Lunprom, Siriporn; Akiyama, Koichi; Takegawa, Kaoru; Kakinuma, Yoshimi

    2015-01-01

    In Saccharomyces cerevisiae, Avt3p and Avt4p mediate the extrusion of several amino acids from the vacuolar lumen into the cytosol. SpAvt3p of Schizosaccharomyces pombe, a homologue of these vacuolar amino acid transporters, has been indicated to be involved in spore formation. In this study, we confirmed that GFP-SpAvt3p localized to the vacuolar membrane in S. pombe. The amounts of various amino acids increased significantly in the vacuolar pool of avt3Δ cells, but decreased in that of avt3+-overexpressing avt3Δ cells. These results suggest that SpAvt3p participates in the vacuolar compartmentalization of amino acids in S. pombe. To examine the export activity of SpAvt3p, we expressed the avt3+ gene in S. cerevisiae cells. We found that the heterologously overproduced GFP-SpAvt3p localized to the vacuolar membrane in S. cerevisiae. Using the vacuolar membrane vesicles isolated from avt3+-overexpressing S. cerevisiae cells, we detected the export activities of alanine and tyrosine in an ATP-dependent manner. These activities were inhibited by the addition of a V-ATPase inhibitor, concanamycin A, thereby suggesting that the activity of SpAvt3p is dependent on a proton electrochemical gradient generated by the action of V-ATPase. In addition, the amounts of various amino acids in the vacuolar pools of S. cerevisiae cells were decreased by the overproduction of SpAvt3p, which indicated that SpAvt3p was functional in S. cerevisiae cells. Thus, SpAvt3p is a vacuolar transporter that is involved in the export of amino acids from S. pombe vacuoles. PMID:26083598

  9. MicroRNA-490-3p inhibits proliferation of A549 lung cancer cells by targeting CCND1

    SciTech Connect

    Gu, Haihua; Yang, Tao; Fu, Shaozi; Chen, Xiaofan; Guo, Lei; Ni, Yiming

    2014-01-31

    Highlights: • We examined the level of miR-490-3p in A549 lung cancer cells compared with normal bronchial epithelial cell line. • We are the first to show the function of miR-490-3p in A549 lung cancer cells. • We demonstrate CCND1 may be one of the targets of miR-490-3p. - Abstract: MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the translation of messenger RNAs by binding their 3′-untranslated region (3′UTR). In this study, we found that miR-490-3p is significantly down-regulated in A549 lung cancer cells compared with the normal bronchial epithelial cell line. To better characterize the role of miR-490-3p in A549 cells, we performed a gain-of-function analysis by transfecting the A549 cells with chemically synthesized miR-490-3P mimics. Overexpression of miR-490-3P evidently inhibits cell proliferation via G1-phase arrest. We also found that forced expression of miR-490-3P decreased both mRNA and protein levels of CCND1, which plays a key role in G1/S phase transition. In addition, the dual-luciferase reporter assays indicated that miR-490-3P directly targets CCND1 through binding its 3′UTR. These findings indicated miR-490-3P could be a potential suppressor of cellular proliferation.

  10. Allelic imbalance regions on chromosomes 8p, 17p and 19p related to metastasis of hepatocellular carcinoma: comparison between matched primary and metastatic lesions in 22 patients by genome-wide microsatellite analysis.

    PubMed

    Zhang, Lian-Hai; Qin, Lun-Xiu; Ma, Zeng-Chen; Ye, Sheng-Long; Liu, Yin-Kun; Ye, Qing-Hai; Wu, Xin; Huang, Wei; Tang, Zhao-You

    2003-05-01

    To understand the molecular mechanisms of metastasis in hepatocellular carcinoma (HCC), it is necessary to identify the accumulating genetic alterations during its progression as well as those responsible for the acquisition of metastatic potential in cancer cells. In our previous study, using comparative genomic hybridization (CGH), we found that loss on chromosome 8p is more frequent in metastatic lesions than in matched primary tumors of HCC. Thus, 8p deletion might contribute to HCC metastasis. To narrow the location of metastasis-related alteration regions, we analyzed 22 primary and matched metastatic lesions of HCC by genome-wide microsatellite analysis. Common regions with high levels of allelic imbalance (AI) were identified on 17p, 8p11-cen, 8p21-23, 4q32-qter, 4q13-23, 16q, and 1p33. Regions with increased AI in metastatic lesions were 8p23.3, 8p11.2, 17p11.2-13.3, 4q21-22, 4q32-qter, 8q24.1, 9p11, 9q31, 11q23.1, 13q14.1-31, 13q32-qter, 16p13.3, 16q13, 16q22, and 19p13.1, and these were considered to be related to the metastasis phenotype. Among them, loss on 8p was again proved to be related to progression and metastasis of HCC, and 8p23.3 and 8p11.2 were two likely regions harboring metastasis-related genes. It was also shown for the first time in HCC that AI of 19p13.1 might also be related to metastatic potential. These results provide some candidate regions for further study to identify putative genes suppressing metastasis of HCC. PMID:12734753

  11. A 1.5 Mb submicroscopic deletion in 17p11.2-p12 is frequently observed in Italian families with hereditary neuropathy with liability to pressure palsies

    SciTech Connect

    Lorenzetti, D.; Roa, B.B.; Abbas, N.E.

    1994-09-01

    Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent mononeuropathies that was recently associated with a 1.5 Mb deletion in chromosome 17p11.2-p12. Duplication of the same region is known to be associated with Charcot-Marie-Tooth disease type 1A (CMT1A), a more severe peripheral neuropathy characterized by symmetrically slowed nerve conduction velocity. The CMT1A duplication and HNPP deletion are reciprocal recombination products involving a repeat element (CMT1A-REP) which flanks the 1.5 Mb region involved in the duplication/deletion. Patients from 9 unrelated HNPP Italian families were clinically, electrophysiologically and histologically evaluated. Families were typed with a polymorphic (CA){sub n} repeat and with RFLPs corresponding to loci D17S122, D17S125 and D17S61, which all map within the deleted region. Lack of allelic transmission from affected parent to affected offspring was observed in four informative families, suggesting the presence of deletion. Southern blot analysis of EcoRI digested genomic DNA from HNPP patients and control subjects was performed using a probe mapping within the CMT1A-REP elements. A reduced hybridization signal of a 6.0 kb EcoRI fragment, mapping within the distal CMT1A-REP, was observed in all HNPP patients suggesting the loss of one copy of this fragment in the HNPP-deleted chromosome. PFGE analysis of SacII digested genomic DNA from selected HNPP subjects showed the presence of a junction fragment which has previously been found in association with the 1.5 Mb HNPP deletion. Evidence for deletion could be demonstrated in all 9 families suggesting that the 17p11.2-p12 deletion is commonly associated with HNPP.

  12. Asymmetry in the triplet 3p-4s Mg lines in cool DZ white dwarfs

    NASA Astrophysics Data System (ADS)

    Allard, N. F.; Leininger, T.; Gadéa, F. X.; Brousseau-Couture, V.; Dufour, P.

    2016-04-01

    The purpose of the present work is to make an exhaustive study of the line shape of the triplet 3p-4s Mg line (Mgb triplet), which is perturbed by He in the extreme physical conditions found in the cool atmosphere of DZ white dwarfs. This study is undertaken by inferring both a unified theory of spectral line broadening and ab initio potential energies. Cool white dwarfs require a specific treatment for line broadening owing to the high helium densities that are involved. Beyond the conventional symmetrical Lorentzian core at low density, we show that the line profiles are asymmetrical and have significant additional contributions on the short wavelength side. This blue asymmetry is a consequence of low maxima in the corresponding Mg-He potential energy difference curves at short and intermediate internuclear distances. The new profiles are shown to provide a good fit to an SDSS (Sloan Digital Sky Survey) observation.

  13. Precision Hyperfine Structure of 2;^3P State of ^3He with External Magnetic

    NASA Astrophysics Data System (ADS)

    Wu, Qixue; Drake, G. W. F.

    2007-06-01

    The theory of the Zeeman effect can be used to extrapolate precise measurements for the fine structure or the hyperfine structure to zero-field strength. In the present work, the hyperfine structure of 2;^3P state of ^3He with external magnetic fields is precisely calculated. The values of the fields for 32 crossings and five anticrossings of the magnetic sublevels are theoretically predicted for magnetic field strengths up to 1 Tesla. The results are compared with experimental work. We include the linear terms, diamagnetic terms, and the 2̂ relativistic correction terms in the Zeeman Hamiltonian. All related matrix elements are calculated with high accuracy by the use of double basis set Hylleraas type variational wave functions[1,2].[1] Z. -C. Yan and G.W.F. Drake, Phys. Rev. A 50, R1980 (1994).[2] Q. Wu and G.W.F. Drake, J. Phys. B 40, 393 (2007).

  14. C-H activation of ethers by pyridine tethered PCsp3P-type iridium complexes.

    PubMed

    Cui, Peng; Babbini, Dominic C; Iluc, Vlad M

    2016-06-14

    Iridium PCsp3P complexes featuring a novel bis(2-diphenylphosphinophenyl)-2-pyridylmethane ligand (PC(Py)HP) are reported. C-H activation reactions between the dihydride complex [(PC(Py)P)Ir(H)2] and tetrahydrofuran or methyl tert-butyl ether in the presence of a hydrogen acceptor, norbornene (NBE), at ambient temperature led exclusively to the hydrido oxyalkyl complexes, [(PC(Py)P)IrH(C4H7O)] and [(PC(Py)P)IrH(CH2O(t)Bu)], respectively. The internal pyridine donor is important and stabilizes these species by coordination to the iridium center. The coordination of pyridine to the iridium center is labile, however, and its dissociation occurs in the presence of a suitable substrate, as demonstrated by the intramolecular nucleophilic attack of pyridine on a vinylidene intermediate generated from PhC[triple bond, length as m-dash]CH. PMID:27052422

  15. Reactions of Atomic Oxygen (O(3P)) with Polybutadienes and Related Polymers

    NASA Technical Reports Server (NTRS)

    Golub, Morton A.; Lerner, Narcinda R.; Wydeven, Theodore

    1987-01-01

    Thin films of the following polymers were exposed at ambient temperature to ground-state oxygen atoms (O(3P)), generated by a radio-frequency glow discharge in O2: cis- and trans-1,4-polybutadienes (CB and TB), amorphous 1,2-polybutadiene (VB), polybutadienes with different 1,4/1,2 contents, trans polypentenamer (TP), cis and trans polyoctenamers (CO and TO), and ethylene-propylene rubber (EPM). Transmission infrared spectra of CB and TB films revealed extensive surface recession, or etching, unaccompanied by any microstructural changes within the films, demonstrating that the reactions were confined to the surface layers. Contrary to the report by Rabek, Lucki, and Ranby (1979), there was no O(3P)-induced cis-trans isomerization in CB or TB. From weight-loss measurements, etch rates for polybutadienes were found to be markedly dependent on vinyl content, decreasing by two orders of magnitude from CB (2% 1,2) to structures with 30 to 40% 1,2 double bonds, thereafter increasing by half an order of magnitude to VB (97% 1,2). Relative etch rates for EMP and the polyalkenamers were in the order: EMP is greater than CO (or TO) is greater than TP is greater than CB. The sole non-elastomer examined, TB, had an etch rate about six times that of CB, ascribable to a morphology difference. Cis/trans content had a negligible effect on the etch rate of the polyalkenamers. Mechanisms involving crosslinking through units are proposed for the unexpected protection imparted to polybutadienes by the 1,2 double bonds.

  16. miRNA-296-3p modulates chemosensitivity of lung cancer cells by targeting CX3CR1

    PubMed Central

    Luo, Wen; Lin, Yuanlong; Meng, Shanshan; Guo, Yuening; Zhang, Jiawen; Zhang, Wei

    2016-01-01

    Lung cancer is the most common type of cancer-related death in developed countries. MicroRNAs (miRNAs) are small non-coding RNAs, which regulates gene expression in cancer. Recent studies demonstrate that the microRNA-293-3p (miR-293-3p) may play as an oncogene or a tumor suppressor. However, its expression and roles in non-small cell lung cancer (NSCLC) is not known. In this study, our purpose is to investigate the expression and roles of miR-296-3p in NSCLC. The findings indicated that miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues. Our study elucidates that miR296-3p plays a suppressive role in NSCLC by inhibiting CX3CR1 expression. PMID:27186308

  17. Expression of miR-199a-3p in human adipocytes is regulated by free fatty acids and adipokines

    PubMed Central

    Gu, Nan; You, Lianghui; Shi, Chunmei; Yang, Lei; Pang, Lingxia; Cui, Xianwei; Ji, Chenbo; Zheng, Wen; Guo, Xirong

    2016-01-01

    Obesity is associated with a notable risk for disease, including risk of cardiovascular disorders, type 2 diabetes mellitus (T2DM) and hypertension. Adipose tissue modulates the metabolism by releasing free fatty acids (FFAs) and adipokines, including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Altered secretion patterns of FFAs and adipokines have been demonstrated to result in obesity-associated insulin resistance (IR) and inflammatory responses. MicroRNA-199a-3p (miR)-199a-3p expression is significantly induced in differentiated human adipose-derived mesenchymal stem cells and indicates the association with T2DM. However, the association between miR-199a-3p levels in adipocytes and obesity-associated IR, as well as inflammatory responses remains to be elucidated. The present study observed an elevation of miR-199a-3p expression level in mature human adipocytes (visceral) compared with pre-adipocytes. In addition, miR-199a-3p expression was higher in visceral adipose deposits from obese subjects. FFA, TNF-α, IL-6 and leptin significantly induced miR-199a-3p expression in mature human adipocytes, while resistin had the opposite effect. miR-199a-3p may represent a factor in the modulation of obesity-associated IR and inflammatory responses. PMID:27279151

  18. miR-224-3p inhibits autophagy in cervical cancer cells by targeting FIP200.

    PubMed

    Fang, Wang; Shu, Shan; Yongmei, Li; Endong, Zhu; Lirong, Yin; Bei, Sun

    2016-01-01

    Cervical cancer (CC) is a malignant solid tumor, which is one of the main causes of morbidity and mortality in women. Persistent High-risk human papillomavirus (hrHPV) infection is closely related to cervical cancer and autophagy has been suggested to inhibit viral infections. miRNAs have been reported to regulate autophagy in many solid tumors with many studies implicating miR-224-3p in the regulation of autophagy. In this study, we performed a miRNA microarray analysis on CC tissues and found that a large number of miRNAs with differential expressions in hrHPV-infected tissues. We identified miR-224-3p as a candidate miRNA selectively up regulated in HPV-infected tissues and cell lines. Further analysis revealed that miR-224-3p regulates autophagy in cervical cancer tissues and cell lines. While the overexpression of miR-224-3p inhibits autophagy in HPV-infected cells, knocking down endogenous miR-224-3p increases autophagy activity in the same cells. In addition, we found that miR-224-3p directly inhibits the expression of autophagy related gene, FAK family-interacting protein of 200 kDa (FIP200). In summary, we found that miR-224-3p regulates autophagy in hrHPV-induced cervical cancer cells through targeting FIP200 expression. PMID:27615604

  19. miRNA-296-3p modulates chemosensitivity of lung cancer cells by targeting CX3CR1.

    PubMed

    Luo, Wen; Lin, Yuanlong; Meng, Shanshan; Guo, Yuening; Zhang, Jiawen; Zhang, Wei

    2016-01-01

    Lung cancer is the most common type of cancer-related death in developed countries. MicroRNAs (miRNAs) are small non-coding RNAs, which regulates gene expression in cancer. Recent studies demonstrate that the microRNA-293-3p (miR-293-3p) may play as an oncogene or a tumor suppressor. However, its expression and roles in non-small cell lung cancer (NSCLC) is not known. In this study, our purpose is to investigate the expression and roles of miR-296-3p in NSCLC. The findings indicated that miR296-3p inhibited NSCLC cell proliferation, enhance the drug resistance, and apoptosis. Data of luciferase reporter assays demonstrated that the CX3CR1 gene was a direct regulator of tumorsuppressive miR296-3p. Moreover, overexpressed CX3CR1 was confirmed in NSCLC clinical specimens. Inhibition of CX3CR1 could inhibit cancer cellular survival and increase chemotherapy sensitivity. There was a negative relationship between miR296-3p and CX3CR1 expression in NSCLC tissues. Our study elucidates that miR296-3p plays a suppressive role in NSCLC by inhibiting CX3CR1 expression. PMID:27186308

  20. Expression of miR-199a-3p in human adipocytes is regulated by free fatty acids and adipokines.

    PubMed

    Gu, Nan; You, Lianghui; Shi, Chunmei; Yang, Lei; Pang, Lingxia; Cui, Xianwei; Ji, Chenbo; Zheng, Wen; Guo, Xirong

    2016-08-01

    Obesity is associated with a notable risk for disease, including risk of cardiovascular disorders, type 2 diabetes mellitus (T2DM) and hypertension. Adipose tissue modulates the metabolism by releasing free fatty acids (FFAs) and adipokines, including leptin, resistin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL‑6). Altered secretion patterns of FFAs and adipokines have been demonstrated to result in obesity‑associated insulin resistance (IR) and inflammatory responses. MicroRNA-199a-3p (miR)-199a-3p expression is significantly induced in differentiated human adipose-derived mesenchymal stem cells and indicates the association with T2DM. However, the association between miR-199a-3p levels in adipocytes and obesity‑associated IR, as well as inflammatory responses remains to be elucidated. The present study observed an elevation of miR‑199a‑3p expression level in mature human adipocytes (visceral) compared with pre-adipocytes. In addition, miR‑199a‑3p expression was higher in visceral adipose deposits from obese subjects. FFA, TNF-α, IL‑6 and leptin significantly induced miR‑199a‑3p expression in mature human adipocytes, while resistin had the opposite effect. miR‑199a‑3p may represent a factor in the modulation of obesity‑associated IR and inflammatory responses. PMID:27279151

  1. Tumor cell-secreted angiogenin induces angiogenic activity of endothelial cells by suppressing miR-542-3p.

    PubMed

    He, Ting; Qi, Feifei; Jia, Lin; Wang, Shan; Wang, Chunying; Song, Nan; Fu, Yan; Li, Lin; Luo, Yongzhang

    2015-11-01

    Therapeutic strategies for targeting angiogenesis have been proven as successful treatments for divergent cancers. We previously discovered an anti-angiogenic miR-542-3p, which directly targeted the key angiogenesis-promoting protein Angiopoietin-2 to inhibit tumor angiogenesis in breast cancer models. In this study, to further investigate the mechanism of miR-542-3p induced angiogenic inhibition, we screened for tumor cell derived factors which were responsible for miR-542-3p alteration in endothelial cells. We found that tumor cell-derived angiogenin downregulated miR-542-3p in endothelial cells. Overexpression of angiogenin in tumor cells facilitated angiogenic activation in both in vitro and in vivo models via inhibition of miR-542-3p. Furthermore, our results showed that angiogenin could suppress CEBPB and POU2F1, which were transcription factors for miR-542-3p, suggesting a novel tumor cell-endothelial cell signal pathway. In addition, the level of angiogenin in primary breast carcinomas correlated with clinical progression. Serum levels of angiogenin were associated with metastatic development of breast cancer patients. Together, these findings reveal a novel regulatory pathway whereby tumor-derived angiogenin directly activates angiogenesis through inhibition of miR-542-3p, suggesting that angiogenin may represent a promising target for anti-angiogenic therapy and a potential marker for monitoring disease progression. PMID:26272182

  2. MicroRNA-23a-3p promotes the development of osteoarthritis by directly targeting SMAD3 in chondrocytes.

    PubMed

    Kang, Liang; Yang, Cao; Song, Yu; Liu, Wei; Wang, Kun; Li, Shuai; Zhang, Yukun

    2016-09-01

    Osteoarthritis (OA) is a common chronic degenerative joint disease. Progressive destruction of the integrity of articular cartilage is an important pathological feature, but treatment options that reverse this damage have not been developed. According to recent studies, microRNAs have important regulatory roles in the initiation and progression of OA. In the current study, the biological effects of miR-23a-3p and its expression in OA tissues were examined. We found that miR-23a-3p expression was obviously higher and SMAD3 expression was significantly lower in OA cartilage than in normal tissues. The hypomethylation status of CpG islands in the promoter region of miR-23a-3p was confirmed by methylation-specific polymerase chain reaction in OA cartilage tissues. Furthermore, a bioinformatics analysis and luciferase reporter assay identified SMAD3 as a target gene of miR-23a-3p and SMAD3 expression at both the protein and mRNA levels was inhibited by miR-23a-3p. A functional analysis demonstrated that miR-23a-3p overexpression suppresses type II collagen and aggrecan expression, while miR-23a-3p inhibition had the opposite effects. Small interfering RNA-mediated knockdown of SMAD3 reversed the effects of the miR-23a-3p inhibitor on the expression of type II collagen and aggrecan. Our results suggested that miR-23a-3p contributes to OA progression by directly targeting SMAD3, providing a potential therapeutic target for OA treatment. PMID:27318087

  3. Genomic characterization of uncommon human G3P[6] rotavirus strains causing diarrhea in children in Italy in 2009.

    PubMed

    Ianiro, Giovanni; Delogu, Roberto; Fiore, Lucia; Ruggeri, Franco M

    2015-07-01

    Group A rotaviruses (RVA) are the leading cause of acute gastroenteritis in young children, causing up to 450,000 deaths worldwide, mostly in developing countries. Most of RVA human infections in developed countries are related to five major G/P combinations: G1P[8], G2P[4], G3P[8], G4P[8] and G9P[8]. During the surveillance activity of RotaNet-Italy, three uncommon G3P[6] RVA strains, designated as RVA/Human-wt/ITA/NA01/2009/G3P[6], RVA/Human-wt/ITA/NA06/2009/G3P[6], and RVA/Human-wt/ITA/NA19/2009/G3P[6], were identified in the stools of children with diarrhea hospitalized in Southern Italy in 2009. Samples NA01, NA06 and NA19 were characterized as genotype G3P[6]. To investigate the three strains further, partial sequencing of the eleven genomic segments was performed. RVA strains NA01, NA06 and NA19 were found to share the rare genotype constellation: G3-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2, which had not been reported previously in continental Italy. The phylogenetic analysis of the eleven genomic segments showed no evidence of zoonosis or inter-species reassortment at the origin of the Italian G3P[6] strains, indicating that they possessed DS-1-like genomic constellations similar to those detected previously in human cases in Africa and Europe. The analysis of the hypervariable regions of VP7 and VP4 (VP8*) revealed high amino acid identity between the Italian G3P[6] RVA strains involved in this study. PMID:25913157

  4. miR-208-3p promotes hepatocellular carcinoma cell proliferation and invasion through regulating ARID2 expression

    SciTech Connect

    Yu, Peng; Wu, Dingguo; You, Yu; Sun, Jing; Lu, Lele; Tan, Jiaxing; Bie, Ping

    2015-08-15

    MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at post-transcriptional level. miRNA dysregulation plays a causal role in cancer progression. In this study, miR-208-3p was highly expressed and directly repressed ARID2 expression. As a result, ARID2 expression in hepatocellular carcinoma (HCC) was decreased. In vitro, miR-208-3p down-regulation and ARID2 over-expression elicited similar inhibitory effects on HCC cell proliferation and invasion. In vivo test results revealed that miR-208-3p down-regulation inhibited HCC tumorigenesis in Hep3B cells. Moreover, ARID2 was possibly a downstream element of transforming growth factor beta1 (TGFβ1)/miR-208-3p/ARID2 regulatory pathway. These findings suggested that miR-208-3p up-regulation is associated with HCC cell progression and may provide a new target for liver cancer treatment. - Highlights: • miR-208-3p was highly expressed and directly repressed the expression of ARID2 in HCC. • miR-208-3p contributed to HCC cell progression both in vitro and in vivo. • Over-expression of ARID2 inhibited the HCC cell proliferation and invasion. • Restoration of ARID2 partly reversed the the effect of miR-208-3p down-regulation on HCC cells. • Newly regulatory pathway: miR-208-3p mediated the repression of ARID2 by TGFβ1 in HCC cells.

  5. microRNA-199a-3p functions as tumor suppressor by regulating glucose metabolism in testicular germ cell tumors.

    PubMed

    Liu, Xiaowen; Duan, Hongyan; Zhou, Shihua; Liu, Zhiyong; Wu, Daobing; Zhao, Ting; Xu, Shan; Yang, Lifang; Li, Dan

    2016-09-01

    microRNA (miR)-199a-3p serves critical roles in cancer development and progression. In order to improve knowledge of the functional mechanism of miR‑199a‑3p in testicular tumors, the present study characterized the regulation of aerobic glycolysis by miR‑199a‑3p and its impact on metabolism. Using 3‑4,5‑dimethylthiazol‑2‑yl‑2,5 diphenyl tetrazolium bromide, wound healing and flow cytometry assays, it was determined that overexpression of miR‑199a‑3p in Ntera‑2 cells caused suppression of cell growth and migration. Further biochemical methods and high‑throughput quantitative polymerase chain reaction array of metabolic genes showed that inhibition of miR‑199a‑3p markedly elevated lactate production and 12 differentially expressed genes, including 2 upregulated and 10 downregulated genes, were identified following treatment with miR‑199a‑3p in Ntera‑2 cells. In clinical samples, four selected genes, lactate dehydrogenase A, monocarboxylate transporter 1, phosphoglycerate kinase 1 and TP53‑inducible glycolysis and apoptosis regulator, were significantly overexpressed in malignant testicular germ cell tumor, and their expression inversely correlated with the expression of miR‑199a‑3p, suggesting that these four genes may be affected by miR‑199a‑3p. Using bioinformatics analysis, the transcription factor Sp1 binding site was identified in the promoter region of the four selected genes. In addition, miR‑199a‑3p was predicted to bind to conservative target sequences in the 3'‑untranslated region of Sp1 mRNA, suggesting that miR-199a-3p may downregulate these four metabolic genes through Sp1. It was demonstrated the dysregulated expression and activation of miR‑199a‑3p may serve important roles in aerobic glycolysis and tumorigenesis in patients with testicular cancer. Therefore, miR-199a-3p may be a potential biomarker in the prognosis and treatment of testicular tumors. PMID:27432288

  6. Measurement of the 3s1/2-3p3/2 resonance line of sodiumlike Eu52+

    DOE PAGESBeta

    Träbert, E.; Beiersdorfer, P.; Hell, N.; Brown, G. V.

    2015-08-20

    We have measured the 3s1/2-3p3/2 transition in sodiumlike Eu52+ situated at 41.232 Å with an uncertainty of 73 ppm. Our measurement extends previous high-precision measurements into the 56< Z< 78 range of atomic numbers. We also present measurements of 3s1/2-3p3/2 and 3p1/2-3d3/2 transitions in the neighboring magnesiumlike, aluminumlike, and siliconlike europium ions.

  7. Prognostic value of miR-221-3p, miR-342-3p and miR-491-5p expression in colon cancer

    PubMed Central

    Tao, Kun; Yang, Jing; Guo, Zhenhua; Hu, Yuemei; Sheng, Haihui; Gao, Hengjun; Yu, Hongyu

    2014-01-01

    Increasing evidence has demonstrated that microRNAs (miRNAs) are involved in colon cancer initiation and progression, and may serve as diagnostic and prognostic biomarkers for colon cancer. Here, we investigated the levels of miR-9-1, miR-203-3p, miR-221-3p, miR-342-3p, miR-491-5p and miR-503-5p in 90 pairs of colon cancer and adjacent normal tissues, and explored the relationship between their expression and clinical outcome of colon cancer. Five miRNAs (miR-203-3p, miR-221-3p, miR-342-3p, miR-491-5p and miR-503-5p) were dysregulated in colon cancer tissue (P < 0.05). The levels of miR-503-5p in larger tumors (≥ 6 cm) were higher than those in smaller ones (< 6 cm) (P = 0.031), while the levels of miR-203-3p and miR-491-5p in patients aged 70 years and older were higher than those in patients aged younger than 70 years (P = 0.019 and 0.049, respectively). The high levels of miR-221-3p (HR = 2.416, 95% CI 1.314-4.445, P = 0.005), miR-342-3p (HR = 1.807, 95% CI 1.003-3.253, P = 0.049) and miR-491-5p (HR = 1.868, 95% CI 1.032-3.384, P = 0.039) were significantly associated with worse survival time. Moreover, combination analysis of miR-221-3p, miR-342-3p and miR-491-5p expression revealed that patients with 3 highly expressed miRNAs had lower survival rates compared with those with zero-to-two highly expressed miRNAs (HR = 2.100, 95% CI 1.157-3.813, P = 0.015), especially those with TNM stages I and II (HR = 4.204,95% CI 1.762-10.030, P = 0.001). Our results suggest that the three-miRNA signature may help doctors better predict prognosis and guide treatment decisions for colon cancer. PMID:25075256

  8. FAST TRACK COMMUNICATION: Generalized geometrical model for photoionization of polarized atoms: II. Magnetic dichroism in the 3p photoemission from the K 3p64s 2S1/2 ground state

    NASA Astrophysics Data System (ADS)

    Grum-Grzhimailo, A. N.; Cubaynes, D.; Heinecke, E.; Hoffmann, P.; Zimmermann, P.; Meyer, M.

    2010-10-01

    The generalized geometrical model for photoionization from polarized atoms is extended to include mixing of configurations in the initial atomic and/or the final photoion states. The theoretical results for angle-resolved linear and circular magnetic dichroism are in good agreement with new high-resolution photoelectron data for 3p-1 photoionization of potassium atoms polarized in the K 3p64s 2S1/2 ground state by laser optical pumping.

  9. Controlled Pd(0)/t Bu3P Catalyzed Suzuki Cross-Coupling Polymerization of AB-Type Monomers with ArPd(t Bu3P)X or Pd2(dba)3/t Bu3P/ArX as the Initiator

    SciTech Connect

    Zhang, Honghai; Xing, Chun-Hui; Hu, Qiao-Sheng; Hong, Kunlun

    2015-02-05

    The synthesis of well-defined and functionalized conjugated polymers, which are essential in the development of efficient organic electronics, through Suzuki cross-coupling polymerizations has been a challenging task. We developed controlled Pd(0)/t-Bu3P-catalyzed Suzuki cross-coupling polymerizations of AB-type monomers via the chain-growth mechanism with a series of in situ generated ArPd(t-Bu3P)X (X = I, Br, Cl) complexes as initiators. Among them, the combinations of Pd2(dba)3/t-Bu3P/p-BrC6H4I, Pd2(dba)3/t-Bu3P/p-BrC6H4CH2OH and Pd2(dba)3/t-Bu3P/p-PhCOC6H4Br were identified as highly robust initiator systems, resulting in polymers with predictable molecular weight and narrow polydispersity (PDI~1.13-1.20). In addition, Pd2(dba)3/t-Bu3P/p-BrC6H4CH2OH and Pd2(dba)3/t-Bu3P/p-PhCOC6H4Br initiator systems afforded functional polymers with >95% fidelity. Our results paved the road to access well-defined conjugated polymers, including conjugated polymers with complex polymer architectures such as block copolymers and branch copolymers.

  10. Controlled Pd(0)/t Bu3P Catalyzed Suzuki Cross-Coupling Polymerization of AB-Type Monomers with ArPd(t Bu3P)X or Pd2(dba)3/t Bu3P/ArX as the Initiator

    DOE PAGESBeta

    Zhang, Honghai; Xing, Chun-Hui; Hu, Qiao-Sheng; Hong, Kunlun

    2015-02-05

    The synthesis of well-defined and functionalized conjugated polymers, which are essential in the development of efficient organic electronics, through Suzuki cross-coupling polymerizations has been a challenging task. We developed controlled Pd(0)/t-Bu3P-catalyzed Suzuki cross-coupling polymerizations of AB-type monomers via the chain-growth mechanism with a series of in situ generated ArPd(t-Bu3P)X (X = I, Br, Cl) complexes as initiators. Among them, the combinations of Pd2(dba)3/t-Bu3P/p-BrC6H4I, Pd2(dba)3/t-Bu3P/p-BrC6H4CH2OH and Pd2(dba)3/t-Bu3P/p-PhCOC6H4Br were identified as highly robust initiator systems, resulting in polymers with predictable molecular weight and narrow polydispersity (PDI~1.13-1.20). In addition, Pd2(dba)3/t-Bu3P/p-BrC6H4CH2OH and Pd2(dba)3/t-Bu3P/p-PhCOC6H4Br initiator systems afforded functional polymers with >95% fidelity. Our results pavedmore » the road to access well-defined conjugated polymers, including conjugated polymers with complex polymer architectures such as block copolymers and branch copolymers.« less

  11. Calculations of resonances parameters for the ((2s2) 1Se, (2s2p) 1,3P0) and ((3s2) 1Se, (3s3p) 1,3P0) doubly excited states of helium-like ions with Z≤10 using a complex rotation method implemented in Scilab

    NASA Astrophysics Data System (ADS)

    Gning, Youssou; Sow, Malick; Traoré, Alassane; Dieng, Matabara; Diakhate, Babacar; Biaye, Mamadi; Wagué, Ahmadou

    2015-01-01

    In the present work a special computational program Scilab (Scientific Laboratory) in the complex rotation method has been used to calculate resonance parameters of ((2s2) 1Se, (2s2p) 1,3P0) and ((3s2) 1Se, (3s3p) 1,3P0) states of helium-like ions with Z≤10. The purpose of this study required a mathematical development of the Hamiltonian applied to Hylleraas wave function for intrashell states, leading to analytical expressions which are carried out under Scilab computational program. Results are in compliance with recent theoretical calculations.

  12. Age- and glycemia-related miR-126-3p levels in plasma and endothelial cells

    PubMed Central

    Spazzafumo, Liana; Gobbi, Mirko; Prattichizzo, Francesco; Recchioni, Rina; Marcheselli, Fiorella; Sala, Lucia La; Galeazzi, Roberta; Rippo, Maria Rita; Fulgenzi, Gianluca; Angelini, Sabrina; Lazzarini, Raffaella; Bonfigli, Anna Rita; Brugè, Francesca; Tiano, Luca; Genovese, Stefano; Ceriello, Antonio; Boemi, Massimo; Franceschi, Claudio; Procopio, Antonio Domenico; Testa, Roberto

    2014-01-01

    Circulating miR-126-3p levels were determined in 136 healthy subjects (CTRs) aged 20-90 years and 193 patients with type-2 diabetes mellitus (T2DMs) aged 40-80 years, to explore the combined effect of age and glycemic state on miR-126-3p expression. Moreover, intra/extracellular miR-126-3p levels were measured in human endothelial cells (HUVECs) undergoing senescence under normo/hyper-glycemic conditions. Plasma miR-126-3p was significantly higher in the oldest compared with the youngest CTRs (<45 vs. >75 years; relative expression: 0.27±0.29 vs. 0.48±0.39, p=0.047). Age-based comparison between CTRs and T2DM demonstrated significantly different miR-126-3p levels only in the oldest (0.48±0.39 vs. 0.22±0.23, p<0.005). After multiple adjustments, miR-126-3p levels were seen to be lower in patients with poor glycemic control, compared with age-matched CTRs. The age-related increase in plasma miR-126-3p found in CTRs was paralleled by a 5/6-fold increase in intra/extracellular miR-126-3p in in vitro-cultured HUVECs undergoing senescence. Notably, significant down-regulation of SPRED-1 protein, a validated miR-126-3p target, was found in senescent HUVECs. Moreover, miR-126-3p expression was down-regulated in intermediate-age HUVECs grown in high-glucose medium until senescence. Aging/senescence-associated miR-126-3p up-regulation is likely a senescence-associated compensatory mechanism that is blunted when endothelial cells are exposed to high glucose levels, a phenomenon that probably occurs in vivo in T2DM patients. PMID:25324472

  13. MicroRNA-103a-3p controls proliferation and osteogenic differentiation of human adipose tissue-derived stromal cells

    PubMed Central

    Sol Kim, Da; Young Lee, Sun; Hee Lee, Jung; Chan Bae, Yong; Sup Jung, Jin

    2015-01-01

    The elucidation of the molecular mechanisms underlying the differentiation and proliferation of human adipose tissue-derived stromal cells (hADSCs) represents a critical step in the development of hADSCs-based cellular therapies. To examine the role of the microRNA-103a-3p (miR-103a-3p) in hADSCs functions, miR-103a-3p mimics were transfected into hADSCs in order to overexpress miR-103a-3p. Osteogenic differentiation was induced for 14 days in an osetogenic differentiation medium and assessed by using an Alizarin Red S stain. The regulation of the expression of CDK6 (cyclin-dependent kinase 6), a predicted target of miR-103a-3p, was determined by western blot, real-time PCR and luciferase reporter assays. Overexpression of miR-103a-3p inhibited the proliferation and osteogenic differentiation of hADSCs. In addition, it downregulated protein and mRNA levels of predicted target of miR-103a-3p (CDK6 and DICER1). In contrast, inhibition of miR-103a-3p with 2′O methyl antisense RNA increased the proliferation and osteogenic differentiation of hADSCs. The luciferase reporter activity of the construct containing the miR-103a-3p target site within the CDK6 and DICER1 3′-untranslated regions was lower in miR-103a-3p-transfected hADSCs than in control miRNA-transfected hADSCs. RNA interference-mediated downregulation of CDK6 and DICER1 in hADSCs inhibited their proliferation and osteogenic differentiation. The results of the current study indicate that miR-103a-3p regulates the osteogenic differentiation of hADSCs and proliferation of hADSCs by direct targeting of CDK6 and DICER1 partly. These findings further elucidate the molecular mechanisms governing the differentiation and proliferation of hADSCs. PMID:26160438

  14. Utilising the `3P-model' to Characterise the Discipline of Didactics of Science

    NASA Astrophysics Data System (ADS)

    Adúriz-Bravo, Agustín; Izquierdo-Aymerich, Mercè

    In our research within didactics of science, we have been exploring contributions of the so called cognitive models from contemporary philosophy of science. We have used these philosophical frameworks on different levels. As an outcome, we have formulated a model of didactics of science according to which this discipline adapts and transforms theoretical contributions from different scholarly fields. In this paper, we concentrate on this description of didactics of science, which we have called the 3P-model (i.e., philosophy + psychology + pedagogy). This model of the internal functioning of the discipline may be useful to make innovations in science curriculum design and re-conceptualise the role of science teachers as professionals. We see didactics of science as a set of interrelated activities, performed by different individuals, and ranging from theoretical production to practice of science education at school. We find the concept of technoscience suitable to account for this diversity of goals. According to this concept, scientific disciplines are identified both with generation of knowledge and with active intervention on the world. Within current didactics of science, we recognise several kinds of research, having goals more or less directed to practical intervention in science education.

  15. An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p

    SciTech Connect

    Kaukonen, J.A.; Suomalainen, A.; Peltonen, L.; Amati, P.; Zeviani, M.

    1996-04-01

    Autosomal dominant progressive external ophthalmoplegia (adPEO) is a disorder characterized by ptosis, progressive weakness of the external eye muscles, and general muscle weakness. The patients have multiple deletions of mtDNA on Southern blots or in PCR analysis of muscle DNA and a mild deficiency of one or more respiratory-chain enzymes carrying mtDNA-encoded subunits. The pattern of inheritance indicates a nuclear gene defect predisposing to secondary mtDNA deletions. Recently, in one Finnish family, we assigned an adPEO locus to chromosome 10q23.3-24.3 but also excluded linkage to this same locus in two Italian adPEO families with a phenotype closely resembling the Finnish one. We applied a random mapping approach to informative non-10q-linked Italian families to assign the second locus for adPEO and found strong evidence for linkage on chromosome 3p14.1-21.2 in three Italian families, with a maximum two-point lod score of 4.62 at a recombination fraction of .0. However, in three additional families, linkage to the same chromosomal region was clearly absent, indicating further genetic complexity of the adPEO trait. 19 refs., 3 figs., 2 tabs.

  16. Precision frequency measurement of 1S0-3P1 intercombination lines of Sr isotopes

    NASA Astrophysics Data System (ADS)

    Liu, Hui; Gao, Feng; Ye-Bing, Wang; Xiao, Tian; Jie, Ren; Ben-Quan, Lu; Qin-Fang, Xu; Yu-Lin, Xie; Hong, Chang

    2015-01-01

    We report on frequency measurement of the intercombination (5s2)1S0-(5s5p)3P1 transition of the four natural isotopes of strontium, including 88Sr (82.58%), 87Sr (7.0%), 86Sr (9.86%), and 84Sr (0.56%). A narrow-linewidth laser that is locked to an ultra-low expansion (ULE) optical cavity with a finesse of 12000 is evaluated at a linewidth of 200 Hz with a fractional frequency drift of 2.8×10-13 at an integration time of 1 s. The fluorescence collector and detector are specially designed, based on a thermal atomic beam. Using a double-pass acousto-optic modulator (AOM) combined with a fiber and laser power stabilization configuration to detune the laser frequency enables high signal-to-noise ratios and precision saturated spectra to be obtained for the six transition lines, which allows us to determine the transition frequency precisely. The optical frequency is measured using an optical frequency synthesizer referenced to an H maser. Both the statistical values and the final values, including the corrections and uncertainties, are derived for a comparison with the values given in other works. Project supported by the National Natural Science Foundation of China (Grant No. 61127901) and the Key Project of the Chinese Academy of Sciences (Grant No. KJZD-EW-W02).

  17. Time-resolved spectroscopy of the Mercury 6 3P1 state

    NASA Technical Reports Server (NTRS)

    Halstead, J. A.; Reeves, R. R.

    1981-01-01

    The time-resolved fluorescence was observed from the Hg 6 3P1 state under the influence of the earth's magnetic field and with applied fields of up to 14 G. Modulation of the fluorescence decay signal was observed as a function of both time and space and can be interpreted in terms of a classical precession of the excited atom about the magnetic field or as quantum beats resulting from interference between coherently populated Zeeman sublevels. This modulation was studied for each of the five resolvable components of the hyperfine structure separately. The fluorescence from the even isotopes was determined to be almost completely modulated while the fluorescence from the odd isotopes was only partially modulated. The frequency of modulation of the fluorescence from the mercury-202 isotope was observed as a function of the applied magnetic field and a value for the Lande factor of 1.46 + or - 0.03 was obtained. This is within experimental error of the accepted value of 1.486. In addition, the frequency of modulation as a function of applied magnetic field was determined for each of the three resolvable components with more than one contributing isotopic hyperfine line. An investigation of the effect of radiation trapping on the degree modulation was also made.

  18. The role of Sec3p in secretory vesicle targeting and exocyst complex assembly

    PubMed Central

    Luo, Guangzuo; Zhang, Jian; Guo, Wei

    2014-01-01

    During membrane trafficking, vesicular carriers are transported and tethered to their cognate acceptor compartments before soluble N-ethylmaleimide–sensitive factor attachment protein (SNARE)-mediated membrane fusion. The exocyst complex was believed to target and tether post-Golgi secretory vesicles to the plasma membrane during exocytosis. However, no definitive experimental evidence is available to support this notion. We developed an ectopic targeting assay in yeast in which each of the eight exocyst subunits was expressed on the surface of mitochondria. We find that most of the exocyst subunits were able to recruit the other members of the complex there, and mistargeting of the exocyst led to secretion defects in cells. On the other hand, only the ectopically located Sec3p subunit is capable of recruiting secretory vesicles to mitochondria. Our assay also suggests that both cytosolic diffusion and cytoskeleton-based transport mediate the recruitment of exocyst subunits and secretory vesicles during exocytosis. In addition, the Rab GTPase Sec4p and its guanine nucleotide exchange factor Sec2p regulate the assembly of the exocyst complex. Our study helps to establish the role of the exocyst subunits in tethering and allows the investigation of the mechanisms that regulate vesicle tethering during exocytosis. PMID:25232005

  19. The SET Domain Protein, Set3p, Promotes the Reliable Execution of Cytokinesis in Schizosaccharomyces pombe

    PubMed Central

    Rentas, Stefan; Saberianfar, Reza; Grewal, Charnpal; Kanippayoor, Rachelle; Mishra, Mithilesh; McCollum, Dannel; Karagiannis, Jim

    2012-01-01

    In response to perturbation of the cell division machinery fission yeast cells activate regulatory networks that ensure the faithful completion of cytokinesis. For instance, when cells are treated with drugs that impede constriction of the actomyosin ring (low doses of Latrunculin A, for example) these networks ensure that cytokinesis is complete before progression into the subsequent mitosis. Here, we identify three previously uncharacterized genes, hif2, set3, and snt1, whose deletion results in hyper-sensitivity to LatA treatment and in increased rates of cytokinesis failure. Interestingly, these genes are orthologous to TBL1X, MLL5, and NCOR2, human genes that encode components of a histone deacetylase complex with a known role in cytokinesis. Through co-immunoprecipitation experiments, localization studies, and phenotypic analysis of gene deletion mutants, we provide evidence for an orthologous complex in fission yeast. Furthermore, in light of the putative role of the complex in chromatin modification, together with our results demonstrating an increase in Set3p levels upon Latrunculin A treatment, global gene expression profiles were generated. While this analysis demonstrated that the expression of cytokinesis genes was not significantly affected in set3Δ backgrounds, it did reveal defects in the ability of the mutant to regulate genes with roles in the cellular response to stress. Taken together, these findings support the existence of a conserved, multi-protein complex with a role in promoting the successful completion of cytokinesis. PMID:22347452

  20. Molecular Changes Involving MEK3-p38 MAPK Activation in Chronic Masticatory Myalgia.

    PubMed

    Meng, H; Gao, Y; Kang, Y F; Zhao, Y P; Yang, G J; Wang, Y; Cao, Y; Gan, Y H; Xie, Q F

    2016-09-01

    The exact mechanism underlying chronic masticatory myalgia (CMM), a conspicuous symptom in temporomandibular disorders, remains unclear. This investigation compared gene expression profiles between CMM patients and healthy subjects. Peripheral blood leukocytes were collected in 8 cases and 8 controls and subjected to whole genome microarray analyses. Data were analyzed with Gene Ontology and interactive pathways analyses. According to Gene Ontology analysis, categories such as ion transport, response to stimuli, and metabolic process were upregulated. The pathway analysis suggested overexpression of the mitogen-activated protein kinase (MAPK) pathway in CMM patients and to a higher degree in a pathway network. Overexpression of representative members of the MAPK pathway-including MAPK kinase 3 (MEK3), calcium voltage-gated channel auxiliary subunit gamma 2 (CACNG2), and growth arrest and DNA damage-inducible gamma (GADD45G)-was validated with real-time polymerase chain reaction. The upregulation of MEK3 was negatively correlated with the age of the CMM group. In the next step, the authors focused on MEK3, the gene that exhibited the greatest degree of differential expression, and its downstream target protein p38 MAPK. The results revealed upregulation of MEK3, as well as phosphorylated MEK3 and phosphorylated p38 MAPK, in CMM patients. These results provide a "fingerprint" for mechanistic studies of CMM in the future and highlight the importance of MEK3-p38 MAPK activation in CMM. PMID:27418173

  1. Reactions of microwave-generated O({sup 3}P) atoms with unsaturated hydrocarbons

    SciTech Connect

    Tanner, D.D.; Das, N.C.; Kandanarachchi, P.; Camaioni, D.M.; Franz, J.A.; Brausen, M.; Vo, C.T.

    1998-07-10

    The reactions of neat olefins or solutions of olefins in acetone at low temperature with oxygen atoms were examined. O({sub 3}P) [ground-state oxygen] atoms were produced by microwave irradiation of He/O{sub 2} mixtures, followed by contact of the plasma with the fluid at low pressure and temperature. Addition of oxygen atoms to olefins results in skeletal rearrangements involving hydrogen and alkyl migration reactions and ring rearrangements of the intermediate oxygen adducts in competition with epoxide formation. While epoxide formation predominates for simple olefins such as 1- and 4-octene with minor yields of rearrangement products, for highly substituted or strained olefins, such as norbornadiene, skeletal rearrangement dominates following oxygen atom addition. When oxidation of norbornadiene is carried out in the presence of a radical inhibitor to suppress secondary oxidation leading to benzene, the novel ring-rearrangement product, bicyclo[3.{sup 2,3}1.0]hex-3-ene-endo-6-carboxaldehyde, is produced from norbornadiene in significant yields.

  2. MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation.

    PubMed

    Cui, Huachun; Banerjee, Sami; Xie, Na; Ge, Jing; Liu, Rui-Ming; Matalon, Sadis; Thannickal, Victor J; Liu, Gang

    2016-06-01

    Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-β1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-β1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, α-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR-27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis. PMID:26600197

  3. Theoretical study on the two-band degenerate-gaps superconductors: Application to SrPt3P

    NASA Astrophysics Data System (ADS)

    Huang, Hai; Hou, Li-Chao; Zhao, Bin-Peng

    2016-09-01

    We study the magnetic properties of two-band degenerate-gaps superconductors with two-band isotropic Ginzburg-Landau theory. The exact solutions of upper critical field and London penetration depth are obtained, and the calculations reproduce the experimental data of the recently observed superconducting crystal SrPt3P in a broad temperature range. It directly underlies that SrPt3P is a multi-band superconductor with equal gaps in two Fermi surface sheets.

  4. MicroRNA-542-3p Suppresses Tumor Cell Invasion via Targeting AKT Pathway in Human Astrocytoma.

    PubMed

    Cai, Junchao; Zhao, JingJing; Zhang, Nu; Xu, Xiaonan; Li, Rong; Yi, Yang; Fang, Lishan; Zhang, Le; Li, Mengfeng; Wu, Jueheng; Zhang, Heng

    2015-10-01

    The molecular mechanism underlying constitutive activation of AKT signaling, which plays essential roles in astrocytoma progression, is not fully characterized. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of astrocytoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we found that microRNA (miR)-542-3p expression was decreased in glioblastoma cell lines and astrocytoma tissues, and reduced levels of miR-542-3p expression correlated with high histopathological grades and poor prognosis of astrocytoma patients. Exogenous miR-542-3p suppressed glioblastoma cell invasion through not only targeting AKT1 itself but also directly down-regulating its two important upstream regulators, namely, integrin-linked kinase and PIK3R1. Notably, overexpressing miR-542-3p decreased AKT1 phosphorylation and directly and indirectly repressed nuclear translocation and transactivation activity of β-catenin to exert its anti-invasive effect. Furthermore, the miR-542-3p expression level negatively correlated with AKT activity as well as levels of integrin-linked kinase and PIK3R1 in human astrocytoma specimens. These findings suggest that miR-542-3p acts as a negative regulator in astrocytoma progression and that miR-542-3p down-regulation contributes to aberrant activation of AKT signaling, leaving open the possibility that miR-542-3p may be a potential therapeutic target for high grade astrocytoma. PMID:26286747

  5. The correlation between microRNA490-3p and TGFα in endometrial carcinoma tumorigenesis and progression

    PubMed Central

    Sun, Kai-Xuan; Chen, Ying; Chen, Shuo; Liu, Bo-Liang; Feng, Miao-Xiao; Zong, Zhi-Hong; Zhao, Yang

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the translation of messenger RNAs by binding their 3′-untranslated region (3′ UTR). MiR-490-3p has been reported to be a suppressor in various human cancers; however, little is known about the biological functions of miR-490-3p in endometrial cancer (EC). In our study, we found that MiR-490-3p mRNA expression was significantly lower in ECs than in normal endometrial tissues. MiR-490-3p mRNA expression was also negatively associated with depth of invasion (mucosa vs. muscular and serosa) and lymph node metastasis (negative vs. positive) in EC. MiR-490-3p overexpression reduced proliferation; promoted G1 arrest and apoptosis; suppressed migration and invasion; and reduced TGFα, NF-kB, cyclin D1, survivin, matrix metalloproteinase 2 (MMP2) mRNA and protein expression, and improved Bax mRNA and protein expression. The dual-luciferase reporter assay indicated that miR-490-3p directly targeted TGFα by binding its 3′ untranslated region. MiR-490-3P transfection also suppressed tumor development and TGFα expression (as determined by immunohistochemistry and western blotting) in vivo in the xenograft mouse model. This is the first demonstration that miR-490-3P might act as a suppressor in EC tumorigenesis and progression by targeting TGFα. Our results provide a theoretical basis for the further study on the molecular target for endometrial cancer. PMID:26843615

  6. Are HO radicals produced in the reaction of O(3P) with 1-C4H8 ?

    NASA Technical Reports Server (NTRS)

    Luria, M.; Simonaitis, R.; Heicklen, J.

    1972-01-01

    The reaction of O(3P) with 1-C4H8 was examined in the presence of CO which scavenges HO radicals to produce CO2. From the CO2 quantum yield, an upper limit to the efficiency of HO production in the reaction of O(3P) with 1-C4H8 was found to be 0.020 at both 298 and 473 K.

  7. Regulation of Mammalian Autophagy by Class II and III PI 3-Kinases through PI3P Synthesis

    PubMed Central

    Devereaux, Kelly; Ogasawara, Yuta; Zhou, Xiang; Wang, Fan; Yamamoto, Akitsugu; De Camilli, Pietro; Di Paolo, Gilbert

    2013-01-01

    Synthesis of phosphatidylinositol-3-phosphate (PI3P) by Vps34, a class III phosphatidylinositol 3-kinase (PI3K), is critical for the initial steps of autophagosome (AP) biogenesis. Although Vps34 is the sole source of PI3P in budding yeast, mammalian cells can produce PI3P through alternate pathways, including direct synthesis by the class II PI3Ks; however, the physiological relevance of these alternate pathways in the context of autophagy is unknown. Here we generated Vps34 knockout mouse embryonic fibroblasts (MEFs) and using a higher affinity 4x-FYVE finger PI3P-binding probe found a Vps34-independent pool of PI3P accounting for ~35% of the total amount of this lipid species by biochemical analysis. Importantly, WIPI-1, an autophagy-relevant PI3P probe, still formed some puncta upon starvation-induced autophagy in Vps34 knockout MEFs. Additional characterization of autophagy by electron microscopy as well as protein degradation assays showed that while Vps34 is important for starvation-induced autophagy there is a significant component of functional autophagy occurring in the absence of Vps34. Given these findings, class II PI3Ks (α and β isoforms) were examined as potential positive regulators of autophagy. Depletion of class II PI3Ks reduced recruitment of WIPI-1 and LC3 to AP nucleation sites and caused an accumulation of the autophagy substrate, p62, which was exacerbated upon the concomitant ablation of Vps34. Our studies indicate that while Vps34 is the main PI3P source during autophagy, class II PI3Ks also significantly contribute to PI3P generation and regulate AP biogenesis. PMID:24098492

  8. MicroRNA-124-3p regulates cell proliferation, invasion, apoptosis, and bioenergetics by targeting PIM1 in astrocytoma.

    PubMed

    Deng, Danni; Wang, Lei; Chen, Yao; Li, Bowen; Xue, Lian; Shao, Naiyuan; Wang, Qiang; Xia, Xiwei; Yang, Yilin; Zhi, Feng

    2016-07-01

    The PIM1 protein is an important regulator of cell proliferation, the cell cycle, apoptosis, and metabolism in various human cancers. MicroRNAs (miRNAs) are powerful post-transcriptional gene regulators that function through translational repression or transcript destabilization. Therefore, we aimed to identify whether a close relationship exists between PIM1 and miRNAs. PIM1 protein levels and mRNA levels were significantly upregulated in astrocytoma tissues, indicating the oncogenic role of PIM1 in astrocytoma. Further bioinformatics analysis indicated that miR-124-3p targeted the 3'-UTR of PIM1. We also observed an inverse correlation between the miR-124-3p levels and PIM1 protein or mRNA levels in astrocytoma samples. Next, we experimentally confirmed that miR-124-3p directly recognizes the 3'-UTR of the PIM1 transcript and regulates PIM1 expression at both the protein and mRNA levels. Furthermore, we examined the biological consequences of miR-124-3p targeting PIM1 in vitro. We showed that the repression of PIM1 in astrocytoma cancer cells by miR-124-3p suppressed proliferation, invasion, and aerobic glycolysis and promoted apoptosis. We observed that the restoration or inhibition of PIM1 activity resulted in effects that were similar to those induced by miR-124-3p inhibitors or mimics in cancer cells. Finally, overexpression of PIM1 rescued the inhibitory effects of miR-124-3p. In summary, these findings aid in understanding the tumor-suppressive role of miR-124-3p in astrocytoma pathogenesis through the inhibition of PIM1 translation. PMID:27088547

  9. Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells' sensitivity to paclitaxel.

    PubMed

    Tambe, Mahesh; Pruikkonen, Sofia; Mäki-Jouppila, Jenni; Chen, Ping; Elgaaen, Bente Vilming; Straume, Anne Hege; Huhtinen, Kaisa; Cárpen, Olli; Lønning, Per Eystein; Davidson, Ben; Hautaniemi, Sampsa; Kallio, Marko J

    2016-03-15

    The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3' UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy. PMID:26943585

  10. Novel Mad2-targeting miR-493-3p controls mitotic fidelity and cancer cells’ sensitivity to paclitaxel

    PubMed Central

    Mäki-Jouppila, Jenni; Chen, Ping; Elgaaen, Bente Vilming; Straume, Anne Hege; Huhtinen, Kaisa; Cárpen, Olli; Lønning, Per Eystein; Davidson, Ben; Hautaniemi, Sampsa; Kallio, Marko J.

    2016-01-01

    The molecular pathways that contribute to the proliferation and drug response of cancer cells are highly complex and currently insufficiently characterized. We have identified a previously unknown microRNA-based mechanism that provides cancer cells means to stimulate tumorigenesis via increased genomic instability and, at the same time, evade the action of clinically utilized microtubule drugs. We demonstrate miR-493-3p to be a novel negative regulator of mitotic arrest deficient-2 (MAD2), an essential component of the spindle assembly checkpoint that monitors the fidelity of chromosome segregation. The microRNA targets the 3′ UTR of Mad2 mRNA thereby preventing translation of the Mad2 protein. In cancer cells, overexpression of miR-493-3p induced a premature mitotic exit that led to increased frequency of aneuploidy and cellular senescence in the progeny cells. Importantly, excess of the miR-493-3p conferred resistance of cancer cells to microtubule drugs. In human neoplasms, miR-493-3p and Mad2 expression alterations correlated with advanced ovarian cancer forms and high miR-493-3p levels were associated with reduced survival of ovarian and breast cancer patients with aggressive tumors, especially in the paclitaxel therapy arm. Our results suggest that intratumoral profiling of miR-493-3p and Mad2 levels can have diagnostic value in predicting the efficacy of taxane chemotherapy. PMID:26943585

  11. miR-338-3p suppresses neuroblastoma proliferation, invasion and migration through targeting PREX2a.

    PubMed

    Chen, Xin; Pan, Min; Han, Lulu; Lu, Hongting; Hao, Xiwei; Dong, Qian

    2013-11-15

    MicroRNAs (miRNA) can regulate cancer cell proliferation and metastasis. Here, we show that miR-338-3p is down-regulated in metastatic tumor tissues compared to primary tumors, and that that miR-338-3p can inhibit cell proliferation by inducing cell cycle arrest, as well as restrain cell migration and invasion. PREX2a is confirmed as a direct target of miR-338-3p. Knockdown of PREX2a inhibits cell proliferation, migration and invasion through the PTEN/Akt pathway. miR-338-3p-dependent inhibition of proliferation and invasion can be rescued by PREXa. Overall, this study demonstrates that miR-338-3p affects the PTEN/Akt pathway by down-regulating PREX2a. This newly identified function of miR-338-3p provides novel insights into neuroblastoma and may foster therapeutic applications. PMID:24140344

  12. Integrated multi-omics analyses reveal the pleiotropic nature of the control of gene expression by Puf3p

    PubMed Central

    Kershaw, Christopher J.; Costello, Joseph L.; Talavera, David; Rowe, William; Castelli, Lydia M.; Sims, Paul F. G.; Grant, Christopher M.; Ashe, Mark P.; Hubbard, Simon J.; Pavitt, Graham D.

    2015-01-01

    The PUF family of RNA-binding proteins regulate gene expression post-transcriptionally. Saccharomyces cerevisiae Puf3p is characterised as binding nuclear-encoded mRNAs specifying mitochondrial proteins. Extensive studies of its regulation of COX17 demonstrate its role in mRNA decay. Using integrated genome-wide approaches we define an expanded set of Puf3p target mRNAs and quantitatively assessed the global impact of loss of PUF3 on gene expression using mRNA and polysome profiling and quantitative proteomics. In agreement with prior studies, our sequencing of affinity-purified Puf3-TAP associated mRNAs (RIP-seq) identified mRNAs encoding mitochondrially-targeted proteins. Additionally, we also found 720  new mRNA targets that predominantly encode proteins that enter the nucleus. Comparing transcript levels in wild-type and puf3∆ cells revealed that only a small fraction of mRNA levels alter, suggesting Puf3p determines mRNA stability for only a limited subset of its target mRNAs. Finally, proteomic and translatomic studies suggest that loss of Puf3p has widespread, but modest, impact on mRNA translation. Taken together our integrated multi-omics data point to multiple classes of Puf3p targets, which display coherent post-transcriptional regulatory properties and suggest Puf3p plays a broad, but nuanced, role in the fine-tuning of gene expression. PMID:26493364

  13. Mixed disulfide formation in vitro between a glycoprotein substrate and yeast oligosaccharyltransferase subunits Ost3p and Ost6p.

    PubMed

    Mohd Yusuf, Siti N H; Bailey, Ulla-Maja; Tan, Nikki Y; Jamaluddin, Muhammad Fairuz; Schulz, Benjamin L

    2013-03-15

    Oligosaccharyltransferase (OTase) glycosylates selected asparagine residues in secreted and membrane proteins in eukaryotes, and asparagine (N)-glycosylation affects the folding, stability and function of diverse glycoproteins. The range of acceptor protein substrates that are efficiently glycosylated depends on the action of several accessory subunits of OTase, including in yeast the homologous proteins Ost3p and Ost6p. A model of Ost3p and Ost6p function has been proposed in which their thioredoxin-like active site cysteines form transient mixed disulfide bonds with cysteines in substrate proteins to enhance the glycosylation of nearby asparagine residues. We tested aspects of this model with a series of in vitro assays. We developed a whole protein mixed disulfide interaction assay that showed that Ost6p could form mixed disulfide bonds with selected cysteines in pre-reduced yeast Gas1p, a model glycoprotein substrate of Ost3p and Ost6p. A complementary peptide affinity chromatography assay for mixed disulfide bond formation showed that Ost3p could also form mixed disulfide bonds with cysteines in selected reduced tryptic peptides from Gas1p. Together, these assays showed that the thioredoxin-like active sites of Ost3p and Ost6p could form transient mixed disulfide bonds with cysteines in a model substrate glycoprotein, consistent with the function of Ost3p and Ost6p in modulating N-glycosylation substrate selection by OTase in vivo. PMID:23416356

  14. miR-526b-3p functions as a tumor suppressor in colon cancer by regulating HIF-1α

    PubMed Central

    Zhang, Rui; Zhao, Jian; Xu, Jian; Wang, Jian; Jia, Jianhui

    2016-01-01

    HIF-1α is an important transcriptional factor, which plays roles in cancer development and progression. But its regulation by miRNAs is not clear. Here, to investigate the regulation of HIF-1α by miRNAs, miRNAs were predicted and miR-526b-3p was verified as a regulator of HIF-1α in colon cancer cells. Using TaqMan RT-PCR analysis, we analyzed the expression of miR-526b-3p in tumor tissues and cell lines and found that miR-526b-3p was consistently under-expressed in cancer tissues and cell lines compared with their normal controls. When miR-526b-3p was induced into the colon cancer cells, cell proliferation, metastasis and glycolysis of colon cancer cells were suppressed. We also found that miR-526b-3p was down-regulated in metastatic colon cancer tissues and negatively with HIF-1α mRNA in colon cancer tissues. In a summary, miR-526b-3p plays as a tumor suppressor by down-regulation of HIF-1α expression in colon cancer and may be a new diagnosis or therapeutic target. PMID:27398161

  15. Regulation of UDP-glucuronosyltransferase 1A1 expression and activity by microRNA 491-3p.

    PubMed

    Dluzen, Douglas F; Sun, Dongxiao; Salzberg, Anna C; Jones, Nate; Bushey, Ryan T; Robertson, Gavin P; Lazarus, Philip

    2014-03-01

    The UDP-glucuronosyltransferase (UGT) 1A enzymes are involved in the phase II metabolism of many important endogenous and exogenous compounds. The nine UGT1A isoforms exhibit high interindividual differences in expression, but their epigenetic regulation is not well understood. The purpose of the present study was to examine microRNA (miRNA) regulation of hepatic UGT1A enzymes and determine whether or not that regulation impacts enzymatic activity. In silico analysis identified miRNA 491-3p (miR-491-3p) as a potential regulator of the UGT1A gene family via binding to the shared UGT1A 3'-untranslated region common to all UGT1A enzymes. Transfection of miR-491-3p mimic into HuH-7 cells significantly repressed UGT1A1 (P < 0.001), UGT1A3 (P < 0.05), and UGT1A6 (P < 0.05) mRNA levels. For UGT1A1, this repression correlated with significantly reduced metabolism of raloxifene into raloxifene-6-glucuronide (ral-6-gluc; P < 0.01) and raloxifene-4'-glucuronide (ral-4'-gluc; P < 0.01). In HuH-7 cells with repressed miR-491-3p expression, there was a significant increase (~80%; P < 0.01) in UGT1A1 mRNA and a corresponding increase in glucuronidation of raloxifene into ral-6-gluc (50%; P < 0.05) and ral-4'-gluc (22%; P < 0.01). Knockdown of endogenous miR-491-3p in HepG2 cells did not significantly alter UGT1A1 mRNA levels but did increase the formation of ral-6-gluc (50%; P < 0.05) and ral-4'-gluc (34%; P < 0.001). A significant inverse correlation between miR-491-3p expression and both UGT1A3 (P < 0.05) and UGT1A6 (P < 0.01) mRNA levels was observed in a panel of normal human liver specimens, with a significant (P < 0.05) increase in UGT1A3 and UGT1A6 mRNA levels observed in miR-491-3p nonexpressing versus expressing liver specimens. These results suggest that miR-491-3p is an important factor in regulating the expression of UGT1A enzymes in vivo. PMID:24399855

  16. miR-148b-3p inhibits malignant biological behaviors of human glioma cells induced by high HOTAIR expression

    PubMed Central

    Wang, Guan; Li, Zhaohui; Tian, Nan; Han, Liang; Fu, Yao; Guo, Zhigang; Tian, Yu

    2016-01-01

    Increasing evidence suggests that long non coding (lnc)RNA and microRNA (miRNA/miR) both regulate the expression of key genes in tumorigenesis and have considerable theranostic potential. Rapid advances in bioinformatics indicate that miRNA may potentially interact with lncRNA to modulate their regulatory roles. miR-148b-3p has been reported to have a vital role in regulating tumor progression. However, the expression pattern of miR-148b-3p in glioma remains largely unknown, and interactions between miR-148b-3p and lncRNA has yet to be identified. The aim of the present study was to insight into the regulatory role of miR-148b-3p in glioma. Using online software, the HOTAIR gene was identified as a possible lncRNA target of miR-148b-3p in the present study. siRNA was used to suppress the expression of HOTAIR and reverse transcription-quantitative polymerase chain reaction was used to detect the expression of miR-148b-3p. The results confirmed that HOTAIR mRNA expression was inversely correlated with miR-148b-3p expression in A172 glioma cells. Furthermore, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the viability of cells, flow cytometry was performed to test cell cycle and a matrigel invasion assay was performed to test cell invasion. The results showed that HOTAIR promotes factors associated with malignancy, including cell proliferation, cell cycle progression and invasion, whereas miR-148b-3p suppresses malignancy. Bioinformatics and luciferase reporter assays showed that miR-148b-3p modulates HOTAIR expression by directly targeting the HOTAIR gene sequence. In summary, the results indicated that miR-148b-3p inhibits malignant biological behaviors of glioma cells by directly targeting HOTAIR. The current data provide important evidence for understanding the key roles of the lncRNA miRNA functional network in glioma. PMID:27446363

  17. Vestiges of Ent3p/Ent5p function in the giardial epsin homolog.

    PubMed

    Feliziani, Constanza; Valdez Taubas, Javier; Moyano, Sofía; Quassollo, Gonzalo; Poprawski, Joanna E; Wendland, Beverly; Touz, Maria C

    2016-04-01

    An accurate way to characterize the functional potential of a protein is to analyze recognized protein domains encoded by the genes in a given group. The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated trafficking. In this work, we investigate the function of the single ENTH-containing protein from the protist Giardia lamblia by testing its function in Saccharomyces cerevisiae. This protein, named GlENTHp (for G. lamblia ENTH protein), is involved in Giardia in endocytosis and in protein trafficking from the ER to the vacuoles, fulfilling the function of the ENTH proteins epsin and epsinR, respectively. There are two orthologs of epsin, Ent1p and Ent2p, and two orthologs of epsinR, Ent3p and Ent5p in S. cerevisiae. Although the expression of GlENTHp neither complemented growth in the ent1Δent2Δ mutant nor restored the GFP-Cps1 vacuolar trafficking defect in ent3Δent5Δ, it interfered with the normal function of Ent3/5 in the wild-type strain. The phenotype observed is linked to a defect in Cps1 localization and α-factor mating pheromone maturation. The finding that GlENTHp acts as dominant negative epsinR in yeast cells reinforces the phylogenetic data showing that GlENTHp belongs to the epsinR subfamily present in eukaryotes prior to their evolution into different taxa. PMID:26851076

  18. Structure and Function of the PLAA/Ufd3-p97/Cdc48 Complex

    SciTech Connect

    Qiu, Liyan; Pashkova, Natasha; Walker, John R.; Winistorfer, Stanley; Allali-Hassani, Abdellah; Akutsu, Masato; Piper, Robert; Dhe-Paganon, Sirano

    2010-02-11

    PLAA (ortholog of yeast Doa1/Ufd3, also know as human PLAP or phospholipase A2-activating protein) has been implicated in a variety of disparate biological processes that involve the ubiquitin system. It is linked to the maintenance of ubiquitin levels, but the mechanism by which it accomplishes this is unclear. The C-terminal PUL (PLAP, Ufd3p, and Lub1p) domain of PLAA binds p97, an AAA ATPase, which among other functions helps transfer ubiquitinated proteins to the proteasome for degradation. In yeast, loss of Doa1 is suppressed by altering p97/Cdc48 function indicating that physical interaction between PLAA and p97 is functionally important. Although the overall regions of interaction between these proteins are known, the structural basis has been unavailable. We solved the high resolution crystal structure of the p97-PLAA complex showing that the PUL domain forms a 6-mer Armadillo-containing domain. Its N-terminal extension folds back onto the inner curvature forming a deep ridge that is positively charged with residues that are phylogenetically conserved. The C terminus of p97 binds in this ridge, where the side chain of p97-Tyr805, implicated in phosphorylation-dependent regulation, is buried. Expressed in doa1{Delta} null cells, point mutants of the yeast ortholog Doa1 that disrupt this interaction display slightly reduced ubiquitin levels, but unlike doa1{Delta} null cells, showed only some of the growth phenotypes. These data suggest that the p97-PLAA interaction is important for a subset of PLAA-dependent biological processes and provides a framework to better understand the role of these complex molecules in the ubiquitin system.

  19. Numerical modelling of soil/atmosphere exchange of POPs with MIN3P

    NASA Astrophysics Data System (ADS)

    Bao, Zhongwen; Beckingham, Barbara; Maier, Uli; Haberer, Christina; Grathwohl, Peter

    2014-05-01

    Soil/atmosphere exchange processes are of vital role not only for the cycling of water and the transport of nutrients and oxygen, but also for the long-term fate of many persistent organic pollutants (POPs). This study focuses on modelling the vapor phase exchange of a representative POP, i.e. phenanthrene, across the soil/atmosphere interface using the numerical code MIN3P, which was extended to include an atmospheric boundary layer. The numerical code was validated with analytical solutions of the advection-dispersion equation and additionally considering pure diffusion with linear sorption in the porous medium. We ran several scenarios to test the relevant processes influencing soil/atmosphere exchange at various time scales, i.e. diffusion/dispersion, advection, sorption, re-volatilization, biodegradation, and temperature changes. The atmospheric boundary layer near the ground surface was assumed to be well mixed, and overall fluxes of phenanthrene were found to be limited within the soil compartment for downward migration from the atmosphere. Sorption to soil organic carbon causes strong retardation of phenanthrene in seepage water, thus affecting re-volatilization and biodegradation. After phenanthrene deposition, sorption limits the spreading in the short term while biodegradation leads to steady-state concentration profiles in the long term (e.g. centuries). Temperature increases, e.g. from nighttime to daytime, lead to a release of sorbed phenanthrene. While the model shows dynamically fluctuating atmospheric concentration gradients for diurnal temperature changes, eddy diffusion is sufficient to mix concentrations in the atmospheric boundary layer for seasonal and longer-term temperature increases. The model can be further used to estimate levels of other POPs in soils with varying physico-chemical properties and under different environmental loadings and climate scenarios to evaluate their long-term fate in soils.

  20. The human homologue of the Drosophila melanogaster flightless-I gene (fliI) maps within the Smith-Magenis microdeletion critical region in 17p11.2

    SciTech Connect

    Chen, K.S.; Gunaratne, P.H.; Greenberg, F.; Shaffer, L.G.; Lupski, J.R.; Hoheisel, J.D.; Young, I.G.; Miklos, G.L.G.; Campbell, H.D.

    1995-01-01

    The Smith-Magenis syndrome (SMS) appears to be a contiguous-gene-deletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2. The spectrum of clinical findings includes short stature, brachydactyly, developmental delay, dysmorphic features, sleep disturbances, and behavioral problems. The complex phenotypic features suggest deletion of several contiguous genes. However, to date, no protein-encoding gene has been mapped to the SMS critical region. Recently, the Drosophila melanogaster flightless-I gene, fliI, and the homologous human cDNA have been isolated. Mutations in fliI result in loss of flight ability and, when severe, cause lethality due to incomplete cellularization with subsequent abnormal gastrulation. Here, we demonstrate that the human homologue (FLI) maps within the SMS critical region. Genomic cosmids were used as probes for FISH, which localized this gene to the 17p11.2 region. Somatic-cell hybrid-panel mapping further localized this gene to the SMS critical region. Southern blot analysis of somatic-cell hybrids and/or FISH analysis of lymphoblastoid cell lines from 12 SMS patients demonstrates the deletion of one copy of FLI in all SMS patients analyzed. 47 refs., 4 figs., 1 tab.

  1. miR-511-3p, embedded in the macrophage mannose receptor gene, contributes to intestinal inflammation.

    PubMed

    Heinsbroek, S E M; Squadrito, M L; Schilderink, R; Hilbers, F W; Verseijden, C; Hofmann, M; Helmke, A; Boon, L; Wildenberg, M E; Roelofs, J J T H; Ponsioen, C Y; Peters, C P; Te Velde, A A; Gordon, S; De Palma, M; de Jonge, W J

    2016-07-01

    MiR-511-3p is embedded in intron 5 of the CD206/MRC1 gene Mrc1, expressed by macrophage and dendritic cell populations. CD206 and miR-511-3p expression are co-regulated, and their contribution to intestinal inflammation is unclear. We investigated their roles in intestinal inflammation in both mouse and human systems. Colons of CD206-deficient mice displayed normal numbers of monocytes, macrophage, and dendritic cells. In experimental colitis, CD206-deficient mice had attenuated inflammation compared with wild-type (WT) mice. However, neither a CD206 antagonist nor a blocking antibody reproduced this phenotype, suggesting that CD206 was not involved in this response. Macrophages isolated from CD206-deficient mice had reduced levels of miR-511-3p and Tlr4 compared with WT, which was associated with reduced pro-inflammatory cytokine production upon lipopolysaccharides (LPS) and fecal supernatant stimulation. Macrophages overexpressing miR-511-3p showed 50% increase of Tlr4 mRNA, whereas knockdown of miR-511-3p reduced Tlr4 mRNA levels by 60%, compared with scrambled microRNA (miRNA)-transduced cells. Response to anti-tumor necrosis factor (TNF) treatment has been associated with elevated macrophage CD206 expression in the mucosa. However, in colon biopsies no statistically significant change in miR-511-3p was detected. Taken together, our data show that miR-511-3p controls macrophage-mediated microbial responses and is involved in the regulation of intestinal inflammation. PMID:26530135

  2. MiR-129-3p promotes docetaxel resistance of breast cancer cells via CP110 inhibition

    PubMed Central

    Zhang, Yuan; Wang, Yu; Wei, Yifang; Li, Mengyang; Yu, Shentong; Ye, Mingxiang; Zhang, Hongmei; Chen, Suning; Liu, Wenchao; Zhang, Jian

    2015-01-01

    Docetaxel is commonly used as an effective chemotherapeutic agent in breast cancer treatment, but the underlying mechanisms of drug resistance are not fully understood. The purpose of this study was to investigate the possible role of miR-129-3p in breast cancer cell resistance to docetaxel. MiR-129 and miR-129-3p inhibitor were transfected into breast cancer cells to investigate their effects on chemoresistance to docetaxel. The function of miR-129-3p was evaluated by apoptosis, cell proliferation, and cell cycle assays. We found that miR-129-3p was up-regulated in MDA-MB-231/Doc cells, concurrent with CP110 down-regulation, compared to the parental MDA-MB-231 cells. In vitro drug sensitivity assays demonstrated that miR-129-3p inhibition sensitized MDA-MB-231/Doc and MCF-7 cells to docetaxel, whereas miR-129 overexpression enhanced MDA-MB-231 and MCF-7 cell resistance to docetaxel. Ectopic miR-129 expression reduced CP110 expression and the luciferase activity of a CP110 3′ untranslated region-based reporter construct in MDA-MB-231 cells, suggesting that CP110 is a direct miR-129-3p target. We demonstrated that restoration of CP110 expression in MDA-MB-231 and MCF-7 cells by miR-129 overexpression rendered the cells sensitive to docetaxel. In a nude xenograft model, miR-129 up-regulation significantly decreased MDA-MB-231 cells’ response to docetaxel. Our findings suggest that miR-129-3p down-regulation potentially sensitizes breast cancer cells to docetaxel treatment. PMID:26487539

  3. Up- regulation of miR-328-3p sensitizes non-small cell lung cancer to radiotherapy

    PubMed Central

    Ma, Wei; Ma, Chao-nan; Zhou, Nan-nan; Li, Xian-dong; Zhang, Yi-jie

    2016-01-01

    MicroRNAs (miRNAs) are believed to be resistant against radiotherapy in certain types of cancers. The aim of our study was to determine the clinical application of miRNAs in non-small cell lung cancer (NSCLC). Sixty NSCLC tissue samples and adjacent histologically normal tissues were obtained for miRNAs microarray analysis and validated by RT-qPCR. Correlation between miRNA expression level and clinicopathological features was evaluated. Our study examined the influence of changed miRNA expression on the damaged DNA and its associated radio sensitivity. Luciferase assay was performed to determine potential effects on the targeted gene. Our study identified fifteen altered miRNAs in which miR-328-3p was down regulated in NSCLC tumour tissue as compared to normal tissues. Down-expression of miR-328-3p was positively associated with an enhanced lymph node metastasis, advanced clinical stage and a shortened survival rate. miR-328-3p expression was decreased in A549 cells compared to other NSCLC cell lines. Up-regulation of miR-328-3p demonstrated a survival inhibition effect in A549 and restored NSCLC cells’ sensitivity to radio therapy. An increased miR-328-3p expression promoted irradiation-induced DNA damage in cells. γ-H2AX was identified as the direct target of miR-328-3p. Over-expressed miR-328-3p can improve the radiosensitvity of cells by altering the DNA damage/repair signalling pathways in NSCLC. PMID:27530148

  4. Up- regulation of miR-328-3p sensitizes non-small cell lung cancer to radiotherapy.

    PubMed

    Ma, Wei; Ma, Chao-Nan; Zhou, Nan-Nan; Li, Xian-Dong; Zhang, Yi-Jie

    2016-01-01

    MicroRNAs (miRNAs) are believed to be resistant against radiotherapy in certain types of cancers. The aim of our study was to determine the clinical application of miRNAs in non-small cell lung cancer (NSCLC). Sixty NSCLC tissue samples and adjacent histologically normal tissues were obtained for miRNAs microarray analysis and validated by RT-qPCR. Correlation between miRNA expression level and clinicopathological features was evaluated. Our study examined the influence of changed miRNA expression on the damaged DNA and its associated radio sensitivity. Luciferase assay was performed to determine potential effects on the targeted gene. Our study identified fifteen altered miRNAs in which miR-328-3p was down regulated in NSCLC tumour tissue as compared to normal tissues. Down-expression of miR-328-3p was positively associated with an enhanced lymph node metastasis, advanced clinical stage and a shortened survival rate. miR-328-3p expression was decreased in A549 cells compared to other NSCLC cell lines. Up-regulation of miR-328-3p demonstrated a survival inhibition effect in A549 and restored NSCLC cells' sensitivity to radio therapy. An increased miR-328-3p expression promoted irradiation-induced DNA damage in cells. γ-H2AX was identified as the direct target of miR-328-3p. Over-expressed miR-328-3p can improve the radiosensitvity of cells by altering the DNA damage/repair signalling pathways in NSCLC. PMID:27530148

  5. Colloidal CdSe/Cu3P/CdSe nanocrystal heterostructures and their evolution upon thermal annealing.

    PubMed

    De Trizio, Luca; De Donato, Francesco; Casu, Alberto; Genovese, Alessandro; Falqui, Andrea; Povia, Mauro; Manna, Liberato

    2013-05-28

    We report the synthesis of colloidal CdSe/Cu(3)P/CdSe nanocrystal heterostructures grown from hexagonal Cu(3)P platelets as templates. One type of heterostructure was a sort of "coral", formed by vertical pillars of CdSe grown preferentially on both basal facets of a Cu(3)P platelet and at its edges. Another type of heterostructure had a "sandwich" type of architecture, formed by two thick, epitaxial CdSe layers encasing the original Cu(3)P platelet. When the sandwiches were annealed under vacuum up to 450 °C, sublimation of P and Cd species with concomitant interdiffusion of Cu and Se species was observed by in situ HR- and EFTEM analyses. These processes transformed the starting sandwiches into Cu2Se nanoplatelets. Under the same conditions, both the pristine (uncoated) Cu(3)P platelets and a control sample made of isolated CdSe nanocrystals were stable. Therefore, the thermal instability of the sandwiches under vacuum might be explained by the diffusion of Cu species from Cu(3)P cores into CdSe domains, which triggered sublimation of Cd, as well as out-diffusion of P species and their partial sublimation, together with the overall transformation of the sandwiches into Cu(2)Se nanocrystals. A similar fate was followed by the coral-like structures. These CdSe/Cu(3)P/CdSe nanocrystals are therefore an example of a nanostructure that is thermally unstable, despite its separate components showing to be stable under the same conditions. PMID:23557168

  6. Mechanisms Controlling Subcellular Localization of the G1 Cyclins Cln2p and Cln3p in Budding Yeast

    PubMed Central

    Miller, Mary E.; Cross, Frederick R.

    2001-01-01

    Different G1 cyclins confer functional specificity to the cyclin-dependent kinase (Cdk) Cdc28p in budding yeast. The Cln3p G1 cyclin is localized primarily to the nucleus, while Cln2p is localized primarily to the cytoplasm. Both binding to Cdc28p and Cdc28p-dependent phosphorylation in the C-terminal region of Cln2p are independently required for efficient nuclear depletion of Cln2p, suggesting that this process may be physiologically regulated. The accumulation of hypophosphorylated Cln2 in the nucleus is an energy-dependent process, but may not involve the RAN GTPase. Phosphorylation of Cln2p is inefficient in small newborn cells obtained by elutriation, and this lowered phosphorylation correlates with reduced Cln2p nuclear depletion in newborn cells. Thus, Cln2p may have a brief period of nuclear residence early in the cell cycle. In contrast, the nuclear localization pattern of Cln3p is not influenced by Cdk activity. Cln3p localization requires a bipartite nuclear localization signal (NLS) located at the C terminus of the protein. This sequence is required for nuclear localization of Cln3p and is sufficient to confer nuclear localization to green fluorescent protein in a RAN-dependent manner. Mislocalized Cln3p, lacking the NLS, is much less active in genetic assays specific for Cln3p, but more active in assays normally specific for Cln2p, consistent with the idea that Cln3p localization explains a significant part of Clnp functional specificity. PMID:11509671

  7. miRNA-132-3p inhibits osteoblast differentiation by targeting Ep300 in simulated microgravity

    PubMed Central

    Hu, Zebing; Wang, Yixuan; Sun, Zhongyang; Wang, Han; Zhou, Hua; Zhang, Lianchang; Zhang, Shu; Cao, Xinsheng

    2015-01-01

    Recent studies have demonstrated that miRNAs can play important roles in osteoblast differentiation and bone formation. However, the function of miRNAs in bone loss induced by microgravity remains unclear. In this study, we investigated the differentially expressed miRNAs in both the femur tissues of hindlimb unloading rats and primary rat osteoblasts (prOB) exposed to simulated microgravity. Specifically, miR-132-3p was found up-regulated and negatively correlated with osteoblast differentiation. Overexpression of miR-132-3p significantly inhibited prOB differentiation, whereas inhibition of miR-132-3p function yielded an opposite effect. Furthermore, silencing of miR-132-3p expression effectively attenuated the negative effects of simulated microgravity on prOB differentiation. Further experiments confirmed that E1A binding protein p300 (Ep300), a type of histone acetyltransferase important for Runx2 activity and stability, was a direct target of miR-132-3p. Up-regulation of miR-132-3p by simulated microgravity could inhibit osteoblast differentiation in part by decreasing Ep300 protein expression, which, in turn, resulted in suppression of the activity and acetylation of Runx2, a key regulatory factor of osteoblast differentiation. Taken together, our findings are the first to demonstrate that miR-132-3p can inhibit osteoblast differentiation and participate in the regulation of bone loss induced by simulated microgravity, suggesting a potential target for counteracting decreases in bone formation. PMID:26686902

  8. Luteolin Inhibits Ischemia/Reperfusion-Induced Myocardial Injury in Rats via Downregulation of microRNA-208b-3p

    PubMed Central

    Zhu, Hong; Pan, Defeng; Liu, Yang; Luo, Yuanyuan; Wu, Pei; Li, Dongye

    2015-01-01

    Background Luteolin (LUT), a kind of flavonoid which is extracted from a variety of diets, has been reported to convey protective effects of various diseases. Recent researches have suggested that LUT can carry out cardioprotective effects during ischemia/reperfusion (I/R). However, there have no reports on whether LUT can exert protective effects against myocardial I/R injury through the actions of specific microRNAs (miRs). The purpose of this study was to determine which miRs and target genes LUT exerted such function through. Methods Expression of various miRs in perfused rat hearts was detected using a gene chip. Target genes were predicted with TargetScan, MiRDB and MiRanda. Anoxia/reoxygenation was used to simulate I/R. Cells were transfected by miR-208b-3p mimic, inhibitor and small interfering RNA of Ets1 (avian erythroblastosis virus E26 (v ets) oncogene homolog 1). MiR-208b-3p and Ets1 mRNA were quantified by real-time quantitative polymerase chain reaction. The percentage of apoptotic cells was detected by annexin V-fluorescein isothiocyanate/propidium iodide dyeing and flow cytometry. The protein expression levels of cleaved caspase-3, Bcl-2, Bax, and Ets1 were examined by western blot analysis. A luciferase reporter assay was used to verify the combination between miR-208b-3p and the 3’-untranslated region of Ets1. Results LUT pretreatment reduced miR-208b-3p expression in myocardial tissue, as compared to the I/R group. And LUT decreased miR-208b-3p expression and apoptosis caused by I/R. However, overexpression of miR-208b-3p further aggravated the changes caused by I/R and blocked all the effects of LUT. Knockdown of miR-208b-3p expression also attenuated apoptosis, while knockdown of Ets1 promoted apoptosis. Further, the luciferase reporter assay showed that miR-208b-3p could inhibit Ets1 expression. Conclusion LUT pretreatment conveys anti-apoptotic effects after myocardial I/R injury by decreasing miR-208b-3p and increasing Ets1 expression

  9. microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer.

    PubMed

    Chen, Bi-Feng; Gu, Shen; Suen, Yick-Keung; Li, Lu; Chan, Wai-Yee

    2014-01-01

    It was previously demonstrated that miR-199a was downregulated in testicular germ cell tumor (TGCT), probably due to hypermethylation of its promoter. Further study found that re-expression of miR-199a in testicular cancer cells (NT2) led to suppression of cell growth, cancer migration, invasion and metastasis. More detailed analyses showed that these properties of miR-199a could be assigned to miR-199a-5p, one of its two derivatives. The biological role of the other derivative, miR-199a-3p in TGCT, remains largely uncharacterized. In this report, we identified DNA (cytosine-5)-methyltransferase 3A (DNMT3A), the de novo methyltransferase, as a direct target of miR-199a-3p using a 3'-UTR reporter assay. Transient expression of miR-199a-3p in NT2 cells led to decrease, while knocking down of miR-199a-3p in a normal human testicular cell line (HT) led to elevation, of DNMT3A2 (DNMT3A gene isoform 2) mRNA and protein levels. In clinical samples, DNMT3A2 was significantly overexpressed in malignant testicular tumor, and the expression of DNMT3A2 was inversely correlated with the expression of miR-199a-3p. However, DNMT3A did not affect miR-199a expression in NT2 cells. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation, partly through targeting DNMT3A. Overexpression of miR-199a-3p restored the expression of APC and MGMT tumor-suppressor genes in NT2 cells by affecting DNA methylation of their promoter regions. Our studies demonstrated the deregulation of miR-199a-3p expression in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potentially therapeutic use of synthetic miR-199a-3p oligonucleotides as effective hypomethylating compounds in the treatment of TGCT. PMID:23959088

  10. MicroRNA-29a-3p attenuates ET-1-induced hypertrophic responses in H9c2 cardiomyocytes.

    PubMed

    Li, Man; Wang, Nan; Zhang, Jian; He, Hong-Peng; Gong, Hui-Qin; Zhang, Rui; Song, Tie-Feng; Zhang, Li-Nan; Guo, Zhi-Xia; Cao, Dong-Sun; Zhang, Tong-Cun

    2016-07-01

    Transcription factor nuclear factor of activated T cells c4 (NFATc4) is the best-characterized target for the development of cardiac hypertrophy. Aberrant microRNA-29 (miR-29) expression is involved in the development of cardiac fibrosis and congestive heart failure. However, whether miR-29 regulates hypertrophic processes is still not clear. In this study, we investigated the potential functions of miR-29a-3p in endothelin-1 (ET-1)-induced cardiomyocyte hypertrophy. We showed that miR-29a-3p was down-regulated in ET-1-treated H9c2 cardiomyocytes. Overexpression of miR-29a-3p significantly reduced ET-1-induced hypertrophic responses in H9c2 cardiomyocytes, which was accompanied by a decrease in NFATc4 expression. miR-29a-3p targeted directly to the 3'-UTR of NFATc4 mRNA and silenced NFATc4 expression. Our results indicate that miR-29a-3p inhibits ET-1-induced cardiomyocyte hypertrophy via inhibiting NFATc4 expression. PMID:26992639

  11. A tumor suppressor locus within 3p14-p12 mediates rapid cell death of renal cell carcinoma in vivo.

    PubMed Central

    Sanchez, Y; el-Naggar, A; Pathak, S; Killary, A M

    1994-01-01

    High frequency loss of alleles and cytogenetic aberrations on the short arm of chromosome 3 have been documented in renal cell carcinoma (RCC). Potentially, three distinct regions on 3p could encode tumor suppressor genes involved in the genesis of this cancer. We report that the introduction of a centric fragment of 3p, encompassing 3p14-q11, into a highly malignant RCC cell line resulted in a dramatic suppression of tumor growth in athymic nude mice. Another defined deletion hybrid contained the region 3p12-q24 of the introduced human chromosome and failed to suppress tumorigenicity. These data functionally define a tumor suppressor locus, nonpapillary renal carcinoma-1 (NRC-1), within 3p14-p12, the most proximal region of high frequency allele loss in sporadic RCC as well as the region containing the translocation breakpoint in familial RCC. Furthermore, we provide functional evidence that NRC-1 controls the growth of RCC cells by inducing rapid cell death in vivo. Images PMID:8159756

  12. The complex interactions of Chs5p, the ChAPs, and the cargo Chs3p

    PubMed Central

    Rockenbauch, Uli; Ritz, Alicja M.; Sacristan, Carlos; Roncero, Cesar; Spang, Anne

    2012-01-01

    The exomer complex is a putative vesicle coat required for the direct transport of a subset of cargoes from the trans-Golgi network (TGN) to the plasma membrane. Exomer comprises Chs5p and the ChAPs family of proteins (Chs6p, Bud7p, Bch1p, and Bch2p), which are believed to act as cargo receptors. In particular, Chs6p is required for the transport of the chitin synthase Chs3p to the bud neck. However, how the ChAPs associate with Chs5p and recognize cargo is not well understood. Using domain-switch chimeras of Chs6p and Bch2p, we show that four tetratricopeptide repeats (TPRs) are involved in interaction with Chs5p. Because these roles are conserved among the ChAPs, the TPRs are interchangeable among different ChAP proteins. In contrast, the N-terminal and the central parts of the ChAPs contribute to cargo specificity. Although the entire N-terminal domain of Chs6p is required for Chs3p export at all cell cycle stages, the central part seems to predominantly favor Chs3p export in small-budded cells. The cargo Chs3p probably also uses a complex motif for the interaction with Chs6, as the C-terminus of Chs3p interacts with Chs6p and is necessary, but not sufficient, for TGN export. PMID:23015758

  13. miR-8-3p regulates mitoferrin in the testes of Bactrocera dorsalis to ensure normal spermatogenesis.

    PubMed

    Tariq, Kaleem; Metzendorf, Christoph; Peng, Wei; Sohail, Summar; Zhang, Hongyu

    2016-01-01

    Genetics-enhanced sterile insect techniques (SIT) are promising novel approaches to control Bactrocera dorsalis, the most destructive horticultural pest in East Asia and the Pacific region. To identify novel genetic agents to alter male fertility of B. dorsalis, previous studies investigated miRNA expression in testes of B. dorsalis. One miRNA, miR-8-3p was predicted to bind the 3'UTR of putative B. dorsalis mitoferrin (bmfrn). The ortholog of bmfrn in D. melanogaster is essential for male fertility. Here we show that bmfrn has all conserved amino acid residues of known mitoferrins and is most abundantly expressed in B. dorsalis testes, making miR-8-3p and mitoferrin candidates for genetics-enhanced SIT. Furthermore, using a dual-luciferase reporter system, we show in HeLa cells that miR-8-3p interacts with the 3'UTR of bmfrn. Dietary treatments of adult male flies with miR-8-3p mimic, antagomiR, or bmfrn dsRNA, altered mitoferrin expression in the testes and resulted in reduced male reproductive capacity due to reduced numbers and viability of spermatozoa. We show for the first time that a mitoferrin is regulated by a miRNA and we demonstrate miR-8-3p as well as bmfrn dsRNA to be promising novel agents that could be used for genetics-enhanced SIT. PMID:26932747

  14. Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells

    PubMed Central

    Zhang, Linlin; lyer, Arun K; Yang, Xiaoqian; Kobayashi, Eisuke; Guo, Yuqi; Mankin, Henry; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics. PMID:25931818

  15. miR-494-3p Induces Cellular Senescence and Enhances Radiosensitivity in Human Oral Squamous Carcinoma Cells.

    PubMed

    Weng, Jui-Hung; Yu, Cheng-Chia; Lee, Yueh-Chun; Lin, Cheng-Wei; Chang, Wen-Wei; Kuo, Yu-Liang

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck. Although radiotherapy is used for OSCC treatment, the occurrence of radioresistant cancer cells limits its efficiency. MicroRNAs (miRNAs) are non-coding RNAs with lengths of 18-25 base pairs and known to be involved in carcinogenesis. We previously demonstrated that by targeting B lymphoma Mo-MLV insertion region 1 homolog (Bmi1), miR-494-3p functions as a putative tumor suppressor miRNA in OSCC. In this study, we further discovered that miR-494-3p could enhance the radiosensitivity of SAS OSCC cells and induce cellular senescence. The overexpression of miR-494-3p in SAS cells increased the population of senescence-associated β-galactosidase positive cells, the expression of p16(INK4a) and retinoblastoma 1 (RB1), as well as downregulated Bmi1. The knockdown of Bmi1 by lentiviral-mediated delivery of specific short hairpin RNAs (shRNAs) also enhanced the radiosensitivity of SAS cells and the activation of the senescence pathway. Furthermore, the inverse correlation between Bmi1 and miR-494-3p expression was observed among OSCC tissues. Results suggest that miR-494-3p could increase the radiosensitivity of OSCC cells through the induction of cellular senescence caused by the downregulation of Bmi1. PMID:27399693

  16. Gga-miR-101-3p Plays a Key Role in Mycoplasma gallisepticum (HS Strain) Infection of Chicken.

    PubMed

    Chen, Jiao; Wang, Zaiwei; Bi, Dingren; Hou, Yue; Zhao, Yabo; Sun, Jianjun; Peng, Xiuli

    2015-01-01

    Mycoplasma gallisepticum (MG), one of the most pathogenic Mycoplasma, has caused tremendous economic loss in the poultry industry. Recently, increasing evidence has suggested that micro ribonucleic acids (miRNAs) are involved in microbial pathogenesis. However, little is known about potential roles of miRNAs in MG infection of chicken. In the present study, using miRNA Solexa sequencing we have found that gga-miR-101-3p was up-regulated in the lungs of MG-infected chicken embryos. Moreover, gga-miR-101-3p regulated expression of the host enhancer of zeste homolog 2 (EZH2) through binding to the 3' un-translated region (3'-UTR) of EZH2 gene. Over-expression of gga-miR-101-3p significantly inhibited EZH2 expression and hence inhibited proliferation of chicken embryonic fibroblast (DF-1 cells) by blocking the G1-to-S phase transition. Similar results were obtained in MG-infected chicken embryos and DF-1 cells, where gga-miR-101-3p was significantly up-regulated, while EZH2 was significantly down-regulated. This study reveals that gga-miR-101-3p plays an important role in MG infection through regulation of EZH2 expression and provides a new insight into the mechanisms of MG pathogenesis. PMID:26633386

  17. Hyperfine quenching of the metastable {sup 3}P{sub 0,2} states in divalent atoms

    SciTech Connect

    Porsev, Sergey G.; Derevianko, Andrei

    2004-04-01

    Hyperfine quenching rates of the lowest-energy metastable {sup 3}P{sub 0} and {sup 3}P{sub 2} states of Mg, Ca, Sr, and Yb atoms are computed. The calculations are carried out using ab initio relativistic many-body methods. The computed lifetimes may be useful for designing novel ultraprecise optical clocks and trapping experiments with the {sup 3}P{sub 2} fermionic isotopes. The resulting natural widths of the {sup 3}P{sub 0}-{sup 1}S{sub 0} clock transition are 0.44 mHz for {sup 25}Mg, 2.2 mHz for {sup 43}Ca, 7.6 mHz for {sup 87}Sr, 43.5 mHz for {sup 171}Yb, and 38.5 mHz for {sup 173}Yb. Compared to the bosonic isotopes, the lifetime of the {sup 3}P{sub 2} states in fermionic isotopes is noticeably shortened by the hyperfine quenching but still remains long enough for trapping experiments.

  18. gga-miR-101-3p Plays a Key Role in Mycoplasma gallisepticum (HS Strain) Infection of Chicken

    PubMed Central

    Chen, Jiao; Wang, Zaiwei; Bi, Dingren; Hou, Yue; Zhao, Yabo; Sun, Jianjun; Peng, Xiuli

    2015-01-01

    Mycoplasma gallisepticum (MG), one of the most pathogenic Mycoplasma, has caused tremendous economic loss in the poultry industry. Recently, increasing evidence has suggested that micro ribonucleic acids (miRNAs) are involved in microbial pathogenesis. However, little is known about potential roles of miRNAs in MG infection of chicken. In the present study, using miRNA Solexa sequencing we have found that gga-miR-101-3p was up-regulated in the lungs of MG-infected chicken embryos. Moreover, gga-miR-101-3p regulated expression of the host enhancer of zeste homolog 2 (EZH2) through binding to the 3’ un-translated region (3’-UTR) of EZH2 gene. Over-expression of gga-miR-101-3p significantly inhibited EZH2 expression and hence inhibited proliferation of chicken embryonic fibroblast (DF-1 cells) by blocking the G1-to-S phase transition. Similar results were obtained in MG-infected chicken embryos and DF-1 cells, where gga-miR-101-3p was significantly up-regulated, while EZH2 was significantly down-regulated. This study reveals that gga-miR-101-3p plays an important role in MG infection through regulation of EZH2 expression and provides a new insight into the mechanisms of MG pathogenesis. PMID:26633386

  19. The WD40 repeat PtdIns(3)P-binding protein EPG-6 regulates progression of omegasomes to autophagosomes.

    PubMed

    Lu, Qun; Yang, Peiguo; Huang, Xinxin; Hu, Wanqiu; Guo, Bin; Wu, Fan; Lin, Long; Kovács, Attila L; Yu, Li; Zhang, Hong

    2011-08-16

    PtdIns(3)P plays critical roles in the autophagy pathway. However, little is known about how PtdIns(3)P effectors act with autophagy proteins in autophagosome formation. Here we identified an essential autophagy gene in C. elegans, epg-6, which encodes a WD40 repeat-containing protein with PtdIns(3)P-binding activity. EPG-6 directly interacts with ATG-2. epg-6 and atg-2 regulate progression of omegasomes to autophagosomes, and their loss of function causes accumulation of enlarged early autophagic structures. Another WD40 repeat PtdIns(3)P effector, ATG-18, plays a distinct role in autophagosome formation. We also established the hierarchical relationship of autophagy genes in degradation of protein aggregates and revealed that the UNC-51/Atg1 complex, EPG-8/Atg14, and binding of lipidated LGG-1 to protein aggregates are required for omegasome formation. Our study demonstrates that autophagic PtdIns(3)P effectors play distinct roles in autophagosome formation and also provides a framework for understanding the concerted action of autophagy genes in protein aggregate degradation. PMID:21802374

  20. miR-8-3p regulates mitoferrin in the testes of Bactrocera dorsalis to ensure normal spermatogenesis

    PubMed Central

    Tariq, Kaleem; Metzendorf, Christoph; Peng, Wei; Sohail, Summar; Zhang, Hongyu

    2016-01-01

    Genetics-enhanced sterile insect techniques (SIT) are promising novel approaches to control Bactrocera dorsalis, the most destructive horticultural pest in East Asia and the Pacific region. To identify novel genetic agents to alter male fertility of B. dorsalis, previous studies investigated miRNA expression in testes of B. dorsalis. One miRNA, miR-8-3p was predicted to bind the 3′UTR of putative B. dorsalis mitoferrin (bmfrn). The ortholog of bmfrn in D. melanogaster is essential for male fertility. Here we show that bmfrn has all conserved amino acid residues of known mitoferrins and is most abundantly expressed in B. dorsalis testes, making miR-8-3p and mitoferrin candidates for genetics-enhanced SIT. Furthermore, using a dual-luciferase reporter system, we show in HeLa cells that miR-8-3p interacts with the 3′UTR of bmfrn. Dietary treatments of adult male flies with miR-8-3p mimic, antagomiR, or bmfrn dsRNA, altered mitoferrin expression in the testes and resulted in reduced male reproductive capacity due to reduced numbers and viability of spermatozoa. We show for the first time that a mitoferrin is regulated by a miRNA and we demonstrate miR-8-3p as well as bmfrn dsRNA to be promising novel agents that could be used for genetics-enhanced SIT. PMID:26932747

  1. MicroRNA-146b-3p regulates retinal inflammation by suppressing adenosine deaminase-2 in diabetes.

    PubMed

    Fulzele, Sadanand; El-Sherbini, Ahmed; Ahmad, Saif; Sangani, Rajnikumar; Matragoon, Suraporn; El-Remessy, Azza; Radhakrishnan, Reshmitha; Liou, Gregory I

    2015-01-01

    Hyperglycemia- (HG-) Amadori-glycated albumin- (AGA-) induced activation of microglia and monocytes and their adherence to retinal vascular endothelial cells contribute to retinal inflammation leading to diabetic retinopathy (DR). There is a great need for early detection of DR before demonstrable tissue damages become irreversible. Extracellular adenosine, required for endogenous anti-inflammation, is regulated by the interplay of equilibrative nucleoside transporter with adenosine deaminase (ADA) and adenosine kinase. ADA, including ADA1 and ADA2, exists in all organisms. However, because ADA2 gene has not been identified in mouse genome, how diabetes alters adenosine-dependent anti-inflammation remains unclear. Studies of pig retinal microglia and human macrophages revealed a causal role of ADA2 in inflammation. Database search suggested miR-146b-3p recognition sites in the 3'-UTR of ADA2 mRNA. Coexpression of miR-146b-3p, but not miR-146-5p or nontargeting miRNA, with 3'-UTR of the ADA2 gene was necessary to suppress a linked reporter gene. In the vitreous of diabetic patients, decreased miR-146b-3p is associated with increased ADA2 activity. Ectopic expression of miR-146b-3p suppressed ADA2 expression, activity, and TNF-α release in the AGA-treated human macrophages. These results suggest a regulatory role of miR-146b-3p in diabetes related retinal inflammation by suppressing ADA2. PMID:25815338

  2. miR-494-3p Induces Cellular Senescence and Enhances Radiosensitivity in Human Oral Squamous Carcinoma Cells

    PubMed Central

    Weng, Jui-Hung; Yu, Cheng-Chia; Lee, Yueh-Chun; Lin, Cheng-Wei; Chang, Wen-Wei; Kuo, Yu-Liang

    2016-01-01

    Oral squamous cell carcinoma (OSCC) is the most common malignancy of head and neck. Although radiotherapy is used for OSCC treatment, the occurrence of radioresistant cancer cells limits its efficiency. MicroRNAs (miRNAs) are non-coding RNAs with lengths of 18–25 base pairs and known to be involved in carcinogenesis. We previously demonstrated that by targeting B lymphoma Mo-MLV insertion region 1 homolog (Bmi1), miR-494-3p functions as a putative tumor suppressor miRNA in OSCC. In this study, we further discovered that miR-494-3p could enhance the radiosensitivity of SAS OSCC cells and induce cellular senescence. The overexpression of miR-494-3p in SAS cells increased the population of senescence-associated β-galactosidase positive cells, the expression of p16INK4a and retinoblastoma 1 (RB1), as well as downregulated Bmi1. The knockdown of Bmi1 by lentiviral-mediated delivery of specific short hairpin RNAs (shRNAs) also enhanced the radiosensitivity of SAS cells and the activation of the senescence pathway. Furthermore, the inverse correlation between Bmi1 and miR-494-3p expression was observed among OSCC tissues. Results suggest that miR-494-3p could increase the radiosensitivity of OSCC cells through the induction of cellular senescence caused by the downregulation of Bmi1. PMID:27399693

  3. miR-129-3p controls centrosome number in metastatic prostate cancer cells by repressing CP110

    PubMed Central

    Bijnsdorp, Irene V.; Hodzic, Jasmina; Lagerweij, Tonny; Westerman, Bart; Krijgsman, Oscar; Broeke, Jurjen; Verweij, Frederik; Nilsson, R. Jonas A.; Rozendaal, Lawrence; van Beusechem, Victor W.; van Moorselaar, Jeroen A.

    2016-01-01

    The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p. High miR-129-3p expression levels increased cell invasion, while increasing CP110 levels decreased cell invasion. Overexpression of CP110 in metastatic PCa cells resulted in a decrease in the number of metastasis. In tissues of PCa patients, low CP110 and high miR-129-3p expression levels correlated with metastasis, but not with the expression of genes related to EMT. Furthermore, overexpression of CP110 in metastatic PCa cells resulted in excessive-CA (E-CA), and a change in F-actin distribution which is in agreement with their reduced metastatic capacity. Our data demonstrate that miR-129-3p functions as a CA gatekeeper in metastatic PCa cells by maintaining pro-metastatic centrosome amplification (CA) and preventing anti-metastatic E-CA. PMID:26918338

  4. Reactions of N+ (3P) ions with H2 and HD molecules at low temperatures

    NASA Astrophysics Data System (ADS)

    Grozdanov, Tasko P.; McCarroll, Ronald; Roueff, Evelyne

    2016-05-01

    formation of ND+. The calculated value is consistent with the available experimental data. Conclusions: The present results allow for the determination of reaction rate coefficients for any given distribution of specific fine structure and rotational state populations of the reactants. In interstellar conditions, where N+ is in its 3P0 state and para- and ortho-H2 respectively in J = 0 and J = 1. Our results enable a study of the influence of the ortho/para evolution of molecular hydrogen on the formation of nitrogen compounds.

  5. 75 FR 23574 - Airworthiness Directives; CFM International, S.A. CFM56-5B1/P, -5B2/P, -5B3/P, -5B3/P1, -5B4/P...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-04

    ... Regulatory Policies and Procedures (44 FR 11034, February 26, 1979); and (3) Will not have a significant..., S.A. CFM56-5B1/P, - 5B2/P, -5B3/P, -5B3/P1, -5B4/P, -5B5/P, -5B6/P, -5B7/P, -5B8/P, -5B9/P, -5B1/2P... INFORMATION: The FAA proposed to amend 14 CFR part 39 by superseding AD 2009-01-01, Amendment......

  6. Doubly excited {sup 3}P{sup e} resonance states of two-electron positive ions in Debye plasmas

    SciTech Connect

    Hu, Xiao-Qing; Wang, Yang; Kar, Sabyasachi E-mail: karsabyasachi@yahoo.com; Jiang, Zishi; Jiang, Pinghui

    2015-11-15

    We investigate the doubly excited {sup 3}P{sup e} resonance states of two-electron positive ions Li{sup +}, Be{sup 2+}, B{sup 3+}, and C{sup 4+} by employing correlated exponential wave functions. In the framework of the stabilization method, we calculate two series (3pnp and 3dnd) of {sup 3}P{sup e} resonances below the N = 3 threshold. The {sup 3}P{sup e} resonance parameters (resonance energies and widths) are reported for the first time as a function of the screening parameter. For free-atomic cases, comparisons are made with the reported results and few resonance states are reported for the first time.

  7. Studies of pH regulation by Btn1p, the yeast homolog of human Cln3p.

    PubMed

    Pearce, D A; Nosel, S A; Sherman, F

    1999-04-01

    Although the gene responsible for Batten disease, CLN3, was positionally cloned in 1995, the function of Cln3p and the molecular basis of the disease still remain elusive. We previously reported that the yeast Saccharomyces cerevisiae contains a homolog to Cln3p, designated Btn1p, and that the human Cln3p complemented the pH-dependent resistance to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1, 3-propanediol in btn1-Delta yeast mutants. We have determined that yeast lacking Btn1p have an elevated ability to acidify media during growth that correlates with an elevated plasma membrane ATPase activity. Btn1p may be involved in maintaining pH homeostasis of yeast cells. PMID:10191121

  8. Spectroscopy of 1S0- 3P1 transition of magnesium atom in an external absorption cell

    NASA Astrophysics Data System (ADS)

    Bagayev, S. N.; Baraulya, V. I.; Bonert, A. E.; Goncharov, A. N.; Seydaliev, M. R.

    2001-09-01

    The results of saturated absorption spectroscopy of the intercombination 1S0- 3P1 transition of magnesium atoms at 457 nm in an external absorption cell are presented. A laser system based on a Ti:Sa laser with frequency doubling in a LBO nonlinear crystal was used in these experiments. Saturated absorption resonances of magnesium in an external cell at the 1S0- 3P1 transition have been obtained for the first time. Pressure broadening of resonances equal to 12.5±1.5 kHz/mTorr has been measured.

  9. Measurement of the lifetimes of the lowest {sup 3}P{sub 1} state of neutral Ba and Ra

    SciTech Connect

    Scielzo, N. D.; Guest, J. R.; Schulte, E. C.; Ahmad, I.; Bailey, K.; Holt, R. J.; O'Connor, T. P.; Potterveld, D. H.; Bowers, D. L.; Lu, Z.-T.

    2006-01-15

    The lifetimes of the lowest {sup 3}P{sub 1} states of Ba and Ra were determined to be 1345{+-}14 ns and 422{+-}20 ns, respectively, by measuring the exponential decay of fluorescence after illuminating a thermal atomic beam with pulses of laser light. In addition, the {sup 1}S{sub 0}(F=1/2)-{sup 3}P{sub 1}(F=3/2) transition frequency in {sup 225}Ra was measured to be 13 999.269{+-}0.001 cm{sup -1} by referencing a nearby I{sub 2} transition.

  10. Measurements of the lifetime of the lowest {sup 3}P{sub 1} state of neutral Ba and Ra.

    SciTech Connect

    Scielzo, N. D.; Guest, J. R.; Schulte, E. C.; Ahmad, I.; Bailey, K.; Bowers, D. L.; Holt, R. J.; Lu, Z.-T.; O'Connor, T.; Potterveld, D. H.; Univ. of Chicago

    2006-01-01

    The lifetimes of the lowest {sup 3}P{sub 1} states of Ba and Ra were determined to be 1345 {+-} 14 ns and 422 {+-} 20 ns, respectively, by measuring the exponential decay of fluorescence after illuminating a thermal atomic beam with pulses of laser light. In addition, the {sup 1}S{sub 0}(F=1/2)-{sup 3}P{sub 1}(F=3/2) transition frequency in {sup 225}Ra was measured to be 13 999.269 {+-} 0.001 cm{sup -1} by referencing a nearby I{sub 2} transition.

  11. Structure of the human gene encoding sterol regulatory element binding protein-1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13

    SciTech Connect

    Hua, X.; Wu, J.; Goldstein, J.L.

    1995-02-10

    Sterol regulatory element binding protein-1 (SREBP1) and SREBP2 are structurally related proteins that control cholesterol homeostasis by stimulating transcription of sterol-regulated genes, including those encoding the low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl CoA synthase. SREBP1 and SREBP2 are 47% identical, and they share a novel structure comprising a transcriptionally active NH{sub 2}-terminal basic helix-loop-helix-leucine zipper (bHLH-Zip) domain followed by a membrane attachment domain. Cleavage by a sterol-regulated protease frees the bHLH-Zip domain from the membrane and allows it to enter the nucleus. SREBP1 exists in several forms, possibly as a result of alternative splicing at both the 5{prime} and the 3{prime} ends of the mRNA. The genes for SREBP1 (SREBF1) and SREBP2 (SREBF2) have not been studied. In this paper we describe the cloning and characterization of the human SREBF1 gene. The gene is 26 kb in length and has 22 exons and 20 introns. The 5{prime} and 3{prime} sequences that differ between the two SREBP1 cDNAs are encoded by discrete exons, conforming the hypothesis that they result from alternative splicing. The chromosomal locations of human SREBF1 and SREBF2 were determined by analysis of human-rodent somatic cell hybrids and fluorescence in situ hybridization. The SREBF1 gene mapped to the proximal short arm of chromosome 17 (17p11.2), and the SREBF2 gene was localized to the long arm of chromosome 22 (22q13). 22 refs., 3 figs., 2 tabs.

  12. The human homologue of the Drosophila melanogaster flightless-I gene (fliI) maps within the Smith-Magenis microdeletion critical region in 17p11.2

    SciTech Connect

    Chen, K.S.; Nguyen, D.; Greenberg, F.

    1994-09-01

    The Smith-Magenis syndrome (SMS) appears to be a contiguous gene deletion syndrome associated with a proximal deletion of the short arm of chromosome 17 in band p11.2. The spectrum of clinical findings includes short stature, brachydactyly, developmental delay, dysmorphic features, sleep disturbances and behavioral problems. The complex phenotypic features suggest deletion of several contiguous genes. However, to date no protein encoding gene has been mapped to the SMS critical region. Recently, Campbell described the cloning and characterization of D. melanogaster fli cDNAs and of homologous cDNAs from caenorhabditis elegans and from humans. Mutations in fliI result in loss of flight ability and, when severe, cause lethality due to incomplete cellularization with subsequent abnormal gastrulation. The amino acid sequence deduced from the FLI cDNA has 52% similarity to the human gelsolin protein and also has a N-terminal leucine-rich domain with 16 consecutive leucine-rich repeats (LRR). Here, we demonstrate that the human homologue (FLI) maps within the SMS critical region. Genomic cosmids were used as probes for fluorescence in situ hybridization (FISH) and localized this gene to the 17p11.2 region. Somatic cell hybrids and/or FISH analysis of lymphoblastoid cell lines form 12 SMS patients demonstrate that one copy of the FLI gene is deleted in all SMS patients analyzed with the common deletion. Further studies are required to determine if haploinsufficiency of FLI or other as yet unidentified genes is important for the expression of the SMS phenotype.

  13. MicroRNA-19b-3p Modulates Japanese Encephalitis Virus-Mediated Inflammation via Targeting RNF11

    PubMed Central

    Ashraf, Usama; Zhu, Bibo; Ye, Jing; Wan, Shengfeng; Nie, Yanru; Chen, Zheng; Cui, Min; Wang, Chong; Duan, Xiaodong; Zhang, Hao; Chen, Huanchun

    2016-01-01

    ABSTRACT Japanese encephalitis virus (JEV) can invade the central nervous system and consequently induce neuroinflammation, which is characterized by profound neuronal cell damage accompanied by astrogliosis and microgliosis. Albeit microRNAs (miRNAs) have emerged as major regulatory noncoding RNAs with profound effects on inflammatory response, it is unknown how astrocytic miRNAs regulate JEV-induced inflammation. Here, we found the involvement of miR-19b-3p in regulating the JEV-induced inflammatory response in vitro and in vivo. The data demonstrated that miR-19b-3p is upregulated in cultured cells and mouse brain tissues during JEV infection. Overexpression of miR-19b-3p led to increased production of inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, interleukin-1β, and chemokine (C-C motif) ligand 5, after JEV infection, whereas knockdown of miR-19b-3p had completely opposite effects. Mechanistically, miR-19b-3p modulated the JEV-induced inflammatory response via targeting ring finger protein 11, a negative regulator of nuclear factor kappa B signaling. We also found that inhibition of ring finger protein 11 by miR-19b-3p resulted in accumulation of nuclear factor kappa B in the nucleus, which in turn led to higher production of inflammatory cytokines. In vivo silencing of miR-19b-3p by a specific antagomir reinvigorates the expression level of RNF11, which in turn reduces the production of inflammatory cytokines, abrogates gliosis and neuronal cell death, and eventually improves the survival rate in the mouse model. Collectively, our results demonstrate that miR-19b-3p positively regulates the JEV-induced inflammatory response. Thus, miR-19b-3p targeting may constitute a thought-provoking approach to rein in JEV-induced inflammation. IMPORTANCE Japanese encephalitis virus (JEV) is one of the major causes of acute encephalitis in humans worldwide. The pathological features of JEV-induced encephalitis are inflammatory reactions and

  14. Phospholipid Flippases Lem3p-Dnf1p and Lem3p-Dnf2p Are Involved in the Sorting of the Tryptophan Permease Tat2p in Yeast*

    PubMed Central

    Hachiro, Takeru; Yamamoto, Takaharu; Nakano, Kenji; Tanaka, Kazuma

    2013-01-01

    The type 4 P-type ATPases are flippases that generate phospholipid asymmetry in membranes. In budding yeast, heteromeric flippases, including Lem3p-Dnf1p and Lem3p-Dnf2p, translocate phospholipids to the cytoplasmic leaflet of membranes. Here, we report that Lem3p-Dnf1/2p are involved in transport of the tryptophan permease Tat2p to the plasma membrane. The lem3Δ mutant exhibited a tryptophan requirement due to the mislocalization of Tat2p to intracellular membranes. Tat2p was relocalized to the plasma membrane when trans-Golgi network (TGN)-to-endosome transport was inhibited. Inhibition of ubiquitination by mutations in ubiquitination machinery also rerouted Tat2p to the plasma membrane. Lem3p-Dnf1/2p are localized to endosomal/TGN membranes in addition to the plasma membrane. Endocytosis mutants, in which Lem3p-Dnf1/2p are sequestered to the plasma membrane, also exhibited the ubiquitination-dependent missorting of Tat2p. These results suggest that Tat2p is ubiquitinated at the TGN and missorted to the vacuolar pathway in the lem3Δ mutant. The NH2-terminal cytoplasmic region of Tat2p containing ubiquitination acceptor lysines interacted with liposomes containing acidic phospholipids, including phosphatidylserine. This interaction was abrogated by alanine substitution mutations in the basic amino acids downstream of the ubiquitination sites. Interestingly, a mutant Tat2p containing these substitutions was missorted in a ubiquitination-dependent manner. We propose the following model based on these results; Tat2p is not ubiquitinated when the NH2-terminal region is bound to membrane phospholipids, but if it dissociates from the membrane due to a low level of phosphatidylserine caused by perturbation of phospholipid asymmetry in the lem3Δ mutant, Tat2p is ubiquitinated and then transported from the TGN to the vacuole. PMID:23250744

  15. Accurate long-range coefficients for two excited like isotope He atoms: He(2 {sup 1}P)-He(2 {sup 1}P), He(2 {sup 1}P)-He(2 {sup 3}P), and He(2 {sup 3}P)-He(2 {sup 3}P)

    SciTech Connect

    Zhang, J.-Y.; Yan, Z.-C.; Vrinceanu, D.; Babb, J. F.; Sadeghpour, H. R.

    2007-07-15

    A general formalism is used to express the long-range potential energies in inverse powers of the separation distance between two like atomic or molecular systems with P symmetries. The long-range molecular interaction coefficients are calculated for the molecular symmetries {delta}, {pi}, and {sigma}, arising from the following interactions: He(2 {sup 1}P)-He(2 {sup 1}P), He(2 {sup 1}P)-He(2 {sup 3}P), and He(2 {sup 3}P)-He(2 {sup 3}P). The electric quadrupole-quadrupole term C{sub 5}, the van der Waals (dispersion) term C{sub 6}, and higher-order terms C{sub 8} and C{sub 10} are calculated ab initio using accurate variational wave functions in Hylleraas coordinates with finite nuclear mass effects. A comparison is made with previously published results where available.

  16. Histidine Methylation of Yeast Ribosomal Protein Rpl3p Is Required for Proper 60S Subunit Assembly

    PubMed Central

    Al-Hadid, Qais; Roy, Kevin; Munroe, William; Dzialo, Maria C.; Chanfreau, Guillaume F.

    2014-01-01

    Histidine protein methylation is an unusual posttranslational modification. In the yeast Saccharomyces cerevisiae, the large ribosomal subunit protein Rpl3p is methylated at histidine 243, a residue that contacts the 25S rRNA near the P site. Rpl3p methylation is dependent upon the presence of Hpm1p, a candidate seven-beta-strand methyltransferase. In this study, we elucidated the biological activities of Hpm1p in vitro and in vivo. Amino acid analyses reveal that Hpm1p is responsible for all of the detectable protein histidine methylation in yeast. The modification is found on a polypeptide corresponding to the size of Rpl3p in ribosomes and in a nucleus-containing organelle fraction but was not detected in proteins of the ribosome-free cytosol fraction. In vitro assays demonstrate that Hpm1p has methyltransferase activity on ribosome-associated but not free Rpl3p, suggesting that its activity depends on interactions with ribosomal components. hpm1 null cells are defective in early rRNA processing, resulting in a deficiency of 60S subunits and translation initiation defects that are exacerbated in minimal medium. Cells lacking Hpm1p are resistant to cycloheximide and verrucarin A and have decreased translational fidelity. We propose that Hpm1p plays a role in the orchestration of the early assembly of the large ribosomal subunit and in faithful protein production. PMID:24865971

  17. The t-SNARE AtVAM3p resides on the prevacuolar compartment in Arabidopsis root cells

    SciTech Connect

    Sanderfoot, A.A.; Kovaleva, V.; Zheng, H.; Raikhel, N.V.

    1999-11-01

    Protein cargo is trafficked between the organelles of the endomembrane system inside transport vesicles, a process mediated by integral membrane proteins called SNAREs (soluble N-ethylmaleimide sensitive factor attachment protein receptors) that reside on the surface of the vesicle (v-SNAREs) and target membrane (t-SNAREs). In examining transport of cargo between the trans-Golgi network and the vacuole in Arabidopsis, the authors have previously characterized AtPEP12p as a t-SNARE residing on the prevacuolar compartment and AtVTl1a as a v-SNARE that interacts with AtPEP12p. Recently, they have begun to characterize AtVAM3p, another Arabidopsis t-SNARE that shows high sequence homology to AtPEP12p. They have found that AtVTl1a also interacts with AtVAM3p, suggesting a role for this t-SNARE in post-Golgi trafficking. AtVAM3p has been suggested to localize to the vacuolar membrane in Arabidopsis cells; however, using specific antisera and expression of epitope-tagged versions of each t-SNARE, the authors have discovered that AtVAM3p is found on the same prevacuolar structure as AtPEP12p in Arabidopsis root cells.

  18. A 5′ cytosine binding pocket in Puf3p specifies regulation of mitochondrial mRNAs

    SciTech Connect

    Zhu, Deyu; Stumpf, Craig R.; Krahn, Joseph M.; Wickens, Marvin; Tanaka Hall, Traci M.

    2010-11-03

    A single regulatory protein can control the fate of many mRNAs with related functions. The Puf3 protein of Saccharomyces cerevisiae is exemplary, as it binds and regulates more than 100 mRNAs that encode proteins with mitochondrial function. Here we elucidate the structural basis of that specificity. To do so, we explore the crystal structures of Puf3p complexes with 2 cognate RNAs. The key determinant of Puf3p specificity is an unusual interaction between a distinctive pocket of the protein with an RNA base outside the 'core' PUF-binding site. That interaction dramatically affects binding affinity in vitro and is required for regulation in vivo. The Puf3p structures, combined with those of Puf4p in the same organism, illuminate the structural basis of natural PUF-RNA networks. Yeast Puf3p binds its own RNAs because they possess a -2C and is excluded from those of Puf4p which contain an additional nucleotide in the core-binding site.

  19. MiR-223-3p targeting SEPT6 promotes the biological behavior of prostate cancer

    PubMed Central

    Wei, Yongbao; Yang, Jinrui; Yi, Lu; Wang, Yinhuai; Dong, Zhitao; Liu, Ziting; Ou-yang, Shifeng; Wu, Hongtao; Zhong, Zhaohui; Yin, Zhuo; Zhou, Keqin; Gao, Yunliang; Yan, Bin; Wang, Zhao

    2014-01-01

    MicroRNAs (miRNAs) present frequently altered expression in urologic cancers including prostate, bladder, and kidney cancer. The altered expression of miR-223 has been reported in cancers and other diseases in recent researches. MiR-223 is up-regulated in systemic lupus erythematosus and rheumatoid arthritis. In neoplastic diseases, miR-223 is proved to be up-expressed in plasma or serum and cancer tissues compared with normal tissues in pancreatic cancer, gastric cancer, et al. However, whether altered expression of miR-223 is associated with prostate cancer (PCa) and what it is potential functions in PCa remained unveiled. In this study, we firstly found miR-223-3p were up-regulated in prostate cancer tissues and then we study functional role of miR-223-3p in PCa using DU145, PC3 and LNCaP cell lines. Our data suggested that miR-223-3p might target gene SEPT6 and promoted the biological behavior of prostate cancer. Notably, we found increasing SEPT6 expression might reverse the biological activity induced by miR-223-3p, which might be a potential therapeutic target for PCa. PMID:25519054

  20. 78 FR 12130 - Social Security Ruling, SSR 13-3p; Appeal of an Initial Medical Disability Cessation...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-21

    ... From the Federal Register Online via the Government Publishing Office SOCIAL SECURITY ADMINISTRATION Social Security Ruling, SSR 13-3p; Appeal of an Initial Medical Disability Cessation Determination or Decision AGENCY: Social Security Administration. ACTION: Notice of Social Security Ruling...

  1. Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons.

    PubMed

    Gunn, Adam P; Wong, Bruce X; Johanssen, Timothy; Griffith, James C; Masters, Colin L; Bush, Ashley I; Barnham, Kevin J; Duce, James A; Cherny, Robert A

    2016-03-18

    Pyroglutamate-modified amyloid-β (pE-Aβ) is a highly neurotoxic amyloid-β (Aβ) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of Aβ oligomerization and alters the interactions of Aβ with Cu(2+) and lipids; however, a link between these properties and the toxicity of pE-Aβ peptides has not been established. We report here that Aβ3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the full-length isoform (Aβ(1-42)). In contrast, Aβ(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas Aβ3pE-42 did not. We also report that Aβ3pE-42 preferentially associates with neuronal membranes and triggers Ca(2+) influx that can be partially blocked by the N-methyl-d-aspartate receptor antagonist MK-801. Aβ3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than Aβ(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of Aβ-dityrosine oligomer formation mediated by copper-redox cycling. PMID:26697885

  2. MicroRNA-195a-3p inhibits angiogenesis by targeting Mmp2 in murine mesenchymal stem cells.

    PubMed

    Gao, Fan; Sun, Meng; Gong, Yumei; Wang, Haiyan; Wang, Yusheng; Hou, Huiyuan

    2016-05-01

    MicroRNAs (miRNAs) modulate complex physiological and pathological processes, including the regulation of angiogenesis. Our previous study reported that bone marrow-derived mesenchymal stem cells (MSCs) are recruited into choroidal neovascularization lesions. miRNA-195 is highly expressed in MSCs, but its function remains unknown. In the present study, miR-195a-3p abundance was significantly decreased in hypoxia-treated murine MSCs; on the other hand, its overexpression reduced MSC proliferation and migration while increasing the activation of anti-angiogenic factor pigment epithelium-derived factor (PEDF). We further discovered that matrix metalloproteinase 2 (Mmp2) transcript is a target of miR-195a-3p, and that silencing Mmp2 phenocopied the reduced proliferation and migration of MSCs. The therapeutic potential of miR-195a-3p as an angiogenesis inhibitor was also demonstrated in a laser-induced choroidal neovascularization mouse model. These findings collectively indicate that miR-195a-3p is a negative modulator of angiogenesis, and could be used as an angiogenesis inhibitor. Mol. Reprod. Dev. 83: 413-423, 2016. © 2016 Wiley Periodicals, Inc. PMID:26989874

  3. Human mitochondrial RNA turnover caught in flagranti: involvement of hSuv3p helicase in RNA surveillance

    PubMed Central

    Szczesny, Roman J.; Borowski, Lukasz S.; Brzezniak, Lien K.; Dmochowska, Aleksandra; Gewartowski, Kamil; Bartnik, Ewa; Stepien, Piotr P.

    2010-01-01

    The mechanism of human mitochondrial RNA turnover and surveillance is still a matter of debate. We have obtained a cellular model for studying the role of hSuv3p helicase in human mitochondria. Expression of a dominant-negative mutant of the hSUV3 gene which encodes a protein with no ATPase or helicase activity results in perturbations of mtRNA metabolism and enables to study the processing and degradation intermediates which otherwise are difficult to detect because of their short half-lives. The hSuv3p activity was found to be necessary in the regulation of stability of mature, properly formed mRNAs and for removal of the noncoding processing intermediates transcribed from both H and L-strands, including mirror RNAs which represent antisense RNAs transcribed from the opposite DNA strand. Lack of hSuv3p function also resulted in accumulation of aberrant RNA species, molecules with extended poly(A) tails and degradation intermediates truncated predominantly at their 3′-ends. Moreover, we present data indicating that hSuv3p co-purifies with PNPase; this may suggest participation of both proteins in mtRNA metabolism. PMID:19864255

  4. A novel mass assay to quantify the bioactive lipid PtdIns3P in various biological samples

    PubMed Central

    Chicanne, Gaëtan; Severin, Sonia; Boscheron, Cécile; Terrisse, Anne-Dominique; Gratacap, Marie-Pierre; Gaits-Iacovoni, Frédérique; Tronchère, Hélène; Payrastre, Bernard

    2012-01-01

    PtdIns3P is recognized as an important player in the control of the endocytotic pathway and in autophagy. Recent data also suggest that PtdIns3P contributes to molecular mechanisms taking place at the plasma membrane and at the midbody during cytokinesis. This lipid is present in low amounts in mammalian cells and remains difficult to quantify either by traditional techniques based on radiolabelling followed by HPLC to separate the different phosphatidylinositol monophosphates, or by high-sensitive liquid chromatography coupled to MS, which is still under development. In the present study, we describe a mass assay to quantify this lipid from various biological samples using the recombinant PtdIns3P 5-kinase, PIKfyve. Using this assay, we show an increase in the mass level of PtdIns3P in mouse and human platelets following stimulation, loss of this lipid in Vps34-deficient yeasts and its relative enrichment in early endosomes isolated from BHK cells. PMID:22830526

  5. miR-142-3p balances proliferation and differentiation of mesenchymal cells during lung development

    PubMed Central

    Carraro, Gianni; Shrestha, Amit; Rostkovius, Jana; Contreras, Adriana; Chao, Cho-Ming; El Agha, Elie; MacKenzie, Breanne; Dilai, Salma; Guidolin, Diego; Taketo, Makoto Mark; Günther, Andreas; Kumar, Maya E.; Seeger, Werner; De Langhe, Stijn; Barreto, Guillermo; Bellusci, Saverio

    2014-01-01

    The regulation of the balance between proliferation and differentiation in the mesenchymal compartment of the lung is largely uncharacterized, unlike its epithelial counterpart. In this study, we determined that miR-142-3p contributes to the proper proliferation of mesenchymal progenitors by controlling the level of WNT signaling. miR-142-3p can physically bind to adenomatous polyposis coli mRNA, functioning to regulate its expression level. In miR-142-3p loss-of-function experiments, proliferation of parabronchial smooth muscle cell progenitors is significantly impaired, leading to premature differentiation. Activation of WNT signaling in the mesenchyme, or Apc loss of function, can both rescue miR-142-3p knockdown. These findings show that in the embryonic lung mesenchyme, the microRNA machinery modulates the level of WNT signaling, adding an extra layer of control in the feedback loop between FGFR2C and β-catenin-mediated WNT signaling. PMID:24553287

  6. Functional screening implicates miR-371-3p and peroxiredoxin 6 in reversible tolerance to cancer drugs

    PubMed Central

    Sahu, Nisebita; Stephan, Jean-Philippe; Cruz, Darlene Dela; Merchant, Mark; Haley, Benjamin; Bourgon, Richard; Classon, Marie; Settleman, Jeff

    2016-01-01

    Acquired resistance to cancer drug therapies almost always occurs in advanced-stage patients even following a significant response to treatment. In addition to mutational mechanisms, various non-mutational resistance mechanisms have now been recognized. We previously described a chromatin-mediated subpopulation of reversibly drug-tolerant persisters that is dynamically maintained within a wide variety of tumour cell populations. Here we explore a potential role for microRNAs in such transient drug tolerance. Functional screening of 879 human microRNAs reveals miR-371-3p as a potent suppressor of drug tolerance. We identify PRDX6 (peroxiredoxin 6) as a key target of miR-371-3p in establishing drug tolerance by regulating PLA2/PKCα activity and reactive oxygen species. PRDX6 expression is associated with poor prognosis in cancers of multiple tissue origins. These findings implicate miR-371-3p as a suppressor of PRDX6 and suggest that co-targeting of peroxiredoxin 6 or modulating miR-371-3p expression together with targeted cancer therapies may delay or prevent acquired drug resistance. PMID:27484502

  7. miRNA863-3p sequentially targets negative immune regulator ARLPKs and positive regulator SERRATE upon bacterial infection

    PubMed Central

    Niu, Dongdong; Lii, Yifan E.; Chellappan, Padmanabhan; Lei, Lei; Peralta, Karl; Jiang, Chunhao; Guo, Jianhua; Coaker, Gitta; Jin, Hailing

    2016-01-01

    Plant small RNAs play important roles in gene regulation during pathogen infection. Here we show that miR863-3p is induced by the bacterial pathogen Pseudomonas syringae carrying various effectors. Early during infection, miR863-3p silences two negative regulators of plant defence, atypical receptor-like pseudokinase1 (ARLPK1) and ARLPK2, both lacking extracellular domains and kinase activity, through mRNA degradation to promote immunity. ARLPK1 associates with, and may function through another negative immune regulator ARLPK1-interacting receptor-like kinase 1 (AKIK1), an active kinase with an extracellular domain. Later during infection, miR863-3p silences SERRATE, which is essential for miRNA accumulation and positively regulates defence, through translational inhibition. This results in decreased miR863-3p levels, thus forming a negative feedback loop to attenuate immune responses after successful defence. This is an example of a miRNA that sequentially targets both negative and positive regulators of immunity through two modes of action to fine-tune the timing and amplitude of defence responses. PMID:27108563

  8. miR-130b-3p Modulates Epithelial-Mesenchymal Crosstalk in Lung Fibrosis by Targeting IGF-1

    PubMed Central

    Li, Shuhong; Geng, Jing; Xu, Xuefeng; Huang, Xiaoxi; Leng, Dong; Jiang, Dingyuan; Liang, Jiurong; Wang, Chen; Jiang, Dianhua; Dai, Huaping

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and usually lethal fibrotic lung disease with largely unknown etiology and pathogenesis. Evidence suggests microRNAs (miRNA) contribute to pathogenesis of IPF. In this study, we sought to identify miRNA expression signatures and determine the role of miR-130b-3p in lung fibrosis. The miRNA expression profile of the lungs from patients with IPF and normal donors was determined by Affymetrix microarray, and transcriptome with Affymetrix array. The functions and signal pathways as well as miRNA-mRNA networks were established by bioinformatics analysis. Luciferase assays and ELISA were used to confirm the miRNA target gene. The effect of miRNA-transfected epithelium on fibroblast activities was assessed using a co-culture system. The fibroblast activities were determined by qRT-PCR, western blotting, Transwell and BrdU assays. Seven miRNAs were significantly decreased in IPF lungs, with miR-130b-3p being the highest in the miRNA-mRNA network. Insulin-like growth factor (IGF-1) was a target gene of miR-130b-3p in the epithelium. miR-130b-3p inhibition in the epithelium induced collagen I expression and enhanced the proliferation and migration ability of fibroblast in co-culture systems, which mimicked the functions of exogenous IGF-1 on fibroblasts. Neutralizing IGF-1 with an antibody significantly reduced the modulatory effects of miR-130b-3p inhibitor-transfected epithelium on the activation of fibroblasts. Our results show that miR-130b-3p was downregulated in IPF lungs. miR-130b-3p downregulation contributed to the activation of fibroblasts and the dysregulated epithelial-mesenchymal crosstalk by promoting IGF-1 secretion from lung epithelium, suggesting a key regulatory role for this miRNA in preventing lung fibrosis. PMID:26953888

  9. Reduced miR-659-3p Levels Correlate with Progranulin Increase in Hypoxic Conditions: Implications for Frontotemporal Dementia.

    PubMed

    Piscopo, Paola; Grasso, Margherita; Fontana, Francesca; Crestini, Alessio; Puopolo, Maria; Del Vescovo, Valerio; Venerosi, Aldina; Calamandrei, Gemma; Vencken, Sebastian F; Greene, Catherine M; Confaloni, Annamaria; Denti, Michela A

    2016-01-01

    Progranulin (PGRN) is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and is activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial frontotemporal lobar degeneration (FTLD). PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts. Several studies have shown microRNAs (miRNAs) involvement in hypoxia. Moreover, in FTLD patients with a genetic variant of GRN (rs5848), the reinforcement of miR-659-3p binding site has been suggested to be a risk factor. Here, we report that miR-659-3p interacts directly with GRN 3'UTR as shown by luciferase assay in HeLa cells and ELISA and Western Blot analysis in HeLa and Kelly cells. Moreover, we demonstrate the physical binding between GRN mRNA and miR-659-3p employing a miRNA capture-affinity technology in SK-N-BE and Kelly cells. In order to study miRNAs involvement in hypoxia-mediated up-regulation of GRN, we evaluated miR-659-3p levels in SK-N-BE cells after 24 h of hypoxic treatment, finding them inversely correlated to GRN transcripts. Furthermore, we analyzed an animal model of asphyxia, finding that GRN mRNA levels increased at post-natal day (pnd) 1 and pnd 4 in rat cortices subjected to asphyxia in comparison to control rats and miR-659-3p decreased at pnd 4 just when GRN reached the highest levels. Our results demonstrate the interaction between miR-659-3p and GRN transcript and the involvement of miR-659-3p in GRN up-regulation mediated by hypoxic/ischemic insults. PMID:27199656

  10. Reduced miR-659-3p Levels Correlate with Progranulin Increase in Hypoxic Conditions: Implications for Frontotemporal Dementia

    PubMed Central

    Piscopo, Paola; Grasso, Margherita; Fontana, Francesca; Crestini, Alessio; Puopolo, Maria; Del Vescovo, Valerio; Venerosi, Aldina; Calamandrei, Gemma; Vencken, Sebastian F.; Greene, Catherine M.; Confaloni, Annamaria; Denti, Michela A.

    2016-01-01

    Progranulin (PGRN) is a secreted protein expressed ubiquitously throughout the body, including the brain, where it localizes in neurons and is activated microglia. Loss-of-function mutations in the GRN gene are an important cause of familial frontotemporal lobar degeneration (FTLD). PGRN has a neurotrophic and anti-inflammatory activity, and it is neuroprotective in several injury conditions, such as oxygen or glucose deprivation, oxidative injury, and hypoxic stress. Indeed, we have previously demonstrated that hypoxia induces the up-regulation of GRN transcripts. Several studies have shown microRNAs (miRNAs) involvement in hypoxia. Moreover, in FTLD patients with a genetic variant of GRN (rs5848), the reinforcement of miR-659-3p binding site has been suggested to be a risk factor. Here, we report that miR-659-3p interacts directly with GRN 3′UTR as shown by luciferase assay in HeLa cells and ELISA and Western Blot analysis in HeLa and Kelly cells. Moreover, we demonstrate the physical binding between GRN mRNA and miR-659-3p employing a miRNA capture-affinity technology in SK-N-BE and Kelly cells. In order to study miRNAs involvement in hypoxia-mediated up-regulation of GRN, we evaluated miR-659-3p levels in SK-N-BE cells after 24 h of hypoxic treatment, finding them inversely correlated to GRN transcripts. Furthermore, we analyzed an animal model of asphyxia, finding that GRN mRNA levels increased at post-natal day (pnd) 1 and pnd 4 in rat cortices subjected to asphyxia in comparison to control rats and miR-659-3p decreased at pnd 4 just when GRN reached the highest levels. Our results demonstrate the interaction between miR-659-3p and GRN transcript and the involvement of miR-659-3p in GRN up-regulation mediated by hypoxic/ischemic insults. PMID:27199656

  11. Perfluorooctane Sulfonate Disturbs Nanog Expression through miR-490-3p in Mouse Embryonic Stem Cells

    PubMed Central

    Chen, Minjian; Han, Xiumei; Du, Guizhen; Ji, Xiaoli; Chang, Chunxin; Rehan, Virender K.; Wang, Xinru; Xia, Yankai

    2013-01-01

    Perfluorooctane sulfonate (PFOS) poses potential risks to reproduction and development. Mouse embryonic stem cells (mESCs) are ideal models for developmental toxicity testing of environmental contaminants in vitro. However, the mechanism by which PFOS affects early embryonic development is still unclear. In this study, mESCs were exposed to PFOS for 24 h, and then general cytotoxicity and pluripotency were evaluated. MTT assay showed that neither PFOS (0.2 µM, 2 µM, 20 µM, and 200 µM) nor control medium (0.1% DMSO) treatments affected cell viability. Furthermore, there were no significant differences in cell cycle and apoptosis between the PFOS treatment and control groups. However, we found that the mRNA and protein levels of pluripotency markers (Sox2, Nanog) in mESCs were significantly decreased following exposure to PFOS for 24 h, while there were no significant changes in the mRNA and protein levels of Oct4. Accordingly, the expression levels of miR-145 and miR-490-3p, which can regulate Sox2 and Nanog expressions were significantly increased. Chrm2, the host gene of miR-490-3p, was positively associated with miR-490-3p expression after PFOS exposure. Dual luciferase reporter assay suggests that miR-490-3p directly targets Nanog. These results suggest that PFOS can disturb the expression of pluripotency factors in mESCs, while miR-145 and miR-490-3p play key roles in modulating this effect. PMID:24098361

  12. Role of miR-222-3p in c-Src-Mediated Regulation of Osteoclastogenesis.

    PubMed

    Takigawa, Shinya; Chen, Andy; Wan, Qiaoqiao; Na, Sungsoo; Sudo, Akihiro; Yokota, Hiroki; Hamamura, Kazunori

    2016-01-01

    MicroRNAs (miRNAs) are small non-coding RNAs that play a mostly post-transcriptional regulatory role in gene expression. Using RAW264.7 pre-osteoclast cells and genome-wide expression analysis, we identified a set of miRNAs that are involved in osteoclastogenesis. Based on in silico analysis, we specifically focused on miR-222-3p and evaluated its role in osteoclastogenesis. The results show that the inhibitor of miR-222-3p upregulated the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and tartrate-resistant acid phosphatase (TRAP), while its mimicking agent downregulated their mRNA levels. Western blot analysis showed that its inhibitor increased the protein levels of TRAP and cathepsin K, while its mimicking agent decreased their levels. Genome-wide mRNA expression analysis in the presence and absence of receptor activator of nuclear factor κ-B ligand (RANKL) predicted c-Src as a potential regulatory target of miR-222-3p. Live cell imaging using a fluorescence resonance energy transfer (FRET) technique revealed that miR-222-3p acted as an inhibitor of c-Src activity, and a partial silencing of c-Src suppressed RANKL-induced expression of TRAP and cathepsin K, as well as the number of multi-nucleated osteoclasts and their pit formation. Collectively, the study herein demonstrates that miR-222-3p serves as an inhibitor of osteoclastogenesis and c-Src mediates its inhibition of cathepsin K and TRAP. PMID:26891296

  13. Role of miR-222-3p in c-Src-Mediated Regulation of Osteoclastogenesis