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Sample records for bmi1 function independently

  1. PTEN inhibits BMI1 function independently of its phosphatase activity

    Directory of Open Access Journals (Sweden)

    Kapoor Anil

    2009-11-01

    (prostatic intraepithelial neoplasia and carcinoma compared to normal prostate epithelium. While PTEN co-localized with BMI1 in 2.4% of normal prostate epithelial cells, co-localization was observed in 37.6% and 18.5% of cells in PIN and carcinoma, respectively. Collectively, we demonstrate that PTEN inhibits BMI1 function via binding to BMI1 in a phosphatase independent manner. Conclusion We demonstrate that nuclear PTEN reduces BMI1 function independently of its phosphatase activity. It was recently observed that nuclear PTEN also suppresses tumorigenesis. Our results, therefore, provide a plausible mechanism by which nuclear PTEN prevents tumorigenesis.

  2. A Novel Aspect of Tumorigenesis—BMI1 Functions in Regulating DNA Damage Response

    Directory of Open Access Journals (Sweden)

    Xiaozeng Lin

    2015-12-01

    Full Text Available BMI1 plays critical roles in maintaining the self-renewal of hematopoietic, neural, intestinal stem cells, and cancer stem cells (CSCs for a variety of cancer types. BMI1 promotes cell proliferative life span and epithelial to mesenchymal transition (EMT. Upregulation of BMI1 occurs in multiple cancer types and is associated with poor prognosis. Mechanistically, BMI1 is a subunit of the Polycomb repressive complex 1 (PRC1, and binds the catalytic RING2/RING1b subunit to form a functional E3 ubiquitin ligase. Through mono-ubiquitination of histone H2A at lysine 119 (H2A-K119Ub, BMI1 represses multiple gene loci; among these, the INK4A/ARF locus has been most thoroughly investigated. The locus encodes the p16INK4A and p14/p19ARF tumor suppressors that function in the pRb and p53 pathways, respectively. Its repression contributes to BMI1-derived tumorigenesis. BMI1 also possesses other oncogenic functions, specifically its regulative role in DNA damage response (DDR. In this process, BMI1 ubiquitinates histone H2A and γH2AX, thereby facilitating the repair of double-stranded DNA breaks (DSBs through stimulating homologous recombination and non-homologous end joining. Additionally, BMI1 compromises DSB-induced checkpoint activation independent of its-associated E3 ubiquitin ligase activity. We review the emerging role of BMI1 in DDR regulation and discuss its impact on BMI1-derived tumorigenesis.

  3. Polycomb Repressor Complex 1 Member, BMI1 Contributes to Urothelial Tumorigenesis through p16-Independent Mechanisms

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    Lia E. De Faveri

    2015-10-01

    Full Text Available Urothelial carcinoma (UC causes significant morbidity and remains the most expensive cancer to treat because of the need for repeated resections and lifelong monitoring for patients with non–muscle-invasive bladder cancer (NMIBC. Novel therapeutics and stratification approaches are needed to improve the outlook for both NMIBC and muscle-invasive bladder cancer. We investigated the expression and effects of B Lymphoma Mo-MLV Insertion Region 1 (BMI1 in UC. BMI1 was found to be overexpressed in most UC cell lines and primary tumors by quantitative real-time polymerase chain reaction and immunohistochemistry. In contrast to some previous reports, no association with tumor stage or grade was observed in two independent tumor panels. Furthermore, upregulation of BMI1 was detected in premalignant bladder lesions, suggesting a role early in tumorigenesis. BMI1 is not located within a common region of genomic amplification in UC. The CDKN2A locus (which encodes the p16 tumor suppressor gene is a transcriptional target of BMI1 in some cellular contexts. In UC cell lines and primary tissues, no correlation between BMI1 and p16 expression was observed. Retroviral-mediated overexpression of BMI1 immortalized normal human urothelial cells (NHUC in vitro and was associated with induction of telomerase activity, bypass of senescence, and repression of differentiation. The effects of BMI1 on gene expression were identified by expression microarray analysis of NHUC-BMI1. Metacore analysis of the gene expression profile implicated downstream effects of BMI1 on α4/β1 integrin-mediated adhesion, cytoskeleton remodeling, and CREB1-mediated transcription.

  4. p21/Cyclin E pathway modulates anticlastogenic function of Bmi-1 in cancer cells.

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    Deng, Wen; Zhou, Yuan; Tiwari, Agnes F Y; Su, Hang; Yang, Jie; Zhu, Dandan; Lau, Victoria Ming Yi; Hau, Pok Man; Yip, Yim Ling; Cheung, Annie L M; Guan, Xin-Yuan; Tsao, Sai Wah

    2015-03-15

    Apart from regulating stem cell self-renewal, embryonic development and proliferation, Bmi-1 has been recently reported to be critical in the maintenance of genome integrity. In searching for novel mechanisms underlying the anticlastogenic function of Bmi-1, we observed, for the first time, that Bmi-1 positively regulates p21 expression. We extended the finding that Bmi-1 deficiency induced chromosome breaks in multiple cancer cell models. Interestingly, we further demonstrated that knockdown of cyclin E or ectopic overexpression of p21 rescued Bmi-1 deficiency-induced chromosome breaks. We therefore conclude that p21/cyclin E pathway is crucial in modulating the anticlastogenic function of Bmi-1. As it is well established that the overexpression of cyclin E potently induces genome instability and p21 suppresses the function of cyclin E, the novel and important implication from our findings is that Bmi-1 plays an important role in limiting genomic instability in cylin E-overexpressing cancer cells by positive regulation of p21.

  5. Bmi1 regulates mitochondrial function and the DNA damage response pathway.

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    Liu, Jie; Cao, Liu; Chen, Jichun; Song, Shiwei; Lee, In Hye; Quijano, Celia; Liu, Hongjun; Keyvanfar, Keyvan; Chen, Haoqian; Cao, Long-Yue; Ahn, Bong-Hyun; Kumar, Neil G; Rovira, Ilsa I; Xu, Xiao-Ling; van Lohuizen, Maarten; Motoyama, Noboru; Deng, Chu-Xia; Finkel, Toren

    2009-05-21

    Mice deficient in the Polycomb repressor Bmi1 develop numerous abnormalities including a severe defect in stem cell self-renewal, alterations in thymocyte maturation and a shortened lifespan. Previous work has implicated de-repression of the Ink4a/Arf (also known as Cdkn2a) locus as mediating many of the aspects of the Bmi1(-/-) phenotype. Here we demonstrate that cells derived from Bmi1(-/-) mice also have impaired mitochondrial function, a marked increase in the intracellular levels of reactive oxygen species and subsequent engagement of the DNA damage response pathway. Furthermore, many of the deficiencies normally observed in Bmi1(-/-) mice improve after either pharmacological treatment with the antioxidant N-acetylcysteine or genetic disruption of the DNA damage response pathway by Chk2 (also known as Chek2) deletion. These results demonstrate that Bmi1 has an unexpected role in maintaining mitochondrial function and redox homeostasis and indicate that the Polycomb family of proteins can coordinately regulate cellular metabolism with stem and progenitor cell function.

  6. Molecular cloning, sequence analysis, and function of the intestinal epithelial stem cell marker Bmi1 in pig intestinal epithelial cells.

    Science.gov (United States)

    Li, C-M; Yan, H-C; Fu, H-L; Xu, G-F; Wang, X-Q

    2014-01-01

    In the present work, we cloned the full-length cDNA of the pig Bmi1 gene (BMI1 polycomb ring finger oncogene), which has been indicated as an intestinal epithelial stem cell (IESC) marker in other mammals. This paper provides the first report of the function of Bmi1 in pig intestinal epithelial cells and a brief description of its underlying mechanism. Rapid amplification of cDNA ends technology was used to clone the complete pig Bmi1 sequence, and a Bmi1-pcDNA3.1 vector was constructed for transfection into an intestinal porcine epithelial cell line (IPEC-1). The proliferation ability of the cells was estimated using the MTT assay and the EdU incorporation method at different time points after seeding. Cell cycle information was detected by flow cytometry. The mRNA abundances of cell cycle-related genes were also measured. The results indicated that the pig Bmi1 cDNA is 3,193 bp in length and consists of a 981 bp open reading frame, a 256 bp 5´ untranslated region (UTR), and a 1,956 bp 3' UTR. The transcript contains no signal peptides, and there are no transmembrane regions in the pig Bmi1 coded protein, which has a total of 326 AA. The overexpression of the pig Bmi1 in the IPEC-1 cells led to increased cell proliferation and a lower percentage of cells in the G1 and S phases (P cells in the G2 phase (P 0.05). Our data suggested that pig Bmi1 can increase the proliferation of IPEC-1 cells by promoting the G1/S transition and the overall cell cycle process.

  7. Dysregulation of the Bmi-1/p16(Ink⁴a) pathway provokes an aging-associated decline of submandibular gland function.

    Science.gov (United States)

    Yamakoshi, Kimi; Katano, Satoshi; Iida, Mayu; Kimura, Hiromi; Okuma, Atsushi; Ikemoto-Uezumi, Madoka; Ohtani, Naoko; Hara, Eiji; Maruyama, Mitsuo

    2015-08-01

    Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16(Ink4a) . Therefore, dysregulation of the Bmi-1/p16(Ink4a) pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16(Ink4a) pathway occurs during aging in vivo. Using real-time in vivo imaging of p16(Ink4a) expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16(Ink4a) pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16(Ink4a) expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly. © 2015 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  8. Identification and characterization of Bmi-1-responding element within the human p16 promoter.

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    Meng, Sha; Luo, Min; Sun, He; Yu, Xin; Shen, Meili; Zhang, Quancang; Zhou, Rudan; Ju, Xiaofang; Tao, Wei; Liu, Di; Deng, Hongkui; Lu, Zhigang

    2010-10-22

    Bmi-1, the first functionally identified polycomb gene family member, plays critical roles in cell cycle regulation, cell immortalization, and cell senescence. Bmi-1 is involved in the development and progression of carcinomas and is a potent target for cancer therapy. One important pathway regulated by Bmi-1 is that involving two cyclin-dependent kinase inhibitors, p16(Ink4a) and p19(Arf), as Bmi-1 represses the INK4a locus on which they are encoded. A close correlation between the up-regulation of Bmi-1 and down-regulation of p16 has been demonstrated in various tumors; however, how Bmi-1 regulates p16 expression is not clear. In this study, we revealed that Bmi-1 regulates the expression of p16 by binding directly to the Bmi-1-responding element (BRE) within the p16 promoter. The BRE resided at bp -821 to -732 upstream of the p16 ATG codon. BRE alone was sufficient to allow Bmi-1-mediated regulation of the CMV promoter. Bmi-1 typically functions by forming a complex with Ring2; however, regulation of p16 was independent of Ring2. Chromatin immunoprecipitation sequencing of Bmi-1-precipitated chromatin DNA revealed that 1536 genes were targeted by Bmi-1, including genes involved in tissue-specific differentiation, cell cycle, and apoptosis. By analyzing the binding sequences of these genes, we found two highly conserved Bmi-1-binding motifs, which were required for Bmi-1-mediated p16 promoter regulation. Taken together, our results revealed the molecular mechanism of Bmi-1-mediated regulation of the p16 gene, thus providing further insights into the functions of Bmi-1 as well as a sensitive high-throughput platform with which to screen Bmi-1-targeted small molecules for cancer therapy.

  9. CD133 and BMI1 expressions and its prognostic role in primary glioblastoma

    Indian Academy of Sciences (India)

    M. K. Sibin; C. H. Lavanya; Dhananjaya I. Bhat; Narasinga Rao; N. Geethashree; W. Vibhuti; G. K. Chetan

    2015-12-01

    Glioblastoma is the most common malignant brain tumour, generated by bulk of malignant cancer stem cells, which express various stem cell factors like CD133, BMI1 and nestin. There are several studies which show the importance of CD133 in cancer, but the function and interaction with other major oncogenes and tumour suppressor genes is still not understood. This study aimed to analyse the expression of CD133 mRNA and its correlations with BMI1 protein expression and 53 mutations in newly diagnosed glioblastoma patients and its role in prognosis. Overexpression of 133 mRNA and BMI1 protein was found in 47.6 and 76.2% patients respectively and 53 mutations was seen in 57.1% of patients in our study. There was no correlation among 53 mutations and expressions of 133 and BMI1. We found that high level of BMI1 expression was favourable for the patient survival (P = 0.0075) and high 133 mRNA expression was unfavourable for the patient survival ( = 0.0226). 133 mRNA and BMI1 protein expression could independently predict the glioblastoma patient survival in multivariate analysis. In conclusion, the overexpression of these stem cell markers is a common event in glioblastoma progression and could be used as potential prognostic markers.

  10. The Role of BMI1 in CRPC

    Science.gov (United States)

    2016-10-01

    proteasome inhibitor; NH4Cl and Chloroquine, lysosome inhibitors. MG132 blocked PTC-209 induced AR degradation. (E, F) BMI1 stable knockdown C4-2 and control...performed with indicated antibodies. Knockdown MDM2 blocked BMI1-loss induced AR decrease. 8 Figure 4. BMI1 is enriched to AR target upstream...stimulated genes KLK3 and TMPRSS2, and androgen-repressed genes MET and SI in BMI1- stable knockdown and control shRNA C4-2 cells. (C) Venn diagrams

  11. Bmi-1 absence causes premature brain degeneration.

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    Guangliang Cao

    Full Text Available Bmi-1, a polycomb transcriptional repressor, is implicated in cell cycle regulation and cell senescence. Its absence results in generalized astrogliosis and epilepsy during the postnatal development, but the underlying mechanisms are poorly understood. Here, we demonstrate the occurrence of oxidative stress in the brain of four-week-old Bmi-1 null mice. The mice showed various hallmarks of neurodegeneration including synaptic loss, axonal demyelination, reactive gliosis and brain mitochondrial damage. Moreover, astroglial glutamate transporters and glutamine synthetase decreased in the Bmi-1 null hippocampus, which might contribute to the sporadic epileptic-like seizures in these mice. These results indicate that Bmi-1 is required for maintaining endogenous antioxidant defenses in the brain, and its absence subsequently causes premature brain degeneration.

  12. Nuclear BMI-1 expression in laryngeal carcinoma correlates with lymph node pathological status

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    Allegra Eugenia

    2012-10-01

    Full Text Available Abstract Background The main cause of treatment failure and death in laryngeal squamous cell carcinoma is metastasis to the regional lymph nodes. The current clinical staging criteria fail to differentiate patients with occult metastasis from patients without metastasis. Identifying molecular markers of the disease might improve our understanding of the molecular mechanisms underlying the pathogenesis and development of laryngeal carcinoma and may help improve clinical staging and treatment. Methods Sixty-four previously untreated patients who underwent surgical excision of laryngeal squamous cell carcinoma with neck dissection were included in this study. The expression of B cell-specific Moloney murine leukemia virus integration site 1 (BMI-1 was examined immunohistochemically on formalin-fixed paraffin-embedded primary tissue specimens. Results Nuclear expression of BMI-1 (nBMI-1 was detected in 32 of the 64 tumors (50%, cytoplasmic expression of BMI-1 (cBMI-1 was detected in 22 (34.4%, and 10 tumors (15.6% showed no BMI-1 immunoreactivity. High nBMI-1 expression levels (≥10 were detected in 28 of the 32 (87.5% nBMI-1-positive patients. Multivariate analysis including age at diagnosis, grade, tumor location, TNM status, and nBMI-1 expression showed that a high nBMI-1 expression level was an independent prognostic factor for lymph node metastasis. Conclusion The expression of BMI-1 in patients with laryngeal carcinoma seems to correlate with lymph node metastasis.

  13. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression.

    Science.gov (United States)

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-10-01

    Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. © 2014 The British Pharmacological Society.

  14. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

    Science.gov (United States)

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-01-01

    Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

  15. Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.

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    Shunsuke Nakamura

    Full Text Available BACKGROUND: The polycomb-group (PcG proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC 1, maintained self-renewing hematopoietic stem cells (HSCs during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FLBmi1. Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FLBmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.

  16. BMI1 attenuates etoposide-induced G2/M checkpoints via reducing ATM activation.

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    Wei, F; Ojo, D; Lin, X; Wong, N; He, L; Yan, J; Xu, S; Major, P; Tang, D

    2015-06-04

    The BMI1 protein contributes to stem cell pluripotency and oncogenesis via multiple functions, including its newly identified role in DNA damage response (DDR). Although evidence clearly demonstrates that BMI1 facilitates the repair of double-stranded breaks via homologous recombination (HR), it remains unclear how BMI1 regulates checkpoint activation during DDR. We report here that BMI1 has a role in G2/M checkpoint activation in response to etoposide (ETOP) treatment. Ectopic expression of BMI1 in MCF7 breast cancer and DU145 prostate cancer cells significantly reduced ETOP-induced G2/M arrest. Conversely, knockdown of BMI1 in both lines enhanced the arrest. Consistent with ETOP-induced activation of the G2/M checkpoints via the ATM pathway, overexpression and knockdown of BMI1, respectively, reduced and enhanced ETOP-induced phosphorylation of ATM at serine 1981 (ATM pS1981). Furthermore, the phosphorylation of ATM targets, including γH2AX, threonine 68 (T68) on CHK2 (CHK2 pT68) and serine 15 (S15) on p53 were decreased in overexpression and increased in knockdown BMI1 cells in response to ETOP. In line with the requirement of NBS1 in ATM activation, we were able to show that BMI1 associates with NBS1 and that this interaction altered the binding of NBS1 with ATM. BMI1 consists of a ring finger (RF), helix-turn-helix-turn-helix-turn (HT), proline/serine (PS) domain and two nuclear localization signals (NLS). Although deletion of either RF or HT did not affect the association of BMI1 with NBS1, the individual deletions of PS and one NLS (KRMK) robustly reduced the interaction. Stable expression of these BMI1 mutants decreased ETOP-induced ATM pS1981 and CHK2 pT68, but not ETOP-elicited γH2AX in MCF7 cells. Furthermore, ectopic expression of BMI1 in non-transformed breast epithelial MCF10A cells also compromised ETOP-initiated ATM pS1981 and γH2AX. Taken together, we provide compelling evidence that BMI1 decreases ETOP-induced G2/M checkpoint activation via

  17. Analysis list: BMI1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available BMI1 Blood,Digestive tract,Neural,Prostate + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BMI...1.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/BMI1.5.tsv http://db...archive.biosciencedbc.jp/kyushu-u/hg19/target/BMI1.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BMI...1.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BMI1.Diges...tive_tract.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/BMI1.Neural.tsv,http://dbarchive.bioscie

  18. Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer.

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    Enfeng Wang

    Full Text Available Undoubtedly ovarian cancer is a vexing, incurable disease for patients with recurrent cancer and therapeutic options are limited. Although the polycomb group gene, Bmi-1 that regulates the self-renewal of normal stem and progenitor cells has been implicated in the pathogenesis of many human malignancies, yet a role for Bmi-1 in influencing chemotherapy response has not been addressed before. Here we demonstrate that silencing Bmi-1 reduces intracellular GSH levels and thereby sensitizes chemoresistant ovarian cancer cells to chemotherapeutics such as cisplatin. By exacerbating ROS production in response to cisplatin, Bmi-1 silencing activates the DNA damage response pathway, caspases and cleaves PARP resulting in the induction apoptosis in ovarian cancer cells. In an in vivo orthotopic mouse model of chemoresistant ovarian cancer, knockdown of Bmi-1 by nanoliposomal delivery significantly inhibits tumor growth. While cisplatin monotherapy was inactive, combination of Bmi-1 silencing along with cisplatin almost completely abrogated ovarian tumor growth. Collectively these findings establish Bmi-1 as an important new target for therapy in chemoresistant ovarian cancer.

  19. Bmi1 overexpression in the cerebellar granule cell lineage of mice affects cell proliferation and survival without initiating medulloblastoma formation

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    Hourinaz Behesti

    2013-01-01

    BMI1 is a potent inducer of neural stem cell self-renewal and neural progenitor cell proliferation during development and in adult tissue homeostasis. It is overexpressed in numerous human cancers – including medulloblastomas, in which its functional role is unclear. We generated transgenic mouse lines with targeted overexpression of Bmi1 in the cerebellar granule cell lineage, a cell type that has been shown to act as a cell of origin for medulloblastomas. Overexpression of Bmi1 in granule cell progenitors (GCPs led to a decrease in cerebellar size due to decreased GCP proliferation and repression of the expression of cyclin genes, whereas Bmi1 overexpression in postmitotic granule cells improved cell survival in response to stress by altering the expression of genes in the mitochondrial cell death pathway and of Myc and Lef-1. Although no medulloblastomas developed in ageing cohorts of transgenic mice, crosses with Trp53−/− mice resulted in a low incidence of medulloblastoma formation. Furthermore, analysis of a large collection of primary human medulloblastomas revealed that tumours with a BMI1high TP53low molecular profile are significantly enriched in Group 4 human medulloblastomas. Our data suggest that different levels and timing of Bmi1 overexpression yield distinct cellular outcomes within the same cellular lineage. Importantly, Bmi1 overexpression at the GCP stage does not induce tumour formation, suggesting that BMI1 overexpression in GCP-derived human medulloblastomas probably occurs during later stages of oncogenesis and might serve to enhance tumour cell survival.

  20. Bmi-1 Regulates Extensive Erythroid Self-Renewal

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    Ah Ram Kim

    2015-06-01

    Full Text Available Red blood cells (RBCs, responsible for oxygen delivery and carbon dioxide exchange, are essential for our well-being. Alternative RBC sources are needed to meet the increased demand for RBC transfusions projected to occur as our population ages. We previously have discovered that erythroblasts derived from the early mouse embryo can self-renew extensively ex vivo for many months. To better understand the mechanisms regulating extensive erythroid self-renewal, global gene expression data sets from self-renewing and differentiating erythroblasts were analyzed and revealed the differential expression of Bmi-1. Bmi-1 overexpression conferred extensive self-renewal capacity upon adult bone-marrow-derived self-renewing erythroblasts, which normally have limited proliferative potential. Importantly, Bmi-1 transduction did not interfere with the ability of extensively self-renewing erythroblasts (ESREs to terminally mature either in vitro or in vivo. Bmi-1-induced ESREs can serve to generate in vitro models of erythroid-intrinsic disorders and ultimately may serve as a source of cultured RBCs for transfusion therapy.

  1. Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.

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    Matthias Becker

    Full Text Available BACKGROUND: We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC. Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1. PRINCIPAL FINDINGS: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a and p19(ARF. SIGNIFICANCE: The data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

  2. Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.

    Science.gov (United States)

    López-Arribillaga, Erika; Rodilla, Verónica; Pellegrinet, Luca; Guiu, Jordi; Iglesias, Mar; Roman, Angel Carlos; Gutarra, Susana; González, Susana; Muñoz-Cánoves, Pura; Fernández-Salguero, Pedro; Radtke, Freddy; Bigas, Anna; Espinosa, Lluís

    2015-01-01

    Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal.

  3. Expression and significance of Notch1 and Bmi-1 protein in lung cancer tissue%Notch1和Bmi-1蛋白在肺癌组织中的表达及意义

    Institute of Scientific and Technical Information of China (English)

    蔡华荣; 江跃全

    2016-01-01

    BACKGROUND:Studies have found that Notch pathway and Bmi-1 gene both have the ability to regulate stem cel self-renew. Functional dysfunction of the both may have a great relationship with tumorigenesis. OBJECTIVE:To investigate the expression and clinical significance of Notch1 and Bmi-1 protein in lung tissue. METHODS:Eighty-seven lung cancer tissue samples (lung cancer group) and forty pathologicaly confirmed normal lung tissue samples (normal group) were obtained from related surgeries and included as research objects. The protein expression of Notch1 and Bmi-1 in specimens of these two groups was measured by immunohistochemistry SP method. The relationship between Notch1 and Bmi-1 protein expression and clinicopathological features of lung cancer patients was analyzed. RESULTS AND CONCLUSION: The positive rate of Notch1, Bmi-1 protein expression was respectively 61% and 47%, which was significantly higher in the lung cancer group than that in the normal group (P 0.05);低分化肺癌、发生淋巴结转移、TNM分期Ⅲ-Ⅳ级患者的Notch1、Bmi-1蛋白阳性表达率显著高于高中分化肺癌、无淋巴结转移、TNM分期Ⅰ、Ⅱ级患者(P <0.05)。结果表明Notch1基因和Bmi-1基因可能与肺癌的发生、发展有一定的关系。

  4. Clathrin-independent endocytosis: mechanisms and function

    DEFF Research Database (Denmark)

    Sandvig, Kirsten; Pust, Sascha; Skotland, Tore

    2011-01-01

    a large fraction of the clathrin-independent uptake is dynamin-independent. Today, two decades later, the field has developed considerably. New techniques have enabled a detailed analysis of several clathrin-independent endocytic mechanisms, and caveolae have been found to be mostly stable structures...... having several functions of their own. This article aims at providing a brief update on the importance of clathrin-independent endocytic mechanisms, how the processes are regulated differentially, for instance on the poles of polarized cells, and the challenges in studying them....

  5. File list: Oth.Neu.10.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  6. File list: Oth.Neu.05.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  7. File list: Oth.ALL.10.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  8. File list: Oth.ALL.20.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  9. File list: Oth.Neu.20.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  10. File list: Oth.Kid.50.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  11. File list: Oth.ALL.05.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  12. File list: Oth.Kid.10.BMI1.AllCell [Chip-atlas[Archive

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  13. File list: Oth.Kid.20.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  14. File list: Oth.Neu.50.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  15. File list: Oth.ALL.50.BMI1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

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  16. Expression of Bmi-1 is a prognostic marker in bladder cancer

    Directory of Open Access Journals (Sweden)

    Xu Li-Hua

    2009-02-01

    Full Text Available Abstract Background The molecular mechanisms of the development and progression of bladder cancer are poorly understood. The objective of this study was to analyze the expression of Bmi-1 protein and its clinical significance in human bladder cancer. Methods We examined the expression of Bmi-1 mRNA and Bmi-1 protein by RT-PCR and Western blot, respectively in 14 paired bladder cancers and the adjacent normal tissues. The expression of Bmi-1 protein in 137 specimens of bladder cancer and 30 specimens of adjacent normal bladder tissue was determined by immunohistochemistry. Statistical analyses were applied to test the relationship between expression of Bmi-1, and clinicopathologic features and prognosis. Results Expression of Bmi-1 mRNA and protein was higher in bladder cancers than in the adjacent normal tissues in 14 paired samples (P P P P P > 0.5. In superficial bladder cancers, the expression of Bmi-1 protein in recurrent cases was higher than in recurrence-free cases (62.5% versus 13.7%, P P P > 0.05. Five-year survival in the group with higher Bmi-1 expression was 50.8%, while it was 78.5% in the group with lower Bmi-1 expression (P P Conclusion Expression of Bmi-1 was greater in bladder cancers than in the adjacent normal tissues. The examination of Bmi-1 protein expression is potentially valuable in prognostic evaluation of bladder cancer.

  17. Bmi1 Is Required for Hedgehog Pathway-Driven Medulloblastoma Expansion

    Directory of Open Access Journals (Sweden)

    Lowell Evan Michael

    2008-12-01

    Full Text Available Inappropriate Hedgehog (Hh signaling underlies development of a subset of medulloblastomas, and tumors with elevated HH signaling activity express the stem cell self-renewal gene BMI1. To test whether Bmi1 is required for Hh-driven medulloblastoma development, we varied Bmi1 gene dosage in transgenic mice expressing an oncogenic Hh effector, SmoA1, driven by a glial fibrillary acidic protein (GFAP promoter. Whereas 100% of SmoA1; Bmi1+/+ or SmoA1;Bmi1+/- mice examined between postnatal (P days 14 and 26 had typical medulloblastomas (N = 29, tumors were not detected in any of the SmoA1;Bmi1-/- animals examined (N = 6. Instead, small ectopic collections of cells were present in the region of greatest tumor load in SmoA1 animals, suggesting that medulloblastomas were initiated but failed to undergo expansion into frank tumors. Cells within these Bmi1-/- lesions expressed SmoA1 but were largely nonproliferative, in contrast to cells in Bmi1+/+ tumors (6.2% vs 81.9% PCNA-positive, respectively. Ectopic cells were negative for the progenitor marker nestin, strongly GFAP-positive, and highly apoptotic, relative to Bmi1+/+ tumor cells (29.6% vs 6.3% TUNEL-positive. The alterations in proliferation and apoptosis in SmoA1;Bmi1-/- ectopic cells are associated with reduced levels of Cyclin D1 and elevated expression of cyclin-dependent kinase inhibitor p19Arf, two inversely regulated downstream targets of Bmi1. These data provide the first demonstration that Bmi1 is required for spontaneous de novo development of a solid tumor arising in the brain, suggest a crucial role for Bmi1-dependent, nestin-expressing progenitor cells in medulloblastoma expansion, and implicate Bmi1 as a key factor required for Hh pathway-driven tumorigenesis.

  18. Down-regulation of Bmi-1 by RNA interference in Jurkat cells%RNAi抑制Bmi-1基因表达对Jurkat细胞的影响

    Institute of Scientific and Technical Information of China (English)

    Shangen Zheng; Qibin Jing; Yaqiong Zheng; Yinjuan Ding; Qianchuan Huang; Guoqiang Zhao

    2012-01-01

    Objective: The aim of our study was to investigate the effects of down-regulation Bmi-1 by RNA interference (RNAi) in T Lymphocytic leukemia Jurkat cells. Methods: Two complementary oligonucleotide strands were synthesized based on the siRNA sequence targeting Bmi-1 gene. After annealing, siRNA strands were recombined into the pRNATU6.2 vector, and then DNA sequencing was carried out following transformation and amplification. The recombinant was transfected into Jurkat cells with liposomes. Positive colonies were obtained through G418 selection. The mRNA and protein expressions of Bmi-1 were detected by RT-PCR and Western-blot, respectively. Effects of Bmi-1 silence on cell proliferation, cell cycle and cell aging of Jurkat cells were detected by MTT assay, flow cytometry, colony formation assay and SA-β-Gal staining, respectively. Results: The siRNA recombinant targeting Bmi-1 gene was successfully constructed. All three siRNA recombinants could significantly inhibit the expression of Bmi-1. The siRNA targeting 825nt-843nt (GACCAGACCACTACT GAAT) has the strongest inhibitory effect on Bmi-1 expression, with almost complete inhibition on Bmi-1 mRNA and protein expressions. Compared with the non-transfection group and the empty vector group, growth velocity and colony formation ability were significantly decreased, while the proportion of cells in G1 phase and the percentage of senile cells were significantly increased in highly transfected group (P < 0.05). Conclusion: Down-regulation Bmi-1 by RNA interference (RNAi) could significantly inhibit the growth of Jurkat cells in vitro.

  19. [PRODUCT OF THE BMI1--A KEY COMPONENT OF POLYCOMB--POSITIVELY REGULATES ADIPOCYTE DIFFERENTIATION OF MOUSE MESENCHYMAL STEM CELLS].

    Science.gov (United States)

    Petrov, N S; Vereschagina, N A; Sushilova, E N; Kropotov, A V; Miheeva, N F; Popov, B V

    2016-01-01

    Bmil is a key component of Polycomb (PcG), which in mammals controls the basic functions of mammalian somatic stem cells (SSC) such as self-renewal and differentiation. Bmi1 supports SSC via transcriptional suppression of genes associated with cell cycle and differentiation. The most studied target genes of Bmi1 are the genes of Ink4 locus, CdkI p16(Ink4a) and p1(Arf), suppression of which due to activating mutations of the BMI1 results in formation of cancer stem cells (CSC) and carcinomas in various tissues. In contrast, inactivation of BMI1 results in cell cycle arrest and cell senescence. Although clinical phenomena of hypo- and hyperactivation of BMI1 are well known, its targets and mechanisms of regulation of tissue specific SSC are still obscure. The goal of this study was to evaluate the regulatory role of BMI1 in adipocyte differentiation (AD) of mouse mesenchymal stem cells (MSC). Induction of AD in mouse MSC of the C3H10T1/2 cell line was associated with an increase in the expression levels of BMI1, the genes of pRb family (RB, p130) and demethylase UTX, but not methyltransferase EZH2, whose products regulate the methylation levels of H3K27. It was observed earlier that H3K27me3 may play the role of the epigenetic switch by promoting AD of human MSC via activating expression of the PPARγ2, the master gene of AD (Hemming et al., 2014). Here we show that inactivation of BMI1 using specific siRNA slows and decreases the levels of AD, but does not abolish it. This is associated with a complete inhibition of the expression of adipogenic marker genes--PPARγ2, ADIPOQ and a decrease in the expression of RB, p130, but not UTX. The results obtained give evidence that the epigenetic mechanism regulating AD differentiation in mouse and human MSC is different.

  20. MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1.

    Science.gov (United States)

    Wang, Ting; Chen, Tengfei; Niu, Hua; Li, Chang; Xu, Chun; Li, Yuanyuan; Huang, Rui; Zhao, Jun; Wu, Shuyan

    2015-07-01

    MicroRNAs (miRNAs or miRs) play a pivotal role in esophageal carcinogenesis either as oncogenes or as tumor suppressor genes. In the present study, we found that the expression level of miR-218 was significantly reduced in esophageal squamous cell carcinoma (ESCC) tissues and ESCC cell lines. Moreover, its expression was found to correlate with the clinicopathological stage of ESCC; miR-218 expression was lower in the stage III tissue samples than in the stage I and II tissue samples. Furthermore, the decreased expression of miR-218 was found to be associated with an enhanced ESCC cell proliferation and metastasis. Western blot analysis and luciferase reporter assay revealed that miR-218 decreased BMI1 expression by binding to the putative binding sites in its 3'-untranslated region (3'-UTR). The BMI1 mRNA expression levels were markedly increased and negatively correlated with the miR-218 expression level in the ESCC tissues. Functional analyses revealed that the restoration of miR-218 expression inhibited ESCC cell proliferation, migration and invasion and promoted apoptosis. The knockdown of BMI1 by siRNA showed the same phenocopy as the effect of miR-218 on ESCC cells, indicating that BMI1 was a major target of miR-218. In the present study, our findings confirm miR-218 as a tumor suppressor and identify BMI1 as a novel target of miR-218 in ESCC. Therefore, miR-218 may prove to be a useful biomarker for monitoring the initiation and development of ESCC, and may thus be an effective therapeutic target in ESCC.

  1. Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.

    Science.gov (United States)

    Baxter, Patricia A; Lin, Qi; Mao, Hua; Kogiso, Mari; Zhao, Xiumei; Liu, Zhigang; Huang, Yulun; Voicu, Horatiu; Gurusiddappa, Sivashankarappa; Su, Jack M; Adesina, Adekunle M; Perlaky, Laszlo; Dauser, Robert C; Leung, Hon-chiu Eastwood; Muraszko, Karin M; Heth, Jason A; Fan, Xing; Lau, Ching C; Man, Tsz-Kwong; Chintagumpala, Murali; Li, Xiao-Nan

    2014-01-01

    Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.

  2. Bmi-1, a polycomb Group Protein, Plays an Essential Role in tumorigenesis and Metastasis

    Institute of Scientific and Technical Information of China (English)

    Libing SONG; Jun LI; Wenting LIAO; Yan FENG; Wanli LIU; Yixin ZENG; Musheng ZENG

    2009-01-01

    @@ Dysregulation of polycomb group protein Bmi-1 expression has been linked with an invasive phenotype of certain human cancers and poor prog-nosis of patients; however, the underlying mechanisms are poorly under-stood. Here, we demonstrate that Bmi-1 expression is inversely correlated with E-cadherin expression in various cancers.

  3. Correlation of Bmi-1 expression and telomerase activity in human ovarian cancer

    NARCIS (Netherlands)

    Zhang, F. B.; Sui, L. H.; Xin, T.

    2008-01-01

    This study investigates the correlation between the oncoprotein Bmi-1 and telomerase activity in ovarian cancer. A real-time polymerase chain reaction (PCR) method is used to detect the messenger RNA (mRNA) expression of Bmi-1 protein in 47 ovarian epithelial cancer cases, and immunohistochemistry i

  4. The Role of Polycomb Group Gene BMI-1 in the Development of Prostate Cancer

    Science.gov (United States)

    2013-07-01

    hepatic stem/progenitor cells [26]. Zhang et al. [23] observed that ovarian CSCs exhibit higher BMI1 levels than differenti- ated tumor cells. BMI1...b) ATP-binding cassette ( ABC ) multidrug resistance, (c) quiescence, and (d) upregula- tion of antiapoptotic genes [45]. Emerging evidences support

  5. Correlation of Bmi-1 expression and telomerase activity in human ovarian cancer

    NARCIS (Netherlands)

    Zhang, F. B.; Sui, L. H.; Xin, T.

    2008-01-01

    This study investigates the correlation between the oncoprotein Bmi-1 and telomerase activity in ovarian cancer. A real-time polymerase chain reaction (PCR) method is used to detect the messenger RNA (mRNA) expression of Bmi-1 protein in 47 ovarian epithelial cancer cases, and immunohistochemistry i

  6. J domain independent functions of J proteins.

    Science.gov (United States)

    Ajit Tamadaddi, Chetana; Sahi, Chandan

    2016-07-01

    Heat shock proteins of 40 kDa (Hsp40s), also called J proteins, are obligate partners of Hsp70s. Via their highly conserved and functionally critical J domain, J proteins interact and modulate the activity of their Hsp70 partners. Mutations in the critical residues in the J domain often result in the null phenotype for the J protein in question. However, as more J proteins have been characterized, it is becoming increasingly clear that a significant number of J proteins do not "completely" rely on their J domains to carry out their cellular functions, as previously thought. In some cases, regions outside the highly conserved J domain have become more important making the J domain dispensable for some, if not for all functions of a J protein. This has profound effects on the evolution of such J proteins. Here we present selected examples of J proteins that perform J domain independent functions and discuss this in the context of evolution of J proteins with dispensable J domains and J-like proteins in eukaryotes.

  7. Overexpression of AtBMI1C, a polycomb group protein gene, accelerates flowering in Arabidopsis.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Polycomb group protein (PcG-mediated gene silencing is emerging as an essential developmental regulatory mechanism in eukaryotic organisms. PcGs inactivate or maintain the silenced state of their target chromatin by forming complexes, including Polycomb Repressive Complex 1 (PRC1 and 2 (PRC2. Three PRC2 complexes have been identified and characterized in Arabidopsis; of these, the EMF and VRN complexes suppress flowering by catalyzing the trimethylation of lysine 27 on histone H3 of FLOWER LOCUS T (FT and FLOWER LOCUS C (FLC. However, little is known about the role of PRC1 in regulating the floral transition, although AtRING1A, AtRING1B, AtBMI1A, and AtBMI1B are believed to regulate shoot apical meristem and embryonic development as components of PRC1. Moreover, among the five RING finger PcGs in the Arabidopsis genome, four have been characterized. Here, we report that the fifth, AtBMI1C, is a novel, ubiquitously expressed nuclear PcG protein and part of PRC1, which is evolutionarily conserved with Psc and BMI1. Overexpression of AtBMI1C caused increased H2A monoubiquitination and flowering defects in Arabidopsis. Both the suppression of FLC and activation of FT were observed in AtBMI1C-overexpressing lines, resulting in early flowering. No change in the H3K27me3 level in FLC chromatin was detected in an AtBMI1C-overexpressing line. Our results suggest that AtBMI1C participates in flowering time control by regulating the expression of FLC; moreover, the repression of FLC by AtBMI1C is not due to the activity of PRC2. Instead, it is likely the result of PRC1 activity, into which AtBMI1C is integrated.

  8. Delta-like 4 differentially regulates murine CD4 T cell expansion via BMI1.

    Directory of Open Access Journals (Sweden)

    Matthew A Schaller

    Full Text Available BACKGROUND: Studies have shown that Notch is essential for the maintenance of a T cell Th2 phenotype in vivo. It has also been shown that Notch ligands have diverse functions during T cell activation. We chose to investigate the role of Notch ligands during the Th2 response. PRINCIPAL FINDINGS: We studied the relationship of two Notch ligands, delta-like 4 and jagged-1, to T cell proliferation in C57 Bl/6 mice. Our findings indicate that jagged-1 does not affect the rate of T cell proliferation in any subset examined. However, delta-like 4 causes an increase in the expansion of Th2 memory cells and a decrease in effector cell proliferation. Our in vivo studies indicate that the Notch system is dynamically regulated, and that blocking one Notch ligand increases the effective concentration of other Notch ligands, thus altering the response. Examination of genes related to the Notch pathway revealed that the Notch receptors were increased in memory T cells. Expression of BMI1, a gene involved in T cell proliferation, was also higher in memory T cells. Further experiments demonstrated that Notch directly regulates the expression of the BMI1 gene in T cells and may govern T cell proliferation through this pathway. CONCLUSIONS: From these experiments we can make several novel conclusions about the role of Notch ligands in T cell biology. The first is that delta-like 4 suppresses effector cell proliferation and enhances Th2 memory cell proliferation. The second is that blocking one Notch ligand in vivo effectively increases the concentration of other Notch ligands, which can then alter the response.

  9. The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival.

    Science.gov (United States)

    Balasubramanian, Sivaprakasam; Adhikary, Gautam; Eckert, Richard L

    2010-03-01

    The polycomb group (PcG) proteins are epigenetic regulators of gene expression that enhance cell survival. This regulation is achieved via action of two multiprotein PcG complexes--PRC2 (EED) and PRC1 [B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1)]. These complexes modulate gene expression by increasing histone methylation and reducing acetylation--leading to a closed chromatin conformation. Activity of these proteins is associated with increased cell proliferation and survival. We show increased expression of key PcG proteins in immortalized keratinocytes and skin cancer cell lines. We examine the role of two key PcG proteins, Bmi-1 and enhancer of zeste homolog 2 (Ezh2), and the impact of the active agent in green tea, (-)-epigallocatechin-3-gallate (EGCG), on the function of these regulators. EGCG treatment of SCC-13 cells reduces Bmi-1 and Ezh2 level and this is associated with reduced cell survival. The reduction in survival is associated with a global reduction in histone H3 lysine 27 trimethylation, a hallmark of PRC2 complex action. This change in PcG protein expression is associated with reduced expression of key proteins that enhance progression through the cell cycle [cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin D1, cyclin E, cyclin A and cyclin B1] and increased expression of proteins that inhibit cell cycle progression (p21 and p27). Apoptosis is also enhanced, as evidenced by increased caspase 9, 8 and 3 cleavage and increased poly(adenosine diphosphate ribose) polymerase cleavage. EGCG treatment also increases Bax and suppresses Bcl-xL expression. Vector-mediated enhanced Bmi-1 expression reverses these EGCG-dependent changes. These findings suggest that green tea polyphenols reduce skin tumor cell survival by influencing PcG-mediated epigenetic regulatory mechanisms.

  10. Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    Science.gov (United States)

    2015-10-01

    identified BMI-1 as a member of the polycomb family of chromatin remodeling complexes that act as transcriptional repressors for epigenetic chromatin ...a combined immunophenotypic and time-of- adherence assay to identify human prostate TICs with increased BMI-1 expression. Our goal is to identify and...emerging. There is a dire need for therapies that are safe, efficacious, and cost- effective for treating CRPC, and can be used in early disease to

  11. The Prognostic Value of Polycomb Group Protein BMI1 in Stage II Colon Cancer Patients

    DEFF Research Database (Denmark)

    Espersen, Maiken Lise Marcker; Linnemann, Dorte; Christensen, Ib J.;

    2016-01-01

    The aim of this study was to investigate the prognostic value of B-cell-specific moloney murine leukemia virus insertion site 1 (BMI1) protein expression in primary tumors of stage II colon cancer patients. BMI1 protein expression was assessed by immunohistochemistry in a retrospective patient...... cohort consisting of 144 stage II colon cancer patients. BMI1 expression at the invasive front of the primary tumors correlated with mismatch repair status of the tumors. Furthermore, BMI1 expression at the luminal surface correlated with T-stage, tumor location, and the histological subtypes....... Likewise, there was no association between 5-year overall survival and BMI1 expression at the invasive front (HR: 1.12; 95% CI 0.80-1.56; p = 0.46) or at the luminal surface of the tumor (HR: 1.16; 95% CI 0.86-1.60; p = 0.33). In conclusion, BMI1 expression in primary tumors of stage II colon cancer...

  12. Functional Independence Measure Penderita Cedera Servikal

    Directory of Open Access Journals (Sweden)

    Muhammad Zafrullah Arifin

    2013-09-01

    Full Text Available Cervical spine injury is one of the most common spinal cord injuries in trauma patients. From 100,000 spinal cord injury cases reported in the United States of America (2008, 2/3 involved cervical spine injury. American Spinal Cord Injury Association (ASIA Impairment Score is used as an initial assessment but further prognostic outcome of these patients is often not paid enough attention. The objective of this study was to find the value of functional independence measure (FIM cervical spine injury patients with conservative management and correlation with age, sex, type of trauma, onset of trauma, cervical bone abnormalities, type of spinal lesion and ASIA Impairment Score. A prospective cohort study was performed to all patients with cervical spine injury which fullfil the inclusion criteria treated in Neurosurgery Department of Dr. Hasan Sadikin Hospital Bandung. The subjects were classified based on age, sex, single/multiple trauma, acute/chronic, cervical bone abnormalities, complete/incomplete lesion, ASIA impairment score and initial complication. The patients were performed to FIM examination in Outpatient clinic of Neurosurgery. T-test and chi-square test with p<0.05 were done to analyze the data. There were 17 cervical spine injury patients treated in Neurosurgery Department of Dr. Hasan Sadikin Hospital Bandung during April 2009–April 2010. The average FIM value of cervical spine injury in those patients was 4+1.63 by cohort prospective study. There were no correlation between FIM value with age (p=0.064, sex (p=0.144, type of trauma (p=0.959, onset of trauma (p=0.220 and cervical bone abnormalities (p=0.869. We found a significant correlation between FIM value with type of cervical spine lesion (p=0.037 and ASIA Impairment Score (p<0.001 in cervical spine patients. In conclusion, type of cervical spine lesion and ASIA impairment score have significant correlation with FIM value of patients in 3 months after cervical injury.

  13. Melanoma biomolecules: independently identified but functionally intertwined.

    Science.gov (United States)

    Dye, Danielle E; Medic, Sandra; Ziman, Mel; Coombe, Deirdre R

    2013-09-24

    The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (CSPG4), and paired box 3 (PAX3). The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology.

  14. Melanoma biomolecules: independently identified but functionally intertwined

    Directory of Open Access Journals (Sweden)

    Danielle Erin Dye

    2013-09-01

    Full Text Available The majority of patients diagnosed with melanoma present with thin lesions and generally these patients have a good prognosis. However, 5% of patients with early melanoma (< 1mm thick will have recurrence and die within 10 years, despite no evidence of local or metastatic spread at the time of diagnosis. Thus, there is a need for additional prognostic markers to help identify those patients that may be at risk of recurrent disease. Many studies and several meta-analyses have compared gene and protein expression in melanocytes, naevi, primary and metastatic melanoma in an attempt to find informative prognostic markers for these patients. However, although a large number of putative biomarkers have been described, few of these molecules are informative when used in isolation. The best approach is likely to involve a combination of molecules. We believe one approach could be to analyze the expression of a group of interacting proteins that regulate different aspects of the metastatic pathway. This is because a primary lesion expressing proteins involved in multiple stages of metastasis may be more likely to lead to secondary disease than one that does not. This review focuses on five putative biomarkers - melanoma cell adhesion molecule (MCAM, galectin-3 (gal-3, matrix metalloproteinase 2 (MMP-2, chondroitin sulfate proteoglycan 4 (CSPG4 and paired box 3 (PAX3. The goal is to provide context around what is known about the contribution of these biomarkers to melanoma biology and metastasis. Although each of these molecules have been independently identified as likely biomarkers, it is clear from our analyses that each are closely linked with each other, with intertwined roles in melanoma biology.

  15. On K-wise Independent Distributions and Boolean Functions

    CERN Document Server

    Benjamini, Itai; Peled, Ron

    2012-01-01

    We pursue a systematic study of the following problem. Let f:{0,1}^n -> {0,1} be a (usually monotone) Boolean function whose behaviour is well understood when the input bits are identically independently distributed. What can be said about the behaviour of the function when the input bits are not completely independent, but only k-wise independent, i.e. every subset of k bits is independent? more precisely, how high should k be so that any k-wise independent distribution "fools" the function, i.e. causes it to behave nearly the same as when the bits are completely independent? We analyze several well known Boolean functions (including AND, Majority, Tribes and Percolation among others), some of which turn out to have surprising properties. In some of our results we use tools from the theory of the classical moment problem, seemingly for the first time in this subject, to shed light on these questions.

  16. Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence.

    Science.gov (United States)

    Gonzalez-Valdes, I; Hidalgo, I; Bujarrabal, A; Lara-Pezzi, E; Padron-Barthe, L; Garcia-Pavia, P; Gómez-del Arco, P; Gomez, P; Redondo, J M; Ruiz-Cabello, J M; Jimenez-Borreguero, L J; Enriquez, J A; de la Pompa, J L; Hidalgo, A; Gonzalez, S

    2015-03-09

    Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16(INK4a) derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16(INK4a) levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

  17. Therapeutic Role of Bmi-1 Inhibitors in Eliminating Prostate Tumor Stem Cells

    Science.gov (United States)

    2013-10-01

    chromatin remodeling complexes that act as transcriptional repressors for epigenetic chromatin modification. BMI-1 encodes a zinc finger protein...Acad Sci USA 2000;97(15):8346–8351. 34. Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin- Castillo B, Menendez JA. The anti- diabetic drug

  18. Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.

    Science.gov (United States)

    Shahi, M H; Farheen, S; Mariyath, M P M; Castresana, J S

    2016-11-01

    Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

  19. The Role of Polycomb Group Gene Bmi-1 in the Development of Prostate Cancer

    Science.gov (United States)

    2011-09-01

    cultured in appropriate media and were kept in a humidified atmosphere of 95% air and 5% CO2 in an incubator at 37 oC. Plasmids and siRNA: The pbabe-Bmi-1...15;62(16):4736-45. 25. Rodriguez- Puebla ML, Robles AI, Conti CJ. ras activity and cyclin D1 expression: an essential mechanism of mouse skin

  20. Method of synchronizing independent functional unit

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Changhoan

    2017-05-16

    A system for synchronizing parallel processing of a plurality of functional processing units (FPU), a first FPU and a first program counter to control timing of a first stream of program instructions issued to the first FPU by advancement of the first program counter; a second FPU and a second program counter to control timing of a second stream of program instructions issued to the second FPU by advancement of the second program counter, the first FPU is in communication with a second FPU to synchronize the issuance of a first stream of program instructions to the second stream of program instructions and the second FPU is in communication with the first FPU to synchronize the issuance of the second stream program instructions to the first stream of program instructions.

  1. Method of synchronizing independent functional unit

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Changhoan

    2017-02-14

    A system for synchronizing parallel processing of a plurality of functional processing units (FPU), a first FPU and a first program counter to control timing of a first stream of program instructions issued to the first FPU by advancement of the first program counter; a second FPU and a second program counter to control timing of a second stream of program instructions issued to the second FPU by advancement of the second program counter, the first FPU is in communication with a second FPU to synchronize the issuance of a first stream of program instructions to the second stream of program instructions and the second FPU is in communication with the first FPU to synchronize the issuance of the second stream program instructions to the first stream of program instructions.

  2. miR-203 inhibits melanoma invasive and proliferative abilities by targeting the polycomb group gene BMI1

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Xiao [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Sun, Yong [Department of Burn and Plastic Surgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an 223300 (China); Han, Siqi [Department of Medical Oncology, Jinling Hospital, Nanjing 210002 (China); Zhu, Wei [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Zhang, Haiping, E-mail: zhanghaiping_2000@163.com [Department of Dermatology and Venereal Disease, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Lian, Shi, E-mail: lianshi_2020@163.com [Department of Dermatology and Venereal Disease, Capital Medical University, Beijing 100069 (China)

    2015-01-02

    Highlights: • First reported deregulation of miR-203 and up-regulation of BMI1 in metastatic melanoma. • miR-203 decreased BMI1 expression by directly binding to 3′UTR. • Further found miR-203 overexpression suppressed cell invasion and stemness. • Re-expression of BMI1 rescued miR-203-mediated suppression. • miR-203-BMI1 axis may be potential therapeutic targets of melanoma metastasis. - Abstract: Metastasis is the major problem in malignant melanoma, posing a therapeutic challenge to clinicians. The investigation of the underlying mechanism driving this progress remains a large unmet need. In this study, we revealed a miR-203-BMI1 axis that regulated melanoma metastasis. We found significantly deregulation of miR-203 and up-regulation of BMI1 in melanoma, particularly in metastatic melanoma. An inverse correlation between the levels of miR-203 and BMI1 was further observed in melanoma tissues and cell lines. We also identified BMI1 as a downstream target gene of miR-203, which bound to the 3′UTR of BMI1. Overexpression of miR-203 was associated with decreased BMI1 expression and impaired cell invasion and tumor sphere formation activities. Re-expression of BMI1 markedly rescued miR-203-mediated suppression of these events. Taken together, our results demonstrated that miR-203 regulated melanoma invasive and proliferative abilities in part by targeting BMI1, providing new insights into potential mechanisms of melanoma metastasis.

  3. Bmi1 promotes prostate tumorigenesis via inhibiting p16 and p14 expression

    OpenAIRE

    Fan, Catherine; He, Lizhi; Kapoor, Anil; Gillis, Aubrey; Rybak, Adrian P.; Cutz, Jean-Claude; Tang, Damu

    2008-01-01

    Bmi1 promotes prostate tumorigenesis via inhibiting p16INK4A and p14ARF expression correspondence: Corresponding authors. Anil Kapoor is to be contacted at Tel.: +1 (905) 522 1155, ext. 33218; fax: +1 (905) 521 6195. Damu Tang, T3310, St. Joseph?s Hospital, 50 Charlton Ave East, Hamilton, ON, Canada L8N 4A6. Tel.: +1 (905) 522 1155, ext. 35168; fax: +1 (905) 521 6181. (Kapoor, Anil) correspondence: Corresponding authors. Anil Ka...

  4. The Role of Polycomb Group Gene BMI1 in the Development of Prostate Cancer

    Science.gov (United States)

    2014-03-01

    crystal violet/ methanol for 2 h and colonies were counted in two colony grids using a microscope. Immunohistochemistry. Briefly, paraffin embedded...hematoxylin. The stained slides were dehydrated and mounted in permount solution. Western blot Analysis. Briefly, cell lysates were prepared by...BMI1 abolishes cell cycle check points p16/p14 in various cell types (which exhibit dif- ferent rates of growth/cell cycle kinetics ) [7]. We

  5. Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer

    Directory of Open Access Journals (Sweden)

    Kung Hsiang-Fu

    2011-01-01

    Full Text Available Abstract Background B-lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1 acts as an oncogene in various tumors, and its overexpression correlates with a poor outcome in several human cancers. Ectopic expression of Bmi-1 can induce epithelial-mesenchymal transition (EMT and enhance the motility and invasiveness of human nasopharyngeal epithelial cells (NPECs, whereas silencing endogenous Bmi-1 expression can reverse EMT and reduce the metastatic potential of nasopharyngeal cancer cells (NPCs. Mouse xenograft studies indicate that coexpression of Bmi-1 and H-Ras in breast cancer cells can induce an aggressive and metastatic phenotype with an unusual occurrence of brain metastasis; although, Bmi-1 overexpression did not result in oncogenic transformation of MCF-10A cells. However, the underlying molecular mechanism of Bmi-1-mediated progression and the metastasis of breast cancer are not fully elucidated at this time. Results Bmi-1 expression is more pronouncedly increased in primary cancer tissues compared to matched adjacent non-cancerous tissues. High Bmi-1 expression is correlated with advanced clinicopathologic classifications (T, N, and M and clinical stages. Furthermore, a high level of Bmi-1 indicates an unfavorable overall survival and serves as a high risk marker for breast cancer. In addition, inverse transcriptional expression levels of Bmi-1 and E-cadherin are detected between the primary cancer tissues and the matched adjacent non-cancerous tissues. Higher Bmi-1 levels are found in the cancer tissue, whereas the paired adjacent non-cancer tissue shows higher E-cadherin levels. Overexpression of Bmi-1 increases the motility and invasive properties of immortalized human mammary epithelial cells, which is concurrent with the increased expression of mesenchymal markers, the decreased expression of epithelial markers, the stabilization of Snail and the dysregulation of the Akt/GSK3β pathway. Consistent with these

  6. Contributory factors for the functional independence of oldest old

    Directory of Open Access Journals (Sweden)

    Dâmarys Kohlbeck de Melo Neu Ribeiro

    2015-02-01

    Full Text Available OBJECTIVE To investigate the socioeconomic and clinical factors that contribute to the functional independence of the oldest old of a community. METHOD Cross-sectional quantitative study whose sample consisted of 214 elderly people registered in Basic Health Units. Data were collected through structured interviews and application of the Functional Independence Measure. We used descriptive statistics, and for association of the variables we used the Student t-test, ANOVA and Tukey's test for multiple comparisons. RESULTS The significant variables that contributed to the functional independence were remaining economically active, practicing physical and leisure activities, having a social life, eating fruits, vegetables and meat. The orientation to conduct these practices reduces the demand for care and help needed in everyday activities. CONCLUSION Maintaining independence is primordial to delay disability and presents itself as an excellent field of work for nursing.

  7. Regulation of the New Arabidopsis Imprinted Gene AtBMI1C Requires the Interplay of Different Epigenetic Mechanisms

    Institute of Scientific and Technical Information of China (English)

    Fabian Bratzel; ChaoYang; Alexandra Ancelova; Gema López-Torrejón; Marcus Koch; Juan Carlos del Pozo; Myriam Calonje

    2012-01-01

    Recently,it has been shown that plants contain homologs to the animal Polycomb repressive complex 1 (PRC1)components BMI1 and RING1A/B.In Arabidopsis,there are three BMI1-like genes,two of which,AtBMI1A and B,are required during post-embryonic plant growth to repress embryonic traits and allow cell differentiation.However,little is known about the third BMI1-like gene,AtBMI1C.In this work,we show that AtBMI1C is only expressed during endosperm and stamen development.AtBMI1C is an imprinted gene expressed from the maternal allele in the endosperm but biallelically expressed in stamen.We found that the characteristic expression pattern of AtBMI1C is the result of a complex epigenetic regulation that involves CG DNA methylation,RNA-directed non-CG DNA methylation (RdDM),and PcG activity.Our results show the orchestrated interplay of different epigenetic mechanisms in regulating gene expression throughout development,shedding light on the current hypotheses for the origin and mechanism of imprinting in plant endosperm.

  8. Bmi-1 extends the life span of normal human oral keratinocytes by inhibiting the TGF-{beta} signaling

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Reuben H., E-mail: rkim@dentistry.ucla.edu [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Dental Research Institute, Los Angeles, CA 90095 (United States); UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095 (United States); Lieberman, Mark B.; Lee, Rachel [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); Shin, Ki-Hyuk [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Dental Research Institute, Los Angeles, CA 90095 (United States); UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095 (United States); Mehrazarin, Shebli; Oh, Ju-Eun [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); Park, No-Hee [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Dental Research Institute, Los Angeles, CA 90095 (United States); UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095 (United States); David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 (United States); Kang, Mo K., E-mail: mkang@dentistry.ucla.edu [UCLA School of Dentistry, Los Angeles, CA 90095 (United States); UCLA Dental Research Institute, Los Angeles, CA 90095 (United States); UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095 (United States)

    2010-10-01

    We previously demonstrated that Bmi-1 extended the in vitro life span of normal human oral keratinocytes (NHOK). We now report that the prolonged life span of NHOK by Bmi-1 is, in part, due to inhibition of the TGF-{beta} signaling pathway. Serial subculture of NHOK resulted in replicative senescence and terminal differentiation and activation of TGF-{beta} signaling pathway. This was accompanied with enhanced intracellular and secreted TGF-{beta}1 levels, phosphorylation of Smad2/3, and increased expression of p15{sup INK4B} and p57{sup KIP2}. An ectopic expression of Bmi-1 in NHOK (HOK/Bmi-1) decreased the level of intracellular and secreted TGF-{beta}1 induced dephosphorylation of Smad2/3, and diminished the level of p15{sup INK4B} and p57{sup KIP2}. Moreover, Bmi-1 expression led to the inhibition of TGF-{beta}-responsive promoter activity in a dose-specific manner. Knockdown of Bmi-1 in rapidly proliferating HOK/Bmi-1 and cancer cells increased the level of phosphorylated Smad2/3, p15{sup INK4B}, and p57{sup KIP2}. In addition, an exposure of senescent NHOK to TGF-{beta} receptor I kinase inhibitor or anti-TGF-{beta} antibody resulted in enhanced replicative potential of cells. Taken together, these data suggest that Bmi-1 suppresses senescence of cells by inhibiting the TGF-{beta} signaling pathway in NHOK.

  9. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1

    Directory of Open Access Journals (Sweden)

    Sudo Satoko

    2011-08-01

    Full Text Available Abstract Background Epithelial-mesenchymal transition (EMT is the key process driving cancer metastasis. Oncogene/self renewal factor BMI-1 has been shown to induce EMT in cancer cells. Recent studies have implied that noncoding microRNAs (miRNAs act as crucial modulators for EMT. The aims of this study was to determine the roles of BMI-1 in inducing EMT of endometrial cancer (EC cells and the possible role of miRNA in controlling BMI-1 expression. Methods and results We evaluated the expression of BMI-1 gene in a panel of EC cell lines, and detected a strong association with invasive capability. Stable silencing of BMI-1 in invasive mesenchymal-type EC cells up-regulated the epithelial marker E-cadherin, down-regulated mesenchymal marker Vimentin, and significantly reduced cell invasion in vitro. Furthermore, we discovered that the expression of BMI-1 was suppressed by miR-194 via direct binding to the BMI-1 3'-untranslated region 3'-UTR. Ectopic expression of miR-194 in EC cells induced a mesenchymal to epithelial transition (MET by restoring E-cadherin, reducing Vimentin expression, and inhibiting cell invasion in vitro. Moreover, BMI-1 knockdown inhibited in vitro EC cell proliferation and clone growth, correlated with either increased p16 expression or decreased expression of stem cell and chemoresistance markers (SOX-2, KLF4 and MRP-1. Conclusion These findings demonstrate the novel mechanism for BMI-1 in contributing to EC cell invasion and that repression of BMI-1 by miR-194 could have a therapeutic potential to suppress EC metastasis.

  10. Functional independence measure in patients with intermittent claudication

    Directory of Open Access Journals (Sweden)

    Caroline Shihara de Assis

    2015-10-01

    Full Text Available AbstractOBJECTIVEOf this study were to evaluate the functional independence of patients with intermittent claudication and to verify its association with sociodemographic and clinical variables, walking ability and physical activity level.METHODThis was a descriptive, exploratory, cross-sectional study with a quantitative approach. Fifty participants (66.4 years; 68% male were recruited from Claudication Unit of a tertiary hospital. Functional Independence Measure were used to evaluate functional incapacity; the Baltimore Activity Scale, to estimate the physical activity level and the Walking Impairement Questionnaire, the walking ability.RESULTSParticipants had complete functional independence (124.8 + 2.0, low levels of physical activity (4.2 + 2.0, and impairment of walking ability; the worst performance was found in walking velocity domain (21.2 + 16.4. The functional independence score was associated with physical activity (r=0,402 and walking ability scores (distance, r=0,485; speed, r=0,463; stairs, r=0,337.CONCLUSIONIn conclusion, the level of functionality is associated with functional capacity in these patients.

  11. [Functional independence measure in patients with intermittent claudication].

    Science.gov (United States)

    Assis, Caroline Shihara de; Batista, Letícia de Carvalho; Wolosker, Nelson; Zerati, Antonio Eduardo; Silva, Rita de Cassia Gengo E

    2015-10-01

    Of this study were to evaluate the functional independence of patients with intermittent claudication and to verify its association with sociodemographic and clinical variables, walking ability and physical activity level. This was a descriptive, exploratory, cross-sectional study with a quantitative approach. Fifty participants (66.4 years; 68% male) were recruited from Claudication Unit of a tertiary hospital. Functional Independence Measure were used to evaluate functional incapacity; the Baltimore Activity Scale, to estimate the physical activity level and the Walking Impairement Questionnaire, the walking ability. Participants had complete functional independence (124.8 + 2.0), low levels of physical activity (4.2 + 2.0), and impairment of walking ability; the worst performance was found in walking velocity domain (21.2 + 16.4). The functional independence score was associated with physical activity (r=0,402) and walking ability scores (distance, r=0,485; speed, r=0,463; stairs, r=0,337). In conclusion, the level of functionality is associated with functional capacity in these patients.

  12. Cisplatin Induces Bmi-1 and Enhances the Stem Cell Fraction in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    Carolina Nör

    2014-02-01

    Full Text Available Recent evidence has unveiled a subpopulation of highly tumorigenic, multipotent cells capable of self-renewal in head and neck squamous cell carcinomas (HNSCCs. These unique cells, named here cancer stem cells (CSCs, proliferate slowly and might be involved in resistance to conventional chemotherapy. We have shown that CSCs are found in perivascular niches and rely on endothelial cell-secreted factors [particularly interleukin-6 (IL-6] for their survival and self-renewal in HNSCC. Here, we hypothesized that cisplatin enhances the stem cell fraction in HNSCC. To address this hypothesis, we generated xenograft HNSCC tumors with University of Michigan-squamous cell carcinoma 22B (UM-SCC-22B cells and observed that cisplatin treatment increased (P = .0013 the fraction of CSCs [i.e., aldehyde dehydrogenase activity high and cluster of differentiation 44 high (ALDHhighCD44high]. Cisplatin promoted self-renewal and survival of CSCs in vitro, as seen by an increase in the number of orospheres in ultralow attachment plates and induction in B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1 and octamer-binding transcription factor 4 expression. Cisplatin-resistant cells expressed more Bmi-1 than cisplatinsensitive cells. IL-6 potentiated cisplatin-induced orosphere formation generated when primary human HNSCC cells were sorted for ALDHhighCD44high immediately after surgery and plated onto ultralow attachment plates. IL-6-induced signal transducer and activator of transcription 3 (STAT3 phosphorylation (indicative of stemness was unaffected by treatment with cisplatin in UM-SCC-22B cells, whereas IL-6-induced extracellular signal-regulated kinase (ERK phosphorylation (indicative of differentiation processes was partially inhibited by cisplatin. Notably, cisplatin-induced Bmi-1 was inhibited by interleukin-6 receptor blockade in parental and cisplatin-resistant cells. Taken together, these results demonstrate that cisplatin enhances the fraction of CSCs

  13. Bmi-1基因调控造血干细胞自我更新的研究进展%Regulatory Effects of Bmi-1 Gene on Self-renewal of Hematopietic Stem Cells --Review

    Institute of Scientific and Technical Information of China (English)

    龚辉; 张义成; 刘文励

    2006-01-01

    造血干细胞(hematopoietic stem cell,HSC)的自我更新维持每天血细胞数量,Bmi-1基因属Polycomb(PcG)基因家族成员.最近研究表明,Bmi-1在调控正常和白血病干细胞的自我更新中起重要作用,本文就Bmi-1的结构,功能和在造血干细胞的自我更新中的作用作一简要综述.

  14. Nucleosome acidic patch promotes RNF168- and RING1B/BMI1-dependent H2AX and H2A ubiquitination and DNA damage signaling.

    Directory of Open Access Journals (Sweden)

    Justin W Leung

    2014-03-01

    Full Text Available Histone ubiquitinations are critical for the activation of the DNA damage response (DDR. In particular, RNF168 and RING1B/BMI1 function in the DDR by ubiquitinating H2A/H2AX on Lys-13/15 and Lys-118/119, respectively. However, it remains to be defined how the ubiquitin pathway engages chromatin to provide regulation of ubiquitin targeting of specific histone residues. Here we identify the nucleosome acid patch as a critical chromatin mediator of H2A/H2AX ubiquitination (ub. The acidic patch is required for RNF168- and RING1B/BMI1-dependent H2A/H2AXub in vivo. The acidic patch functions within the nucleosome as nucleosomes containing a mutated acidic patch exhibit defective H2A/H2AXub by RNF168 and RING1B/BMI1 in vitro. Furthermore, direct perturbation of the nucleosome acidic patch in vivo by the expression of an engineered acidic patch interacting viral peptide, LANA, results in defective H2AXub and RNF168-dependent DNA damage responses including 53BP1 and BRCA1 recruitment to DNA damage. The acidic patch therefore is a critical nucleosome feature that may serve as a scaffold to integrate multiple ubiquitin signals on chromatin to compose selective ubiquitinations on histones for DNA damage signaling.

  15. RNAi抑制人大肠癌LOVO细胞Bmi-1基因的表达%Effects of RNAi on expression of Bmi-1 gene in human colorectal carcinoma LOVO cells

    Institute of Scientific and Technical Information of China (English)

    卢敏; 沙卫红; 王启仪

    2011-01-01

    目的 探讨RNA干扰(RNAi)技术沉默Bmi-1基因表达对人大肠癌细胞株LOVO增殖和侵袭力的影响及机制.方法 将化学法合成的针对Bmi-1 mRNA不同位点设计的3对siRNA序列(siR-NA1~3)和1对带有荧光标记的FAM-siRNA(siRNA4)转染至人大肠癌LOVO细胞,荧光显微镜下观察siRNA的转染效率,QRT-PCR检测Bmi-1 mRNA表达抑制作用,Western Blot检测Bmi-1蛋白表达变化,MTT法检测LOVO细胞体外增殖变化,小室侵袭实验检测LOVO细胞侵袭能力.结果 利用荧光标记的Oligo观察到siRNA转染效率达70%.siRNA1对mRNA表达抑制率最高,从而筛选出沉默效应最强的siRNA序列为siRNA1.siRNA1转染组LOVO细胞Bmi-1蛋白表达,增殖及侵袭力明显低于阴性对照组和空白对照组(P<0.05).结论 化学合成的靶向Bmi-1 siRNA转染人大肠癌LOVO细胞能有效抑制Bmi-1的mRNA和蛋白质表达水平,Bmi-1基因的RNA干扰可有效抑制人大肠癌LOVO细胞的增殖和侵袭能力.%Objective To investigate the mechanism and effect of small interfering RNA (siRNA) on Bmi-1 in the human colorectal carcinoma LOVO cells. Methods Three si RNA sequences targeting Bmi-1 (siRNAI, siRNA2, siRNA3), a fluorescein-labeled double-stranded RNA (dsRNA) oligomer (siRNA4), and the negative control were chemically synthesized. All siRNA sequences were transinfected into LOVO cells. Inverse microscopy was used to observe the efficacy of transinfecion. Bmi-1 mRNA expression and protein expression were detected by real time quantitative PCR (QRT-PCR) and Western blot, respectively. The proliferation and invasion of LOVO cells were detected by MTT and transwell invasion assay, respectively. Results The efficacy of transfection was 70%. The Bmi-1 mRNA expression inhibition rate of siRNAI was the most effective, and therefore was selected to interfere with the expression of Bmi-1 gene. The Bmi-1 protein expression and cell proliferation and invasion were significantly fewer than that in the

  16. 多梳基因Bmi-1与胃癌关系研究进展%Advances in Studies on Relationship between Polycomb Group Gene Bmi-1 and Gastric Cancer

    Institute of Scientific and Technical Information of China (English)

    刘朋伟

    2011-01-01

    多梳基因(PcG)在胚胎发育、细胞周期调节、造血干细胞更新、肿瘤发生中起重要作用.转录抑制因子Bmi-1是PcG家族成员之一,与多种人类恶性肿瘤的发生、发展有关.最新研究发现Bmi-1高表达与胃癌的发生、发展、浸润、转移、预后等密切相关.本文就Bmi-1的分子结构、作用机制及其与胃癌关系的研究进展作一综述.%Polycomb group gene (PcG) play a crucial role in regulation of embryonic development, cell cycle, selfrenewal of hematopoietic stem cells and tumor genesis. Bmi-1, which is a transcription repressor, is a member of PcG family. It was found to be related with the genesis and development of several human malignancies. Recent studies have shown that overexpression of Bmi-1 was correlated with the genesis, development, invasion, metastasis and prognosis of gastric cancer. This article reviewed the molecular structure and mechanism of action of Bmi-1, and its relationship with gastric cancer.

  17. Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons.

    Directory of Open Access Journals (Sweden)

    Mohamed Abdouh

    Full Text Available Aging increases the risk to develop several neurodegenerative diseases, although the underlying mechanisms are poorly understood. Inactivation of the Polycomb group gene Bmi1 in mice results in growth retardation, cerebellar degeneration, and development of a premature aging-like phenotype. This progeroid phenotype is characterized by formation of lens cataracts, apoptosis of cortical neurons, and increase of reactive oxygen species (ROS concentrations, owing to p53-mediated repression of antioxidant response (AOR genes. Herein we report that Bmi1 expression progressively declines in the neurons of aging mouse and human brains. In old brains, p53 accumulates at the promoter of AOR genes, correlating with a repressed chromatin state, down-regulation of AOR genes, and increased oxidative damages to lipids and DNA. Comparative gene expression analysis further revealed that aging brains display an up-regulation of the senescence-associated genes IL-6, p19(Arf and p16(Ink4a, along with the pro-apoptotic gene Noxa, as seen in Bmi1-null mice. Increasing Bmi1 expression in cortical neurons conferred robust protection against DNA damage-induced cell death or mitochondrial poisoning, and resulted in suppression of ROS through activation of AOR genes. These observations unveil that Bmi1 genetic deficiency recapitulates aspects of physiological brain aging and that Bmi1 over-expression is a potential therapeutic modality against neurodegeneration.

  18. Distribution-Independent Evolvability of Linear Threshold Functions

    CERN Document Server

    Feldman, Vitaly

    2011-01-01

    Valiant's (2007) model of evolvability models the evolutionary process of acquiring useful functionality as a restricted form of learning from random examples. Linear threshold functions and their various subclasses, such as conjunctions and decision lists, play a fundamental role in learning theory and hence their evolvability has been the primary focus of research on Valiant's framework (2007). One of the main open problems regarding the model is whether conjunctions are evolvable distribution-independently (Feldman and Valiant, 2008). We show that the answer is negative. Our proof is based on a new combinatorial parameter of a concept class that lower-bounds the complexity of learning from correlations. We contrast the lower bound with a proof that linear threshold functions having a non-negligible margin on the data points are evolvable distribution-independently via a simple mutation algorithm. Our algorithm relies on a non-linear loss function being used to select the hypotheses instead of 0-1 loss in V...

  19. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.

    Science.gov (United States)

    Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin

    2016-05-25

    The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: (1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) (2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) (3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and (4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1.

  20. BMI1 gene expression and significance in chronic myeloid leukemia%慢性粒细胞白血病BMI1基因表达及意义

    Institute of Scientific and Technical Information of China (English)

    葛熙; 赵枰

    2015-01-01

    Objective:To detect the expressions of BMI1 mRNA in chronic myeloid leukemia(CML)and explore their clinical significance.Methods:Using real-time PCR technique,expression of BMI1 mRNA was detected in 41 CML patients and 10 healthy adults.Results: A positive rate of BMI1 in the patients was 68.3%,significantly higher than that of the controls(P<0.01). BMI1 expression was much higher in accelerated phase and acute transfomation phase than in chronic phase(t=3.421、4.231, P<0.01).Conclusions:The BMI1 gene is closely related to the advancement and prognosis of CML,which is valuable molecular markers to be used for monitoring the disease.%目的:检测慢性粒细胞白血病(CML)病人BMI1 mRNA的表达情况,以探讨其在CML病情进展及预后中的意义。方法:应用定量实时荧光PCR(real-time PCR)技术检测4l例CML病人和10例健康者上述基因的表达。结果:BMI1 mRNA在CML病人的阳性表达率为68.3%,明显高于正常对照组10.0%(P<0.01),在CML的加速期、急变期的表达水平明显高于慢性期(t =3.421、4.231,P<0.01)。结论:BMI1基因与CML的病情进展密切相关,是监测CML病情进展及判断预后的有价值的分子标记物。

  1. Colour-independent partition functions in coloured vertex models

    Energy Technology Data Exchange (ETDEWEB)

    Foda, O., E-mail: omar.foda@unimelb.edu.au [Dept. of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010 (Australia); Wheeler, M., E-mail: mwheeler@lpthe.jussieu.fr [Laboratoire de Physique Théorique et Hautes Energies, CNRS UMR 7589 (France); Université Pierre et Marie Curie – Paris 6, 4 place Jussieu, 75252 Paris cedex 05 (France)

    2013-06-11

    We study lattice configurations related to S{sub n}, the scalar product of an off-shell state and an on-shell state in rational A{sub n} integrable vertex models, n∈{1,2}. The lattice lines are colourless and oriented. The state variables are n conserved colours that flow along the line orientations, but do not necessarily cover every bond in the lattice. Choosing boundary conditions such that the positions where the colours flow into the lattice are fixed, and where they flow out are summed over, we show that the partition functions of these configurations, with these boundary conditions, are n-independent. Our results extend to trigonometric A{sub n} models, and to all n. This n-independence explains, in vertex-model terms, results from recent studies of S{sub 2} (Caetano and Vieira, 2012, [1], Wheeler, (arXiv:1204.2089), [2]). Namely, 1.S{sub 2}, which depends on two sets of Bethe roots, {b_1} and {b_2}, and cannot (as far as we know) be expressed in single determinant form, degenerates in the limit {b_1}→∞, and/or {b_2}→∞, into a product of determinants, 2. Each of the latter determinants is an A{sub 1} vertex-model partition function.

  2. Parathyroid hormone administration improves bone marrow microenvironment and partially rescues haematopoietic defects in Bmi1-null mice.

    Directory of Open Access Journals (Sweden)

    Ruinan Lu

    Full Text Available The epigenetic regulator Bmi1 is key in haematopoietic stem cells, and its inactivation leads to defects in haematopoiesis. Parathyroid hormone (PTH, an important modulator of bone homeostasis, also regulates haematopoiesis, so we asked whether PTH administration improves bone marrow microenvironment and rescues the haematopoietic defects in Bmi1-null mice. The mice were treated with PTH1-34 (containing the first 34 residues of mature PTH, an anabolic drug currently used for treating osteoporosis, and compared with the vehicle-treated Bmi1-/- and wild-type littermates in terms of skeletal and haematopoietic phenotypes. We found that the administration significantly increased all parameters related to osteoblastic bone formation and significantly reduced the adipocyte number and PPARγ expression. The bone marrow cellularity, numbers of haematopoietic progenitors and stem cells in the femur, and numbers of lymphocytes and other white blood cells in the peripheral blood all increased significantly when compared to vehicle-treated Bmi1-/- mice. Moreover, the number of Jagged1-positive cells and percentage of Notch intracellular domain-positive bone marrow cells and protein expression levels of Jagged1 and NICD in bone tissue were also increased in Bmi1-/- mice upon PTH1-34 administration,whereas the up-regulation of PTH on both Notch1 and Jagged1 gene expression was blocked by the Notch inhibitor DAPT administration. These results thus indicate that PTH administration activates the notch pathway and partially rescues haematopoietic defects in Bmi1-null mice, further suggesting that haematopoietic defects in the animals are not only a result of reduced self-renewal of haematopoietic stem cells but also due to impaired bone marrow microenvironment.

  3. Different expression of EZH2, BMI1 and Ki67 in low and high grade neuroendocrine tumors of the lung

    DEFF Research Database (Denmark)

    Bondgaard, Anna-Louise Reinert Ørsum; Poulsen, Thomas Tuxen; Poulsen, Hans Skovgaard

    2012-01-01

    Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated their exp......Enhancer of Zeste Homolog 2 (EZH2) and B lymphoma Mo-MLV Insertion region 1 polycomb ring finger (BMI1) are involved in malignant transformation of many human carcinomas. Still, in neuroendocrine tumors of the lung (NELT) their expression pattern is largely unknown. This study evaluated...

  4. Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment.

    Science.gov (United States)

    Bolomsky, Arnold; Schlangen, Karin; Schreiner, Wolfgang; Zojer, Niklas; Ludwig, Heinz

    2016-03-02

    The polycomb complex protein BMI-1 (BMI-1) is a putative oncogene reported to be overexpressed in multiple myeloma (MM). Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM. BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP) data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose) polymerase (PARP), JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed. We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1) and v-myc avian myelocytomatosis viral oncogene homolog (MYC) expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009) and subsequent downregulation of myeloid cell leukemia 1 (MCL-1) protein levels, which likely mediates the apoptotic effects of PTC-209

  5. Gauge-independent Wigner functions. II. Inclusion of radiation reaction

    Science.gov (United States)

    Javanainen, J.; Varró, S.; Serimaa, O. T.

    1987-04-01

    We investigate the effects of quantized radiation reaction fields on the motion of a charged particle using the gauge-independent Wigner operator (GIWO) and gauge-independent Wigner function (GIWF) introduced earlier [Phys. Rev. A 33, 2913 (1986)]. To complement the equation of motion of the GIWO, the Heisenberg equations of motion of the quantized electromagnetic fields are solved within the Markov approximation. After considering the operator orderings and orders of magnitude of the radiation reaction terms, we eliminate the quantum fields from the evolution equation of the GIWO, and obtain for the GIWF a closed equation containing relaxation terms. As an example of the formalism we derive a Fokker-Planck equation (FPE) for the GIWF of a particle in a constant magnetic field. To the order ħ 0 the classical radiation damping ensues, and the first quantum correction proportional to ħ emerges as diffusion. The diffusion operator turns out to be indefinite and the FPE consequently defies our attempts at a complete analysis, but we demonstrate that at least the coherent states constructed from the Landau levels exhibit a manifestly physical time evolution under the FPE. We point out that the GIWF calculated with quantized electromagnetic fields is divergent even if the fields are in the vacuum state, and suggest that the GIWF should be associated with the particle state by ignoring the quantized fields altogether.

  6. Colour-independent partition functions in coloured vertex models

    CERN Document Server

    Foda, O

    2013-01-01

    We study lattice configurations related to S_n, the scalar product of an off-shell state and an on-shell state in rational A_n integrable vertex models, n = {1, 2}. The lattice lines are colourless and oriented. The state variables are n conserved colours that flow along the line orientations, but do not necessarily cover every bond in the lattice. Choosing boundary conditions such that the positions where the colours flow into the lattice are fixed, and where they flow out are summed over, we show that the partition functions of these configurations, with these boundary conditions, are n-independent. Our results extend to trigonometric A_n models, and to all n. This n-independence explains, in vertex-model terms, results from recent studies of S_2 [1, 2]. Namely, 1. S_2 which depends on two sets of Bethe roots, b_1 and b_2, and cannot (as far as we know) be expressed in single determinant form, degenerates in the limit b_1 -> infinity, and/or b_2 -> infinity, into a product of determinants, 2. Each of the la...

  7. The differential expression pattern of the BMI-1, SALL4 and ABCA3 genes in myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Shen Qi

    2012-10-01

    Full Text Available Abstract Background and methods In order to characterize the expression pattern of SALL4, BMI-1 and ABCA3 genes in patients with myeloid leukemia and those who achieved complete remission (CR after chemotherapy. Real-time PCR was used to determine the expression level of these genes in peripheral blood mononuclear cells from 24 patients with AML, eight patients with AML-CR, 13 patients with CML in the chronic phase (CML-CP, 12 patients with CML in blast crisis (CML-BC, 13 patients with CML-CR and 11 healthy individuals (HI. Results Overexpression of the BMI-1 gene was found in the AML, CML-CP and CML-BC groups as compared with HI group, while the BMI-1 expression level was lower in patients who achieved CR. In contrast, significantly increased SALL4 expression was only found in AML group, additionally, SALL4 expression was lower in the CML-CP and CML-CR groups compared with the HI group, while the SALL4 expression level in the CML-BC group was higher and significantly greater than that in the CML-CP and CML-CR groups. Moreover, a positive correlation between the expression of SALL4 and BMI-1 genes was found in samples from most groups. There was no significant difference of ABCA3 expression level in AML and CML-BC group in comparison with HI group. Interestingly, the ABCA3 expression level was significantly decreased in the CML-CP, AML-CR and CML-CR in comparison with the HI group. Moreover, the ABCA3 expression level in all of the CR groups was lower than that in their corresponding groups. Conclusions These results describe the altered SALL4, ABCA3 and BMI-1 expression pattern in different phases of myeloid leukemia, which may relate to the development and progression to different diseases. SALL4 expression was strongly correlated with BMI-1 in most of the myeloid leukemia patient groups, providing a potential link between SALL4 and BMI-1 in leukemogenesis.

  8. Targeting of BMI-1 with PTC-209 shows potent anti-myeloma activity and impairs the tumour microenvironment

    Directory of Open Access Journals (Sweden)

    Arnold Bolomsky

    2016-03-01

    Full Text Available Abstract Background The polycomb complex protein BMI-1 (BMI-1 is a putative oncogene reported to be overexpressed in multiple myeloma (MM. Silencing of BMI-1 was shown to impair the growth and survival of MM cells. However, therapeutic agents specifically targeting BMI-1 were not available so far. Here, we investigated PTC-209, a novel small molecule inhibitor of BMI-1, for its activity in MM. Methods BMI-1 expression was analysed in human MM cell lines and primary MM cells by using publically available gene expression profiling (GEP data. The anti-MM activity of PTC-209 was investigated by viability testing, cell cycle analysis, annexin V and 7-AAD staining, quantification of cleaved poly(ADP-ribose polymerase (PARP, JC-1 as well as colony formation assays. Deregulation of central myeloma growth and survival genes was studied by quantitative PCR and flow cytometry, respectively. In addition, the impact of PTC-209 on in vitro osteoclast, osteoblast and tube formation was analysed. Results We confirmed overexpression of BMI-1 in MM patients by using publically available GEP datasets. Of note, BMI-1 expression was further increased at relapse which translated into significantly shorter overall survival in relapsed/refractory patients treated with bortezomib or dexamethasone. Treatment with PTC-209 significantly decreased viable cell numbers in human MM cell lines, induced a G1 cell cycle arrest, promoted apoptosis and demonstrated synergistic activity with pomalidomide and carfilzomib. The anti-MM activity of PTC-209 was accompanied by a significant decrease of cyclin D1 (CCND1 and v-myc avian myelocytomatosis viral oncogene homolog (MYC expression as well as upregulation of cyclin-dependent kinase inhibitor 1A (CDKN1A and cyclin-dependent kinase inhibitor 1B (CDKN1B. We also observed upregulation of NOXA (up to 3.6 ± 1.2-fold induction, P = 0.009 and subsequent downregulation of myeloid cell leukemia 1 (MCL-1 protein levels, which likely

  9. Bmi-1和EZH2基因在皮肤血管瘤组织中的表达及意义%Expression and signifieance of Bmi-1 and EZH2 in Human Dermal Hemangiomas

    Institute of Scientific and Technical Information of China (English)

    刘涓; 王赟; 张端莲

    2012-01-01

    Objective To investigate the effect of Bmi-1 and EZH2 in human dermalhemangioma. Methods Specimens from 40 cases (15 males and 25 females) of hemangioma were collected from the Department of Pathology in Renmin Hospital of Wuhan University from 2008 to 2011. We examined the expression of Bmi-1 and EZH2 in proliferative, involuting hemangioma and normal skin tissues by using im-munohistochemical technique. Average optical density and positive area rates of expression of Bmi-1 and EZH2 were measured by image analysis (HPIAS-1000). Results 1. Bmi-1 expression was significantly higher in the proliferative phase of angioma in endothelial cells than in involuting hemangioma and normal skin (P0. 05). 2. EZH2 expression was significantly higher in the proliferative phase of angioma in endothelial cells than in involuting hemangioma and normal skin (P0. 05). Conclusion Bmi-1 and EZH2 expressions high in proliferating hemangioma, indicating that both Bmi-1 and EZH2 are engaged in the occurrence and development of hemangioma.%目的 探讨Bmi-1和EZH2基因在血管瘤组织中的表达及其意义.方法 收集武汉大学人民医院病理科2008年-2011年皮肤毛细血管瘤存档蜡块40例,其中男性15例,女性25例.采用免疫组织化学SP法检测40例皮肤血管瘤增生期、退化期及正常皮肤组织Bmi-1和EZH2基因表达水平,采用HPIAS 1000图文报告管理系统对Bmi-1和EZH2基因的表达进行定量分析,并用SPSS11.5软件对各组免疫组织化学反应阳性颗粒的平均光密度、阳性面积率做单因素方差分析和SNK(q)检验.结果 (1)Bmi-1的表达增生期血管瘤血管内皮细胞中可见密集分布的棕黄色颗粒,Bmi-1呈高表达,正常皮肤组及退化组血管内皮细胞中可见少量的棕黄色颗粒,Bmi-1呈低表达.增生期组Bmi-1的表达明显高于退化期组和正常皮肤组(P<0.05),而后两组比较差异无统计学意义(P>0.05).(2)EZH2的表达 增生期血管瘤血管内皮细胞中

  10. The novel expression of Oct3/4 and Bmi1 in the root development of mouse molars.

    Science.gov (United States)

    Nakagawa, Eizo; Zhang, Li; Shin, Jeong-Oh; Kim, Eun-Jung; Cho, Sung-Won; Ohshima, Hayato; Chen, Zhi; Jung, Han-Sung

    2012-02-01

    The root apex of the tooth elongates until the completion of root development. Although the signaling molecules inducing root elongation have been studied, the characteristic of the cells having the ability to maintain the root elongation remains unclear. This study aimed to investigate the characteristics of the cells involved in the root elongation. Octamer-binding factor 3/4 (Oct3/4) is known as one of the key regulators in maintaining the pluripotency and self-renewal properties of embryonic stem cells. Bmi1, the polycomb-group transcriptional repressor, has emerged as a key regulator in several cellular processes including stem cell self-renewal and cancer cell proliferation. At the beginning of root formation, ameloblasts expressed Oct3/4 in the nucleus, except in the apex of the cervical loop, in which Bmi1and cyclinD were expressed. At PN6, the expression of Oct3/4 in the ameloblasts shifted from the nucleus to the cytoplasm, whereas ameloblastin-negative Hertwig's epithelial root sheath (HERS) cells expressed Bmi1 and cyclinD. By PN10, the cells in the apex of HERS began to express Oct3/4 in their nucleus, whereas Bmi1 and cyclinD began to decrease in their expressions. The odontoblasts consistently expressed Oct3/4 in their cytoplasm. Our results suggest that (1) Oct3/4 creates the border between the ameloblasts from the proliferative region of HERS, (2) Bmi1-positive cells would be one of the candidates resulting in root elongation and (3) the Oct3/4 expression in the cytoplasm of odontoblasts may be related to maintain the odontoblastic characteristics.

  11. Antagonistic interplay between necdin and Bmi1 controls proliferation of neural precursor cells in the embryonic mouse neocortex.

    Science.gov (United States)

    Minamide, Ryohei; Fujiwara, Kazushiro; Hasegawa, Koichi; Yoshikawa, Kazuaki

    2014-01-01

    Neural precursor cells (NPCs) in the neocortex exhibit a high proliferation capacity during early embryonic development and give rise to cortical projection neurons after maturation. Necdin, a mammal-specific MAGE (melanoma antigen) family protein that possesses anti-mitotic and pro-survival activities, is expressed abundantly in postmitotic neurons and moderately in tissue-specific stem cells or progenitors. Necdin interacts with E2F transcription factors and suppresses E2F1-dependent transcriptional activation of the cyclin-dependent kinase Cdk1 gene. Here we show that necdin serves as a suppressor of NPC proliferation in the embryonic neocortex. Necdin is moderately expressed in the ventricular zone of mouse embryonic neocortex, in which proliferative cell populations are significantly increased in necdin-null mice. In the neocortex of necdin-null embryos, expression of Cdk1 and Sox2, a stem cell marker, is significantly increased, whereas expression of p16, a cyclin-dependent kinase inhibitor, is markedly diminished. Cdk1 and p16 expression levels are also significantly increased and decreased, respectively, in primary NPCs prepared from necdin-null embryos. Intriguingly, necdin interacts directly with Bmi1, a Polycomb group protein that suppresses p16 expression and promotes NPC proliferation. In HEK293A cells transfected with luciferase reporter constructs, necdin relieves Bmi1-dependent repression of p16 promoter activity, whereas Bmi1 counteracts necdin-mediated repression of E2F1-dependent Cdk1 promoter activity. In lentivirus-infected primary NPCs, necdin overexpression increases p16 expression, suppresses Cdk1 expression, and inhibits NPC proliferation, whereas Bmi1 overexpression suppresses p16 expression, increases Cdk1 expression, and promotes NPC proliferation. Our data suggest that embryonic NPC proliferation in the neocortex is regulated by the antagonistic interplay between necdin and Bmi1.

  12. Bmi1 gene silencing inhibits the proliferation and invasiveness of human hepatocellular carcinoma cells and increases their sensitivity to 5-fluorouracil.

    Science.gov (United States)

    Zhang, Rui; Xu, Lei-Bo; Yue, Xiu-Jing; Yu, Xian-Huan; Wang, Jie; Liu, Chao

    2013-03-01

    The Bmi1 gene has been reported to play important roles in cancer initiation and progression. The aim of this study was to investigate the effects of RNA interference (RNAi)-mediated silencing of Bmi1 gene expression on the proliferation and invasiveness of hepatocellular carcinoma (HCC) cells and on the efficacy of chemotherapy in HCC patients. The Bmi1 gene was silenced by Bmi1-siRNA (small interfering RNA) in the human HCC cell lines HepG2 and Bel-7402, and the gene expression levels were assayed by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. The proliferation and migration of Bmi1-silenced tumor cells and their sensitivity to 5-FU treatment were determined by Cell Counting Kit-8 (CCK-8), transwell assays and 4',6-diamidino-2-phenylindole (DAPI) staining and flow cytometry, respectively. Bmi1-siRNA inhibited the Bmi1 expression at both the mRNA and protein levels in HCC cells. Proliferation and migration of HCC cells treated with Bmi1-siRNA was significantly lower compared to that of the control cells. Moreover, Bmi1 gene silencing increased the percentage of apoptotic cells treated by 5-FU and decreased the IC50 values of 5-FU to a greater extent. Downregulation of the Bmi1 gene by RNAi can inhibit the proliferation and invasivesness of HCC cells and increase their sensitivity to 5-FU treatment.

  13. Smooth muscle cells largely develop independently of functional hemogenic endothelium

    Directory of Open Access Journals (Sweden)

    Monika Stefanska

    2014-01-01

    Full Text Available Vascular smooth muscle cells represent a major component of the cardiovascular system. In vitro studies have shown that FLK1+ cells derived from embryonic stem (ES cells can differentiate into both endothelial and smooth muscle cells. These FLK1+ cells also contain a mesodermal precursor, the hemangioblast, able to produce endothelial, blood and smooth muscle cells. The generation of blood precursors from the hemangioblast was recently shown to occur through a transient cell population of specialised endothelium, a hemogenic endothelium. To date, the lineage relationship between this cell population and smooth muscle cell progenitors has not been investigated. In this study, we generated a reporter ES cell line in which expression of the fluorescent protein H2B-VENUS is driven by the α-smooth muscle actin (α-SMA regulatory sequences. We demonstrated that this reporter cell line efficiently trace smooth muscle development during ES cell differentiation. Although some smooth muscle cells are associated with broad endothelial development, we established that smooth muscle cells are mostly generated independently from a specialised functional hemogenic endothelium. This study provides new and important insights into hematopoietic and vascular development, which may help in driving further progress towards the development of bioengineered vascular grafts for regenerative medicine.

  14. Correlation between demographic characteristics, cognitive functioning and functional independence in stroke patients

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    Arsić Slađana

    2016-01-01

    Full Text Available Introduction. It has been assumed that there is causality of the achieved level of functional independence with the degree of preservation of cognitive function in stroke patients. Demographic characteristics may be important for monitoring the achieved level of functional independence. Objective. The aim of this study was to examine the relationship of demographic characteristics and functional independence in regard to the level of cognitive impairment in stroke patients. Methods. The study included 50 stroke patients after rehabilitation, as well as age- and gender-matched 50 subjects selected randomly, according to the demographic characteristics of the studied sample, who in their medical history had no neurological disorders. For the assessment of functional independence, the Functional Independence Measure (FIM test was used. The general cognition was estimated by the Mini-Mental State Examination (MMSE test. The statistical analyses included the Mann-Whitney test, for two independent samples, measures of canonical correlation, and χ2 test. Results. There was a statistically significant difference between the groups in relation to risk factors, hypertension and diabetes mellitus type II (p<0.001; There was a statistically significant difference within the groups in relation to the cognitive impairment in all the examined demographic characteristics (p<0.001; the differences within the groups in relation to the cognitive impairment are present on all subscales of the FIM test (p<0.05; the differences within the groups in relation to handedness, hemiparesis, show that mild cognitive impairment is more common among left hemiparesis, while a more severe one is more common among right-sided hemiparesis (p<0.05; More severe cognitive impairment is common among women, the elderly and in persons with lower education (p<0.05. Conclusion. By prevention of risk factors, and prevention of possible cognitive impairment, consequences of stroke can be

  15. The relationship between motor function, cognition, independence and quality of life in myelomeningocele patients.

    Science.gov (United States)

    Luz, Carolina Lundberg; Moura, Maria Clara Drummond Soares de; Becker, Karine Kyomi; Teixeira, Rosani Aparecida Antunes; Voos, Mariana Callil; Hasue, Renata Hydee

    2017-08-01

    Motor function, cognition, functional independence and quality of life have been described in myelomeningocele patients, but no study has investigated their relationships. We aimed to investigate the relationships between motor function, cognition, functional independence, quality of life, age, and lesion level in myelomeningocele patients, and investigate the influence of hydrocephalus on these variables. We assessed 47 patients with the Gross Motor Function Measure (motor function), Raven's Colored Progressive Matrices (cognition), Pediatric Evaluation of Disability Inventory (functional independence) and the Autoquestionnaire Qualité de vie Enfant Imagé (quality of life). Spearman's correlation tests determined relationships between the variables. The Friedman ANOVAs determined the influence of hydrocephalus. Motor function was strongly related to mobility and lesion level, and moderately related to cognition, self-care and social function. Cognition and quality of life were moderately related to functional independence. Age correlated moderately with functional independence and quality of life. Hydrocephalus resulted in poorer motor/cognitive outcomes and lower functional independence.

  16. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication

    OpenAIRE

    Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin

    2016-01-01

    The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on t...

  17. Bmi1-positive cells in the lingual epithelium could serve as cancer stem cells in tongue cancer.

    Science.gov (United States)

    Tanaka, Toshihiro; Atsumi, Naho; Nakamura, Naohiro; Yanai, Hirotsugu; Komai, Yoshihiro; Omachi, Taichi; Tanaka, Kiyomichi; Ishigaki, Kazuhiko; Saiga, Kazuho; Ohsugi, Haruyuki; Tokuyama, Yoko; Imahashi, Yuki; Hisha, Hiroko; Yoshida, Naoko; Kumano, Keiki; Okazaki, Kazuichi; Ueno, Hiroo

    2016-12-22

    We recently reported that the polycomb complex protein Bmi1 is a marker for lingual epithelial stem cells (LESCs), which are involved in the long-term maintenance of lingual epithelial tissue in the physiological state. However, the precise role of LESCs in generating tongue tumors and Bmi1-positive cell lineage dynamics in tongue cancers are unclear. Here, using a mouse model of chemically (4-nitroquinoline-1-oxide: 4-NQO) induced tongue cancer and the multicolor lineage tracing method, we found that each unit of the tumor was generated by a single cell and that the assembly of such cells formed a polyclonal tumor. Although many Bmi1-positive cells within the tongue cancer specimens failed to proliferate, some proliferated continuously and supplied tumor cells to the surrounding area. This process eventually led to the formation of areas derived from single cells after 1-3 months, as determined using the multicolor lineage tracing method, indicating that such cells could serve as cancer stem cells. These results indicate that LESCs could serve as the origin for tongue cancer and that cancer stem cells are present in tongue tumors.

  18. Algebraic Independence of Certain Values of Exponential Function

    Institute of Scientific and Technical Information of China (English)

    Yao Chen ZHU

    2006-01-01

    The algebraic independence of eθ1,...,eθs is proved, where θ1,...,θs are certain gap series or power series of algebraic numbers, or certain transcendental continued fractions with algebraic elements.

  19. Adolescent Support Seeking as a Path to Adult Functional Independence

    Science.gov (United States)

    Szwedo, David E.; Hessel, Elenda T.; Loeb, Emily L.; Hafen, Christopher A.; Allen, Joseph P.

    2017-01-01

    The potential importance of depending on others during adolescence to establish independence in young adulthood was examined across adolescence to emerging adulthood. Participants included 184 teens (46% male; 42% non-White), their mothers, best friends, and romantic partners, assessed at ages 13-14, 18, 21-22, and 25. Path analyses showed that…

  20. Social Resources That Preserve Functional Independence After Memory Loss

    Science.gov (United States)

    2015-05-01

    behavioral , and instrumental accommodations can foster continued independence.(3) Individual level modifiers for example, physical activity or not...in Instrumental Activities of Daily Living (IADLs). The manuscript titled “Do physical activity , smoking, drinking or depression modify transitions...probability below. We used the same modifiers as those used in our ADL analyses (physical activity , smoking, alcohol consumption, depression and income

  1. Creators' Intentions Bias Judgments of Function Independently from Causal Inferences

    Science.gov (United States)

    Chaigneau, Sergio E.; Castillo, Ramon D.; Martinez, Luis

    2008-01-01

    Participants learned about novel artifacts that were created for function X, but later used for function Y. When asked to rate the extent to which X and Y were a given artifact's function, participants consistently rated X higher than Y. In Experiments 1 and 2, participants were also asked to rate artifacts' efficiency to perform X and Y. This…

  2. The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target.

    Directory of Open Access Journals (Sweden)

    Iris Alchanati

    Full Text Available BACKGROUND: The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha. METHODOLOGY/PRINCIPAL FINDINGS: We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2alpha degradation, increases the persistence of Top2alpha-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2alpha in-vitro and cellular overexpression of Bmi1 increases drug induced Top2alpha ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2alpha ubiquitination and drug-induced Top2alpha degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner. CONCLUSIONS/SIGNIFICANCE: The discovery that poisoned Top2alpha is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1.

  3. How Disabling Are Pediatric Burns? Functional Independence in Dutch Pediatric Patients with Burns

    Science.gov (United States)

    Disseldorp, Laurien M.; Niemeijer, Anuschka S.; Van Baar, Margriet E.; Reinders-Messelink, Heleen A.; Mouton, Leonora J.; Nieuwenhuis, Marianne K.

    2013-01-01

    Although the attention for functional outcomes after burn injury has grown over the past decades, little is known about functional independence in performing activities of daily living in children after burn injury. Therefore, in this prospective cohort study functional independence was measured by burn care professionals with the WeeFIM[R]…

  4. The BMI1 inhibitor PTC-209 is a potential compound to halt cellular growth in biliary tract cancer cells.

    Science.gov (United States)

    Mayr, Christian; Wagner, Andrej; Loeffelberger, Magdalena; Bruckner, Daniela; Jakab, Martin; Berr, Frieder; Di Fazio, Pietro; Ocker, Matthias; Neureiter, Daniel; Pichler, Martin; Kiesslich, Tobias

    2016-01-05

    BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and is up-regulated in biliary tract cancer (BTC), contributing to aggressive clinical features. In this study we investigated the cytotoxic effects of PTC-209, a recently developed inhibitor of BMI1, in BTC cells. PTC-209 reduced overall viability in BTC cell lines in a dose-dependent fashion (0.04 - 20 µM). Treatment with PTC-209 led to slightly enhanced caspase activity and stop of cell proliferation. Cell cycle analysis revealed that PTC-209 caused cell cycle arrest at the G1/S checkpoint. A comprehensive investigation of expression changes of cell cycle-related genes showed that PTC-209 caused significant down-regulation of cell cycle-promoting genes as well as of genes that contribute to DNA synthesis initiation and DNA repair, respectively. This was accompanied by significantly elevated mRNA levels of cell cycle inhibitors. In addition, PTC-209 reduced sphere formation and, in a cell line-dependent manner, aldehyde dehydrogease-1 positive cells. We conclude that PTC-209 might be a promising drug for future in vitro and in vivo studies in BTC.

  5. Predicting functional capacity during treadmill testing independent of exercise protocol.

    Science.gov (United States)

    Foster, C; Crowe, A J; Daines, E; Dumit, M; Green, M A; Lettau, S; Thompson, N N; Weymier, J

    1996-06-01

    Clinically useful estimates of VO2max from treadmill tests (GXT) may be made using protocol-specific equations. In many cases, GXT may proceed more effectively if the clinician is free to adjust speed and grade independent of a specific protocol. We sought to determine whether VO2max could be predicted from the estimated steady-state VO2 of the terminal exercise stage. Seventy clinically stable individuals performed GXT with direct measurement of VO2. Exercise was incremented each minute to optimize clinical examination. Measured VO2max was compared to the estimated steady-state VO2 of the terminal stage based on ACSM equations. Equations for walking or running were used based on the patient's observed method of ambulation. The measured VO2max was always less than the ACSM estimate, with a regular relationship between measured and estimated VO2max. No handrail support: VO2max = 0.869.ACSM -0.07; R2 = 0.955, SEE = 4.8 ml.min-1.kg-1 (N = 30). With handrail support: VO2max = 0.694.ACSM + 3.33; R2 = 0.833, SEE = 4.4 ml.min-1.kg-1 (N = 40). The equations were cross-validated with 20 patients. The correlation between predicted and observed values was r = 0.98 and 0.97 without and with handrail support, respectively. The mean absolute prediction error (3.1 and 4.1 ml.min-1.kg-1) were similar to protocol-specific equations. We conclude that VO2max can be predicted independent of treadmill protocol with approximately the same error as protocol-specific equations.

  6. p38 MAPK-Mediated Bmi-1 down-regulation and defective proliferation in ATM-deficient neural stem cells can be restored by Akt activation.

    Directory of Open Access Journals (Sweden)

    Jeesun Kim

    Full Text Available A-T (ataxia telangiectasia is a genetic disease caused by a mutation in the Atm (A-T mutated gene that leads to neurodegeneration. Despite an increase in the numbers of studies in this area in recent years, the mechanisms underlying neurodegeneration in human A-T are still poorly understood. Previous studies demonstrated that neural stem cells (NSCs isolated from the subventricular zone (SVZ of Atm(-/- mouse brains show defective self-renewal and proliferation, which is accompanied by activation of chronic p38 mitogen-activated protein kinase (MAPK and a lower level of the polycomb protein Bmi-1. However, the mechanism underlying Bmi-1 down-regulation and its relevance to defective proliferation in Atm(-/- NSCs remained unclear. Here, we show that over-expression of Bmi-1 increases self-renewal and proliferation of Atm(-/- NSCs to normal, indicating that defective proliferation in Atm(-/- NSCs is a consequence of down-regulation of Bmi-1. We also demonstrate that epidermal growth factor (EGF-induced Akt phosphorylation renders Bmi-1 resistant to the proteasomal degradation, leading to its stabilization and accumulation in the nucleus. However, inhibition of the Akt-dependent Bmi-1 stabilizing process by p38 MAPK signaling reduces the levels of Bmi-1. Treatment of the Atm(-/- NSCs with a specific p38 MAPK inhibitor SB203580 extended Bmi-1 posttranscriptional turnover and H2A ubiquitination in Atm(-/- NSCs. Our observations demonstrate the molecular basis underlying the impairment of self-renewal and proliferation in Atm(-/- NSCs through the p38 MAPK-Akt-Bmi-1-p21 signaling pathway.

  7. Functional Independent Scaling Relation for ORR/OER Catalysts

    DEFF Research Database (Denmark)

    Christensen, Rune; Hansen, Heine Anton; Dickens, Colin F.

    2016-01-01

    A widely used adsorption energy scaling relation between OH* and OOH* intermediates in the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), has previously been determined using density functional theory and shown to dictate a minimum thermodynamic overpotential for both reacti...

  8. Functional Independent Scaling Relation for ORR/OER Catalysts

    DEFF Research Database (Denmark)

    Christensen, Rune; Hansen, Heine Anton; Dickens, Colin F.

    2016-01-01

    reactions. Here, we show that the oxygen-oxygen bond in the OOH* intermediate is, however, not well described with the previously used class of exchange-correlation functionals. By quantifying and correcting the systematic error, an improved description of gaseous peroxide species versus experimental data...

  9. Renal function is independently associated with circulating betatrophin

    Science.gov (United States)

    Maurer, Lukas; Schwarz, Franziska; Fischer-Rosinsky, Antje; Schlueter, Nina; Brachs, Sebastian; Möhlig, Matthias; Pfeiffer, Andreas; Mai, Knut; Bobbert, Thomas

    2017-01-01

    Objective Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. Subjects We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. Results In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model (β = -0.197, pwaist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans. PMID:28257453

  10. Renal function is independently associated with circulating betatrophin.

    Science.gov (United States)

    Maurer, Lukas; Schwarz, Franziska; Fischer-Rosinsky, Antje; Schlueter, Nina; Brachs, Sebastian; Möhlig, Matthias; Pfeiffer, Andreas; Mai, Knut; Spranger, Joachim; Bobbert, Thomas

    2017-01-01

    Betatrophin has been identified as a marker linking liver with beta cell function and lipid metabolism in murine models. Until now, the regulation of circulating betatrophin in humans is not entirely clear. We here analyzed the relation of betatrophin levels to phenotypes of the metabolic syndrome and speculated that renal function might influence circulating betatrophin levels and explain age-dependent changes of betatrophin. We analyzed blood samples from 535 individuals participating in the Metabolic Syndrome Berlin Potsdam study. In a crude analysis we found a positive correlation between betatrophin levels and HbA1c (r = 0.24; p < 0.001), fasting glucose (r = 0.20; p < 0.001) and triglycerides (r = 0.12; p = 0.007). Furthermore betatrophin was positively correlated with age (r = 0.47; p <0.001), systolic blood pressure (r = 0.17; p < 0.001), intima media thickness (r = 0.26; p < 0.001) and negatively correlated with CKD-EPI eGFR (r = -0.33; p < 0.001) as an estimate of renal function. Notably, eGFR remained highly associated with betatrophin after adjustment for age, waist circumference, gender, HbA1c and lipid parameters in a multivariate linear regression model (β = -0.197, p< 0.001). Our data suggest that circulating levels of betatrophin depend on age, gender, waist circumference, total/HDL cholesterol ratio and renal function. Especially the association to eGFR highlights the importance for future studies to address renal function as possible influence on betatrophin regulation and consider eGFR as potential confounder when analyzing the role of betatrophin in humans.

  11. On English Independent Structure Syntactic and Pragmatic Functions

    Institute of Scientific and Technical Information of China (English)

    刘玲玲

    2014-01-01

    Many western linguists began to pay much attention to small clause since 1980s. There is little specialized research on the structure of small clause,and the related explanations in the grammar book are about its surface features instead of its internal syntactic structure. Syntax as an independent science has not finished explaining all the linguistic phenomena,for the structure of small clause is a disputable topic which needs explanation and research. Last but not least,I would also like to thank with all my heart my parents for their love, understanding,support,and encouragement throughout my writing of the thesis and the complete two and a half years of graduate study. It was he who was always ready to solve my problems in studies and research. It was he who offered me suggestions and references for this thesis. And it was he who helped me in reviewing the whole thesis. My words are too weak to express my gratefulness to him.

  12. Determinants of functional independence and quality of life in children with spina bifida

    NARCIS (Netherlands)

    Schoenmakers, MAGC; Uiterwaal, CSPM; Gulmans, VAM; Gooskens, RHJM; Helders, PJM

    Objective: To investigate determinants of functional independence and study which functional abilities were determinants for 'health-related quality of life' in children with myelomeningocele. Design: Cross-sectional study by means of clinical assessment, 'disability' measurement and questionnaires.

  13. Independent contribution of individual white matter pathways to language function in pediatric epilepsy patients

    Directory of Open Access Journals (Sweden)

    Michael J. Paldino, M.D.

    2014-01-01

    Conclusions: Scalar metrics derived from the left uncinate, inferior fronto-occipital, and arcuate fasciculi were independently associated with language function. These results support the importance of these pathways in human language function in patients with MCDs.

  14. DELLA genes restrict inflorescence meristem function independently of plant height.

    Science.gov (United States)

    Serrano-Mislata, Antonio; Bencivenga, Stefano; Bush, Max; Schiessl, Katharina; Boden, Scott; Sablowski, Robert

    2017-08-21

    DELLA proteins associate with transcription factors to control plant growth in response to gibberellin (1) . Semi-dwarf DELLA mutants with improved harvest index and decreased lodging greatly improved global food security during the 'green revolution' in the 1960-1970s (2) . However, DELLA mutants are pleiotropic and the developmental basis for their effects on plant architecture remains poorly understood. Here, we show that DELLA proteins have genetically separable roles in controlling stem growth and the size of the inflorescence meristem, where flowers initiate. Quantitative three-dimensional image analysis, combined with a genome-wide screen for DELLA-bound loci in the inflorescence tip, revealed that DELLAs limit meristem size in Arabidopsis by directly upregulating the cell-cycle inhibitor KRP2 in the underlying rib meristem, without affecting the canonical WUSCHEL-CLAVATA meristem size regulators (3) . Mutation of KRP2 in a DELLA semi-dwarf background restored meristem size, but not stem growth, and accelerated flower production. In barley, secondary mutations in the DELLA gain-of-function mutant Sln1d (4) also uncoupled meristem and inflorescence size from plant height. Our work reveals an unexpected and conserved role for DELLA genes in controlling shoot meristem function and suggests how dissection of pleiotropic DELLA functions could unlock further yield gains in semi-dwarf mutants.During gibberellic acid signalling, DELLAs restrict the size of the shoot apical meristem by targeting the cell cycle regulator KRP2. The roles of DELLAs in the shoot apical meristem and stem growth can be genetically uncoupled in Arabidopsis and barley.

  15. The relationship between motor function, cognition, independence and quality of life in myelomeningocele patients

    Directory of Open Access Journals (Sweden)

    Carolina Lundberg Luz

    Full Text Available ABSTRACT Motor function, cognition, functional independence and quality of life have been described in myelomeningocele patients, but no study has investigated their relationships. We aimed to investigate the relationships between motor function, cognition, functional independence, quality of life, age, and lesion level in myelomeningocele patients, and investigate the influence of hydrocephalus on these variables. We assessed 47 patients with the Gross Motor Function Measure (motor function, Raven’s Colored Progressive Matrices (cognition, Pediatric Evaluation of Disability Inventory (functional independence and the Autoquestionnaire Qualité de vie Enfant Imagé (quality of life. Spearman’s correlation tests determined relationships between the variables. The Friedman ANOVAs determined the influence of hydrocephalus. Motor function was strongly related to mobility and lesion level, and moderately related to cognition, self-care and social function. Cognition and quality of life were moderately related to functional independence. Age correlated moderately with functional independence and quality of life. Hydrocephalus resulted in poorer motor/cognitive outcomes and lower functional independence.

  16. Evaluation of potential prognostic value of Bmi-1 gene product and selected markers of proliferation (Ki-67 and apoptosis (p53 in the neuroblastoma group of tumors

    Directory of Open Access Journals (Sweden)

    Katarzyna Taran

    2016-02-01

    Full Text Available Introduction: Cancer in children is a very important issue in pediatrics. The least satisfactory treatment outcome occurs among patients with clinically advanced neuroblastomas. Despite much research, the biology of this tumor still remains unclear, and new prognostic factors are sought. The Bmi-1 gene product is a currently highly investigated protein which belongs to the Polycomb group (PcG and has been identified as a regulator of primary neural crest cells. It is believed that Bmi‑1 and N-myc act together and are both involved in the pathogenesis of neuroblastoma. The aim of the study was to assess the potential prognostic value of Bmi-1 protein and its relations with mechanisms of proliferation and apoptosis in the neuroblastoma group of tumors.Material/Methods: 29 formalin-fixed and paraffin-embedded neuroblastoma tissue sections were examined using mouse monoclonal antibodies anti-Bmi-1, anti-p53 and anti-Ki-67 according to the manufacturer’s instructions.Results: There were found statistically significant correlations between Bmi-1 expression and tumor histology and age of patients.Conclusions: Bmi-1 seems to be a promising marker in the neuroblastoma group of tumors whose expression correlates with widely accepted prognostic parameters. The pattern of BMI-1 expression may indicate that the examined protein is also involved in maturation processes in tumor tissue.

  17. A retrospective review of the prognostic value of ALDH-1, Bmi-1 and Nanog stem cell markers in esophageal squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Cheng-Cheng Hwang

    Full Text Available Stem cell markers are upregulated in various cancers and have potential as prognostic indicators. The objective of this study was to determine the expression of three stem cell markers, aldehyde dehydrogenase 1 (ALDH-1, B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1, and Nanog, in esophageal squamous cell carcinoma (ESCC tissues. Immunohistochemistry was used to measure the expression of ALDH-1, Bmi-1, and Nanog in ESCC tissues from 41 patients who received pre-operative chemoradiation. We evaluated the relationship between expression of these markers, and clinicopathological features, tumor regression grade (TRG, and 5-year overall survival (OS. There were no significant associations of ALDH-1 or Bmi-1 expression with age, gender, clinical stage, and treatments (p>0.05. However, patients with Nanog-positive tumors were significantly older than those whose tumors were Nanog-negative (p = 0.033. TRG after treatment was significantly associated with expression of ALDH-1 (p = 0.001, Bmi-1 (p = 0.004, and Nanog (p<0.001. Although OS was significantly better in patients with low TRGs (p = 0.001, there were no significant correlations between ALDH-1, Bmi-1, or Nanog with OS. Expression of ALDH-1, Bmi-1, and Nanog correlated with TRG, but not OS. Further large studies are necessary to fully elucidate the prognostic value of these stem cell markers for ESCC patients.

  18. The influence of demographic, environmental and physical factors on functional independence post stroke

    Directory of Open Access Journals (Sweden)

    M.V. Mamabolo

    2008-02-01

    Full Text Available Purpose: The magnitude of disability observed in strokesurvivors is believed to be dependent in part, on the severity of neurological deficits incurred. A s important but less well understood, is thecontribution of demographic, physical and environmental factors. The objective of this study was to establish what demographic, environmentaland physical factors influence functional independence post stroke. Method: Convenience sampling was used in the selection of subjects from four stroke outpatient public health facilities in the Gauteng Province of South Africa. The data were collected using a structured questionnaire. The analytical tools used included descriptive statistics to measure percentages and cross tabulations to measure the level of associations between functional independence and some of the demographic factors. The Barthel Index was computed to establish the degree of functional independence. Finally the influence of factors on functional independence was investigated using bivariate logistic regressions.Results: The results showed that younger patients (18 - 34 yrs may have a higher likelihood of functional independence compared to older patients at the time of discharge from hospital (18 - 34 years: Odds Ratio = 1. Patients without helpers were more likely to be functionally independent than those with a helper (p = 0.03. Involvement in household activities (p = 0.01, participation in community activities (p = 0.02 and bowel and bladder continence (p = 0.003 and p = 0.04 improved the likelihood of functional independence.Conclusion and im plications: Factors that influence functional independence post stroke are: age, bowel and bladder continence, the presence of a caregiver, participation in household and community activities. It is also of value to encourage patients to participate in household and community activities post stroke as well as being less dependent on helpers in an effort to attain functional independence post

  19. Ability of Functional Independence Measure to accurately predict functional outcome of stroke-specific population: Systematic review

    OpenAIRE

    Madeleine Spencer, DPT, PT; Karen Skop, DPT, PT; Kristina Shesko, DPT, PT; Kristen Nollinger, DPT, PT; Douglas Chumney, DPT, PT; Roberta A. Newton, PT, PhD

    2010-01-01

    Stroke is a leading cause of functional impairments. The ability to quantify the functional ability of poststroke patients engaged in a rehabilitation program may assist in prediction of their functional outcome. The Functional Independence Measure (FIM) is widely used and accepted as a functional-level assessment tool that evaluates the functional status of patients throughout the rehabilitation process. From February to March 2009, we searched MEDLINE, Ovid, CINAHL, and EBSCO for full-text ...

  20. Functional Outcomes and Consumer Satisfaction in the Independent Living Program for Older Individuals Who Are Blind

    Science.gov (United States)

    Moore, J. Elton; Steinman, Bernard A.; Giesen, J. Martin; Frank, John J.

    2006-01-01

    This study of a national sample of elders served by the Independent Living Program for Older Individuals Who Are Blind found that, overall, they were highly satisfied with the quality and timeliness of services and help in achieving independent living goals. A slight improvement was found in their perceptions of functional outcomes from 1999 to…

  1. The Functional Independence of Mands and Tacts: Has It Been Demonstrated Empirically?

    Science.gov (United States)

    Gamba, Jonas; Goyos, Celso; Petursdottir, Anna Ingeborg

    2015-01-01

    Recently, there has been a proliferation of research on the functional independence of two of Skinner's (1957) verbal operants, the mand, and the tact. This research has produced highly variable results. In this article, we provide a critical review of the literature on mand-tact independence, a literature that has implications for both theory and…

  2. The Transfer Function Is Alive and Well at the Private/Independent Junior College.

    Science.gov (United States)

    Schachter, Pam Brown

    1986-01-01

    Reports on an examination of the transfer function a sample of 10 private/independent junior colleges. Reviews data obtained through analyses of college catalogs and available descriptive information and through survey research focusing on college goals. Reveals evidence of the private/independent junior college's commitment to the transfer…

  3. Evaluating functional independence in older adults using subscales of the Berg Balance Scale

    Directory of Open Access Journals (Sweden)

    Yuan-Yang Cheng, MD

    2014-12-01

    Conclusion: In our study, the subscale “sitting to standing” was shown to be the most sensitive among the subscales of the BBS to evaluate functional independence. Therefore, the performance of “sitting to standing” is suggested to be an objective measure to evaluate the functional independence in activities of daily living of older adults; it is easy and simple to perform in everyday clinical practice.

  4. Independent effects of both right and left ventricular function on plasma brain natriuretic peptide

    DEFF Research Database (Denmark)

    Vogelsang, Thomas Wiis; Jensen, Ruben J; Monrad, Astrid L;

    2007-01-01

    BACKGROUND: Brain natriuretic peptide (BNP) is increased in heart failure; however, the relative contribution of the right and left ventricles is largely unknown. AIM: To investigate if right ventricular function has an independent influence on plasma BNP concentration. METHODS: Right (RVEF), left......, which is a strong prognostic marker in heart failure, independently depends on both left and right ventricular systolic function. This might, at least in part, explain why BNP holds stronger prognostic value than LVEF alone....

  5. A new method of heart sound signal analysis based on independent function element

    Directory of Open Access Journals (Sweden)

    Cheng Xie-feng

    2014-09-01

    Full Text Available In this paper, a new method is presented for heart sound signal processing in statistical domain. The multiple components obtained from the conventional linear transformation are possibly irrelevant, but usually do not possess the characteristics of statistical independence. First, the definition and obtaining method of independent function element are discussed; the method of signal decomposition and reconstruction based on the independent function element, not only inherits the advantages of linear transformation, but also has the capability of signal representation in the statistical domain. After that, the application of independent function element in heart sound signal analysis is analyzed in detail. The validity and practicability of the method are demonstrated through two experiments.

  6. Discovery of novel Bmy1 alleles increasing β-amylase activity in Chinese landraces and Tibetan wild barley for improvement of malting quality via MAS.

    Directory of Open Access Journals (Sweden)

    Xue Gong

    Full Text Available China has a large barley germplasm collection which has not been well characterized and is therefore underutilized. The Bmy1 locus encoding the β-amylase enzyme on chromosome 4H has been well characterized in the worldwide barley germplasm collections due to its importance in the malting and brewing industry. The Bmy1 locus was chosen as an indicator to understand genetic potential for improvement of malting quality in Chinese landraces and Tibetan wild barley. The genetic diversity of 91 barley accessions was assessed using allele specific Multiplex-ready molecular markers. Eight accessions were further sequenced, based on the Multiplex-ready marker diversity for Bmy1 in the germplasm. Six of the eight accessions clustered together in a unique group, and showed similarities to 'Haruna Nijo', wild barley accession PI296896 and 'Ashqelon'. Sequence comparisons with the known Bmy1 alleles identified not only the existing 13 amino acid substitutions, but also a new substitution positioned at A387T from a Chinese landrace W127, which has the highest β-amylase activity. Two new alleles/haplotypes namely Bmy1-Sd1c and Bmy1-Sd5 were designated based on different amino acid combinations. We identified new amino acid combination of C115, D165, V233, S347 and V430 in the germplasm. The broad variation in both β-amylase activity and amino acid composition provides novel alleles for the improvement of malting quality for different brewing styles, which indicates the high potential value of the Chinese landraces and Tibetan wild barley.

  7. Combined introduction of Bmi-1 and hTERT immortalizes human adipose tissue-derived stromal cells with low risk of transformation

    Energy Technology Data Exchange (ETDEWEB)

    Tatrai, Peter, E-mail: peter.tatrai@biomembrane.hu [Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Karolina ut 29, H-1113 Budapest (Hungary); Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Egyetem ter 1, H-4032 Debrecen (Hungary); Szepesi, Aron, E-mail: aron.szepesi@biomembrane.hu [Creative Cell Ltd., Puskas Tivadar utca 13, H-1119 Budapest (Hungary); Matula, Zsolt, E-mail: matula.zsolt@gmail.com [Creative Cell Ltd., Puskas Tivadar utca 13, H-1119 Budapest (Hungary); Szigeti, Anna, E-mail: anna.szigeti@biomembrane.hu [Creative Cell Ltd., Puskas Tivadar utca 13, H-1119 Budapest (Hungary); Buchan, Gyoengyi, E-mail: buchan@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Egyetem ter 1, H-4032 Debrecen (Hungary); Madi, Andras, E-mail: madi@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Egyetem ter 1, H-4032 Debrecen (Hungary); Stem Cell, Apoptosis and Genomics Research Group of the Hungarian Academy of Sciences, University of Debrecen, Egyetem ter 1, H-4032 Debrecen (Hungary); Uher, Ferenc, E-mail: uher@biomembrane.hu [Stem Cell Laboratory, Hungarian National Blood Transfusion Service, Dioszegi ut 64, H-1113 Budapest (Hungary); and others

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer We immortalized human adipose stromal cells (ASCs) with hTERT, Bmi-1, and SV40T. Black-Right-Pointing-Pointer hTERT-only ASCs are prone to transformation, while Bmi-only ASCs become senescent. Black-Right-Pointing-Pointer SV40T introduced along with hTERT abrogates proliferation control and multipotency. Black-Right-Pointing-Pointer hTERT combined with Bmi-1 yields stable phenotype up to 140 population doublings. -- Abstract: Adipose tissue-derived stromal cells (ASCs) are increasingly being studied for their usefulness in regenerative medicine. However, limited life span and donor-dependent variation of primary cells such as ASCs present major hurdles to controlled and reproducible experiments. We therefore aimed to establish immortalized ASC cell lines that provide steady supply of homogeneous cells for in vitro work while retain essential features of primary cells. To this end, combinations of human telomerase reverse transcriptase (hTERT), murine Bmi-1, and SV40 large T antigen (SV40T) were introduced by lentiviral transduction into ASCs. The resulting cell lines ASC{sup hTERT}, ASC{sup Bmi-1}, ASC{sup Bmi-1+hTERT} and ASC{sup SV40T+hTERT} were tested for transgene expression, telomerase activity, surface immunomarkers, proliferation, osteogenic and adipogenic differentiation, karyotype, tumorigenicity, and cellular senescence. All cell lines have maintained expression of characteristic surface immunomarkers, and none was tumorigenic. However, ASC{sup Bmi-1} had limited replicative potential, while the rapidly proliferating ASC{sup SV40T+hTERT} acquired chromosomal aberrations, departed from MSC phenotype, and lost differentiation capacity. ASC{sup hTERT} and ASC{sup hTERT+Bmi-1}, on the other hand, preserved all essential MSC features and did not senesce after 100 population doublings. Notably, a subpopulation of ASC{sup hTERT} also acquired aberrant karyotype and showed signs of transformation after long-term culture

  8. Measure of functional independence dominates discharge outcome prediction after inpatient rehabilitation for stroke.

    Science.gov (United States)

    Brown, Allen W; Therneau, Terry M; Schultz, Billie A; Niewczyk, Paulette M; Granger, Carl V

    2015-04-01

    Identifying clinical data acquired at inpatient rehabilitation admission for stroke that accurately predict key outcomes at discharge could inform the development of customized plans of care to achieve favorable outcomes. The purpose of this analysis was to use a large comprehensive national data set to consider a wide range of clinical elements known at admission to identify those that predict key outcomes at rehabilitation discharge. Sample data were obtained from the Uniform Data System for Medical Rehabilitation data set with the diagnosis of stroke for the years 2005 through 2007. This data set includes demographic, administrative, and medical variables collected at admission and discharge and uses the FIM (functional independence measure) instrument to assess functional independence. Primary outcomes of interest were functional independence measure gain, length of stay, and discharge to home. The sample included 148,367 people (75% white; mean age, 70.6±13.1 years; 97% with ischemic stroke) admitted to inpatient rehabilitation a mean of 8.2±12 days after symptom onset. The total functional independence measure score, the functional independence measure motor subscore, and the case-mix group were equally the strongest predictors for any of the primary outcomes. The most clinically relevant 3-variable model used the functional independence measure motor subscore, age, and walking distance at admission (r(2)=0.107). No important additional effect for any other variable was detected when added to this model. This analysis shows that a measure of functional independence in motor performance and age at rehabilitation hospital admission for stroke are predominant predictors of outcome at discharge in a uniquely large US national data set. © 2015 American Heart Association, Inc.

  9. Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

    NARCIS (Netherlands)

    Hoffmann, M.J.; Engers, R.; Florl, A.R.; Otte, A.P.; Müller, M.; Schulz, W.A.

    2007-01-01

    The polycomb proteins BMI-1, EZH2, and SIRT1 are characteristic components of the PRC1, PRC2, and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate

  10. Expression changes in EZH2, but not in BMI-1, SIRT1, DNMT1 or DNMT3B are associated with DNA methylation changes in prostate cancer

    NARCIS (Netherlands)

    Hoffmann, M.J.; Engers, R.; Florl, A.R.; Otte, A.P.; Müller, M.; Schulz, W.A.

    2007-01-01

    The polycomb proteins BMI-1, EZH2, and SIRT1 are characteristic components of the PRC1, PRC2, and PRC4 repressor complexes, respectively, that modify chromatin. Moreover, EZH2 may influence DNA methylation by direct interaction with DNA methyltransferases. EZH2 expression increases during prostate c

  11. Expression of Bmi-1 and EZH2 in tissues adjacent to human epithelial ovarian cancer cells of orthotopic implantation in nude mice

    Institute of Scientific and Technical Information of China (English)

    Genhai Zhu; Lan Hong; Shengtan Wang; Zhaoxin Yang; Chunying Chen; Shixuan Wang

    2015-01-01

    Objective This study investigated the feasibility of screening residual normal ovarian tissues based on the expression of Bmi-1 and EZH2 in tissues adjacent to orthotopic ovarian carcinomas in nude mice. Methods The human epithelial ovarian cancer cel line OVCAR3 was grown in subcutaneous tissues and the tumor tissues were orthotopical y implanted. The expression levels of Bmi-1 and EZH2 were detected by immunohistochemical staining and RT-PCR in cancer tissues, proximal and remote tissues with respect to the cancer tissues, and normal ovarian tissues of nude mice. Results Thirty-five ovarian tissue samples with normal biopsy results were obtained from 40 cases of human epithelial ovarian cancer in the nude mice in which the tumor tissues were orthotopical y implanted. Bmi-1 and EZH2 expression levels were lower in proximal paraneoplastic tissue samples than in cancer tissue samples (P Conclusion The expression levels of Bmi-1 and EZH2 were reduced with increasing distance from the cancer tissues. Negative expression of these tumor-associated genes can be used as a standard for the screening of normal ovarian tissues adjacent to tumor tissues. Normal ovarian tissues can be obtained from the tissues adjacent to tumors.

  12. Prediction of moisture content of alfalfa using density-independent functions of microwave dielectric properties

    Science.gov (United States)

    Shrestha, Bijay L.; Wood, Hugh C.; Sokhansanj, Shahab

    2005-05-01

    The use of density-independent functions of the dielectric properties of chopped alfalfa, calculated from microwave reflection coefficients from 300 MHz to 18 GHz, was studied for determining moisture content in the range from 12% to 73%, wet basis, at bulk densities from 0.139 to 0.716 g cm-3 at 20 °C. Prediction of moisture content with worst-case relative errors of about 3% or less over the range from 20% to 73% confirmed promising prospects for use of such density-independent functions for reliable moisture measurement for important plant materials.

  13. Enhanced independence: experiences after regaining grip function in people with tetraplegia.

    Science.gov (United States)

    Wangdell, Johanna; Carlsson, Gunnel; Fridén, Jan

    2013-01-01

    To explore how surgical reconstruction of grip affects everyday life for patients with tetraplegia, with special emphasis on patients perspective of their perceived changes. Qualitative method. Eleven people (aged 22-73) with tetraplegia who had undergone surgical reconstruction to restore grip function. Qualitative interviews were conducted 7-17 months after surgery and analysed using Grounded theory. The core concept describing the participants experienced gains after grip reconstructive surgery was "enhanced independence". It was associated with changes in both practical and psychological aspects of independence. Practical aspects identified were: "perform more activities", "smoother everyday life", "renewed ability to participate in social activities", "less dependence on assistance" and "less restricted by physical environment". Psychological aspects of independence included "regained privacy", "increased manageability", "regained identity", "recapture a part of the body" and "share positive experiences with relatives and friends". Encompassing all categories was the concept "self-efficacy in hand control". It was seen as a result included in the enhanced independency core but also as an important factor for the development of all the other categories. Participants in this study experienced enhanced independence after grip reconstructive surgery and rehabilitation. The enhanced independence included both practical and physical aspects and it influenced all domains using the International Classification of Function, Disability and Health model; body function and structure, activities, participation, personal factors and environmental factors. Implications for Rehabilitation Patients with tetraplegia experience grip reconstruction as a useful intervention, an enhanced independence, related to their improved hand control. The increased hand control impacted not only physical aspects but also practical and psychological aspects. It also influenced social and

  14. Functional independence and health-related functional status following spinal cord injury : a prospective study of the association with physical capacity

    NARCIS (Netherlands)

    Haisma, Janneke A.; Post, Marcel W.; van der Woude, Lucas H.; Stam, Henk J.; Bergen, Michael P.; Sluis, Tebbe A.; van den Berg-Emons, Hendrika J.; Bussmann, Johannes B.

    2008-01-01

    Objective: To determine changes in functional independence following spinal cord injury and to evaluate the association between functional independence and physical capacity. Design: Multi-centre prospective cohort study. Subjects: Patients with spinal cord injury admitted for initial rehabilitation

  15. Detection of independent functional networks during music listening using electroencephalogram and sLORETA-ICA.

    Science.gov (United States)

    Jäncke, Lutz; Alahmadi, Nsreen

    2016-04-13

    The measurement of brain activation during music listening is a topic that is attracting increased attention from many researchers. Because of their high spatial accuracy, functional MRI measurements are often used for measuring brain activation in the context of music listening. However, this technique faces the issues of contaminating scanner noise and an uncomfortable experimental environment. Electroencephalogram (EEG), however, is a neural registration technique that allows the measurement of neurophysiological activation in silent and more comfortable experimental environments. Thus, it is optimal for recording brain activations during pleasant music stimulation. Using a new mathematical approach to calculate intracortical independent components (sLORETA-IC) on the basis of scalp-recorded EEG, we identified specific intracortical independent components during listening of a musical piece and scales, which differ substantially from intracortical independent components calculated from the resting state EEG. Most intracortical independent components are located bilaterally in perisylvian brain areas known to be involved in auditory processing and specifically in music perception. Some intracortical independent components differ between the music and scale listening conditions. The most prominent difference is found in the anterior part of the perisylvian brain region, with stronger activations seen in the left-sided anterior perisylvian regions during music listening, most likely indicating semantic processing during music listening. A further finding is that the intracortical independent components obtained for the music and scale listening are most prominent in higher frequency bands (e.g. beta-2 and beta-3), whereas the resting state intracortical independent components are active in lower frequency bands (alpha-1 and theta). This new technique for calculating intracortical independent components is able to differentiate independent neural networks associated

  16. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects

    NARCIS (Netherlands)

    Heerspink, Hiddo J. L.; Desai, Mehul; Jardine, Meg; Balis, Dainius; Meininger, Gary; Perkovic, Vlado

    Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a

  17. The use of multiple hierarchically independent gene ontology terms in gene function prediction and genome annotation

    NARCIS (Netherlands)

    Kourmpetis, Y.I.A.; Burgt, van der A.; Bink, M.C.A.M.; Braak, ter C.J.F.; Ham, van R.C.H.J.

    2007-01-01

    The Gene Ontology (GO) is a widely used controlled vocabulary for the description of gene function. In this study we quantify the usage of multiple and hierarchically independent GO terms in the curated genome annotations of seven well-studied species. In most genomes, significant proportions (6 -

  18. Investigation of Cool and Hot Executive Function in ODD/CD Independently of ADHD

    Science.gov (United States)

    Hobson, Christopher W.; Scott, Stephen; Rubia, Katya

    2011-01-01

    Background: Children with oppositional defiant disorder/conduct disorder (ODD/CD) have shown deficits in "cool" abstract-cognitive, and "hot" reward-related executive function (EF) tasks. However, it is currently unclear to what extent ODD/CD is associated with neuropsychological deficits, independently of attention deficit hyperactivity disorder…

  19. Repeated increases in blood flow, independent of exercise, enhance conduit artery vasodilator function in humans

    NARCIS (Netherlands)

    Naylor, L.H.; Carter, H.; Fitzsimons, M.G.; Cable, N.T.; Thijssen, D.H.J.; Green, D.J.

    2011-01-01

    This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated

  20. Independent prognostic value of left ventricular mass, diastolic function, and fasting plasma glucose

    DEFF Research Database (Denmark)

    Pareek, Manan; Nielsen, Mette Lundgren; Leósdóttir, Margrét

    2016-01-01

    OBJECTIVE: To explore the independent prognostic value of left ventricular (LV) mass, diastolic function, and fasting plasma glucose (FPG) for the prediction of incident cardiac events in a random population sample. DESIGN AND METHOD: 415 women and 999 men aged 56-79 years, included between 2002...

  1. The Revised Direct Assessment of Functional Status for Independent Older Adults

    Science.gov (United States)

    McDougall, Graham J.; Becker, Heather; Vaughan, Phillip W.; Acee, Taylor W.; Delville, Carol L.

    2010-01-01

    Purpose: The original version of the Direct Assessment of Functional Status (DAFS), a measure of instrumental activities of daily living (IADLs), was found to have a ceiling effect in older adults living independently in the community. This suggested that the tasks measured, although relevant, do not require full use of this population's…

  2. Intersection local times of independent Brownian motions as generalized white noise functionals

    OpenAIRE

    Albeverio, Sergio; Oliveira, Maria João; Streit, Ludwig

    2001-01-01

    The original publication is available at http://www.springerlink.com/content/14jtbl19nh37ggtx/fulltext.pdf A "chaos expansion" of the intersection local time functional of two independent Brownian motions in Rd is given. The expansion is in terms of normal products of white noise (corresponding to multiple Wiener integrals). As a consequence of the local structure of the normal products, the kernel functions in the expansion are explicitly given and exhibit clearly the dimension depende...

  3. Effect of siRNA-mediated silencing Bmi-1 gene expression on the proliferation of lung cancer cell line A549 in vitro and in vivo%Bmi-1-siRNA对肺腺癌A549细胞体内外增殖能力的影响

    Institute of Scientific and Technical Information of China (English)

    郑翔宇; 朱杰; 王艺芳; 刘纯青; 刘奔; 杨春辉; 刘丹丹; 孟秀香

    2013-01-01

    背景与目的:原癌基因Bmi-1是多梳基因家族中的一员,能调节正常干细胞和肿瘤干细胞的自我更新能力。近年来发现其在多种恶性肿瘤中表达上调。本文旨在观察Bmi-1基因沉默对肺腺癌A549细胞体内外增殖的影响,并初步探讨其机制。方法:根据本实验室设计的4条针对Bmi-1的小干扰RNA(siRNA)序列,选择一条已经证实最有效的序列作为靶序列和一条随机序列作为阴性对照,构建重组逆转录病毒siRNA表达载体并将其转染入A549细胞中;应用RT-PCR和蛋白质印迹法(Western blot)检测对Bmi-1基因的沉默效果;应用MTT比色法、台盼蓝拒染法及平板克隆形成实验检测Bmi-1-siRNA对A549细胞体外增殖的影响;利用流式细胞仪分析各组细胞的细胞周期;通过裸鼠腋窝皮下接种各组细胞,观察Bmi-1-siRNA对A549细胞在裸鼠体内的致瘤能力的影响;Western blot检测PTEN、p-AKT、cyclin D1、P21、P27蛋白表达。结果:Bmi-1-siRNA有效地沉默了Bmi-1基因mRNA和蛋白的表达;沉默Bmi-1基因的表达能够抑制A549细胞的体内外增殖能力,使干扰组细胞的细胞周期阻滞于G1期;沉默Bmi-1基因的表达后,干扰组细胞中PTEN、P21、P27蛋白增加,p-AKT、cyclin D1蛋白表达降低。结论:Bmi-1-siRNA通过使细胞周期阻滞于G1期来抑制肺腺癌A549的体内外增殖能力,这种抑制作用涉及cyclin D1和p-AKT表达下降以及P21/P27和PTEN的表达上调。%Background and purpose:The pro-oncogene Bmi-1 is a member of the polycomb-group family, can regulation of the proliferation and self-renewal of normal and tumor stem cells. In recent years, Bmi-1 has been found that it is overexpressed in varieties of human malignant tumors. The study aimed to observe the effects of Bmi-1-siRNA on the growth capacity of lung cancer cell line A549 in vivo and in vivo, and explore its mechanism. Methods:The most effective one as a target

  4. B-type natriuretic peptide is an independent predictor of endothelial function in man.

    Science.gov (United States)

    Pauriah, Maheshwar; Khan, Faisel; Lim, Tiong K; Elder, Douglas H; Godfrey, Valerie; Kennedy, Gwen; Belch, Jill J F; Booth, Nuala A; Struthers, Allan D; Lang, Chim C

    2012-09-01

    BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium

  5. On physical functioning after pediatric burns : Physical fitness and functional independence

    NARCIS (Netherlands)

    Disseldorp, Laurien Maria

    2015-01-01

    Burn injury can negatively impact physical functioning. This is not only due to the local damage of the skin or subsequent scarring, but also due to the disturbance of physiological processes and a period of physical inactivity. If limitations in physical functioning persist, it can affect health an

  6. On physical functioning after pediatric burns : Physical fitness and functional independence

    NARCIS (Netherlands)

    Disseldorp, Laurien Maria

    2015-01-01

    Burn injury can negatively impact physical functioning. This is not only due to the local damage of the skin or subsequent scarring, but also due to the disturbance of physiological processes and a period of physical inactivity. If limitations in physical functioning persist, it can affect health

  7. The functional independence of trait self-knowledge: commentary on Sakaki (2007).

    Science.gov (United States)

    Klein, Stanley B; Robertson, Theresa E; Gangi, Cynthia E; Loftus, Judith

    2008-01-01

    In a recent paper, Sakaki (2007) proposed that Klein and Loftus's conclusion that semantic and episodic trait self-knowledge are functionally independent (e.g., Klein, Babey, & Sherman, 1997; Klein & Loftus, 1993a; Klein, Loftus, Trafton, & Fuhrman, 1992b) was based on questionable assumptions and not supported by the available evidence. In this paper we show that Sakaki (2007) has misinterpreted our position on the independence of self-knowledge, omitted mention of large portions of the relevant research at odds with her contention, and conducted her studies with procedures we explicitly warned against due to interpretive ambiguities associated with their use.

  8. IMPROVING FUNCTIONAL INDEPENDENCE OF PATIENTS WITH MULTIPLE SCLEROSIS BY PHYSICAL THERAPY AND OCCUPATIONAL THERAPY

    Directory of Open Access Journals (Sweden)

    Ana-Maria Ticărat

    2011-06-01

    Full Text Available Introduction. Patients with multiple sclerosis can have a normal life despite of their real or possible disability and of the progressive nature of it. Scope. Patients who follow physical therapy and occupational therapy will have an increased quality of life and a greater functional independence.Methods. The randomized study was made on 7 patients with multiple sclerosis, from Oradea Day Centre, 3 times/week, ages between 35 – 55 years, functional level between mild and sever. Assessment and rehabilitation methods: inspection, BARTHEL Index. Frenkel method, brething exercises, weights exercises, gait exercises, writind exercises and games were used in the rehabilitation process. Group therapies: sociotherapy, arttherapy, music therapy. Results analysis consisted of the comparison of baseline and final means.Results. By analizing baseline and final means for Barthel Index for each functon separately, it was shown a mild improvement of functional independence for almost assessed functions, with at least 1-1,5 points.Conclusions. Persons with multiple sclerosis who follow physical therapy and occupational therapy presents a better functional independence after the treatment.

  9. Balance, autonomy and functional independence of active and sedentary elderly: a preliminary study

    Directory of Open Access Journals (Sweden)

    Arthur Matheus da Silva

    2016-01-01

    Full Text Available Both the body balance (BB, as the functional autonomy (FA and the level of functional independence (FI of 10 sedentary elderly (GI were evaluated and compared to related data in 10 active elderly (GII, all of the health program family in Araxá-MG, after signing the informed consent, were submitted to the evaluation tests of the EC, the AF and the NIF, besides the identification of BMI. Although body overweight and equal NIF between both the EC and AF were significantly higher in GII than in GI, we concluded that the practice of therapeutic exercise promotes functional health in the elderly.  

  10. Field dependence-independence (FDI) cognitive style: an analysis of attentional functioning.

    Science.gov (United States)

    Guisande, M Adelina; Páramo, M Fernanda; Tinajero, Carolina; Almeida, Leandro S

    2007-11-01

    Previous research has indicated that field-dependent children display poorer performance than field-independent children in almost all academic subjects and cognitive tasks. However, the processes underlying this poorer performance remain unclear. The present study aimed to assess whether children with different FDI cognitive styles show differences in performance of tasks measuring aspects of attentional functioning. Specifically, 149 children aged 8 - 11 years were classified according to FDI cognitive style (field-dependent, intermediate, or field-independent), and to storage capacity (Digits Forward Test), verbal working memory (Digits Backward Test), capacity to focus, shift, and maintain attention (Digit Symbol Test), and capacity for sustained attention (Visual Search and Attention Test). Field-independent children displayed better performance than intermediate and field-dependent children on all tests except the Digits Forward Test. Theoretical and practical implications of these results are discussed.

  11. Sedentary behavior and physical activity are independently related to functional fitness in older adults.

    Science.gov (United States)

    Santos, Diana A; Silva, Analiza M; Baptista, Fátima; Santos, Rute; Vale, Susana; Mota, Jorge; Sardinha, Luís B

    2012-12-01

    The last decades of life have been traditionally viewed as a time of inevitable disease and frailty. Sedentary living and physical activity may influence capacity to perform activities that are needed to maintain physical independence in daily living. A total of 117 males and 195 females, aged 65-103years, were assessed for physical activity and sedentary time with accelerometers and for functional fitness with the Senior Fitness Test battery. Based on the individual scores for each fitness item, a Z-score was created. Associations between functional fitness with sedentary time and moderate-to-vigorous physical activity (MVPA) were analyzed. A negative association was found between the composite Z-score for functional fitness and the sedentary time, even adjusting for MVPA and other confounders. On the other hand, MVPA was positively associated with the composite Z-score for functional fitness, independently of the sedentary time. In conclusion elderly who spend more time in physical activity or less time in sedentary behaviors exhibit improved functional fitness and other confounders. The results reinforce the importance of promoting both the reduction of sedentary behaviors and the increase of MVPA in this age group, as it may interfere at older ages in order to preserve functional fitness and performance of daily functioning tasks.

  12. Microwave DENSITY—INDEPENDENT Permittivity Functions as Spring Oats Kernels' Moisture Calibrators: a New Approach

    Science.gov (United States)

    Das, Priyanka; Ahmad, Zeeshan; Singh, P. N.; Prasad, Ashutosh

    2011-11-01

    The present work makes use of experimental data for real part of microwave complex permittivity of spring oats (Avena sativa L.) at 2.45 GHz and 24 °C as a function of moisture content, as extracted from the literature. These permittivity data were individually converted to those for solid materials using seven independent mixture equations for effective permittivity of random media. Moisture dependent quadratic models for complex permittivity of spring oats (Avena sativa L.), as developed by the present group, were used to evaluate the dielectric loss factor of spring oats kernels. Using these data, seven density—independent permittivity functions were evaluated and plotted as a function of moisture content of the samples. Second and third order polynomial regression equations were used for curve fittings with these data and their performances are reported. Coefficients of determination (r2) approaching unity (˜ 0.95-0.9999) and very small Standard Deviation (SD) ˜0.001-8.87 show good acceptability for these models. The regularity in the nature of these variations revealed the usefulness of the density—independent permittivity functions as indicators/calibrators of moisture content of spring oats kernels. Keeping in view the fact that moisture content of grains and seeds is an important factor determining quality and affecting the storage, transportation, and milling of grains and seeds, the work has the potentiality of its practical applications.

  13. P wave dispersion and maximum P wave duration are independently associated with rapid renal function decline.

    Directory of Open Access Journals (Sweden)

    Ho-Ming Su

    Full Text Available The P wave parameters measured by 12-lead electrocardiogram (ECG are commonly used as noninvasive tools to assess for left atrial enlargement. There are limited studies to evaluate whether P wave parameters are independently associated with decline in renal function. Accordingly, the aim of this study is to assess whether P wave parameters are independently associated with progression to renal end point of ≥25% decline in estimated glomerular filtration rate (eGFR. This longitudinal study included 166 patients. The renal end point was defined as ≥25% decline in eGFR. We measured two ECG P wave parameters corrected by heart rate, i.e. corrected P wave dispersion (PWdisperC and corrected P wave maximum duration (PWdurMaxC. Heart function and structure were measured from echocardiography. Clinical data, P wave parameters, and echocardiographic measurements were compared and analyzed. Forty-three patients (25.9% reached renal end point. Kaplan-Meier curves for renal end point-free survival showed PWdisperC > median (63.0 ms (log-rank P = 0.004 and PWdurMaxC > median (117.9 ms (log-rank P<0.001 were associated with progression to renal end point. Multivariate forward Cox-regression analysis identified increased PWdisperC (hazard ratio [HR], 1.024; P = 0.001 and PWdurMaxC (HR, 1.029; P = 0.001 were independently associated with progression to renal end point. Our results demonstrate that increased PWdisperC and PWdurMaxC were independently associated with progression to renal end point. Screening patients by means of PWdisperC and PWdurMaxC on 12 lead ECG may help identify a high risk group of rapid renal function decline.

  14. "Real world" functioning in schizophrenia patients and healthy adults: assessing validity of the Multidimensional Scale of Independent Functioning.

    Science.gov (United States)

    Miles, Ashley A; Heinrichs, R Walter; Ammari, Narmeen

    2011-03-30

    As treatment efforts to enhance cognitive abilities in schizophrenia increase, so too does the need for a critical appraisal of instruments that measure functionality and adjustment to community living. The Multidimensional Scale of Independent Functioning (MSIF; Jaeger et al., 2003) is a promising instrument that assesses functionality in relation to different life settings, performance levels, responsibilities and environmental supports. However, its applicability to the schizophrenia population has been questioned because relevant data are scarce. This study provides descriptive and validity-related information by reporting MSIF scores in healthy community-dwelling adults (n=71) and in schizophrenia outpatients (n=156). Results show that healthy adults performed within defined "normal" ranges in most MSIF domains in comparison to schizophrenia patients who showed moderate to severe impairments. Moreover, the MSIF distinguished between the two groups with accuracy rates as high as 98% and effect sizes (standardized mean group difference) above 2.0 in almost all domains. Accordingly, the MSIF is a potentially valuable measure of community independence that can inform treatment initiatives and may be adaptable to the evaluation of functionality changes over time. The unique structure and content of information obtained by the MSIF makes it a candidate for inclusion in studies aimed at developing a new generation of instruments for the assessment of real world functioning in schizophrenia.

  15. Independent effects of early-life experience and trait aggression on cardiovascular function.

    Science.gov (United States)

    Rana, Samir; Pugh, Phyllis C; Katz, Erin; Stringfellow, Sara A; Lin, Chee Paul; Wyss, J Michael; Stauss, Harald M; White, C Roger; Clinton, Sarah M; Kerman, Ilan A

    2016-08-01

    Early-life experience (ELE) can significantly affect life-long health and disease, including cardiovascular function. Specific dimensions of emotionality also modify risk of disease, and aggressive traits along with social inhibition have been established as independent vulnerability factors for the progression of cardiovascular disease. Yet, the biological mechanisms mediating these associations remain poorly understood. The present study utilized the inherently stress-susceptible and socially inhibited Wistar-Kyoto rats to determine the potential influences of ELE and trait aggression (TA) on cardiovascular parameters throughout the lifespan. Pups were exposed to maternal separation (MS), consisting of daily 3-h separations of the entire litter from postnatal day (P)1 to P14. The rats were weaned at P21, and as adults were instrumented for chronic radiotelemetry recordings of blood pressure and heart rate (HR). Adult aggressive behavior was assessed using the resident-intruder test, which demonstrated that TA was independent of MS exposure. MS-exposed animals (irrespective of TA) had significantly lower resting HR accompanied by increases in HR variability. No effects of MS on resting blood pressure were detected. In contrast, TA correlated with increased resting mean, systolic, and diastolic arterial pressures but had no effect on HR. TA rats (relative to nonaggressive animals) also manifested increased wall-to-lumen ratio in the thoracic aorta, increased sensitivity to phenylephrine-induced vascular contractility, and increased norepinephrine content in the heart. Together these data suggest that ELE and TA are independent factors that impact baseline cardiovascular function.

  16. Diastolic function is strongly and independently associated with cardiorespiratory fitness in central obesity.

    Science.gov (United States)

    Turzyniecka, M; Wild, S H; Krentz, A J; Chipperfield, A J; Clough, G F; Byrne, C D

    2010-06-01

    Cardiorespiratory fitness [maximal O2 consumption (VO2max)] is an independent risk factor for type 2 diabetes; but in individuals at risk, factors influencing VO2max are poorly understood. We tested the hypothesis that VO2max is associated with diastolic function [subendocardial variability ratio (SEVR), %], as diastolic function influences myocardial perfusion. We studied 47 men and women with central obesity without diabetes. We measured fitness (VO2max) by treadmill testing and diastolic function (SEVR%) by pulse-wave analysis. We measured other factors influencing this relationship: insulin sensitivity [whole body glucose uptake-to-insulin concentration ratio (M/I)] by hyperinsulinemic euglycemic clamp, fatness by MR imaging and dual-energy X-ray absorptiometry, physical activity energy expenditure (metabolic equivalents of tasks) by the Sensewear Pro2 device, and muscle microvascular exchange capacity (capillary filtration coefficient) by venous plethysmography. Mean age of the subjects was 51+/-9 (SD) yr. VO2max was associated with SEVR% (r=0.50, P=0.001), fatness (r=-0.39, P=0.008), and HbA1c (r=-0.35, P=0.018), but not with whole body glucose uptake-to-insulin concentration ratio, metabolic equivalents of tasks, or capillary filtration coefficient. In regression modeling with age, sex, fatness, and SEVR% as explanatory variables, only age, sex, and SEVR% were independently associated with VO2max (SEVR%--standardized B coefficient=0.37, 95% confidence interval=0.003-0.18, P=0.007). This model identified 46% of the variance in VO2max (R2=0.46, P=0.0001). There was a strong, independent association between VO2max and a measure of diastolic function in sedentary individuals with central obesity.

  17. The independent contribution of executive functions to health related quality of life in older women

    Directory of Open Access Journals (Sweden)

    Marra Carlo A

    2010-04-01

    Full Text Available Abstract Background Cognition is a multidimensional construct and to our knowledge, no previous studies have examined the independent contribution of specific domains of cognition to health related quality of life. To determine whether executive functions are independently associated with health related quality of life assessed using Quality Adjusted Life Years (QALYs calculated from the EuroQol EQ-5D (EQ-5D in older women after adjusting for known covariates, including global cognition. Therefore, we conducted a secondary analysis of community-dwelling older women aged 65-75 years who participated in a 12-month randomized controlled trial of resistance training. We assessed global cognition using the Mini-Mental State Examination (MMSE and executive functions using the: 1 Stroop Test; 2 Trail Making Test (Part B and 3 Digits Verbal Span Backwards Test. We calculated QALYs from the EQ-5D administered at baseline, 6 months and 12 months. Results Our multivariate linear regression model demonstrated the specific executive processes of set shifting and working memory, as measured by Trail Making Test (Part B and Digits Verbal Span Backward Test (p Conclusions Our study highlights the specific executive processes of set shifting and working memory were independently associated with QALYs -- a measure of health related quality of life. Given that executive functions explain variability in QALYs, clinicians may need to consider assessing executive functions when measuring health related quality of life. Further, the EQ-5D may be used to track changes in health status over time and serve as a screening tool for clinicians. Trial Registration ClinicalTrials.gov Identifier: NCT00426881.

  18. Task-evoked brain functional magnetic susceptibility mapping by independent component analysis (χICA).

    Science.gov (United States)

    Chen, Zikuan; Calhoun, Vince D

    2016-03-01

    Conventionally, independent component analysis (ICA) is performed on an fMRI magnitude dataset to analyze brain functional mapping (AICA). By solving the inverse problem of fMRI, we can reconstruct the brain magnetic susceptibility (χ) functional states. Upon the reconstructed χ dataspace, we propose an ICA-based brain functional χ mapping method (χICA) to extract task-evoked brain functional map. A complex division algorithm is applied to a timeseries of fMRI phase images to extract temporal phase changes (relative to an OFF-state snapshot). A computed inverse MRI (CIMRI) model is used to reconstruct a 4D brain χ response dataset. χICA is implemented by applying a spatial InfoMax ICA algorithm to the reconstructed 4D χ dataspace. With finger-tapping experiments on a 7T system, the χICA-extracted χ-depicted functional map is similar to the SPM-inferred functional χ map by a spatial correlation of 0.67 ± 0.05. In comparison, the AICA-extracted magnitude-depicted map is correlated with the SPM magnitude map by 0.81 ± 0.05. The understanding of the inferiority of χICA to AICA for task-evoked functional map is an ongoing research topic. For task-evoked brain functional mapping, we compare the data-driven ICA method with the task-correlated SPM method. In particular, we compare χICA with AICA for extracting task-correlated timecourses and functional maps. χICA can extract a χ-depicted task-evoked brain functional map from a reconstructed χ dataspace without the knowledge about brain hemodynamic responses. The χICA-extracted brain functional χ map reveals a bidirectional BOLD response pattern that is unavailable (or different) from AICA. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Evolution of selenophosphate synthetases: emergence and relocation of function through independent duplications and recurrent subfunctionalization.

    Science.gov (United States)

    Mariotti, Marco; Santesmasses, Didac; Capella-Gutierrez, Salvador; Mateo, Andrea; Arnan, Carme; Johnson, Rory; D'Aniello, Salvatore; Yim, Sun Hee; Gladyshev, Vadim N; Serras, Florenci; Corominas, Montserrat; Gabaldón, Toni; Guigó, Roderic

    2015-09-01

    Selenoproteins are proteins that incorporate selenocysteine (Sec), a nonstandard amino acid encoded by UGA, normally a stop codon. Sec synthesis requires the enzyme Selenophosphate synthetase (SPS or SelD), conserved in all prokaryotic and eukaryotic genomes encoding selenoproteins. Here, we study the evolutionary history of SPS genes, providing a map of selenoprotein function spanning the whole tree of life. SPS is itself a selenoprotein in many species, although functionally equivalent homologs that replace the Sec site with cysteine (Cys) are common. Many metazoans, however, possess SPS genes with substitutions other than Sec or Cys (collectively referred to as SPS1). Using complementation assays in fly mutants, we show that these genes share a common function, which appears to be distinct from the synthesis of selenophosphate carried out by the Sec- and Cys- SPS genes (termed SPS2), and unrelated to Sec synthesis. We show here that SPS1 genes originated through a number of independent gene duplications from an ancestral metazoan selenoprotein SPS2 gene that most likely already carried the SPS1 function. Thus, in SPS genes, parallel duplications and subsequent convergent subfunctionalization have resulted in the segregation to different loci of functions initially carried by a single gene. This evolutionary history constitutes a remarkable example of emergence and evolution of gene function, which we have been able to trace thanks to the singular features of SPS genes, wherein the amino acid at a single site determines unequivocally protein function and is intertwined to the evolutionary fate of the entire selenoproteome.

  20. Independent Effects of Bilingualism and Socioeconomic Status on Language Ability and Executive Functioning

    Science.gov (United States)

    Calvo, Alejandra; Bialystok, Ellen

    2014-01-01

    One hundred and seventy-five children who were 6-years old were assigned to one of four groups that differed in socioeconomic status (SES; working class or middle class) and language background (monolingual or bilingual). The children completed tests of nonverbal intelligence, language tests assessing receptive vocabulary and attention based on picture naming, and two tests of executive functioning. All children performed equivalently on the basic intelligence tests, but performance on the language and executive functioning tasks was influenced by both SES and bilingualism. Middle-class children outperformed working-class children on all measures, and bilingual children obtained lower scores than monolingual children on language tests but higher scores than monolingual children on the executive functioning tasks. There were no interactions with either group factors or task factors. Thus, each of SES and bilingualism contribute significantly and independently to children’s development irrespective of the child’s level on the other factor. PMID:24374020

  1. Tamoxifen and its active metabolites inhibit dopamine transporter function independently of the estrogen receptors.

    Science.gov (United States)

    Mikelman, Sarah R; Guptaroy, Bipasha; Gnegy, Margaret E

    2017-04-01

    As one of the primary mechanisms by which dopamine signaling is regulated, the dopamine transporter (DAT) is an attractive pharmacological target for the treatment of diseases based in dopaminergic dysfunction. In this work we demonstrate for the first time that the commonly prescribed breast cancer therapeutic tamoxifen and its major metabolites, 4-hydroxytamoxifen and endoxifen, inhibit DAT function. Tamoxifen inhibits [(3) H]dopamine uptake into human DAT (hDAT)-N2A cells via an uncompetitive or mixed mechanism. Endoxifen, an active metabolite of tamoxifen, asymmetrically inhibits DAT function in hDAT-N2A cells, showing a preference for the inhibition of amphetamine-stimulated dopamine efflux as compared to dopamine uptake. Importantly, we demonstrate that the effects of tamoxifen and its metabolites on the DAT occur independently of its activity as selective estrogen receptor modulators. This work suggests that tamoxifen is inhibiting DAT function through a previously unidentified mechanism. © 2017 International Society for Neurochemistry.

  2. Independent effects of bilingualism and socioeconomic status on language ability and executive functioning.

    Science.gov (United States)

    Calvo, Alejandra; Bialystok, Ellen

    2014-03-01

    One hundred and seventy-five children who were 6-years old were assigned to one of four groups that differed in socioeconomic status (SES; working class or middle class) and language background (monolingual or bilingual). The children completed tests of nonverbal intelligence, language tests assessing receptive vocabulary and attention based on picture naming, and two tests of executive functioning. All children performed equivalently on the basic intelligence tests, but performance on the language and executive functioning tasks was influenced by both SES and bilingualism. Middle-class children outperformed working-class children on all measures, and bilingual children obtained lower scores than monolingual children on language tests but higher scores than monolingual children on the executive functioning tasks. There were no interactions with either group factors or task factors. Thus, each of SES and bilingualism contribute significantly and independently to children's development irrespective of the child's level on the other factor. Copyright © 2013 Elsevier B.V. All rights reserved.

  3. 拮抗细菌BMY-1菌株对几种水果储藏病原真菌的抑制作用%Inhibition of Antagonistic Bacterium BMY-1 on Fungal Pathogens of Some Postharvest Fruits and Controls on Fruit Rots

    Institute of Scientific and Technical Information of China (English)

    暴增海; 李一; 曹冬阳

    2007-01-01

    采用平板对峙培养法测定从土壤中分离获得的拮抗细菌BMY-1菌株对柑桔绿霉病菌(Penicillium digatatum)、柑桔青霉病菌(Penicillium italicum)、苹果炭疽病菌(Glomerella cingulata)、苹果轮纹病菌(Physalospora piricola)、梨扩展青霉病菌(Penicillium expansum)、葡萄白腐病菌(Coniothyrium dlodiella)等6种水果产后病原真菌的抑制作用.结果表明,BMY-1菌株对苹果炭疽病菌(G.cingulata)和梨扩展青霉菌(P.expansum)的生长有较好的作用,抑菌率分别达48.43%和50.37%.采用液体共培养法观察到BMY-1菌株对病原真菌的菌丝有破坏作用,使苹果炭疽病菌菌丝扭曲和断裂,葡萄白腐病菌菌丝膨大畸形.对几种水果同时接种拮抗细菌BMY-1和病原真菌,BMY-1菌株对苹果炭疽病病斑和梨扩青病病斑扩展有较强的抑制作用,并能有效延迟葡萄白腐病发病时间.

  4. Independence of hot and cold executive function deficits in high-functioning adults with autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    David Laird Zimmerman

    2016-02-01

    Full Text Available Individuals with autistic spectrum disorder (ASD display diverse deficits in social, cognitive and behavioral functioning. To date, there has been mixed findings on the profile of executive function deficits for high-functioning adults (IQ >70 with ASD. A conceptual distinction is commonly made between cold and hot executive functions. Cold executive functions refer to mechanistic higher-order cognitive operations (e.g., working memory, whereas hot executive functions entail cognitive abilities supported by emotional awareness and social perception (e.g., social cognition. This study aimed to determine the independence of deficits in hot and cold executive functions for high-functioning adults with ASD. Forty-two adults with ASD (64% male, aged 18-66 years and 40 age and gender matched controls were administered The Awareness of Social Inference Test (TASIT; emotion recognition and social inference, Letter Number Sequencing (working memory and Hayling Sentence Completion Test (response initiation and suppression. Between-group analyses identified that the ASD group performed significantly worse than matched controls on all measures of cold and hot executive functions (d = .54-1.5. Hierarchical multiple regression analyses revealed that the ASD sample performed more poorly on emotion recognition and social inference tasks than matched controls after controlling for cold executive functions and employment status. The findings also indicated that the ability to recognise emotions and make social inferences was supported by working memory and response initiation and suppression processes. Overall, this study supports the distinction between hot and cold executive function impairments for adults with ASD. Moreover, it advances understanding of higher-order impairments underlying social interaction difficulties for this population which, in turn, may assist with diagnosis and inform intervention programs.

  5. Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria.

    Science.gov (United States)

    Chiodi, Ilaria; Mondello, Chiara

    2012-01-01

    Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.

  6. CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.

    Directory of Open Access Journals (Sweden)

    Selena Viganò

    2014-09-01

    Full Text Available Expression of co-inhibitory molecules is generally associated with T-cell dysfunction in chronic viral infections such as HIV or HCV. However, their relative contribution in the T-cell impairment remains unclear. In the present study, we have evaluated the impact of the expression of co-inhibitory molecules such as 2B4, PD-1 and CD160 on the functions of CD8 T-cells specific to influenza, EBV and CMV. We show that CD8 T-cell populations expressing CD160, but not PD-1, had reduced proliferation capacity and perforin expression, thus indicating that the functional impairment in CD160(+ CD8 T cells may be independent of PD-1 expression. The blockade of CD160/CD160-ligand interaction restored CD8 T-cell proliferation capacity, and the extent of restoration directly correlated with the ex vivo proportion of CD160(+ CD8 T cells suggesting that CD160 negatively regulates TCR-mediated signaling. Furthermore, CD160 expression was not up-regulated upon T-cell activation or proliferation as compared to PD-1. Taken together, these results provide evidence that CD160-associated CD8 T-cell functional impairment is independent of PD-1 expression.

  7. Independent component analysis of high-resolution imaging data identifies distinct functional domains

    DEFF Research Database (Denmark)

    Reidl, Juergen; Starke, Jens; Omer, David

    2007-01-01

    . Here we demonstrate that principal component analysis (PCA) followed by spatial independent component analysis (sICA), can be exploited to reduce the dimensionality of data sets recorded in the olfactory bulb and the somatosensory cortex of mice as well as the visual cortex of monkeys, without loosing...... be automatically detected. In the visual cortex orientation columns can be extracted. In all cases artifacts due to movement, heartbeat or respiration were separated from the functional signal by sICA and could be removed from the data set. sICA is therefore a powerful technique for data compression, unbiased...

  8. (Prorenin receptor triggers distinct angiotensin II-independent extracellular matrix remodeling and deterioration of cardiac function.

    Directory of Open Access Journals (Sweden)

    Anne-Mari Moilanen

    Full Text Available BACKGROUND: Activation of the renin-angiotensin-system (RAS plays a key pathophysiological role in heart failure in patients with hypertension and myocardial infarction. However, the function of (prorenin receptor ((PRR is not yet solved. We determined here the direct functional and structural effects of (PRR in the heart. METHODOLOGY/PRINCIPAL FINDINGS: (PRR was overexpressed by using adenovirus-mediated gene delivery in normal adult rat hearts up to 2 weeks. (PRR gene delivery into the anterior wall of the left ventricle decreased ejection fraction (P<0.01, fractional shortening (P<0.01, and intraventricular septum diastolic and systolic thickness, associated with approximately 2-fold increase in left ventricular (PRR protein levels at 2 weeks. To test whether the worsening of cardiac function and structure by (PRR gene overexpression was mediated by angiotensin II (Ang II, we infused an AT(1 receptor blocker losartan via osmotic minipumps. Remarkably, cardiac function deteriorated in losartan-treated (PRR overexpressing animals as well. Intramyocardial (PRR gene delivery also resulted in Ang II-independent activation of extracellular-signal-regulated kinase1/2 phosphorylation and myocardial fibrosis, and the expression of transforming growth factor-β1 and connective tissue growth factor genes. In contrast, activation of heat shock protein 27 phosphorylation and apoptotic cell death by (PRR gene delivery was Ang II-dependent. Finally, (PRR overexpression significantly increased direct protein-protein interaction between (PRR and promyelocytic zinc-finger protein. CONCLUSIONS/SIGNIFICANCE: These results indicate for the first time that (PRR triggers distinct Ang II-independent myocardial fibrosis and deterioration of cardiac function in normal adult heart and identify (PRR as a novel therapeutic target to optimize RAS blockade in failing hearts.

  9. Principal and independent component analysis of concomitant functional near infrared spectroscopy and magnetic resonance imaging data

    Science.gov (United States)

    Schelkanova, Irina; Toronov, Vladislav

    2011-07-01

    Although near infrared spectroscopy (NIRS) is now widely used both in emerging clinical techniques and in cognitive neuroscience, the development of the apparatuses and signal processing methods for these applications is still a hot research topic. The main unresolved problem in functional NIRS is the separation of functional signals from the contaminations by systemic and local physiological fluctuations. This problem was approached by using various signal processing methods, including blind signal separation techniques. In particular, principal component analysis (PCA) and independent component analysis (ICA) were applied to the data acquired at the same wavelength and at multiple sites on the human or animal heads during functional activation. These signal processing procedures resulted in a number of principal or independent components that could be attributed to functional activity but their physiological meaning remained unknown. On the other hand, the best physiological specificity is provided by broadband NIRS. Also, a comparison with functional magnetic resonance imaging (fMRI) allows determining the spatial origin of fNIRS signals. In this study we applied PCA and ICA to broadband NIRS data to distill the components correlating with the breath hold activation paradigm and compared them with the simultaneously acquired fMRI signals. Breath holding was used because it generates blood carbon dioxide (CO2) which increases the blood-oxygen-level-dependent (BOLD) signal as CO2 acts as a cerebral vasodilator. Vasodilation causes increased cerebral blood flow which washes deoxyhaemoglobin out of the cerebral capillary bed thus increasing both the cerebral blood volume and oxygenation. Although the original signals were quite diverse, we found very few different components which corresponded to fMRI signals at different locations in the brain and to different physiological chromophores.

  10. Oral hygiene caregivers' educational programme improves oral health conditions in institutionalised independent and functional elderly.

    Science.gov (United States)

    Portella, Fernando F; Rocha, Aline W; Haddad, Daniel C; Fortes, Carmem B B; Hugo, Fernando N; Padilha, Dalva M P; Samuel, Susana M W

    2015-03-01

    The goal of this study was to determine the impact of an oral hygiene education programme for caregivers on the oral health of institutionalised elderly and to examine the effect of disability and low muscle strength on programme outcomes. The subjects of this study were geriatric patients (n = 80) from a nursing home. Katz Index for activities of daily living, handgrip strength and mucosal-plaque score (MPS) was evaluated at baseline and 1 year after intervention. The intervention consisted of an educational programme and specific guidelines for caregivers (to perform oral hygiene for dependent elderly and to supervise the independent elderly during oral hygiene practices). Differences on MPS were evaluated using a paired-sample t-test. A stratified analysis was carried out to identify differences in response to the programme according to the Katz Index and handgrip strength of elderly. The MPS was significantly reduced (p = 0.001) at follow-up; however, a separate analysis showed that only the independent elderly (p = 0.002) and those with normal muscle strength (p = 0.006) showed a reduction in MPS during the follow-up examination. The oral hygiene education programme for caregivers resulted in a positive impact on oral hygiene of the independent and functional elderly. © 2013 The Gerodontology Society and John Wiley & Sons A/S.

  11. Transcription-independent function of Polycomb group protein PSC in cell cycle control.

    Science.gov (United States)

    Mohd-Sarip, Adone; Lagarou, Anna; Doyen, Cecile M; van der Knaap, Jan A; Aslan, Ülkü; Bezstarosti, Karel; Yassin, Yasmin; Brock, Hugh W; Demmers, Jeroen A A; Verrijzer, C Peter

    2012-05-11

    Polycomb group (PcG) proteins control development and cell proliferation through chromatin-mediated transcriptional repression. We describe a transcription-independent function for PcG protein Posterior sex combs (PSC) in regulating the destruction of cyclin B (CYC-B). A substantial portion of PSC was found outside canonical PcG complexes, instead associated with CYC-B and the anaphase-promoting complex (APC). Cell-based experiments and reconstituted reactions established that PSC and Lemming (LMG, also called APC11) associate and ubiquitylate CYC-B cooperatively, marking it for proteosomal degradation. Thus, PSC appears to mediate both developmental gene silencing and posttranslational control of mitosis. Direct regulation of cell cycle progression might be a crucial part of the PcG system's function in development and cancer.

  12. Independent influence of dietary protein on markers of kidney function and disease in obesity.

    Science.gov (United States)

    Friedman, Allon N; Yu, Zhangsheng; Juliar, Beth E; Nguyen, James T; Strother, Matthew; Quinney, Sara K; Li, Lang; Inman, Margaret; Gomez, Gerardo; Shihabi, Zak; Moe, Sharon

    2010-10-01

    Obesity is associated with glomerular hyperfiltration and increased urinary protein excretion, as well as structural and functional changes that lead to kidney disease and failure. Dietary protein mimics obesity's effects on the glomerular filtration rate (GFR) and proteinuria and, in certain circumstances, may have the potential to adversely affect kidney function. Here we tested the hypothesis that dietary protein independently explains elevations in the GFR and proteinuria found in obese persons with a normal serum creatinine. Seventeen patients were randomized in a double-blind, crossover fashion for 1-week periods to high (140 g/day) and low (50 g/day) protein diets with a 1-week washout interval separating these periods. High protein consumption was associated with a very modest but significant increase in the GFR of 5 ± 6 ml/min. Hence, while dietary protein does modulate kidney parameters, it is unlikely to fully account for the elevations in GFR and proteinuria found in obesity.

  13. Unpolarized structure functions and the parton distributions for nucleon in an independent quark model

    Indian Academy of Sciences (India)

    N Barik; R N Mishra

    2001-04-01

    Considering the nucleon as consisting entirely of its valence quarks confined independently in a scalar-vector harmonic potential; unpolarized structure functions 1(,2) and 2(x,2) are derived in the Bjorken limit under certain simplifying assumptions; from which valence quark distribution functions (,2) and (,2) are appropriately extracted satisfying the normalization constraints. QCD-evolution of these input distributions from a model scale of 2=0.07 GeV2 to a higher $Q^{2}$ scale of $Q^{2}_{0} = 15$ GeV2 yields (, $Q^{2}_{0}$) and (, $Q^{2}_{0}$) in good agreement with experimental data. The gluon and sea-quark distributions such as (,$Q^{2}_{0}$) and (, $Q^{2}_{0}$) are dynamically generated with a reasonable qualitative agreement with the available data; using the leading order renormalization group equations with appropriate valence-quark distributions as the input.

  14. Independent functional connectivity networks underpin food and monetary reward sensitivity in excess weight.

    Science.gov (United States)

    Verdejo-Román, Juan; Fornito, Alex; Soriano-Mas, Carles; Vilar-López, Raquel; Verdejo-García, Antonio

    2017-02-01

    Overvaluation of palatable food is a primary driver of obesity, and is associated with brain regions of the reward system. However, it remains unclear if this network is specialized in food reward, or generally involved in reward processing. We used functional magnetic resonance imaging (fMRI) to characterize functional connectivity during processing of food and monetary rewards. Thirty-nine adults with excess weight and 37 adults with normal weight performed the Willingness to Pay for Food task and the Monetary Incentive Delay task in the fMRI scanner. A data-driven graph approach was applied to compare whole-brain, task-related functional connectivity between groups. Excess weight was associated with decreased functional connectivity during the processing of food rewards in a network involving primarily frontal and striatal areas, and increased functional connectivity during the processing of monetary rewards in a network involving principally frontal and parietal areas. These two networks were topologically and anatomically distinct, and were independently associated with BMI. The processing of food and monetary rewards involve segregated neural networks, and both are altered in individuals with excess weight.

  15. Circulating Adiponectin Is Associated with Renal Function Independent of Age and Serum Lipids in West Africans

    Directory of Open Access Journals (Sweden)

    A. P. Doumatey

    2012-01-01

    Full Text Available Adiponectin, a protein secreted by adipose tissue, has been associated with renal dysfunction. However, these observations have not been adequately investigated in large epidemiological studies of healthy individuals in general and in African populations in particular. Hence, we designed this study to evaluate the relationship between adiponectin and renal function in a large group of nondiabetic West Africans. Total adiponectin was measured in 792 participants. MDRD and Cockroft-Gault (CG- estimated GFR were used as indices of renal function. Linear and logistic regression models were used to determine the relationship between adiponectin and renal function. Adiponectin showed an inverse relationship with eGFR in univariate (BetaMDRD=-0.18, BetaCG=-0.26 and multivariate (BetaMDRD=-0.10, BetaCG=-0.09 regression analyses. The multivariate models that included age, sex, BMI, hypertension, smoking, HDL-C, LDL-C, triglycerides, and adiponectin explained 30% and 55.6% of the variance in GFR estimated by MDRD and CG methods, respectively. Adiponectin was also a strong predictor of moderate chronic kidney disease (defined as eGFR < 60 mL/min/1.73 m2. We demonstrate that adiponectin is associated with renal function in nondiabetic West Africans. The observed relationship is independent of age and serum lipids. Our findings suggest that adiponectin may have clinical utility as a biomarker of renal function.

  16. Personality traits, education, physical exercise, and childhood neurological function as independent predictors of adult obesity.

    Directory of Open Access Journals (Sweden)

    Helen Cheng

    Full Text Available OBJECTIVE: To investigate whether personality traits, education, physical exercise, parental socio-economic conditions, and childhood neurological function are independently associated with obesity in 50 year old adults in a longitudinal birth cohort study. METHOD: The sample consisted of 5,921 participants born in Great Britain in 1958 and followed up at 7, 11, 33, 42, and 50 years with data on body mass index measured at 42 and 50 years. RESULTS: There was an increase of adult obesity from 14.2% at age 42 to 23.6% at 50 years. Cohort members who were reported by teachers on overall clumsiness as "certainly applied" at age 7 were more likely to become obese at age 50. In addition, educational qualifications, traits Conscientiousness and Extraversion, psychological distress, and physical exercise were all significantly associated with adult obesity. The associations remained to be significant after controlling for birth weight and gestation, maternal and paternal BMI, childhood BMI, childhood intelligence and behavioural adjustment, as well as diet. CONCLUSION: Neurological function in childhood, education, trait Conscientiousness, and exercise were all significantly and independently associated with adult obesity, each explained unique individual variability.

  17. Personality Traits, Education, Physical Exercise, and Childhood Neurological Function as Independent Predictors of Adult Obesity

    Science.gov (United States)

    Cheng, Helen; Furnham, Adrian

    2013-01-01

    Objective To investigate whether personality traits, education, physical exercise, parental socio-economic conditions, and childhood neurological function are independently associated with obesity in 50 year old adults in a longitudinal birth cohort study. Method The sample consisted of 5,921 participants born in Great Britain in 1958 and followed up at 7, 11, 33, 42, and 50 years with data on body mass index measured at 42 and 50 years. Results There was an increase of adult obesity from 14.2% at age 42 to 23.6% at 50 years. Cohort members who were reported by teachers on overall clumsiness as “certainly applied” at age 7 were more likely to become obese at age 50. In addition, educational qualifications, traits Conscientiousness and Extraversion, psychological distress, and physical exercise were all significantly associated with adult obesity. The associations remained to be significant after controlling for birth weight and gestation, maternal and paternal BMI, childhood BMI, childhood intelligence and behavioural adjustment, as well as diet. Conclusion Neurological function in childhood, education, trait Conscientiousness, and exercise were all significantly and independently associated with adult obesity, each explained unique individual variability. PMID:24250828

  18. Personality traits, education, physical exercise, and childhood neurological function as independent predictors of adult obesity.

    Science.gov (United States)

    Cheng, Helen; Furnham, Adrian

    2013-01-01

    To investigate whether personality traits, education, physical exercise, parental socio-economic conditions, and childhood neurological function are independently associated with obesity in 50 year old adults in a longitudinal birth cohort study. The sample consisted of 5,921 participants born in Great Britain in 1958 and followed up at 7, 11, 33, 42, and 50 years with data on body mass index measured at 42 and 50 years. There was an increase of adult obesity from 14.2% at age 42 to 23.6% at 50 years. Cohort members who were reported by teachers on overall clumsiness as "certainly applied" at age 7 were more likely to become obese at age 50. In addition, educational qualifications, traits Conscientiousness and Extraversion, psychological distress, and physical exercise were all significantly associated with adult obesity. The associations remained to be significant after controlling for birth weight and gestation, maternal and paternal BMI, childhood BMI, childhood intelligence and behavioural adjustment, as well as diet. Neurological function in childhood, education, trait Conscientiousness, and exercise were all significantly and independently associated with adult obesity, each explained unique individual variability.

  19. Variation in Functional Independence among Stroke Survivors Having Fatigue and Depression

    Directory of Open Access Journals (Sweden)

    Umaru Muhammad Badaru

    2013-01-01

    Full Text Available Objective. This study evaluated variation in functional independence in activities of daily living (ADL and instrumental activities of daily living (IADL among individuals with poststroke fatigue (PSF and poststroke depression (PSD. Methods. A cross-sectional survey involved 65 consenting poststroke survivors who were purposively recruited from physiotherapy clinics of the University College Hospital, Ibadan, Adeoyo Maternity Teaching Hospital, Ibadan, and Federal Medical Center, Gusau. Participants were assessed for symptoms of PSD with short geriatric depression scale-15, PSF with fatigue severity scale, ADL with Barthel Index and IADL with Nottingham extended ADL scale. Data analysis was done using Chi-square and unpaired t-test with significance level being 0.05. Results. Participants’ age ranged from 58 to 80 years. PSD alone (P=0.002 and both PSF and PSD (P=0.02 were significantly associated with ADL, while PSF alone was not (P=0.233. PSD alone (P=0.001 and both PSF and PSD (P=0.001 significantly negatively affected IADL, while PSF alone had no significant effect (P=0.2. Conclusions. Participants with PSD alone and those with both PSF and PSD had lower functional independence in ADL and IADL.

  20. Numerical approach to model independently reconstruct f (R ) functions through cosmographic data

    Science.gov (United States)

    Pizza, Liberato

    2015-06-01

    The challenging issue of determining the correct f (R ) among several possibilities is revised here by means of numerical reconstructions of the modified Friedmann equations around the redshift interval z ∈[0 ,1 ] . Frequently, a severe degeneracy between f (R ) approaches occurs, since different paradigms correctly explain present time dynamics. To set the initial conditions on the f (R ) functions, we involve the use of the so-called cosmography of the Universe, i.e., the technique of fixing constraints on the observable Universe by comparing expanded observables with current data. This powerful approach is essentially model independent, and correspondingly we got a model-independent reconstruction of f (R (z )) classes within the interval z ∈[0 ,1 ]. To allow the Hubble rate to evolve around z ≤1 , we considered three relevant frameworks of effective cosmological dynamics, i.e., the Λ CDM model, the Chevallier-Polarski-Linder parametrization, and a polynomial approach to dark energy. Finally, cumbersome algebra permits passing from f (z ) to f (R ), and the general outcome of our work is the determination of a viable f (R ) function, which effectively describes the observed Universe dynamics.

  1. The urea carboxylase and allophanate hydrolase activities of urea amidolyase are functionally independent.

    Science.gov (United States)

    Lin, Yi; Boese, Cody J; St Maurice, Martin

    2016-10-01

    Urea amidolyase (UAL) is a multifunctional biotin-dependent enzyme that contributes to both bacterial and fungal pathogenicity by catalyzing the ATP-dependent cleavage of urea into ammonia and CO2 . UAL is comprised of two enzymatic components: urea carboxylase (UC) and allophanate hydrolase (AH). These enzyme activities are encoded on separate but proximally related genes in prokaryotes while, in most fungi, they are encoded by a single gene that produces a fusion enzyme on a single polypeptide chain. It is unclear whether the UC and AH activities are connected through substrate channeling or other forms of direct communication. Here, we use multiple biochemical approaches to demonstrate that there is no substrate channeling or interdomain/intersubunit communication between UC and AH. Neither stable nor transient interactions can be detected between prokaryotic UC and AH and the catalytic efficiencies of UC and AH are independent of one another. Furthermore, an artificial fusion of UC and AH does not significantly alter the AH enzyme activity or catalytic efficiency. These results support the surprising functional independence of AH from UC in both the prokaryotic and fungal UAL enzymes and serve as an important reminder that the evolution of multifunctional enzymes through gene fusion events does not always correlate with enhanced catalytic function.

  2. Measurement of functional independence level and falls-risk in individuals with undiagnosed phenylketonuria.

    LENUS (Irish Health Repository)

    Mazur, Artur

    2009-01-01

    The aim of the study was to determine the level of functional independence in adult patients with previously undiagnosed or untreated phenylketonuria (PKU). The study was conducted among 400 intellectually impaired adult residents of Social Welfare Homes in South-Eastern Poland born prior to the introduction of neonatal PKU screening programs. PKU was screened by filter paper test using tandem mass spectrometry methods, and confirmed by gas chromatography-mass spectrometric analysis of PKU organic acids in urine. Degree of functional independence included the assessment of activities of daily living (Barthel Index) and measures of balance and gait (Tinetti scale). Eleven individuals with previously untreated PKU were identified whereby eight presented with moderate disability and three with mild disability. Six had a high risk of falls and five had a moderate risk of falls. This study indicates that there is considerable number of undiagnosed PKU patients within the Polish population who require assessment and management in order to reduce the impact of the neurological and neuropsychiatric problems associated with the condition. Appropriate therapy for those with undiagnosed PKU should, in particular, address the risk of falls.

  3. Independent value added by diffusion MRI for prediction of cognitive function in older adults

    Directory of Open Access Journals (Sweden)

    Julia A Scott

    2017-01-01

    Full Text Available The purpose of this study was to determine whether white matter microstructure measured by diffusion magnetic resonance imaging (dMRI provides independent information about baseline level or change in executive function (EF or memory (MEM in older adults with and without cognitive impairment. Longitudinal data was acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI study from phases GO and 2 (2009–2015. ADNI participants included were diagnosed as cognitively normal (n = 46, early mild cognitive impairment (MCI (n = 48, late MCI (n = 29, and dementia (n = 39 at baseline. We modeled the association between dMRI-based global white matter mean diffusivity (MD and baseline level and change in EF and MEM composite scores, in models controlling for baseline bilateral hippocampal volume, regional cerebral FDG PET metabolism and global cerebral AV45 PET uptake. EF and MEM composite scores were measured at baseline, 6, 12, 24 and 36 months. In the baseline late MCI and dementia groups, greater global MD was associated with lesser baseline EF, but not EF change nor MEM baseline or change. As expected, lesser hippocampal volume and lesser FDG PET metabolism was associated with greater rates of EF and MEM decline. In ADNI-GO/2 participants, white matter integrity provided independent information about current executive function, but was not sensitive to future cognitive change. Since individuals experiencing executive function declines progress to dementia more rapidly than those with only memory impairment, better biomarkers of future executive function decline are needed.

  4. Reduced lung function is independently associated with increased risk of type 2 diabetes in Korean men

    Directory of Open Access Journals (Sweden)

    Kwon Chang-Hee

    2012-04-01

    Full Text Available Abstract Background Reduced lung function is associated with incident insulin resistance and diabetes. The aim of this study was to assess the relationship between lung function and incident type 2 diabetes in Korean men. Methods This study included 9,220 men (mean age: 41.4 years without type 2 diabetes at baseline who were followed for five years. Subjects were divided into four groups according to baseline forced vital capacity (FVC (% predicted and forced expiratory volume in one second (FEV1 (% predicted quartiles. The incidence of type 2 diabetes at follow-up was compared according to FVC and FEV1 quartiles. Results The overall incidence of type 2 diabetes was 2.2%. Reduced lung function was significantly associated with the incidence of type 2 diabetes after adjusting for age, BMI, education, smoking, exercise, alcohol, and HOMA-IR. Both FVC and FEV1 were negatively associated with type 2 diabetes (P 1 had a significantly higher odds ratio for type 2 diabetes compared with the highest quartile after adjusting for age and BMI (2.15 [95% CI 1.02-4.57] and 2.19 [95% CI 1.09-4.42]. Conclusions Reduced lung function is independently associated with the incidence of type 2 diabetes in Korean men.

  5. Loss of BMI-1 dampens migration and EMT of colorectal cancer in inflammatory microenvironment through TLR4/MD-2/MyD88-mediated NF-κB signaling.

    Science.gov (United States)

    Ye, Kai; Chen, Qi-Wei; Sun, Ya-Feng; Lin, Jian-An; Xu, Jian-Hua

    2017-08-16

    Increasing evidence from various clinical and experimental studies has demonstrated that the inflammatory microenvironment created by immune cells facilitates tumor migration. Epithelial-mesenchymal transition (EMT) is involved in the progression of cancer invasion and metastasis in an inflammatory microenvironment. B-lymphoma Moloney murine leukemia virus insertion region 1 (BMI-1) acts as an oncogene in various tumors. Ectopic expression of Bmi-1 have an effect on EMT and invasiveness. The purpose of this study was to investigate the efficacy of BMI-1 on inflammation-induced tumor migration and EMT and the underlying mechanism. We observed that the expression of BMI-1, TNF-α and IL-1β was significantly increased in HT29 and HCT116 cells after THP-1 Conditioned-Medium (THP-1-CM) stimulation. Additionally, inhibition of BMI-1 impeded cell invasion induced by THP-1-CM-stimulation in both HT29 and HCT116 cells. BMI-1 knockdown remarkably repressed THP-1-CM -induced EMT by regulating the expression of EMT biomarkers with an increase in E-cadherin accompanied by decrease in N-cadherin and vimentin. Furthermore, downregulation of BMI-1 dramatically impeded THP-1-CM-triggered Toll-like receptor 4(TLR4)/myeloid differentiation protein 2(MD-2)/ myeloid differentiation factor 88(MyD88) activity by repressing the expression of the TLR4/MD-2 complex and MyD88. Further data demonstrated that knockout of BMI-1 also dampened NF-κB THP-1-CM-triggered activity. Taken all data together, our findings established that BMI-1 modulated TLR4/MD-2/MyD88 complex-mediated NF-κB signaling involved in inflammation-induced cancer cells invasion and EMT, and therefore could be a potential chemopreventive agent against inflammation-associated colorectal cancer. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. High CO2 levels impair alveolar epithelial function independently of pH.

    Directory of Open Access Journals (Sweden)

    Arturo Briva

    Full Text Available BACKGROUND: In patients with acute respiratory failure, gas exchange is impaired due to the accumulation of fluid in the lung airspaces. This life-threatening syndrome is treated with mechanical ventilation, which is adjusted to maintain gas exchange, but can be associated with the accumulation of carbon dioxide in the lung. Carbon dioxide (CO2 is a by-product of cellular energy utilization and its elimination is affected via alveolar epithelial cells. Signaling pathways sensitive to changes in CO2 levels were described in plants and neuronal mammalian cells. However, it has not been fully elucidated whether non-neuronal cells sense and respond to CO2. The Na,K-ATPase consumes approximately 40% of the cellular metabolism to maintain cell homeostasis. Our study examines the effects of increased pCO2 on the epithelial Na,K-ATPase a major contributor to alveolar fluid reabsorption which is a marker of alveolar epithelial function. PRINCIPAL FINDINGS: We found that short-term increases in pCO2 impaired alveolar fluid reabsorption in rats. Also, we provide evidence that non-excitable, alveolar epithelial cells sense and respond to high levels of CO2, independently of extracellular and intracellular pH, by inhibiting Na,K-ATPase function, via activation of PKCzeta which phosphorylates the Na,K-ATPase, causing it to endocytose from the plasma membrane into intracellular pools. CONCLUSIONS: Our data suggest that alveolar epithelial cells, through which CO2 is eliminated in mammals, are highly sensitive to hypercapnia. Elevated CO2 levels impair alveolar epithelial function, independently of pH, which is relevant in patients with lung diseases and altered alveolar gas exchange.

  7. Independent Component Analysis of Resting-State Functional Magnetic Resonance Imaging in Pedophiles.

    Science.gov (United States)

    Cantor, J M; Lafaille, S J; Hannah, J; Kucyi, A; Soh, D W; Girard, T A; Mikulis, D J

    2016-10-01

    Neuroimaging and other studies have changed the common view that pedophilia is a result of childhood sexual abuse and instead is a neurologic phenomenon with prenatal origins. Previous research has identified differences in the structural connectivity of the brain in pedophilia. To identify analogous differences in functional connectivity. Functional magnetic resonance images were recorded from three groups of participants while they were at rest: pedophilic men with a history of sexual offenses against children (n = 37) and two control groups: non-pedophilic men who committed non-sexual offenses (n = 28) and non-pedophilic men with no criminal history (n = 39). Functional magnetic resonance imaging data were subjected to independent component analysis to identify known functional networks of the brain, and groups were compared to identify differences in connectivity with those networks (or "components"). The pedophilic group demonstrated wide-ranging increases in functional connectivity with the default mode network compared with controls and regional differences (increases and decreases) with the frontoparietal network. Of these brain regions (total = 23), 20 have been identified by meta-analytic studies to respond to sexually relevant stimuli. Conversely, of the brain areas known to be those that respond to sexual stimuli, nearly all emerged in the present data as significantly different in pedophiles. This study confirms the presence of significant differences in the functional connectivity of the brain in pedophilia consistent with previously reported differences in structural connectivity. The connectivity differences detected here and elsewhere are opposite in direction from those associated with anti-sociality, arguing against anti-sociality and for pedophilia as the source of the neuroanatomic differences detected. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

  8. Seed germination strategies: an evolutionary trajectory independent of vegetative functional traits

    Directory of Open Access Journals (Sweden)

    Gemma eHoyle

    2015-10-01

    Full Text Available 1.Seed germination strategies vary dramatically among species but relatively little is known about how germination traits correlate with other elements of plant strategy systems. Understanding drivers of germination strategy is critical to our understanding of the evolutionary biology of plant reproduction.2.We present a novel assessment of seed germination strategies focussing on Australian alpine species as a case study. We describe the distribution of germination strategies and ask whether these are correlated with, or form an independent axis to, other plant functional traits. Our approach to describing germination strategy mimicked realistic temperatures that seeds experience in situ following dispersal. Strategies were subsequently assigned using an objective clustering approach. We hypothesised that two main strategies would emerge, involving dormant or non-dormant seeds, and that while these strategies would be correlated with seed traits (e.g. mass or endospermy they would be largely independent of vegetative traits when analysed in a phylogenetically structured manner. 3.Across all species, three germination strategies emerged. The majority of species postponed germination until after a period of cold, winter-like temperatures indicating physiological and/or morphological dormancy mechanisms. Other species exhibited immediate germination at temperatures representative of those at dispersal. Interestingly, seeds of an additional 13 species 'staggered' germination over time. Germination strategies were generally conserved within families. Across a broad range of ecological traits only seed mass and endospermy showed any correlation with germination strategy when phylogenetic relatedness was accounted for; vegetative traits showed no significant correlations with germination strategy. The results indicate that germination traits correlate with other aspects of seed ecology but form an independent axis relative to vegetative traits.

  9. Protein plasticity underlines activation and function of ATP-independent chaperones.

    Science.gov (United States)

    Suss, Ohad; Reichmann, Dana

    2015-01-01

    One of the key issues in biology is to understand how cells cope with protein unfolding caused by changes in their environment. Self-protection is the natural immediate response to any sudden threat and for cells the critical issue is to prevent aggregation of existing proteins. Cellular response to stress is therefore indistinguishably linked to molecular chaperones, which are the first line of defense and function to efficiently recognize misfolded proteins and prevent their aggregation. One of the major protein families that act as cellular guards includes a group of ATP-independent chaperones, which facilitate protein folding without the consumption of ATP. This review will present fascinating insights into the diversity of ATP-independent chaperones, and the variety of mechanisms by which structural plasticity is utilized in the fine-tuning of chaperone activity, as well as in crosstalk within the proteostasis network. Research into this intriguing class of chaperones has introduced new concepts of stress response to a changing cellular environment, and paved the way to uncover how this environment affects protein folding.

  10. Functional status and amount of hip displacement independently affect acetabular dysplasia in cerebral palsy.

    Science.gov (United States)

    Chung, Myung Ki; Zulkarnain, Arif; Lee, Jae Bong; Cho, Byung Chae; Chung, Chin Youb; Lee, Kyoung Min; Sung, Ki Hyuk; Park, Moon Seok

    2017-07-01

    Acetabular dysplasia is the one of main causes of hip displacement in patients with cerebral palsy (CP). Although several studies have shown a relationship between hip displacement and acetabular dysplasia, relatively few have evaluated the association between quantitative acetabular dysplasia and related factors, such as Gross Motor Function Classification System (GMFCS) level. We performed a morphometric analysis of the acetabulum in patients with CP using multiplanar reformation of computed tomography data. The three directional acetabular indices (anterosuperior, superolateral, and posterosuperior) were used to evaluate acetabular dysplasia. Consequently, linear mixed-effects models were used to adjust for related factors such as age, sex, GMFCS level, and migration percentage. A total of 176 patients (mean age 9y 5mo, range 2y 4mo-19y 6mo; 104 males, 72 females) with CP and 55 typically developing individuals (mean age 13y 6mo, range 2y 5mo-19y 10mo; 37 males, 18 females) in a comparison group were enrolled in this study. Statistical modelling showed that all three directional acetabular indices independently increased with GMFCS level (pdysplasia was independently affected by both the amount of hip displacement and the GMFCS level. Thus, physicians should consider not only the migration percentage but also three-dimensional evaluation in patients at high GMFCS levels. © 2017 Mac Keith Press.

  11. A numerical approach to model independently reconstruct $f(R)$ functions through cosmographic data

    CERN Document Server

    Pizza, Liberato

    2014-01-01

    The challenging issue of determining the correct $f(R)$ among several possibilities is here revised by means of numerical reconstructions of the modified Friedmann equations around the redshift interval $z\\in[0,1]$. Frequently, a severe degeneracy between $f(R)$ approaches occurs, since different paradigms correctly explain present time dynamics. To set the initial conditions on the $f(R)$ functions, we involve the use of the so called cosmography of the Universe, i.e. the technique of fixing constraints on the observable Universe by comparing expanded observables with current data. This powerful approach is essentially model independent and correspondingly we got a model independent reconstruction of $f(z)$ classes within the interval $z\\in[0,1]$. To allow the Hubble rate to evolve around $z\\leq1$, we considered three relevant frameworks of effective cosmological dynamics, i.e. the $\\Lambda$CDM model, the CPL parametrization and a polynomial approach to dark energy. Finally cumbersome algebra permits to pass...

  12. Acetylation of pregnane X receptor protein determines selective function independent of ligand activation

    Energy Technology Data Exchange (ETDEWEB)

    Biswas, Arunima; Pasquel, Danielle [Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461 (United States); Tyagi, Rakesh Kumar [Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067 (India); Mani, Sridhar, E-mail: sridhar.mani@einstein.yu.edu [Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461 (United States)

    2011-03-18

    Research highlights: {yields} Pregnane X receptor (PXR), a major regulatory protein, is modified by acetylation. {yields} PXR undergoes dynamic deacetylation upon ligand-mediated activation. {yields} SIRT1 partially mediates PXR deacetylation. {yields} PXR deacetylation per se induces lipogenesis mimicking ligand-mediated activation. -- Abstract: Pregnane X receptor (PXR), like other members of its class of nuclear receptors, undergoes post-translational modification [PTM] (e.g., phosphorylation). However, it is unknown if acetylation (a major and common form of protein PTM) is observed on PXR and, if it is, whether it is of functional consequence. PXR has recently emerged as an important regulatory protein with multiple ligand-dependent functions. In the present work we show that PXR is indeed acetylated in vivo. SIRT1 (Sirtuin 1), a NAD-dependent class III histone deacetylase and a member of the sirtuin family of proteins, partially mediates deacetylation of PXR. Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation.

  13. Some Convex Functions Based Measures of Independence and Their Application to Strange Attractor Reconstruction

    Directory of Open Access Journals (Sweden)

    Kazuyuki Aihara

    2011-04-01

    Full Text Available The classical information-theoretic measures such as the entropy and the mutual information (MI are widely applicable to many areas in science and engineering. Csiszar generalized the entropy and the MI by using the convex functions. Recently, we proposed the grid occupancy (GO and the quasientropy (QE as measures of independence. The QE explicitly includes a convex function in its definition, while the expectation of GO is a subclass of QE. In this paper, we study the effect of different convex functions on GO, QE, and Csiszar’s generalized mutual information (GMI. A quality factor (QF is proposed to quantify the sharpness of their minima. Using the QF, it is shown that these measures can have sharper minima than the classical MI. Besides, a recursive algorithm for computing GMI, which is a generalization of Fraser and Swinney’s algorithm for computing MI, is proposed. Moreover, we apply GO, QE, and GMI to chaotic time series analysis. It is shown that these measures are good criteria for determining the optimum delay in strange attractor reconstruction.

  14. Spectral correlation functions of the sum of two independent complex Wishart matrices with unequal covariances

    Science.gov (United States)

    Akemann, Gernot; Checinski, Tomasz; Kieburg, Mario

    2016-08-01

    We compute the spectral statistics of the sum H of two independent complex Wishart matrices, each of which is correlated with a different covariance matrix. Random matrix theory enjoys many applications including sums and products of random matrices. Typically ensembles with correlations among the matrix elements are much more difficult to solve. Using a combination of supersymmetry, superbosonisation and bi-orthogonal functions we are able to determine all spectral k-point density correlation functions of H for arbitrary matrix size N. In the half-degenerate case, when one of the covariance matrices is proportional to the identity, the recent results by Kumar for the joint eigenvalue distribution of H serve as our starting point. In this case the ensemble has a bi-orthogonal structure and we explicitly determine its kernel, providing its exact solution for finite N. The kernel follows from computing the expectation value of a single characteristic polynomial. In the general non-degenerate case the generating function for the k-point resolvent is determined from a supersymmetric evaluation of the expectation value of k ratios of characteristic polynomials. Numerical simulations illustrate our findings for the spectral density at finite N and we also give indications how to do the asymptotic large-N analysis.

  15. Central and peripheral nervous system functions are independently disturbed in HIV-1 infected patients.

    Science.gov (United States)

    von Giesen, Hans-Jürgen; Köller, Hubertus; Hefter, Harald; Arendt, Gabriele

    2002-06-01

    We examined the peripheral nervous system (PNS) (nerve conduction velocity (NCV)) and the central nervous system (CNS) (basal ganglia-mediated psychomotor speed) in 93 males seropositive for human immunodeficiency virus type 1 (HIV-1) with no prior history of opportunistic brain disease, antiretroviral treatment or intravenous drug use. Patients with different degrees of slowing of peroneal and sural NCV showed no significant differences in psychomotor speed as assessed by tremor peak frequency, most rapid alternating movements, reaction times and contraction times. There was no significant correlation between psychomotor measures and NCV. Psychomotor slowing test findings were independent from peripheral nervous system damage indicating uncorrelated disturbances of CNS and PNS function in HIV-1 infection. Differences in HIV-1 viral quasispecies or host responses may determine the predominance of CNS or PNS injury.

  16. Implementation of Ring-Oscillators-Based Physical Unclonable Functions with Independent Bits in the Response

    Directory of Open Access Journals (Sweden)

    Florent Bernard

    2012-01-01

    Full Text Available The paper analyzes and proposes some enhancements of Ring-Oscillators-based Physical Unclonable Functions (PUFs. PUFs are used to extract a unique signature of an integrated circuit in order to authenticate a device and/or to generate a key. We show that designers of RO PUFs implemented in FPGAs need a precise control of placement and routing and an appropriate selection of ROs pairs to get independent bits in the PUF response. We provide a method to identify which comparisons are suitable when selecting pairs of ROs. Dealing with power consumption, we propose a simple improvement that reduces the consumption of the PUF published by Suh et al. in 2007 by up to 96.6%. Last but not least, we point out that ring oscillators significantly influence one another and can even be locked. This questions the reliability of the PUF and should be taken into account during the design.

  17. Exercising body and mind: an integrated approach to functional independence in hospitalized older people.

    Science.gov (United States)

    Mudge, Alison M; Giebel, Andrea J; Cutler, Alison J

    2008-04-01

    To evaluate the effect of a structured, multi-component, early rehabilitation program on functional status, delirium, and discharge outcomes of older acute medical inpatients. Prospective controlled trial with blinded outcome evaluation. Internal medicine service of a metropolitan tertiary teaching hospital in Brisbane, Australia. One hundred twenty-four consecutive inpatients aged 65 and older admitted from the emergency department to control or intervention medical ward. Exclusions included patients completely dependent before admission or admitted from a nursing home, patients too ill to participate or terminally ill, and patients with length of stay less than 72 hours. Early physiotherapy review with provision of an individualized graduated exercise program and activity diary, progressive encouragement of functional independence by nursing staff and other members of the multidisciplinary team, and cognitive stimulation sessions. Modified Barthel Index (MBI) at admission and discharge, timed up-and-go at admission and discharge, incidence of delirium and falls, measured activity, length of hospital stay, discharge destination, 30-day readmission rate. Intervention and control participants were well matched in terms of age, sex, diagnosis, and functional status. The intervention group had greater improvement in functional status than the control group, with a median MBI improvement of 8.5 versus 3.5 points (P=.03). In the intervention group, there was a reduction in delirium (19.4% vs 35.5%, P=.04) and a trend to reduced falls (4.8% vs 11.3%, P=.19). Length of stay, timed up-and-go, discharge destination, and readmissions did not differ between the groups. This intervention was effective in improving function in a vulnerable patient group.

  18. Analysis of the Functional Independence Measure Value of Cervical Spine Injury Patients with Conservative Management

    Directory of Open Access Journals (Sweden)

    M. Zafrullah Arifin

    2012-06-01

    Full Text Available Analysis of the Functional Independence Measure Value of Cervical Spine Injury Patients with Conservative Management. Cervical spine injury is one of the most common spinal cord injuries in trauma patients. From 100,000 spinal cord injury cases reported in the United States of America (2008, sixty seven percent involve cervical spine injury. American Spinal Cord Injury Association (ASIA impairment score is used as an initial assessment but not enough attention prognostic outcome of these patients was paid to. The objective of this study is to analyze the value of functional independence measure (FIM cervical spine injury patients with conservative management and its correlation with age, sex, type of trauma, onset of trauma, cervical abnormalities, type of cervical spine lesion and ASIA impairment score. A prospective cohort study was performed to all patients with cervical spine injury treated inNeurosurgery Department of Dr. Hasan Sadikin Hospital Bandung that fullfiled the inclusion criteria. The subjects were classified based on age, sex, single/multiple trauma, acute /chronic, cervical abnormalities, complete/incomplete lesion and ASIA impairment score. The FIM examination was performed in Outpatient clinic of Neurosurgery. T-test and chi-square test was done to analyze the data. There were 17 cervical spine injury patients treated in Neurosurgery Department of Dr. Hasan Sadikin Hospital during April 2009–April 2010. The average FIM value of cervical spine injury in those patients is 4+ 1.63 by cohort prospective study. There were no correlation between FIM value with age, sex, type of trauma, onset of trauma and cervical abnormalities. Significant correlations were found between FIM value with type of cervical spine lesion and ASIA impairment score in cervical spine patients. Type of cervical spine lesion and ASIA impairment score have significant correlation with FIM value of patients in 6 months after cervical injury.

  19. Functional expression of a heterologous nickel-dependent, ATP-independent urease in Saccharomyces cerevisiae.

    Science.gov (United States)

    Milne, N; Luttik, M A H; Cueto Rojas, H F; Wahl, A; van Maris, A J A; Pronk, J T; Daran, J M

    2015-07-01

    In microbial processes for production of proteins, biomass and nitrogen-containing commodity chemicals, ATP requirements for nitrogen assimilation affect product yields on the energy producing substrate. In Saccharomyces cerevisiae, a current host for heterologous protein production and potential platform for production of nitrogen-containing chemicals, uptake and assimilation of ammonium requires 1 ATP per incorporated NH3. Urea assimilation by this yeast is more energy efficient but still requires 0.5 ATP per NH3 produced. To decrease ATP costs for nitrogen assimilation, the S. cerevisiae gene encoding ATP-dependent urease (DUR1,2) was replaced by a Schizosaccharomyces pombe gene encoding ATP-independent urease (ure2), along with its accessory genes ureD, ureF and ureG. Since S. pombe ure2 is a Ni(2+)-dependent enzyme and Saccharomyces cerevisiae does not express native Ni(2+)-dependent enzymes, the S. pombe high-affinity nickel-transporter gene (nic1) was also expressed. Expression of the S. pombe genes into dur1,2Δ S. cerevisiae yielded an in vitro ATP-independent urease activity of 0.44±0.01 µmol min(-1) mg protein(-1) and restored growth on urea as sole nitrogen source. Functional expression of the Nic1 transporter was essential for growth on urea at low Ni(2+) concentrations. The maximum specific growth rates of the engineered strain on urea and ammonium were lower than those of a DUR1,2 reference strain. In glucose-limited chemostat cultures with urea as nitrogen source, the engineered strain exhibited an increased release of ammonia and reduced nitrogen content of the biomass. Our results indicate a new strategy for improving yeast-based production of nitrogen-containing chemicals and demonstrate that Ni(2+)-dependent enzymes can be functionally expressed in S. cerevisiae.

  20. Joint independent component analysis of structural and functional images reveals complex patterns of functional reorganisation in stroke aphasia.

    Science.gov (United States)

    Specht, Karsten; Zahn, Roland; Willmes, Klaus; Weis, Susanne; Holtel, Christiane; Krause, Bernd J; Herzog, Hans; Huber, Walter

    2009-10-01

    Previous functional activation studies in patients with aphasia have mostly relied on standard group comparisons of aphasic patients with healthy controls, which are biased towards regions showing the most consistent effects and disregard variability within groups. Groups of aphasic patients, however, show considerable variability with respect to lesion localisation and extent. Here, we use a novel method, joint independent component analysis (jICA), which allowed us to investigate abnormal patterns of functional activation with O(15)-PET during lexical decision in aphasic patients after middle cerebral artery stroke and to directly relate them to lesion information from structural MRI. Our results demonstrate that with jICA we could detect a network of compensatory increases in activity within bilateral anterior inferior temporal areas (BA20), which was not revealed by standard group comparisons. In addition, both types of analyses, jICA and group comparison, showed increased activity in the right posterior superior temporal gyrus in aphasic patients. Further, whereas standard analyses revealed no decreases in activation, jICA identified that left perisylvian lesions were associated with decreased activation of left posterior inferior frontal cortex, damaged in most patients, and extralesional remote decreases of activity within polar parts of the inferior temporal gyrus (BA38/20) and the occipital cortex (BA19). Taken together, our results demonstrate that jICA may be superior in revealing complex patterns of functional reorganisation in aphasia.

  1. Evaluation of functional recovery by motor functional independence measure test of elderly after hip fracture in Serbia.

    Science.gov (United States)

    Radosavljevic, Natasa; Nikolic, Dejan; Lazovic, Milica; Radosavljevic, Zoran; Jeremic, Aleksandar

    2014-01-01

    Introdução: o objectivo do estudo é a avaliação do nível de independência funcional através da aplicação da escala de Medida da Independência Funcional (Functional Independence Measure [FIM]) em doentes com idade superior a 65 anos, após fractura da anca.Material e Métodos: Foram estudados 203 doentes após fractura da anca, aplicando a escala MIF em 3 momentos: admissão do doente no hospital (Período 1), no momento da alta (Período 2) e 3 meses após a alta (Período 3); os doentes foram englobados em 3 grupos etários: Grupo65-74 , Grupo75-84 e Grupo+85 e em dois grupos, consoante o Índice de Gravidade (IG): grupo 0-1,99 (IG1) e grupo ≥ 2 (IG2).Resultados: No grupo de doentes com idêntico IG, observou-se um aumento dos valores da MIF no Período 2 e 3 em ambos osgéneros e nas primeiras duas classes etárias, ao passo que em doentes acima dos 85 anos, com IG mais elevado, observámos uma variação não significativa dos valores da MIF entre o momento da alta hospitalar e 3 meses após a alta.Discussão: A melhoria mais significativa da MIF foi obtida em doentes do sexo feminino no primeiro e terceiro grupos etários e com IG mais elevado.Conclusão: O género não constitui um factor preditivo significativo da recuperação da independência funcional medida através da aplicação da escala MIF em doentes com fractura da anca, embora a MIF no momento da admissão seja um bom indicador de recuperação funcional em doentes do sexo feminino em certos grupos etários (primeiro e terceiro grupos etários).

  2. Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

    Science.gov (United States)

    Zhang, Yanrong; Cuevas, Santiago; Asico, Laureano D; Escano, Crisanto; Yang, Yu; Pascua, Annabelle M; Wang, Xiaoyan; Jones, John E; Grandy, David; Eisner, Gilbert; Jose, Pedro A; Armando, Ines

    2012-01-01

    Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2)-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2)R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2)R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2)R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2)R expression and function.

  3. Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure.

    Directory of Open Access Journals (Sweden)

    Yanrong Zhang

    Full Text Available Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2 receptor gene (DRD2 are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2-/- have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2 receptor (D(2R function increases vulnerability to renal inflammation independently of blood pressure, is an immediate cause of renal injury, and contributes to the subsequent development of hypertension. In D(2-/- mice, treatment with apocynin normalized blood pressure and decreased oxidative stress, but did not affect the expression of inflammatory factors. In mouse RPTCs Drd2 silencing increased the expression of TNFα and MCP-1, while treatment with a D(2R agonist abolished the angiotensin II-induced increase in TNF-α and MCP-1. In uni-nephrectomized wild-type mice, selective Drd2 silencing by subcapsular infusion of Drd2 siRNA into the remaining kidney produced the same increase in renal cytokines/chemokines that occurs after Drd2 deletion, increased the expression of markers of renal injury, and increased blood pressure. Moreover, in mice with two intact kidneys, short-term Drd2 silencing in one kidney, leaving the other kidney undisturbed, induced inflammatory factors and markers of renal injury in the treated kidney without increasing blood pressure. Our results demonstrate that the impact of decreased D(2R function on renal inflammation is a primary effect, not necessarily associated with enhanced oxidant activity, or blood pressure; renal damage is the cause, not the result, of hypertension. Deficient renal D(2R function may be of clinical relevance since common polymorphisms of the human DRD2 gene result in decreased D(2R expression and function.

  4. Quadratic independence of coordinate functions of certain homogeneous spaces and action of compact quantum groups

    Indian Academy of Sciences (India)

    Debashish Goswami

    2015-02-01

    Let be one of the classical compact, simple, centre-less, connected Lie groups of rank with a maximal torus , the Lie algebra $\\mathcal{G}$ and let $\\{E_{i},F_{i},H_{i},i=1,\\ldots,n\\}$ be tha standard set of generators corresponding to a basis of the root system. Consider the adjoint-orbit space $M=\\{\\text{Ad}_{g}(H_{1}), g\\in G\\}$, identified with the homogeneous space / where $L=\\{g\\in G : \\text{Ad}_{g}(H_{1})=H_{1}\\}$. We prove that the coordinate functions $f_{i}(g):=_{i}(\\text{Ad}_{g}(H_{1}))$, $i=1,\\ldots,n$, where $\\{_{1},\\ldots,_{n}\\}$ is basis of $\\mathcal{G}'$ are `quadratically independent' in the sense that they do not satisfy any nontrivial homogeneous quadratic relations among them. Using this, it is proved that there is no genuine compact quantum group which can act faithfully on $C(M)$ such that the action leaves invariant the linear span of the above coordinate functions. As a corollary, it is also shown that any compact quantum group having a faithful action on the noncommutative manifold obtained by Rieffel deformation of satisfying a similar `linearity' condition must be a Rieffel-Wang type deformation of some compact group.

  5. Attribution of emotions to body postures: an independent component analysis study of functional connectivity in autism.

    Science.gov (United States)

    Libero, Lauren E; Stevens, Carl E; Kana, Rajesh K

    2014-10-01

    The ability to interpret others' body language is a vital skill that helps us infer their thoughts and emotions. However, individuals with autism spectrum disorder (ASD) have been found to have difficulty in understanding the meaning of people's body language, perhaps leading to an overarching deficit in processing emotions. The current fMRI study investigates the functional connectivity underlying emotion and action judgment in the context of processing body language in high-functioning adolescents and young adults with autism, using an independent components analysis (ICA) of the fMRI time series. While there were no reliable group differences in brain activity, the ICA revealed significant involvement of occipital and parietal regions in processing body actions; and inferior frontal gyrus, superior medial prefrontal cortex, and occipital cortex in body expressions of emotions. In a between-group analysis, participants with autism, relative to typical controls, demonstrated significantly reduced temporal coherence in left ventral premotor cortex and right superior parietal lobule while processing emotions. Participants with ASD, on the other hand, showed increased temporal coherence in left fusiform gyrus while inferring emotions from body postures. Finally, a positive predictive relationship was found between empathizing ability and the brain areas underlying emotion processing in ASD participants. These results underscore the differential role of frontal and parietal brain regions in processing emotional body language in autism.

  6. Extracting functional components of neural dynamics with Independent Component Analysis and inverse Current Source Density.

    Science.gov (United States)

    Lęski, Szymon; Kublik, Ewa; Swiejkowski, Daniel A; Wróbel, Andrzej; Wójcik, Daniel K

    2010-12-01

    Local field potentials have good temporal resolution but are blurred due to the slow spatial decay of the electric field. For simultaneous recordings on regular grids one can reconstruct efficiently the current sources (CSD) using the inverse Current Source Density method (iCSD). It is possible to decompose the resultant spatiotemporal information about the current dynamics into functional components using Independent Component Analysis (ICA). We show on test data modeling recordings of evoked potentials on a grid of 4 × 5 × 7 points that meaningful results are obtained with spatial ICA decomposition of reconstructed CSD. The components obtained through decomposition of CSD are better defined and allow easier physiological interpretation than the results of similar analysis of corresponding evoked potentials in the thalamus. We show that spatiotemporal ICA decompositions can perform better for certain types of sources but it does not seem to be the case for the experimental data studied. Having found the appropriate approach to decomposing neural dynamics into functional components we use the technique to study the somatosensory evoked potentials recorded on a grid spanning a large part of the forebrain. We discuss two example components associated with the first waves of activation of the somatosensory thalamus. We show that the proposed method brings up new, more detailed information on the time and spatial location of specific activity conveyed through various parts of the somatosensory thalamus in the rat.

  7. The independent and interacting effects of hedonic hunger and executive function on binge eating.

    Science.gov (United States)

    Manasse, Stephanie M; Espel, Hallie M; Forman, Evan M; Ruocco, Anthony C; Juarascio, Adrienne S; Butryn, Meghan L; Zhang, Fengqing; Lowe, Michael R

    2015-06-01

    Poor executive function (EF; pre-frontal cognitive control processes governing goal-directed behavior) and elevated hedonic hunger (i.e., preoccupation with palatable foods in the absence of physiological hunger) are theoretical risk and maintenance factors for binge eating (BE) distinct from general obesity. Recent theoretical models posit that dysregulated behavior such as BE may result from a combination of elevated appetitive drive (e.g., hedonic hunger) and decreased EF (e.g., inhibitory control and delayed discounting). The present study sought to test this model in distinguishing BE from general obesity by examining the independent and interactive associations of EF and hedonic hunger with BE group status (i.e., odds of categorization in BE group versus non-BE group). Treatment-seeking overweight and obese women with BE (n = 31) and without BE (OW group; n = 43) were assessed on measures of hedonic hunger and EF (inhibitory control and delay discounting). Elevated hedonic hunger increased the likelihood of categorization in the BE group, regardless of EF. When hedonic hunger was low, poor EF increased the likelihood of categorization in the BE group. Results indicate that the interplay of increased appetitive drives and decreased cognitive function may distinguish BE from overweight/obesity. Future longitudinal investigations of the combinatory effect of hedonic hunger and EF in increasing risk for developing BE are warranted, and may inform future treatment development to target these factors.

  8. The Impact of Fear of Falling on Functional Independence Among Older Adults Receiving Home Health Services

    Directory of Open Access Journals (Sweden)

    Katherine A. Lawson OTR, LMSSW, PhD

    2014-07-01

    Full Text Available Background: Falls are the fifth leading cause of death for adults aged 65 years and older. Several intrinsic and extrinsic fall risk factors have been identified, butthere is less understanding of the impact of a fear of falling on falls. Seventy percent of recent fallers and 40% percent of non-fallers report a fear of falling. Therefore, the purpose of this study was to examine the correlation between a fear of falling and a history of falls, as well as the impact on the functional independence of community-dwelling older adults receiving home health services. Methods: The participants completed the Falls Efficacy Scale, the Modified Timed Up and Go Test, self- reported fear of falling, and the KATZ ADL-staircase. The participants were primarily Hispanic females. Results: There was not a significant correlation between a fear of falling and a history of falls. Only participants' age, gender, and the number of medical diagnoses were predictive of past falls. There was a moderate correlation between impaired functional mobility and dependence with activities of daily living (ADL. Additionally, a fear of falling was associated with dependence to perform ADLs as measured objectively. Conclusion: Future studies need to examine the effectiveness of interventions that include dual-task challenges during therapeutic interventions and ADL retraining to reduce fall risk among older adults.

  9. Molecular functions and significance of the MTA family in hormone-independent cancer.

    Science.gov (United States)

    Ning, Zhifeng; Gan, Jinfeng; Chen, Chaoying; Zhang, Dianzheng; Zhang, Hao

    2014-12-01

    The members of the metastasis-associated protein (MTA) family play pivotal roles in both physiological and pathophysiological processes, especially in cancer development and metastasis, and their role as master regulators has come to light. Due to the fact that they were first identified as crucial factors in estrogen receptor-mediated breast cancer metastasis, most of the early studies focused on their hormone-dependent functions. However, the accumulating evidence shows that the members of MTA family are deregulated in most, if not all, the cancers studied so far. Therefore, the levels as well as the activities of the MTA family members are widely accepted as potential biomarkers for diagnosis, prognosis, and predictors of overall survival. They function differently in different cancers with specific mechanisms. p53 and HIF-1α appear to be the respectively common upstream and downstream regulator of the MTA family in both development and metastasis of a wide spectrum of cancers. Here, we review the expression and clinical significance of the MTA family, focusing on hormone-independent cancers. To illustrate the molecular mechanisms, we analyze the MTA family-related signaling pathways in different cancers. Finally, targeting the MTA family directly or the pathways involved in the MTA family indirectly could be invaluable strategies in the development of cancer therapeutics.

  10. A Kinase-Independent Function of CDK6 Links the Cell Cycle to Tumor Angiogenesis

    Science.gov (United States)

    Kollmann, Karoline; Heller, Gerwin; Schneckenleithner, Christine; Warsch, Wolfgang; Scheicher, Ruth; Ott, Rene G.; Schäfer, Markus; Fajmann, Sabine; Schlederer, Michaela; Schiefer, Ana-Iris; Reichart, Ursula; Mayerhofer, Matthias; Hoeller, Christoph; Zöchbauer-Müller, Sabine; Kerjaschki, Dontscho; Bock, Christoph; Kenner, Lukas; Hoefler, Gerald; Freissmuth, Michael; Green, Anthony R.; Moriggl, Richard; Busslinger, Meinrad; Malumbres, Marcos; Sexl, Veronika

    2013-01-01

    Summary In contrast to its close homolog CDK4, the cell cycle kinase CDK6 is expressed at high levels in lymphoid malignancies. In a model for p185BCR-ABL+ B-acute lymphoid leukemia, we show that CDK6 is part of a transcription complex that induces the expression of the tumor suppressor p16INK4a and the pro-angiogenic factor VEGF-A. This function is independent of CDK6’s kinase activity. High CDK6 expression thus suppresses proliferation by upregulating p16INK4a, providing an internal safeguard. However, in the absence of p16INK4a, CDK6 can exert its full tumor-promoting function by enhancing proliferation and stimulating angiogenesis. The finding that CDK6 connects cell-cycle progression to angiogenesis confirms CDK6’s central role in hematopoietic malignancies and could underlie the selection pressure to upregulate CDK6 and silence p16INK4a. PMID:23948297

  11. Variants of the yeast MAPK Mpk1 are fully functional independently of activation loop phosphorylation

    Science.gov (United States)

    Goshen-Lago, Tal; Goldberg-Carp, Anat; Melamed, Dganit; Darlyuk-Saadon, Ilona; Bai, Chen; Ahn, Natalie G.; Admon, Arie; Engelberg, David

    2016-01-01

    MAP kinases of the ERK family are conserved from yeast to humans. Their catalytic activity is dependent on dual phosphorylation of their activation loop’s TEY motif, catalyzed by MAPK kinases (MEKs). Here we studied variants of Mpk1, a yeast orthologue of Erk, which is essential for cell wall integrity. Cells lacking MPK1, or the genes encoding the relevant MEKs, MKK1 and MKK2, do not proliferate under cell wall stress, imposed, for example, by caffeine. Mutants of Mpk1, Mpk1(Y268C) and Mpk1(Y268A), function independently of Mkk1 and Mkk2. We show that these variants are phosphorylated at their activation loop in mkk1∆mkk2∆ and mkk1∆mkk2∆pbs2∆ste7∆ cells, suggesting that they autophosphorylate. However, strikingly, when Y268C/A mutations were combined with the kinase-dead mutation, K54R, or mutations at the TEY motif, T190A+Y192F, the resulting proteins still allowed mkk1∆mkk2∆ cells to proliferate under caffeine stress. Mutating the equivalent residue, Tyr-280/Tyr-261, in Erk1/Erk2 significantly impaired Erk1/2’s catalytic activity. This study describes the first case in which a MAPK, Erk/Mpk1, imposes a phenotype via a mechanism that is independent of TEY phosphorylation and an unusual case in which an equivalent mutation in a highly conserved domain of yeast and mammalian Erks causes an opposite effect. PMID:27413009

  12. Plasminogen activator inhibitor-1 is elevated in patients with COPD independent of metabolic and cardiovascular function

    Directory of Open Access Journals (Sweden)

    Waschki B

    2017-03-01

    Full Text Available Benjamin Waschki,1–3 Henrik Watz,2,3 Olaf Holz,4,5 Helgo Magnussen,2,3 Beata Olejnicka,6 Tobias Welte,5,7 Klaus F Rabe,1,3 Sabina Janciauskiene5,7 1Pneumology, LungenClinic Grosshansdorf, Grosshansdorf, Germany; 2Pulmonary Research Institute at LungenClinic Grosshansdorf, Grosshansdorf, Germany; 3Airway Research Center North (ARCN, German Center for Lung Research (DZL, Grosshansdorf, Germany; 4Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; 5Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH, German Center for Lung Research (DZL, Hannover, Germany; 6Department of Medicine, Trelleborg Hospital, Trelleborg, Sweden; 7Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany Introduction: Plasminogen activator inhibitor-1 (PAI-1, a major inhibitor of fibrinolysis, is associated with thrombosis, obesity, insulin resistance, dyslipidemia, and premature aging, which all are coexisting conditions of chronic obstructive pulmonary disease (COPD. The role of PAI-1 in COPD with respect to metabolic and cardiovascular functions is unclear. Methods: In this study, which was nested within a prospective cohort study, the serum levels of PAI-1 were cross-sectionally measured in 74 stable COPD patients (Global Initiative for Chronic Obstructive Lung Disease [GOLD] Stages I–IV and 18 controls without lung disease. In addition, triglycerides, high-density lipoprotein cholesterol, fasting plasma glucose, waist circumference, blood pressure, smoking status, high-sensitive C-reactive protein (hs-CRP, adiponectin, ankle–brachial index, N-terminal pro-B-type natriuretic peptide, and history of comorbidities were also determined. Results: The serum levels of PAI-1 were significantly higher in COPD patients than in controls, independent of a broad spectrum of possible confounders including metabolic and cardiovascular dysfunction. A multivariate regression analysis revealed

  13. Obsessive compulsive symptoms are associated with better functioning independently of cognition in schizophrenia.

    Science.gov (United States)

    Kontis, Dimitrios; Theochari, Eirini; Nikolakopoulou, Mary; Andreopoulou, Angeliki; Vassos, Dimitrios; Grigoriou, Vasileios; Vassilouli, Spyridoula; Giannakopoulou, Dimitra; Kouloumbi, Maria; Tsaltas, Eleftheria

    2016-10-01

    Although the relationship of obsessive-compulsive symptoms (OCSs) with both cognition and social functioning (SF) has already been the focus of research in schizophrenia, the moderation of the relationship of OCSs with SF by cognition has not been explored to date. We investigated the association of OCSs with SF and its interaction with cognition in schizophrenia. We recruited 110 schizophrenia patients and assessed OCSs (Yale-Brown Scale), schizophrenia symptoms (Positive and Negative Syndrome Scale), SF (Strauss-Carpenter Scale) and cognition. 51 patients had one obsessive-compulsive symptom or more, whereas 59 patients had no obsessive compulsive-symptom, according to the Yale-Brown Scale. We mainly investigated: a) the predictive effect of OCSs on SF, controlling for cognition, illness duration and symptoms' severity and b) the moderating effect of cognition on the OCSs-SF relationship. The mean score of OCSs for patients having at least one symptom was 13.43 (SD=8.32). Higher OCSs predicted increased SF (B=0.98, t=2.41, df=88, p=0.018). This relationship was driven by the association of compulsions with job functioning (B=0.074, t=2.029, df=88, p=0.046). Patients without OCSs demonstrated worse functioning compared with those having at least one obsessive-compulsive symptom (mean difference=2.496, t=3.732, df=88, pcognition moderates the effect of OCSs on SF. There may be a beneficial effect of OCSs on SF in patients with schizophrenia which is independent of their cognitive performance. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Model-independent analyses of non-Gaussianity in Planck CMB maps using Minkowski functionals

    Science.gov (United States)

    Buchert, Thomas; France, Martin J.; Steiner, Frank

    2017-05-01

    Despite the wealth of Planck results, there are difficulties in disentangling the primordial non-Gaussianity of the Cosmic Microwave Background (CMB) from the secondary and the foreground non-Gaussianity (NG). For each of these forms of NG the lack of complete data introduces model-dependences. Aiming at detecting the NGs of the CMB temperature anisotropy δ T , while paying particular attention to a model-independent quantification of NGs, our analysis is based upon statistical and morphological univariate descriptors, respectively: the probability density function P(δ T) , related to v0, the first Minkowski Functional (MF), and the two other MFs, v1 and v2. From their analytical Gaussian predictions we build the discrepancy functions {{ Δ }k} (k  =  P, 0, 1, 2) which are applied to an ensemble of 105 CMB realization maps of the Λ CDM model and to the Planck CMB maps. In our analysis we use general Hermite expansions of the {{ Δ }k} up to the 12th order, where the coefficients are explicitly given in terms of cumulants. Assuming hierarchical ordering of the cumulants, we obtain the perturbative expansions generalizing the second order expansions of Matsubara to arbitrary order in the standard deviation {σ0} for P(δ T) and v0, where the perturbative expansion coefficients are explicitly given in terms of complete Bell polynomials. The comparison of the Hermite expansions and the perturbative expansions is performed for the Λ CDM map sample and the Planck data. We confirm the weak level of non-Gaussianity (1-2)σ of the foreground corrected masked Planck 2015 maps.

  15. On the association between adolescent autonomy and psychosocial functioning: examining decisional independence from a self-determination theory perspective.

    Science.gov (United States)

    Van Petegem, Stijn; Beyers, Wim; Vansteenkiste, Maarten; Soenens, Bart

    2012-01-01

    In the present study, we focus on the concept of adolescent autonomy and its relation with psychosocial functioning. Specifically, we aim to differentiate between 2 prevailing conceptualizations of autonomy, that is, (a) autonomy defined as independence versus dependence and (b) autonomy defined as self-endorsed versus controlled functioning. A 2nd goal is to examine the relative contribution of each autonomy operationalization in the prediction of adolescents' adjustment (i.e., well-being, problem behavior, and intimacy). Data were gathered in a sample of 707 Belgian adolescents. Using a newly developed questionnaire, we assessed both the degree of independent decision making per se and the self-endorsed versus controlled motives underlying both independent and dependent decision making. The degree of independent decision making could clearly be differentiated from the underlying motives for doing so. Moreover, independent decision making as such showed unique associations with more problem behavior. Further, as expected, self-endorsed motives for both independent and dependent decision making generally related to an adaptive pattern of psychosocial functioning, and controlled motives were associated with maladjustment. The discussion focuses on the difference between the 2 perspectives on autonomy and on the different meaning of the motives underlying independent, relative to dependent, decision making.

  16. The relationship between multiple joint flexibility and functional performance in independent and physically active elderly women

    Directory of Open Access Journals (Sweden)

    Maria Joana de Carvalho

    2007-09-01

    Full Text Available Multi-joint flexibility assessment seems to be more appropriate for analyzing the association between fl exibility and functional fitness, but there is a lack of studies to confi rm this possibility in elderly people. The present study investigated the relationship between a multiple joint fl exibility assessment and the functional performance of 30 independent and physically active elderly women (age=68±1yr. Flexibility was assessed using the Chair Sit-and-Reach Test (CSRT. Functional performance was tested by a combination of three tasks: a Step Length (SL; b Time to Put on Sneakers (TPS; c Climbing Stairs (CS. The association between fl exibility and functional performance was tested by both simple and multiple correlation techniques. Pearson’s correlation was signifi cant for TPS (r = -.37; p ABSTRACT

  17. A robust independent component analysis (ICA) model for functional magnetic resonance imaging (fMRI) data

    Science.gov (United States)

    Ao, Jingqi; Mitra, Sunanda; Liu, Zheng; Nutter, Brian

    2011-03-01

    The coupling of carefully designed experiments with proper analysis of functional magnetic resonance imaging (fMRI) data provides us with a powerful as well as noninvasive tool to help us understand cognitive processes associated with specific brain regions and hence could be used to detect abnormalities induced by a diseased state. The hypothesisdriven General Linear Model (GLM) and the data-driven Independent Component Analysis (ICA) model are the two most commonly used models for fMRI data analysis. A hybrid ICA-GLM model combines the two models to take advantages of benefits from both models to achieve more accurate mapping of the stimulus-induced activated brain regions. We propose a modified hybrid ICA-GLM model with probabilistic ICA that includes a noise model. In this modified hybrid model, a probabilistic principle component analysis (PPCA)-based component number estimation is used in the ICA stage to extract the intrinsic number of original time courses. In addition, frequency matching is introduced into the time course selection stage, along with temporal correlation, F-test based model fitting estimation, and time course combination, to produce a more accurate design matrix for GLM. A standard fMRI dataset is used to compare the results of applying GLM and the proposed hybrid ICA-GLM in generating activation maps.

  18. ARF functions as a melanoma tumor suppressor by inducing p53-independent senescence

    Science.gov (United States)

    Ha, Linan; Ichikawa, Takeshi; Anver, Miriam; Dickins, Ross; Lowe, Scott; Sharpless, Norman E.; Krimpenfort, Paul; DePinho, Ronald A.; Bennett, Dorothy C.; Sviderskaya, Elena V.; Merlino, Glenn

    2007-01-01

    Inactivation of the p53 pathway represents the most common molecular defect of human cancer. But in the setting of melanoma, a highly aggressive and invariably fatal malignancy in its advanced disseminated form, mutation/deletion of p53 is relatively rare, whereas its positive regulator ARF is often lost. Here, we show that genetic deficiency in Arf but not p53 facilitates rapid development of melanoma in a genetically engineered mouse model. This difference is accounted for, at least in part, by the unanticipated observation that, unlike fibroblasts, senescence control in melanocytes is strongly regulated by Arf and not p53. Moreover, oncogenic NRAS collaborates with deficiency in Arf, but not p53, to fully transform melanocytes. Our data demonstrate that ARF and p53, although linked in a common pathway, suppress tumorigenesis through distinct, lineage-dependent mechanisms and suggest that ARF helps restrict melanoma progression by executing the oncogene-induced senescence program in benign nevi. Thus, therapeutics designed to restore wild-type p53 function may be insufficient to counter melanoma and other malignancies in which ARF holds p53-independent tumor suppressor activity. PMID:17576930

  19. Effects of antidiabetes drugs on functional independence measure on a subacute rehabilitation ward for stroke patients.

    Science.gov (United States)

    Kose, E; Toyoshima, M; Tachi, T; Teramachi, H; Kawakubo, T; Hayashi, H

    2015-07-01

    It has been reported that the improvement of activities of daily living (ADL) by rehabilitation affects glycemic control. However, there are no reports about antidiabetes drugs as factors affecting the outcomes of rehabilitation. Therefore, we investigated the effects of antidiabetes drugs on functional independence measure (FIM) [total (T), motor (M), and cognition (C) items] in stroke patients with diabetes who were discharged from the subacute rehabilitation ward. We chose the frequently used antidiabetes drugs [sulfonylurea (SU), dipeptidyl peptidase-IV inhibitors (DPP-IVIs), and α-glycosidase inhibitors (α-GIs)] as the basis for categorizing the patients. We compared the patients' background features and laboratory data among the three groups. As a result, when SU was used in stroke patients with diabetes, it is difficult to obtain significant FIM-M gain, FIM-C gain, FIM-M efficiency, and FIM-C efficiency compared with of-GIs. As a reason for this, we hypothesize the possibility of the involvement of insulin resistance. Therefore, we consider that insulin resistance should be determined early and that it is important to reduce insulin resistance comprehensively by involving experts.

  20. Functional pleiotropy and mating system evolution in plants: frequency-independent mating.

    Science.gov (United States)

    Jordan, Crispin Y; Otto, Sarah P

    2012-04-01

    Mutations that alter the morphology of floral displays (e.g., flower size) or plant development can change multiple functions simultaneously, such as pollen export and selfing rate. Given the effect of these various traits on fitness, pleiotropy may alter the evolution of both mating systems and floral displays, two characters with high diversity among angiosperms. The influence of viability selection on mating system evolution has not been studied theoretically. We model plant mating system evolution when a single locus simultaneously affects the selfing rate, pollen export, and viability. We assume frequency-independent mating, so our model characterizes prior selfing. Pleiotropy between increased viability and selfing rate reduces opportunities for the evolution of pure outcrossing, can favor complete selfing despite high inbreeding depression, and notably, can cause the evolution of mixed mating despite very high inbreeding depression. These results highlight the importance of pleiotropy for mating system evolution and suggest that selection by nonpollinating agents may help explain mixed mating, particularly in species with very high inbreeding depression. © 2012 The Author(s). Evolution© 2012 The Society for the Study of Evolution.

  1. Retraining of interjoint arm coordination after stroke using robot-assisted time-independent functional training

    Directory of Open Access Journals (Sweden)

    Elizabeth B. Brokaw, MS

    2011-05-01

    Full Text Available We have developed a haptic-based approach for retraining of interjoint coordination following stroke called time-independent functional training (TIFT and implemented this mode in the ARMin III robotic exoskeleton. The ARMin III robot was developed by Drs. Robert Riener and Tobias Nef at the Swiss Federal Institute of Technology Zurich (Eidgenossische Technische Hochschule Zurich, or ETH Zurich, in Zurich, Switzerland. In the TIFT mode, the robot maintains arm movements within the proper kinematic trajectory via haptic walls at each joint. These arm movements focus training of interjoint coordination with highly intuitive real-time feedback of perform-ance; arm movements advance within the trajectory only if their movement coordination is correct. In initial testing, 37 nondisabled subjects received a single session of learning of a complex pattern. Subjects were randomized to TIFT or visual demonstration or moved along with the robot as it moved though the pattern (time-dependent [TD] training. We examined visual demonstration to separate the effects of action observation on motor learning from the effects of the two haptic guidance methods. During these training trials, TIFT subjects reduced error and interaction forces between the robot and arm, while TD subject performance did not change. All groups showed significant learning of the trajectory during unassisted recall trials, but we observed no difference in learning between groups, possibly because this learning task is dominated by vision. Further testing in stroke populations is warranted.

  2. Regularization independent analysis of the origin of two loop contributions to N=1 Super Yang-Mills beta function

    Energy Technology Data Exchange (ETDEWEB)

    Fargnoli, H.G.; Sampaio, Marcos; Nemes, M.C. [Federal University of Minas Gerais, ICEx, Physics Department, P.O. Box 702, Belo Horizonte, MG (Brazil); Hiller, B. [Coimbra University, Faculty of Science and Technology, Physics Department, Center of Computational Physics, Coimbra (Portugal); Baeta Scarpelli, A.P. [Setor Tecnico-Cientifico, Departamento de Policia Federal, Lapa, Sao Paulo (Brazil)

    2011-05-15

    We present both an ultraviolet and an infrared regularization independent analysis in a symmetry preserving framework for the N=1 Super Yang-Mills beta function to two loop order. We show explicitly that off-shell infrared divergences as well as the overall two loop ultraviolet divergence cancel out, whilst the beta function receives contributions of infrared modes. (orig.)

  3. Application of an excited state LDA exchange energy functional for the calculation of transition energy of atoms within time-independent density functional theory

    Energy Technology Data Exchange (ETDEWEB)

    Shamim, Md; Harbola, Manoj K, E-mail: sami@iitk.ac.i, E-mail: mkh@iitk.ac.i [Department of Physics, Indian Institute of Technology, Kanpur 208 016 (India)

    2010-11-14

    Transition energies of a new class of excited states (two-gap systems) of various atoms are calculated in time-independent density functional formalism by using a recently proposed local density approximation exchange energy functional for excited states. It is shown that the excitation energies calculated with this functional compare well with those calculated with exact exchange theories.

  4. A Multidimensional Rasch Analysis of the Functional Independence Measure Based on the National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems National Database.

    Science.gov (United States)

    Pretz, Christopher R; Kean, Jacob; Heinemann, Allen W; Kozlowski, Allan J; Bode, Rita K; Gebhardt, Eveline

    2016-07-15

    A number of studies have evaluated the psychometric properties of the Functional Independence Measure (FIM™) using Rasch analysis, although none has done so using the National Institute on Disability, Independent Living, and Rehabilitation Research Traumatic Brain Injury Model Systems National Database, a longitudinal database that captures demographic and outcome information on persons with moderate to severe traumatic brain injury across the United States. In the current study, we examine the psychometric properties of the FIM as represented by persons within this database and demonstrate that the FIM comprises three subscales representing cognitive, self-care, and mobility domains. These subscales were analyzed simultaneously using a multivariate Rasch model in combination with a time dependent concurrent calibration scheme with the goal of creating a raw score-to-logit transformation that can be used to improve the accuracy of parametric statistical analyses. The bowel and bladder function items were removed because of misfit with the motor and cognitive items. Some motor items exhibited step disorder, which was addressed by collapsing Categories 1-3 for Toileting, Stairs, Locomotion, Tub/Shower Transfers; Categories 1 and 2 for Toilet and Bed Transfers; and Categories 2 and 3 for Grooming. The strong correlations (r = 0.82-0.96) among the three subscales suggest they should be modeled together. Coefficient alpha of 0.98 indicates high internal consistency. Keyform maps are provided to enhance clinical interpretation and application of study results.

  5. Canagliflozin Slows Progression of Renal Function Decline Independently of Glycemic Effects.

    Science.gov (United States)

    Heerspink, Hiddo J L; Desai, Mehul; Jardine, Meg; Balis, Dainius; Meininger, Gary; Perkovic, Vlado

    2017-01-01

    Sodium-glucose cotransporter 2 inhibition with canagliflozin decreases HbA1c, body weight, BP, and albuminuria, implying that canagliflozin confers renoprotection. We determined whether canagliflozin decreases albuminuria and reduces renal function decline independently of its glycemic effects in a secondary analysis of a clinical trial in 1450 patients with type 2 diabetes receiving metformin and randomly assigned to either once-daily canagliflozin 100 mg, canagliflozin 300 mg, or glimepiride uptitrated to 6-8 mg. End points were annual change in eGFR and albuminuria over 2 years of follow-up. Glimepiride, canagliflozin 100 mg, and canagliflozin 300 mg groups had eGFR declines of 3.3 ml/min per 1.73 m(2) per year (95% confidence interval [95% CI], 2.8 to 3.8), 0.5 ml/min per 1.73 m(2) per year (95% CI, 0.0 to 1.0), and 0.9 ml/min per 1.73 m(2) per year (95% CI, 0.4 to 1.4), respectively (Pcanagliflozin group versus glimepiride). In the subgroup of patients with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, urinary albumin-to-creatinine ratio decreased more with canagliflozin 100 mg (31.7%; 95% CI, 8.6% to 48.9%; P=0.01) or canagliflozin 300 mg (49.3%; 95% CI, 31.9% to 62.2%; Pcanagliflozin 100 mg, or canagliflozin 300 mg had reductions in HbA1c of 0.81%, 0.82%, and 0.93%, respectively, at 1 year and 0.55%, 0.65%, and 0.74%, respectively, at 2 years. In conclusion, canagliflozin 100 or 300 mg/d, compared with glimepiride, slowed the progression of renal disease over 2 years in patients with type 2 diabetes, and canagliflozin may confer renoprotective effects independently of its glycemic effects. Copyright © 2016 by the American Society of Nephrology.

  6. Structure-function analysis of Methanobacterium thermoautotrophicum RNA ligase – engineering a thermostable ATP independent enzyme

    Directory of Open Access Journals (Sweden)

    Zhelkovsky Alexander M

    2012-07-01

    Mutational analysis of the heat stable RNA ligase from Methanobacterium thermoautotrophicum resulted in the creation of an ATP independent ligase. The K97A mutant is defective in the first two steps of ligation but retains full activity in ligation of either RNA or ssDNA to a pre-adenylated linker. The ability of the ligase to function at 65°C should reduce the constraints of RNA secondary structure in RNA ligation experiments.

  7. Evidence for alteration of EZH2, BMI1, and KDM6A and epigenetic reprogramming in human papillomavirus type 16 E6/E7-expressing keratinocytes.

    Science.gov (United States)

    Hyland, Paula L; McDade, Simon S; McCloskey, Rachel; Dickson, Glenda J; Arthur, Ken; McCance, Dennis J; Patel, Daksha

    2011-11-01

    A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future.

  8. Evidence for Alteration of EZH2, BMI1, and KDM6A and Epigenetic Reprogramming in Human Papillomavirus Type 16 E6/E7-Expressing Keratinocytes ▿

    Science.gov (United States)

    Hyland, Paula L.; McDade, Simon S.; McCloskey, Rachel; Dickson, Glenda J.; Arthur, Ken; McCance, Dennis J.; Patel, Daksha

    2011-01-01

    A number of epigenetic alterations occur in both the virus and host cellular genomes during human papillomavirus (HPV)-associated carcinogenesis, and investigations of such alterations, including changes in chromatin proteins and histone modifications, have the potential to lead to therapeutic epigenetic reversion. We report here that transformed HPV16 E6/E7-expressing primary human foreskin keratinocytes (HFKs) (E6/E7 cells) demonstrate increased expression of the PRC2 methyltransferase EZH2 at both the mRNA and protein levels but do not exhibit the expected increase in trimethylated H3K27 (H3K27me3) compared to normal keratinocytes. In contrast, these cells show a reduction in global H3K27me3 levels in vitro, as well as upregulation of the KDM6A demethylase. We further show for the first time that transformation with the HPV16 E6 and E7 oncogenes also results in an increase in phosphorylated EZH2 serine 21 (P-EZH2-Ser21), mediated by active Akt, and in a downregulation of the PRC1 protein BMI1 in these cells. High-grade squamous cervical intraepithelial lesions also showed a loss of H3K27me3 in the presence of increased expression of EZH2. Correlating with the loss of H3K27me3, E6/E7 cells exhibited derepression of specific EZH2-, KMD6A-, and BMI1-targeted HOX genes. These results suggest that the observed reduction in H3K27me3 may be due to a combination of reduced activities/levels of specific polycomb proteins and increases in demethylases. The dysregulation of multiple chromatin proteins resulting in the loss of global H3K27me3 and the transcriptional reprogramming in HPV16 E6/E7-infected cells could provide an epigenetic signature associated with risk and/or progression of HPV16-associated cancers, as well as the potential for epigenetic reversion in the future. PMID:21865393

  9. Validación de la Escala de Independencia Funcional Validation of the Functional Independence Scale

    Directory of Open Access Journals (Sweden)

    Pablo Martínez-Martín

    2009-02-01

    Full Text Available Objetivo: Evaluar la calidad psicométrica de un instrumento diseñado para medir la independencia funcional (Escala de Independencia Funcional, EIF en varios dominios de actividades de la vida diaria y ser aplicado por entrevistadores entrenados no expertos en el ámbito sanitario. El estudio se realizó en población mayor no institucionalizada residente en la Comunidad de Madrid. Métodos: Estudio transversal de validación. Se aplicaron la EIF, el test de Pfeiffer, la subescala de depresión de la Hospital Anxiety and Depression Scale, un indicador de comorbilidad, el Índice de Barthel y el EQ-5D, a población residente en medio comunitario (n=500 y a pacientes ambulatorios en medio hospitalario (n=100 de edad ≥65 años. Se analizaron los siguientes atributos psicométricos de la EIF: aceptabilidad, asunciones escalares, consistencia interna, validez de constructo y precisión. Resultados: La escala resultó totalmente computable en el 94,3% de los sujetos, con efecto techo (60,65% y sin efecto suelo (0,22% en el medio comunitario. En el medio hospitalario no se evidenció efecto suelo ni techo. La escala mostró asunciones escalares satisfactorias y elevada consistencia interna (correlaciones ítem-total: 0,57-0,91; alfa de Cronbach: 0,94, así como una estructura multidimensional (tres factores; 74,3% de la varianza. Los índices de validez convergente, interna y para grupos conocidos, al igual que la precisión (error estándar de la medida: 2,49; intervalo de confianza del 95%: 4,88 resultaron satisfactorios. Conclusiones: En suma, la EIF es una escala de uso sencillo con atributos métricos apropiados, y su aplicación por parte de personal no sanitario resulta útil para muestras amplias de individuos mayores no institucionalizados.Objective: To assess the psychometric quality of an instrument designed to measure functional independence (Functional Independence Scale [FIS] in several activities of daily living domains and to be

  10. Associations Between Ankle-Brachial Index and Cognitive Function: Results from the Lifestyle Interventions and Independence for Elders Trial

    Science.gov (United States)

    Espeland, Mark A.; Newman, Anne B.; Sink, Kaycee; Gill, Thomas M.; King, Abby C.; Miller, Michael E.; Guralnik, Jack; Katula, Jeff; Church, Timothy; Manini, Todd; Reid, Kieran F.; McDermott, Mary M.

    2015-01-01

    OBJECTIVE To evaluate cross-sectional and longitudinal associations between ankle-brachial index (ABI) and indicators of cognitive function DESIGN Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial) SETTING Eight US academic centers PARTICIPANTS 1,601 adults (ages 70–89 years, sedentary, non-demented, and with functional limitations MEASUREMENTS Baseline ABI and interviewer- and computer-administered cognitive function assessments were obtained from which compared a physical activity intervention with a health education control. Cognitive function was re-assessed 24 months later (interviewer-administered) and 18 or 30 months later (computer-administered) and central adjudication was used to classify individuals as having mild cognitive impairment, probable dementia, or neither. RESULTS Lower ABI had a modest independent association poorer cognitive functioning at baseline (partial r=0.09; p<0.001). While, lower baseline ABI was not associated with overall changes in cognitive function test scores, it was associated with higher odds for two-year progression to a composite of either mild cognitive impairment or probable dementia (OR=2.60 per unit lower ABI; 95% confidence interval [1.06,6.37]). Across two years, changes in ABI were not associated with changes in cognitive function. CONCLUSION In an older cohort of non-demented sedentary individuals with functional limitations, lower baseline ABI was independently correlated with cognitive function and associated with greater 2-year risk for progression to mild cognitive impairment or probable dementia. PMID:25869993

  11. Characterizing tissue microstructure using an ultrasound system-independent spatial autocorrelation function

    Science.gov (United States)

    Dong, Fang

    1999-09-01

    The research described in this dissertation is related to characterization of tissue microstructure using a system- independent spatial autocorrelation function (SAF). The function was determined using a reference phantom method, which employed a well-defined ``point- scatterer'' reference phantom to account for instrumental factors. The SAF's were estimated for several tissue-mimicking (TM) phantoms and fresh dog livers. Both phantom tests and in vitro dog liver measurements showed that the reference phantom method is relatively simple and fairly accurate, providing the bandwidth of the measurement system is sufficient for the size of the scatterer being involved in the scattering process. Implementation of this method in clinical scanner requires that distortions from patient's body wall be properly accounted for. The SAF's were estimated for two phantoms with body-wall-like distortions. The experimental results demonstrated that body wall distortions have little effect if echo data are acquired from a large scattering volume. One interesting application of the SAF is to form a ``scatterer size image''. The scatterer size image may help providing diagnostic tools for those diseases in which the tissue microstructure is different from the normal. Another method, the BSC method, utilizes information contained in the frequency dependence of the backscatter coefficient to estimate the scatterer size. The SAF technique produced accurate scatterer size images of homogeneous TM phantoms and the BSC method was capable of generating accurate size images for heterogeneous phantoms. In the scatterer size image of dog kidneys, the contrast-to-noise-ratio (CNR) between renal cortex and medulla was improved dramatically compared to the gray- scale image. The effect of nonlinear propagation was investigated by using a custom-designed phantom with overlaying TM fat layer. The results showed that the correlation length decreased when the transmitting power increased. The

  12. Ion flux dependent and independent functions of ion channels in the vertebrate heart: lessons learned from zebrafish.

    Science.gov (United States)

    Keßler, Mirjam; Just, Steffen; Rottbauer, Wolfgang

    2012-01-01

    Ion channels orchestrate directed flux of ions through membranes and are essential for a wide range of physiological processes including depolarization and repolarization of biomechanical activity of cells. Besides their electrophysiological functions in the heart, recent findings have demonstrated that ion channels also feature ion flux independent functions during heart development and morphogenesis. The zebrafish is a well-established animal model to decipher the genetics of cardiovascular development and disease of vertebrates. In large scale forward genetics screens, hundreds of mutant lines have been isolated with defects in cardiovascular structure and function. Detailed phenotyping of these lines and identification of the causative genetic defects revealed new insights into ion flux dependent and independent functions of various cardiac ion channels.

  13. Ion Flux Dependent and Independent Functions of Ion Channels in the Vertebrate Heart: Lessons Learned from Zebrafish

    Directory of Open Access Journals (Sweden)

    Mirjam Keßler

    2012-01-01

    Full Text Available Ion channels orchestrate directed flux of ions through membranes and are essential for a wide range of physiological processes including depolarization and repolarization of biomechanical activity of cells. Besides their electrophysiological functions in the heart, recent findings have demonstrated that ion channels also feature ion flux independent functions during heart development and morphogenesis. The zebrafish is a well-established animal model to decipher the genetics of cardiovascular development and disease of vertebrates. In large scale forward genetics screens, hundreds of mutant lines have been isolated with defects in cardiovascular structure and function. Detailed phenotyping of these lines and identification of the causative genetic defects revealed new insights into ion flux dependent and independent functions of various cardiac ion channels.

  14. Changes in executive functions and self-efficacy are independently associated with improved usual gait speed in older women

    Directory of Open Access Journals (Sweden)

    Hsu Chun

    2010-05-01

    Full Text Available Abstract Background Improved usual gait speed predicts substantial reduction in mortality. A better understanding of the modifiable factors that are independently associated with improved gait speed would ensure that intervention strategies are developed based on a valid theoretical framework. Thus, we examined the independent association of change in executive functions and change in falls-related self-efficacy with improved gait speed among community-dwelling senior women. Methods A secondary analysis of the 135 senior women aged 65 to 75 years old who completed a 12-month randomized controlled trial of resistance training. Usual gait speed was assessed using a 4-meter walk. Three executive processes were assessed by standard neuropsychological tests: 1 set shifting; 2 working memory; and 3 selective attention and response inhibition. A linear regression model was constructed to determine the independent association of change in executive functions and falls-related self-efficacy with change in gait speed. Results Improved selective attention and conflict resolution, and falls-related self-efficacy, were independently associated with improved gait speed after accounting for age, global cognition, baseline gait speed, and change in quadriceps strength. The total variance explained was 24%. Conclusions Interventions that target executive functions and falls-related self-efficacy, in addition to physical functions, to improve gait speed may be more efficacious than those that do not. Trial Registration ClinicalTrials.gov Identifier: NCT00426881

  15. Ion Flux Dependent and Independent Functions of Ion Channels in the Vertebrate Heart: Lessons Learned from Zebrafish

    OpenAIRE

    Mirjam Keßler; Steffen Just; Wolfgang Rottbauer

    2012-01-01

    Ion channels orchestrate directed flux of ions through membranes and are essential for a wide range of physiological processes including depolarization and repolarization of biomechanical activity of cells. Besides their electrophysiological functions in the heart, recent findings have demonstrated that ion channels also feature ion flux independent functions during heart development and morphogenesis. The zebrafish is a well-established animal model to decipher the genetics of cardiovascular...

  16. Advances in the Studies on Relationship between Bmi-1 Gene and Caners%Bmi-1基因在恶性肿瘤中的研究进展

    Institute of Scientific and Technical Information of China (English)

    王攀; 赵会传(综述); 曾同祥(审校)

    2015-01-01

    Bmi-1属于核染色质调控因子多梳基因家族,是与干细胞和肿瘤干细胞相关基因。直接参与细胞周期、凋亡和衰老的调控,在维持干细胞的自我更新及多向分化方面起重要作用;在多数肿瘤中表达失调,并且与恶性肿瘤的侵袭、转移和预后显著相关。它为恶性肿瘤患者的早期诊断、肿瘤的治疗和生存率的预测提供了一条重要途径,鉴于 Bmi-1在人类肿瘤中的重要作用,今后应着重开展关于Bmi-1与各种肿瘤干细胞关系的研究。%Bmi-1(Blymphoma Mo-MLV insertion region1homolog) is a member of the chromatin regula-tor polycomb group of genes( PcGs) ,which is a stem cell factor implicated in many cancers .Bmi-1 directly involves in the regulation of cell cycle,apoptosis and senescence.It plays an important role in maintaining the stem cell self-renewal and multi-differentiation.The expression of the Bmi-1 gets imbalanced in many caners, and it correlates with the cancer invasion ,metastasis and prognosis significantly .Bmi-1 gene offers a potential way for early diagnosis,treatment of cancer and prediction of survival rate in cancer patients.Given the important role of Bmi-1 in human tumors,research on the relationship between Bmi-1 and cancer stem cells should be focused on.

  17. Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure

    NARCIS (Netherlands)

    D. Westermann (Dirk); A. Riad (Alexander); O. Lettau (Olga); A.J.M. Roks (Anton); K. Sawatis (Konstantinos); P.M. Becher (Peter Moritz); F. Escher (Felicitas); A.H.J. Danser (Jan); H.P. Schultheiss (Heinz-Peter); C. Tschöpe (Carsten)

    2008-01-01

    textabstractPharmacological renin inhibition with aliskiren is an effective antihypertensive drug treatment, but it is currently unknown whether aliskiren is able to attenuate cardiac failure independent of its blood pressure-lowering effects. We investigated the effect of aliskiren on cardiac remod

  18. Is impaired kidney function an independent predictor of the risk of myocardial infarction in HIV-infected individuals?

    Science.gov (United States)

    Lang, Sylvie; Mary-Krause, Murielle; Partisani, Marialuisa; Gilquin, Jacques; Simon, Anne; Cotte, Laurent; Boccara, Franck; Costagliola, Dominique

    2014-08-24

    We examined whether impaired kidney function is an independent risk factor for myocardial infarction in HIV-infected individuals without pre-existing coronary artery disease. The odds ratio for impaired kidney function fell from 1.22 (95% confidence interval 0.90-1.66) to 0.99 (95% confidence interval 0.69-1.41) after adjustment for cardiovascular risk factors and HIV-related parameters, with hypertension, high-density lipoprotein cholesterol, smoking and the CD4 T-cell nadir as most influential confounders. In this setting, no association was found between impaired kidney function and the risk of myocardial infarction.

  19. Renal function but not asymmetric dimethylarginine is independently associated with retinopathy in type 2 diabetes.

    Science.gov (United States)

    Krzyzanowska, Katarzyna; Mittermayer, Friedrich; Schernthaner, Gerit H; Brunner, Simon; Brix, Johanna M; Aschauer, Stefan; Höllerl, Florian; Wolzt, Michael; Schernthaner, Guntram

    2011-01-01

    Background. Asymmetric dimethylarginine (ADMA) is associated with macrovascular disease and possibly with microangiopathy in type 2 diabetes (T2DM). We tested the hypothesis that ADMA is related to diabetic retinopathy (DR) independently of macrovascular disease. Methods. This cross-sectional study included 127 T2DM patients selected to achieve equal distributions of patients with and without macrovascular disease in the groups with and without DR. Results. Patients with DR had increased ADMA, longer diabetes duration, and reduced glomerular filtration rate (GFR). ADMA correlated with GFR (ρ = -0.35; P < .001), diabetes duration (ρ = 0.19; P = .048), and age (ρ = 0.19; P = .033). Logistic regression analysis revealed an association of ADMA with DR. After adjustment for macrovascular disease, this association remained significant (OR 1.48; 95% CI: 1.02-2.15; P = .039). Inclusion of GFR and T2DM duration into the model abolished this significant relationship. GFR remained the only independent predictor for DR. A 10 mL/min/1.73 m(2) GFR decrease was associated with DR in a multivariate model (OR 1.30; 95% CI: 1.08-1.56; P = .006). Conclusions. These findings indicate an association between ADMA and DR in T2DM independent of macrovascular disease. This relationship is modified by GFR, the only parameter significantly related to DR in multivariate analysis.

  20. Renal Function but Not Asymmetric Dimethylarginine Is Independently Associated with Retinopathy in Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Katarzyna Krzyzanowska

    2011-01-01

    Full Text Available Background. Asymmetric dimethylarginine (ADMA is associated with macrovascular disease and possibly with microangiopathy in type 2 diabetes (T2DM. We tested the hypothesis that ADMA is related to diabetic retinopathy (DR independently of macrovascular disease. Methods. This cross-sectional study included 127 T2DM patients selected to achieve equal distributions of patients with and without macrovascular disease in the groups with and without DR. Results. Patients with DR had increased ADMA, longer diabetes duration, and reduced glomerular filtration rate (GFR. ADMA correlated with GFR (=−0.35; <.001, diabetes duration (=0.19; =.048, and age (=0.19; =.033. Logistic regression analysis revealed an association of ADMA with DR. After adjustment for macrovascular disease, this association remained significant (OR 1.48; 95% CI: 1.02–2.15; =.039. Inclusion of GFR and T2DM duration into the model abolished this significant relationship. GFR remained the only independent predictor for DR. A 10 mL/min/1.73 m2 GFR decrease was associated with DR in a multivariate model (OR 1.30; 95% CI: 1.08–1.56; =.006. Conclusions. These findings indicate an association between ADMA and DR in T2DM independent of macrovascular disease. This relationship is modified by GFR, the only parameter significantly related to DR in multivariate analysis.

  1. Gap junction and hemichannel-independent actions of connexins on cell and tissue functions--an update.

    Science.gov (United States)

    Zhou, Jade Z; Jiang, Jean X

    2014-04-17

    Connexins, a family of transmembrane proteins, are components of both gap junction channels and hemichannels, which mediate the exchange of ions and small molecules between adjacent cells, and between the inside and outside of the cell, respectively. Substantial advancements have been made in the comprehension of the role of gap junctions and hemichannels in coordinating cellular events. In recent years, a plethora of studies demonstrate a role of connexin proteins in the regulation of tissue homeostasis that occurs independently of their channel activities. This is shown in the context of cell growth, adhesion, migration, apoptosis, and signaling. The major mechanisms of these channel-independent activities still remain to be discovered. In this review, we provide an updated overview on the current knowledge of gap junction- and hemichannel-independent functions of connexins, in particular, their effects on tumorigenesis, neurogenesis and disease development. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  2. A Layered Searchable Encryption Scheme with Functional Components Independent of Encryption Methods

    Directory of Open Access Journals (Sweden)

    Guangchun Luo

    2014-01-01

    from the core searchable structure. Based on this observation, we propose a layered searchable encryption (LSE scheme, which provides compatibility, flexibility, and security for various settings and functionalities. In this scheme, the outputs of the core searchable component based on either symmetric or asymmetric setting are converted to some uniform mappings, which are then transmitted to loosely coupled functional components to further filter the results. In such a way, all functional components could directly support both symmetric and asymmetric settings. Based on LSE, we propose two representative and novel constructions for ranked keyword query (previously only available in symmetric scheme and range query (previously only available in asymmetric scheme.

  3. Brief report: Does PTH increase with age, independent of 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium?

    Science.gov (United States)

    Carrivick, Simon J; Walsh, John P; Brown, Suzanne J; Wardrop, Robert; Hadlow, Narelle C

    2015-05-01

    Circulating PTH concentrations increase with age. It is uncertain whether an age-related PTH increase occurs independent of changes in circulating 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. The purpose of this article was to analyze the relationship between PTH and age, controlling for 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium. This was a retrospective, cross-sectional study analyzing the relationship between PTH and age in 2 independent datasets (laboratory 1, n = 17 275 and laboratory 2, n = 4878). We further analyzed subgroups after excluding participants with estimated glomerular filtration rate of increase in age was associated with a 5.0% increase in PTH (95% confidence interval [CI], 4.4%-5.6%; P increase in laboratory 2 (95% CI, 3.0%-5.4%; P increase in age was associated with a 6.1% increase in PTH (95% CI, 5.5%-6.8%; P increase (95% CI 3.5%-6.2%; P increase with age, independent of 25-hydroxyvitamin D, ionized calcium, phosphate, and renal function. Further research is required to explore the underlying mechanisms and clinical relevance and to determine whether the use of age-related PTH reference ranges improves diagnostic accuracy, particularly in elderly individuals.

  4. Disturbed cognitive functioning and clinical symptoms : two independent problem areas in schizophrenia

    NARCIS (Netherlands)

    Pijnenborg, GHM; van Beilen, M; Arends, J; Holthausen, EAE; Withaar, FK

    2003-01-01

    Background: Research findings on the relationship between cognitive functioning and psychiatric symptoms in schizophrenia have yielded inconsistent results. Although several models were postulated linking cognition and symptoms, the most recent studies point in the direction of cognition and symptom

  5. Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation

    OpenAIRE

    2009-01-01

    Postsynaptic neuroligins are thought to perform essential functions in synapse validation and synaptic transmission by binding to, and dimerizing, presynaptic α- and β-neurexins. To test this hypothesis, we examined the functional effects of neuroligin-1 mutations that impair only α-neurexin binding, block both α- and β-neurexin binding, or abolish neuroligin-1 dimerization. Abolishing α-neurexin binding abrogated neuroligin-induced generation of neuronal synapses onto transfected non-neurona...

  6. Association of waist circumference with impaired six-minute walk in type 2 diabetes mellitus is independent of cardiac function.

    Science.gov (United States)

    Wang, Ying; Yang, Hong; Nolan, Mark; Negishi, Kazuaki; Burgess, John; Marwick, Thomas H

    2016-04-01

    Subclinical left ventricular dysfunction has been associated with impaired exercise capacity in type 2 diabetes mellitus. In this community-based study of 274 asymptomatic T2DM patients (71±4 years, 55% men) with preserved ejection fraction, a comprehensive resting echocardiogram was performed to gather sensitive systolic and diastolic function parameters (including speckle tracking echocardiography), and a standard six-minute walk test was performed. Tertiles of increasing waist circumference were associated with worsening walk distance. In this community-based study, we found an association of waist circumference with impaired exercise capacity, independent of age, gender, diabetes duration, insulin and angiotensin blockade, LV mass, systolic and diastolic function.

  7. A layered searchable encryption scheme with functional components independent of encryption methods.

    Science.gov (United States)

    Luo, Guangchun; Peng, Ningduo; Qin, Ke; Chen, Aiguo

    2014-01-01

    Searchable encryption technique enables the users to securely store and search their documents over the remote semitrusted server, which is especially suitable for protecting sensitive data in the cloud. However, various settings (based on symmetric or asymmetric encryption) and functionalities (ranked keyword query, range query, phrase query, etc.) are often realized by different methods with different searchable structures that are generally not compatible with each other, which limits the scope of application and hinders the functional extensions. We prove that asymmetric searchable structure could be converted to symmetric structure, and functions could be modeled separately apart from the core searchable structure. Based on this observation, we propose a layered searchable encryption (LSE) scheme, which provides compatibility, flexibility, and security for various settings and functionalities. In this scheme, the outputs of the core searchable component based on either symmetric or asymmetric setting are converted to some uniform mappings, which are then transmitted to loosely coupled functional components to further filter the results. In such a way, all functional components could directly support both symmetric and asymmetric settings. Based on LSE, we propose two representative and novel constructions for ranked keyword query (previously only available in symmetric scheme) and range query (previously only available in asymmetric scheme).

  8. Closed-form fiducial confidence intervals for some functions of independent binomial parameters with comparisons.

    Science.gov (United States)

    Krishnamoorthy, K; Lee, Meesook; Zhang, Dan

    2017-02-01

    Approximate closed-form confidence intervals (CIs) for estimating the difference, relative risk, odds ratio, and linear combination of proportions are proposed. These CIs are developed using the fiducial approach and the modified normal-based approximation to the percentiles of a linear combination of independent random variables. These confidence intervals are easy to calculate as the computation requires only the percentiles of beta distributions. The proposed confidence intervals are compared with the popular score confidence intervals with respect to coverage probabilities and expected widths. Comparison studies indicate that the proposed confidence intervals are comparable with the corresponding score confidence intervals, and better in some cases, for all the problems considered. The methods are illustrated using several examples.

  9. Antibody-Independent Function of Human B Cells Contributes to Antifungal T Cell Responses.

    Science.gov (United States)

    Li, Rui; Rezk, Ayman; Li, Hulun; Gommerman, Jennifer L; Prat, Alexandre; Bar-Or, Amit

    2017-03-08

    Fungal infections (e.g., Candida albicans) can manifest as serious medical illnesses, especially in the elderly and immune-compromised hosts. T cells are important for Candida control. Whether and how B cells are involved in antifungal immunity has been less clear. Although patients with agammaglobulinemia exhibit normal antifungal immunity, increased fungal infections are reported following B cell-depleting therapy, together pointing to Ab-independent roles of B cells in controlling such infections. To test how human B cells may contribute to fungal-associated human T cell responses, we developed a novel Ag-specific human T cell/B cell in vitro coculture system and found that human B cells could induce C. albicans-associated, MHC class II-restricted responses of naive T cells. Activated B cells significantly enhanced C. albicans-mediated Th1 and Th17 T cell responses, which were both strongly induced by CD80/CD86 costimulation. IL-6(+)GM-CSF(+) B cells were the major responding B cell subpopulation to C. albicans and provided efficient costimulatory signals to the T cells. In vivo B cell depletion in humans resulted in reduced C. albicans-associated T responses. Of note, the decreased Th17, but not Th1, responses could be reversed by soluble factors from B cells prior to depletion, in an IL-6-dependent manner. Taken together, our results implicate an Ab-independent cytokine-defined B cell role in human antifungal T cell responses. These findings may be particularly relevant given the prospects of chronic B cell depletion therapy use in lymphoma and autoimmune disease, as patients age and are exposed to serial combination therapies.

  10. Differential effects of water-based exercise on the cognitive function in independent elderly adults.

    Science.gov (United States)

    Sato, Daisuke; Seko, Chihiro; Hashitomi, Tatsuya; Sengoku, Yasuo; Nomura, Takeo

    2015-04-01

    Physical exercise has been reported to be the most effective method to improve cognitive function and brain health, but there is as yet no research on the effect of water-based exercise. The aim of the present study was to compare the effects of water-based exercise with and without cognitive stimuli on cognitive and physical functions. The design is a single-blind randomized controlled study. Twenty-one participants were randomly assigned to a normal water-based exercise (Nor-WE) group or a cognitive water-based exercise (Cog-WE) group. The exercise sessions were divided into two exercise series: a 10-min series of land-based warm-up, consisting of flexibility exercises, and a 50-min series of exercises in water. The Nor-WE consisted of 10 min of walking, 30 min of strength and stepping exercise, including stride over, and 10 min of stretching and relaxation in water. The Cog-WE consisted of 10 min of walking, 30 min of water-cognitive exercises, and 10 min of stretching and relaxation in water. Cognitive function, physical function, and ADL were measured before the exercise intervention (pre-intervention) and 10 weeks after the intervention (post-intervention). Participation in the Cog-WE performed significantly better on the pegboard test and the choice stepping reaction test and showed a significantly improved attention, memory, and learning, and in the general cognitive function (measured as the total score in the 5-Cog test). Participation in the Nor-WE dramatically improved walking ability and lower limb muscle strength. Our results reveal that the benefits elderly adults may obtain from water-based exercise depend on the characteristics of each specific exercise program. These findings highlight the importance of prescription for personalized water-based exercises to elderly adults to improve cognitive function.

  11. Automatic denoising of functional MRI data: combining independent component analysis and hierarchical fusion of classifiers.

    Science.gov (United States)

    Salimi-Khorshidi, Gholamreza; Douaud, Gwenaëlle; Beckmann, Christian F; Glasser, Matthew F; Griffanti, Ludovica; Smith, Stephen M

    2014-04-15

    Many sources of fluctuation contribute to the fMRI signal, and this makes identifying the effects that are truly related to the underlying neuronal activity difficult. Independent component analysis (ICA) - one of the most widely used techniques for the exploratory analysis of fMRI data - has shown to be a powerful technique in identifying various sources of neuronally-related and artefactual fluctuation in fMRI data (both with the application of external stimuli and with the subject "at rest"). ICA decomposes fMRI data into patterns of activity (a set of spatial maps and their corresponding time series) that are statistically independent and add linearly to explain voxel-wise time series. Given the set of ICA components, if the components representing "signal" (brain activity) can be distinguished form the "noise" components (effects of motion, non-neuronal physiology, scanner artefacts and other nuisance sources), the latter can then be removed from the data, providing an effective cleanup of structured noise. Manual classification of components is labour intensive and requires expertise; hence, a fully automatic noise detection algorithm that can reliably detect various types of noise sources (in both task and resting fMRI) is desirable. In this paper, we introduce FIX ("FMRIB's ICA-based X-noiseifier"), which provides an automatic solution for denoising fMRI data via accurate classification of ICA components. For each ICA component FIX generates a large number of distinct spatial and temporal features, each describing a different aspect of the data (e.g., what proportion of temporal fluctuations are at high frequencies). The set of features is then fed into a multi-level classifier (built around several different classifiers). Once trained through the hand-classification of a sufficient number of training datasets, the classifier can then automatically classify new datasets. The noise components can then be subtracted from (or regressed out of) the original

  12. Successful aging as a continuum of functional independence: lessons from physical disability models of aging.

    NARCIS (Netherlands)

    Lowry, K.A.; Vallejo, A.N.; Studenski, S.A.

    2012-01-01

    Successful aging is a multidimensional construct that could be viewed as a continuum of achievement. Based on the disability model proposed by the WHO International Classification of Functioning, Disability and Health, successful aging includes not only the presence or absence of disease, but also

  13. Human regulatory T cell suppressive function is independent of apoptosis induction in activated effector T cells.

    Directory of Open Access Journals (Sweden)

    Yvonne Vercoulen

    Full Text Available BACKGROUND: CD4(+CD25(+FOXP3(+ Regulatory T cells (Treg play a central role in the immune balance to prevent autoimmune disease. One outstanding question is how Tregs suppress effector immune responses in human. Experiments in mice demonstrated that Treg restrict effector T cell (Teff responses by deprivation of the growth factor IL-2 through Treg consumption, resulting in apoptosis of Teff. PRINCIPAL FINDINGS: In this study we investigated the relevance of Teff apoptosis induction to human Treg function. To this end, we studied naturally occurring Treg (nTreg from peripheral blood of healthy donors, and, to investigate Treg function in inflammation in vivo, Treg from synovial fluid of Juvenile Idiopathic Arthritis (JIA patients (SF-Treg. Both nTreg and SF-Treg suppress Teff proliferation and cytokine production efficiently as predicted. However, in contrast with murine Treg, neither nTreg nor SF-Treg induce apoptosis in Teff. Furthermore, exogenously supplied IL-2 and IL-7 reverse suppression, but do not influence apoptosis of Teff. SIGNIFICANCE: Our functional data here support that Treg are excellent clinical targets to counteract autoimmune diseases. For optimal functional outcome in human clinical trials, future work should focus on the ability of Treg to suppress proliferation and cytokine production of Teff, rather than induction of Teff apoptosis.

  14. Successful aging as a continuum of functional independence: lessons from physical disability models of aging.

    NARCIS (Netherlands)

    Lowry, K.A.; Vallejo, A.N.; Studenski, S.A.

    2012-01-01

    Successful aging is a multidimensional construct that could be viewed as a continuum of achievement. Based on the disability model proposed by the WHO International Classification of Functioning, Disability and Health, successful aging includes not only the presence or absence of disease, but also a

  15. Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity

    NARCIS (Netherlands)

    S. Middendorp; A.J.E. Zijlstra (Esther); R. Kersseboom (Rogier); G.M. Dingjan (Gemma); H. Jumaa; R.W. Hendriks (Rudi)

    2005-01-01

    textabstractDuring B-cell development in the mouse, Bruton tyrosine kinase (Btk) and the adaptor protein SLP-65 (Src homology 2 [SH2] domain-containing leukocyte protein of 65 kDa) limit the expansion and promote the differentiation of pre-B cells. Btk is thought to mainly function

  16. Evaluation of Treatment in the Smart Home IRIS in terms of Functional Independence and Occupational Performance and Satisfaction

    Science.gov (United States)

    Ocepek, Julija; Roberts, Anne E. K.; Vidmar, Gaj

    2013-01-01

    The development of assistive technologies, home modifications, and smart homes has rapidly advanced in the last two decades. Health professionals have recognised the benefits of these technologies in improving individual's quality of life. The Smart Home IRIS was established in 2008 within the University Rehabilitation Institute in Ljubljana with the aim to enable persons with disabilities and elderly people to test various assistive technologies and technical solutions for their independent living. We investigated the effect of treatments in the Smart Home IRIS. A convenience sample of 59 persons with disabilities and elderly people (aged 24–81 years) who were treated in the Smart Home IRIS from April to December 2011 participated. Standardised instruments—the Canadian Occupational Performance Measure (COPM) and the Functional Independence Measure (FIM)—were administered at the first assessment in the Smart Home IRIS and at a second assessment at the participant's home after 6–12 months. All the outcomes statistically significantly improved from the first to the second assessment. The treatments in the Smart Home IRIS appeared to contribute to higher occupational performance and satisfaction with performance and higher functional independence of persons with disabilities and elderly people. PMID:24348748

  17. Trophic Mode-Dependent Proteomic Analysis Reveals Functional Significance of Light-Independent Chlorophyll Synthesis in Synechocystis sp. PCC 6803.

    Science.gov (United States)

    Fang, Longfa; Ge, Haitao; Huang, Xiahe; Liu, Ye; Lu, Min; Wang, Jinlong; Chen, Weiyang; Xu, Wu; Wang, Yingchun

    2017-01-09

    The photosynthetic model organism Synechocystis sp. PCC 6803 can grow in different trophic modes, depending on the availability of light and exogenous organic carbon source. However, how the protein profile changes to facilitate the cells differentially propagate in different modes has not been comprehensively investigated. Using isobaric labeling-based quantitative proteomics, we simultaneously identified and quantified 45% Synechocystis proteome across four different trophic modes, i.e., autotrophic, heterotrophic, photoheterotrophic, and mixotrophic modes. Among the 155 proteins that are differentially expressed across four trophic modes, proteins involved in nitrogen assimilation and light-independent chlorophyll synthesis are dramatically upregulated in the mixotrophic mode, concomitant with a dramatic increase of PII phosphorylation that senses carbon and nitrogen assimilation status. Moreover, functional study using a mutant defective in light-independent chlorophyll synthesis revealed that this pathway is important for chlorophyll accumulation under a cycled light/dark illumination regime, a condition mimicking day/night cycles in certain natural habitats. Collectively, these results provide the most comprehensive information on trophic mode-dependent protein expression in cyanobacterium, and reveal the functional significance of light-independent chlorophyll synthesis in trophic growth.

  18. Evaluation of treatment in the Smart Home IRIS in terms of functional independence and occupational performance and satisfaction.

    Science.gov (United States)

    Ocepek, Julija; Roberts, Anne E K; Vidmar, Gaj

    2013-01-01

    The development of assistive technologies, home modifications, and smart homes has rapidly advanced in the last two decades. Health professionals have recognised the benefits of these technologies in improving individual's quality of life. The Smart Home IRIS was established in 2008 within the University Rehabilitation Institute in Ljubljana with the aim to enable persons with disabilities and elderly people to test various assistive technologies and technical solutions for their independent living. We investigated the effect of treatments in the Smart Home IRIS. A convenience sample of 59 persons with disabilities and elderly people (aged 24-81 years) who were treated in the Smart Home IRIS from April to December 2011 participated. Standardised instruments--the Canadian Occupational Performance Measure (COPM) and the Functional Independence Measure (FIM)--were administered at the first assessment in the Smart Home IRIS and at a second assessment at the participant's home after 6-12 months. All the outcomes statistically significantly improved from the first to the second assessment. The treatments in the Smart Home IRIS appeared to contribute to higher occupational performance and satisfaction with performance and higher functional independence of persons with disabilities and elderly people.

  19. Evaluation of Treatment in the Smart Home IRIS in terms of Functional Independence and Occupational Performance and Satisfaction

    Directory of Open Access Journals (Sweden)

    Julija Ocepek

    2013-01-01

    Full Text Available The development of assistive technologies, home modifications, and smart homes has rapidly advanced in the last two decades. Health professionals have recognised the benefits of these technologies in improving individual’s quality of life. The Smart Home IRIS was established in 2008 within the University Rehabilitation Institute in Ljubljana with the aim to enable persons with disabilities and elderly people to test various assistive technologies and technical solutions for their independent living. We investigated the effect of treatments in the Smart Home IRIS. A convenience sample of 59 persons with disabilities and elderly people (aged 24–81 years who were treated in the Smart Home IRIS from April to December 2011 participated. Standardised instruments—the Canadian Occupational Performance Measure (COPM and the Functional Independence Measure (FIM—were administered at the first assessment in the Smart Home IRIS and at a second assessment at the participant’s home after 6–12 months. All the outcomes statistically significantly improved from the first to the second assessment. The treatments in the Smart Home IRIS appeared to contribute to higher occupational performance and satisfaction with performance and higher functional independence of persons with disabilities and elderly people.

  20. The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells.

    Science.gov (United States)

    Poulin, Lionel Franz; Henri, Sandrine; de Bovis, Béatrice; Devilard, Elisabeth; Kissenpfennig, Adrien; Malissen, Bernard

    2007-12-24

    Langerhans cells (LCs) constitute a subset of dendritic cells (DCs) that express the lectin langerin and that reside in their immature state in epidermis. Paradoxically, in mice permitting diphtheria toxin (DT)-mediated ablation of LCs, epidermal LCs reappeared with kinetics that lagged behind that of their putative progeny found in lymph nodes (LNs). Using bone marrow (BM) chimeras, we showed that a major fraction of the langerin(+), skin-derived DCs found in LNs originates from a developmental pathway that is independent from that of epidermal LCs. This pathway, the existence of which was unexpected, originates in the dermis and gives rise to langerin(+) dermal DCs (DDCs) that should not be confused with epidermal LCs en route to LNs. It explains that after DT treatment, some langerin(+), skin-derived DCs reappear in LNs long before LC-derived DCs. Using CD45 expression and BrdU-labeling kinetics, both LCs and langerin(+) DDCs were found to coexist in wild-type mice. Moreover, DT-mediated ablation of epidermal LCs opened otherwise filled niches and permitted repopulation of adult noninflammatory epidermis with BM-derived LCs. Our results stress that the langerin(+) DC network is more complex than originally thought and have implications for the development of transcutaneous vaccines and the improvement of humanized mouse models.

  1. Inflammasome-Mediated Inhibition of Listeria monocytogenes-Stimulated Immunity Is Independent of Myelomonocytic Function

    Science.gov (United States)

    Williams, Cassandra R.; Dustin, Michael L.; Sauer, John-Demian

    2013-01-01

    Activation of the Nlrc4 inflammasome results in the secretion of IL-1β and IL-18 through caspase-1 and induction of pyroptosis. L. monocytogenes engineered to activate Nlrc4 by expression of Legionella pneumophilia flagellin (L. monocytogenes L.p.FlaA) are less immunogenic for CD8+ T cell responses than wt L. monocytogenes. It is also known that IL-1β orchestrates recruitment of myelomonocytic cells (MMC), which have been shown to interfere with T cell-dendritic cells (DC) interactions in splenic white pulp (WP), limiting T cell priming and protective immunity. We have further analyzed the role of MMCs in the immunogenicity of L. monocytogenes L.p.FlaA. We confirmed that MMCs infiltrate the WP between 24–48 hours in response to wt L. monocytogenes infection and that depletion of MMCs enhances CD8+ T cell priming and protective memory. L. monocytogenes L.p.FlaA elicited accelerated recruitment of MMCs into the WP. While MMCs contribute to control of L. monocytogenes L.p.FlaA, MMC depletion did not increase immunogenicity of L.p.FlaA expressing strains. There was a significant decrease in L. monocytogenes L.p.FlaA in CD8α+ DCs independent of MMCs. These findings suggest that limiting inflammasome activation is important for bacterial accumulation in CD8α+ DCs, which are known to be critical for T cell response to L. monocytogenes. PMID:24349458

  2. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

    Directory of Open Access Journals (Sweden)

    Katharine L. Dobson

    2015-01-01

    Full Text Available In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia.

  3. Localization of Presynaptic Plasticity Mechanisms Enables Functional Independence of Synaptic and Ectopic Transmission in the Cerebellum

    Science.gov (United States)

    Dobson, Katharine L.; Bellamy, Tomas C.

    2015-01-01

    In the cerebellar molecular layer parallel fibre terminals release glutamate from both the active zone and from extrasynaptic “ectopic” sites. Ectopic release mediates transmission to the Bergmann glia that ensheathe the synapse, activating Ca2+-permeable AMPA receptors and glutamate transporters. Parallel fibre terminals exhibit several forms of presynaptic plasticity, including cAMP-dependent long-term potentiation and endocannabinoid-dependent long-term depression, but it is not known whether these presynaptic forms of long-term plasticity also influence ectopic transmission to Bergmann glia. Stimulation of parallel fibre inputs at 16 Hz evoked LTP of synaptic transmission, but LTD of ectopic transmission. Pharmacological activation of adenylyl cyclase by forskolin caused LTP at Purkinje neurons, but only transient potentiation at Bergmann glia, reinforcing the concept that ectopic sites lack the capacity to express sustained cAMP-dependent potentiation. Activation of mGluR1 caused depression of synaptic transmission via retrograde endocannabinoid signalling but had no significant effect at ectopic sites. In contrast, activation of NMDA receptors suppressed both synaptic and ectopic transmission. The results suggest that the signalling mechanisms for presynaptic LTP and retrograde depression by endocannabinoids are restricted to the active zone at parallel fibre synapses, allowing independent modulation of synaptic transmission to Purkinje neurons and ectopic transmission to Bergmann glia. PMID:26171253

  4. Inflammasome-mediated inhibition of Listeria monocytogenes-stimulated immunity is independent of myelomonocytic function.

    Directory of Open Access Journals (Sweden)

    Cassandra R Williams

    Full Text Available Activation of the Nlrc4 inflammasome results in the secretion of IL-1β and IL-18 through caspase-1 and induction of pyroptosis. L. monocytogenes engineered to activate Nlrc4 by expression of Legionella pneumophilia flagellin (L. monocytogenes L.p.FlaA are less immunogenic for CD8(+ T cell responses than wt L. monocytogenes. It is also known that IL-1β orchestrates recruitment of myelomonocytic cells (MMC, which have been shown to interfere with T cell-dendritic cells (DC interactions in splenic white pulp (WP, limiting T cell priming and protective immunity. We have further analyzed the role of MMCs in the immunogenicity of L. monocytogenes L.p.FlaA. We confirmed that MMCs infiltrate the WP between 24-48 hours in response to wt L. monocytogenes infection and that depletion of MMCs enhances CD8(+ T cell priming and protective memory. L. monocytogenes L.p.FlaA elicited accelerated recruitment of MMCs into the WP. While MMCs contribute to control of L. monocytogenes L.p.FlaA, MMC depletion did not increase immunogenicity of L.p.FlaA expressing strains. There was a significant decrease in L. monocytogenes L.p.FlaA in CD8α(+ DCs independent of MMCs. These findings suggest that limiting inflammasome activation is important for bacterial accumulation in CD8α(+ DCs, which are known to be critical for T cell response to L. monocytogenes.

  5. Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation

    DEFF Research Database (Denmark)

    Munk, O L; Keiding, S; Bass, L

    2003-01-01

    Modeling physiological processes using tracer kinetic methods requires knowledge of the time course of the tracer concentration in blood supplying the organ. For liver studies, however, inaccessibility of the portal vein makes direct measurement of the hepatic dual-input function impossible...... sampling in aorta and portal vein were made in 13 anesthetized pigs following inhalation of intravascular [15O]CO or injections of diffusible 3-O-[11C]methylglucose (MG). The parameters of the impulse-response function have a physiological interpretation in terms of the distribution of washout constants...... and are mathematically equivalent to the mean transit time (T) and standard deviation of transit times. The results include estimates of mean transit times from the aorta to the portal vein in pigs: T = 0.35 +/- 0.05 min for CO and 1.7 +/- 0.1 min for MG. The prediction of the portal venous time-activity curve benefits...

  6. Deficient Dopamine D2 Receptor Function Causes Renal Inflammation Independently of High Blood Pressure

    OpenAIRE

    Yanrong Zhang; Santiago Cuevas; Asico, Laureano D.; Crisanto Escano; Yu Yang; Pascua, Annabelle M.; Xiaoyan Wang; Jones, John E.; David Grandy; Gilbert Eisner; Pedro A. Jose; Ines Armando

    2012-01-01

    Renal dopamine receptors participate in the regulation of blood pressure. Genetic factors, including polymorphisms of the dopamine D(2) receptor gene (DRD2) are associated with essential hypertension, but the mechanisms of their contribution are incompletely understood. Mice lacking Drd2 (D(2)-/-) have elevated blood pressure, increased renal expression of inflammatory factors, and renal injury. We tested the hypothesis that decreased dopamine D(2) receptor (D(2)R) function increases vulnerab...

  7. An Energy-Independent Pro-longevity Function of Triacylglycerol in Yeast

    OpenAIRE

    Witawas Handee; Xiaobo Li; Hall, Kevin W; Xiexiong Deng; Pan Li; Christoph Benning; Williams, Barry L; Min-Hao Kuo

    2016-01-01

    Author Summary Triacylglycerol (TAG) is a ubiquitous lipid species well-known for its roles in storing surplus energy, providing insulation, and maintaining cellular lipid homeostasis. Here we present evidence for a novel pro-longevity function of TAG in the budding yeast, a model organism for aging research. Yeast cells that are genetically engineered to store more TAG live significantly longer without suffering obvious growth defects, whereas those lean cells that are depleted of TAG die ea...

  8. Does Sensory Function Decline Independently or Concomitantly with Age? Data from the Baltimore Longitudinal Study of Aging

    Science.gov (United States)

    Gadkaree, Shekhar K.; Sun, Daniel Q.; Li, Carol; Lin, Frank R.; Ferrucci, Luigi; Simonsick, Eleanor M.

    2016-01-01

    Objectives. To investigate whether sensory function declines independently or in parallel with age within a single individual. Methods. Cross-sectional analysis of Baltimore Longitudinal Study of Aging (BLSA) participants who underwent vision (visual acuity threshold), proprioception (ankle joint proprioceptive threshold), vestibular function (cervical vestibular-evoked myogenic potential), hearing (pure-tone average audiometric threshold), and Health ABC physical performance battery testing. Results. A total of 276 participants (mean age 70 years, range 26–93) underwent all four sensory tests. The function of all four systems declined with age. After age adjustment, there were no significant associations between sensory systems. Among 70–79-year-olds, dual or triple sensory impairment was associated with poorer physical performance. Discussion. Our findings suggest that beyond the common mechanism of aging, other distinct (nonshared) etiologic mechanisms may contribute to decline in each sensory system. Multiple sensory impairments influence physical performance among individuals in middle old-age (age 70–79).

  9. Successful tactile based visual sensory substitution use functions independently of visual pathway integrity

    Directory of Open Access Journals (Sweden)

    Vincent eLee

    2014-05-01

    Full Text Available Purpose: We explored the microstructural differences between perinatally blind (PB, acquired blind (AB, and normally sighted controls (SC and related these differences to performance on functional tasks using a sensory substitution device (BrainPort. Methods: We enrolled 52 subjects (PB n=11; AQ n=35; NS n=6. Subjects spent 15 hours undergoing BrainPort device training. Outcomes of light perception, motion, direction, temporal resolution, grating, and acuity were tested at baseline and after training. Twenty-six of the subjects were scanned with a 3 Tesla MRI scanner for diffusion tensor imaging (DTI, and with a positron emission tomography (PET scanner for mapping regional brain glucose consumption during sensory substitution function. Non-parametric models were used to analyze fractional anisotropy (FA; a DTI measure of microstructural integrity of the brain via region-of-interest (ROI analysis and tract-based spatial statistics (TBSS. Results: At baseline, all subjects performed all tasks at chance level. After training, light perception, time resolution, location and grating acuity tasks improved significantly for all subject groups. ROI and TBSS analyses of FA maps show statistically significant differences (p≤0.025 in the bilateral optic radiations and some visual association areas between all 3 groups. No relationship was found between FA and functional performance with the BrainPort. Discussion: : All subjects showed performance improvements using the BrainPort irrespective of nature and duration of blindness. Definite brain areas with significant microstructural integrity changes exist among PB, AB, and NC, and these variations are most pronounced in the visual pathways. However, the use of sensory substitution devices is feasible irrespective of of microstructural integrity of the primary visual pathways between the eye and the brain. Therefore, tongue based devices devices may be usable for a broad array of non sighted persons.

  10. Speech discrimination difficulties in High-Functioning Autism Spectrum Disorder are likely independent of auditory hypersensitivity.

    Directory of Open Access Journals (Sweden)

    William Andrew Dunlop

    2016-08-01

    Full Text Available Autism Spectrum Disorder (ASD, characterised by impaired communication skills and repetitive behaviours, can also result in differences in sensory perception. Individuals with ASD often perform normally in simple auditory tasks but poorly compared to typically developed (TD individuals on complex auditory tasks like discriminating speech from complex background noise. A common trait of individuals with ASD is hypersensitivity to auditory stimulation. No studies to our knowledge consider whether hypersensitivity to sounds is related to differences in speech-in-noise discrimination. We provide novel evidence that individuals with high-functioning ASD show poor performance compared to TD individuals in a speech-in-noise discrimination task with an attentionally demanding background noise, but not in a purely energetic noise. Further, we demonstrate in our small sample that speech-hypersensitivity does not appear to predict performance in the speech-in-noise task. The findings support the argument that an attentional deficit, rather than a perceptual deficit, affects the ability of individuals with ASD to discriminate speech from background noise. Finally, we piloted a novel questionnaire that measures difficulty hearing in noisy environments, and sensitivity to non-verbal and verbal sounds. Psychometric analysis using 128 TD participants provided novel evidence for a difference in sensitivity to non-verbal and verbal sounds, and these findings were reinforced by participants with ASD who also completed the questionnaire. The study was limited by a small and high-functioning sample of participants with ASD. Future work could test larger sample sizes and include lower-functioning ASD participants.

  11. Oxidative Stress in Hypertensive Patients Induces an Increased Contractility in Vein Grafts Independent of Endothelial Function

    Directory of Open Access Journals (Sweden)

    Claudio Joo Turoni

    2011-01-01

    Full Text Available Objective. To evaluate the impact of oxidative stress on vascular reactivity to vasoconstrictors and on nitric oxide (NO bioavailability in saphenous vein (SV graft with endothelial dysfunction from hypertensive patients (HT. Methods. Endothelial function, vascular reactivity, oxidative state, nitrites and NO release were studied in isolated SV rings from HT and normotensive patients (NT. Only rings with endothelial dysfunction were used. Results. HT rings presented a hyperreactivity to vasoconstrictors that was reverted by diphenylene iodonium (DPI. In NT, no effect of DPI was obtained, but Nω-nitro-L-arginine methyl ester (L-NAME increased the contractile response. NO was present in SV rings without endothelial function. Nitrites were higher in NT than in HT (1066.1 ± 86.3 pmol/mg; n=11 versus 487.8 ± 51.6; n=23; P<0.01 and inhibited by nNOS inhibitor. L-arginine reversed this effect. Antioxidant agents increased nitrites and NO contents only in HT. The anti-nNOS-stained area by immunohistochemistry was higher in NT than HT. HT showed an elevation of oxidative state. Conclusions. Extraendothelial NO counter-regulates contractility in SV. However, this action could be altered in hypertensive situations by an increased oxidative stress or a decreased ability of nNOS to produce NO. Further studies should be performed to evaluate the implication of these results in graft patency rates.

  12. Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1 mice.

    Science.gov (United States)

    Peng, Yunhua; Hou, Chen; Yang, Ziqi; Li, Caixia; Jia, Liyan; Liu, Jing; Tang, Ying; Shi, Le; Li, Yongqin; Long, Jiangang; Liu, Jiankang

    2016-11-01

    Olive products, the hallmark of Mediterranean diet, are associated with reduced risk of mild cognitive impairment and Alzheimer's disease (AD). We and other groups have shown that hydroxytyrosol (HT), a bioactive compound of olive products, ameliorates oxidative stress, mitochondrial dysfunction, and neural toxicity. However, whether HT in Mediterranean diet acts as a functional ingredient in delaying AD pathogenesis remains unclear. In the present study, APP/PS1 mice, an animal model of AD, were administrated for 6 months with 5 mg/kg/day of HT, a comparable level of HT in daily Mediterranean diet. HT improved electroencephalography activity and marginally benefited cognitive behavior of transgenic mice. In addition, HT treatment ameliorated mitochondrial dysfunction, reduced mitochondrial carbonyl protein, enhanced superoxide dismutase 2 expression, reversed the phase 2 enzyme system and reduced the levels of brain inflammatory markers, but had no effect on brain β-amyloid (Aβ) accumulation in APP/PS1 mice. These results suggest that HT may represent as a functional ingredient in Mediterranean diet in ameliorating AD-involved neuronal impairment via modulating mitochondrial oxidative stress, neuronal inflammation, and apoptosis without affecting APP processing. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Reduced serotonin reuptake transporter (SERT) function causes insulin resistance and hepatic steatosis independent of food intake.

    Science.gov (United States)

    Chen, Xiaoning; Margolis, Kara J; Gershon, Michael D; Schwartz, Gary J; Sze, Ji Y

    2012-01-01

    Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

  14. Reduced serotonin reuptake transporter (SERT function causes insulin resistance and hepatic steatosis independent of food intake.

    Directory of Open Access Journals (Sweden)

    Xiaoning Chen

    Full Text Available Serotonin reuptake transporter (SERT is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs, that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes.

  15. Postural balance and functional independence of elderly people according to gender and age: cross-sectional study.

    Science.gov (United States)

    Nakagawa, Helen Benincasa; Ferraresi, Juliana Rizzatto; Prata, Melina Galetti; Scheicher, Marcos Eduardo

    2017-01-01

    Aging causes changes in men and women. Studies have shown that women have worse postural balance and greater functional dependence than men, but there is no consensus regarding this. The aim of this study was to compare the balance and functional independence of elderly people according to sex and age, and to evaluate the association between postural balance and the number of drugs taken. Cross-sectional at a state university. 202 elderly people were evaluated regarding balance (Berg Scale), independence (Barthel Index), age, sex, number of medications and physical activity. The subjects comprised 117 women (70.2 ± 5.6 years old) and 85 men (71.1 ± 6.9 years old). For balance, there was no significant difference regarding sex, but there was a difference regarding age (P Elderly people who took three or more medications/day showed higher risk of falling than those who took up two drugs/day (odds ratio = 5.53, P balance. However, people who were more elderly presented a high risk of falling. Functional dependence was worse among females. There was an association between the number of medication drugs and risk of falling.

  16. Left ventricular long axis function assessed during cine-cardiovascular magnetic resonance is an independent predictor of adverse cardiac events.

    Science.gov (United States)

    Rangarajan, Vibhav; Chacko, Satish Jacob; Romano, Simone; Jue, Jennifer; Jariwala, Nikhil; Chung, Jaehoon; Farzaneh-Far, Afshin

    2016-06-07

    Left ventricular pump function requires a complex interplay involving myocardial fibers orientated in the longitudinal, oblique and circumferential directions. Long axis dysfunction appears to be an early marker for a number of pathological states. We hypothesized that mitral annular plane systolic excursion (MAPSE) measured during cine-cardiovascular magnetic resonance (CMR) reflects changes in long axis function and may be an early marker for adverse cardiovascular outcomes. The aims of this study were therefore: 1) To assess the feasibility and reproducibility of MAPSE measurements during routine cine-CMR; and 2) To assess whether MAPSE, as a surrogate for long axis function, is a predictor of major adverse cardiovascular events (MACE). Four hundred consecutive patients undergoing CMR were prospectively enrolled. MAPSE was measured in the 4-chamber cine view. Patients were prospectively followed for major adverse cardiac events (MACE) - death, non-fatal myocardial infarction, hospitalization for heart failure or unstable angina, and late revascularization. Cox proportional hazards regression modeling was used to identify factors independently associated with MACE. Net reclassification improvement (NRI) was calculated to assess whether addition of MAPSE resulted in improved risk reclassification of MACE. Seventy-two MACE occurred during a median follow-up of 14.5 months. By Kaplan-Meier analysis, patients with lateral MAPSE cine-CMR is an independent predictor of MACE.

  17. FIT: Computer Program that Interactively Determines Polynomial Equations for Data which are a Function of Two Independent Variables

    Science.gov (United States)

    Arbuckle, P. D.; Sliwa, S. M.; Roy, M. L.; Tiffany, S. H.

    1985-01-01

    A computer program for interactively developing least-squares polynomial equations to fit user-supplied data is described. The program is characterized by the ability to compute the polynomial equations of a surface fit through data that are a function of two independent variables. The program utilizes the Langley Research Center graphics packages to display polynomial equation curves and data points, facilitating a qualitative evaluation of the effectiveness of the fit. An explanation of the fundamental principles and features of the program, as well as sample input and corresponding output, are included.

  18. Scheme-Independent Series Expansions at an Infrared Zero of the Beta Function in Asymptotically Free Gauge Theories

    CERN Document Server

    Ryttov, T A

    2016-01-01

    We consider an asymptotically free vectorial gauge theory, with gauge group $G$ and $N_f$ fermions in a representation $R$ of $G$, having an infrared (IR) zero in the beta function at $\\alpha_{IR}$. We present general formulas for scheme-independent series expansions of quantities, evaluated at $\\alpha_{IR}$, as powers of an $N_f$-dependent expansion parameter, $\\Delta_f$. First, we apply these to calculate the derivative $d\\beta/d\\alpha$ evaluated at $\\alpha_{IR}$, denoted $\\beta'_{IR}$, which is equal to the anomalous dimension of the ${\\rm Tr}(F_{\\mu\

  19. Sexuality in relation to independence in daily functions among young people with spina bifida living in Israel.

    Science.gov (United States)

    Shoshan, Levana; Ben-Zvi, Dvora; Meyer, Shirley; Katz-Leurer, Michal

    2012-01-01

    To describe the basic knowledge of body anatomy and functioning, and the sexual knowledge of young adults with spina bifida (SB) and to investigate the associations between independence in daily functions and communication skills on the one hand and sexual knowledge and activity on the other among young people with SB. Twenty-five patients with SB over the age of 16 years, who are under follow-up at the Alyn Children's Rehabilitation Hospital in Jerusalem, Israel, were enrolled in the study. Each patient was interviewed individually using the Sexual Knowledge Interview Schedule and the Functional Independence Measure. There were 17 females and eight males aged 16-35 years, eight of the 25 with a lesion level of L2 and above. At the time of the interview three of the participants had a partner (12%) and seven (28%) indicated that they had had intimate sexual relationships. One subject answered correctly on all questions related to body anatomy, and seven answered correctly on all questions related to body part functions. Positive and significant associations were noted between motor abilities, sphincter management and sexual knowledge (r(p) 0.44-0.65). Knowledge of anatomy and function associated positively with sexual knowledge and experience (r(p) 0.48-0.59). Young adults with SB who live in Israel exhibit a relatively low level of sexual experience. Since knowledge is associated with sexuality, it would be reasonable therefore to provide a structured educational program for this group of young adults, targeted to their unique disability. The rehabilitation nurse is in an optimal position to provide such education given her specialized training in sphincter management and her ongoing holistic view of these young patients. © 2012 Association of Rehabilitation Nurses.

  20. A culture-independent approach to unravel uncultured bacteria and functional genes in a complex microbial community.

    Directory of Open Access Journals (Sweden)

    Yun Wang

    Full Text Available Most microorganisms in nature are uncultured with unknown functionality. Sequence-based metagenomics alone answers 'who/what are there?' but not 'what are they doing and who is doing it and how?'. Function-based metagenomics reveals gene function but is usually limited by the specificity and sensitivity of screening strategies, especially the identification of clones whose functional gene expression has no distinguishable activity or phenotypes. A 'biosensor-based genetic transducer' (BGT technique, which employs a whole-cell biosensor to quantitatively detect expression of inserted genes encoding designated functions, is able to screen for functionality of unknown genes from uncultured microorganisms. In this study, BGT was integrated with Stable isotope probing (SIP-enabled Metagenomics to form a culture-independent SMB toolbox. The utility of this approach was demonstrated in the discovery of a novel functional gene cluster in naphthalene contaminated groundwater. Specifically, metagenomic sequencing of the (13C-DNA fraction obtained by SIP indicated that an uncultured Acidovorax sp. was the dominant key naphthalene degrader in-situ, although three culturable Pseudomonas sp. degraders were also present in the same groundwater. BGT verified the functionality of a new nag2 operon which co-existed with two other nag and two nah operons for naphthalene biodegradation in the same microbial community. Pyrosequencing analysis showed that the nag2 operon was the key functional operon in naphthalene degradation in-situ, and shared homology with both nag operons in Ralstonia sp. U2 and Polaromonas naphthalenivorans CJ2. The SMB toolbox will be useful in providing deep insights into uncultured microorganisms and unravelling their ecological roles in natural environments.

  1. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Directory of Open Access Journals (Sweden)

    Aabida Saferali

    Full Text Available Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29. Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122 or in COPD controls (p = 0.1430. Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078, telomere length was correlated between the two tissue types (p = 0.0122. Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  2. Longer telomere length in COPD patients with α1-antitrypsin deficiency independent of lung function.

    Science.gov (United States)

    Saferali, Aabida; Lee, Jee; Sin, Don D; Rouhani, Farshid N; Brantly, Mark L; Sandford, Andrew J

    2014-01-01

    Oxidative stress is involved in the pathogenesis of airway obstruction in α1-antitrypsin deficient patients. This may result in a shortening of telomere length, resulting in cellular senescence. To test whether telomere length differs in α1-antitrypsin deficient patients compared with controls, we measured telomere length in DNA from peripheral blood cells of 217 α1-antitrypsin deficient patients and 217 control COPD patients. We also tested for differences in telomere length between DNA from blood and DNA from lung tissue in a subset of 51 controls. We found that telomere length in the blood was significantly longer in α1-antitrypsin deficient COPD patients compared with control COPD patients (p = 1×10(-29)). Telomere length was not related to lung function in α1-antitrypsin deficient patients (p = 0.3122) or in COPD controls (p = 0.1430). Although mean telomere length was significantly shorter in the blood when compared with the lungs (p = 0.0078), telomere length was correlated between the two tissue types (p = 0.0122). Our results indicate that telomere length is better preserved in α1-antitrypsin deficient COPD patients than in non-deficient patients. In addition, measurement of telomere length in the blood may be a suitable surrogate for measurement in the lung.

  3. Xrs2 Dependent and Independent Functions of the Mre11-Rad50 Complex.

    Science.gov (United States)

    Oh, Julyun; Al-Zain, Amr; Cannavo, Elda; Cejka, Petr; Symington, Lorraine S

    2016-10-20

    The Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex orchestrates the cellular response to DSBs through its structural, enzymatic, and signaling roles. Xrs2/Nbs1 is essential for nuclear translocation of Mre11, but its role as a component of the complex is not well defined. Here, we demonstrate that nuclear localization of Mre11 (Mre11-NLS) is able to bypass several functions of Xrs2, including DNA end resection, meiosis, hairpin resolution, and cellular resistance to clastogens. Using purified components, we show that the MR complex has equivalent activity to MRX in cleavage of protein-blocked DNA ends. Although Xrs2 physically interacts with Sae2, we found that end resection in its absence remains Sae2 dependent in vivo and in vitro. MRE11-NLS was unable to rescue the xrs2Δ defects in Tel1/ATM kinase signaling and non-homologous end joining, consistent with the role of Xrs2 as a chaperone and adaptor protein coordinating interactions between the MR complex and other repair proteins. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. ULTRAPETALA1 and LEAFY pathways function independently in specifying identity and determinacy at the Arabidopsis floral meristem.

    Science.gov (United States)

    Engelhorn, Julia; Moreau, Fanny; Fletcher, Jennifer C; Carles, Cristel C

    2014-11-01

    The morphological variability of the flower in angiosperms, combined with its relatively simple structure, makes it an excellent model to study cell specification and the establishment of morphogenetic patterns. Flowers are the products of floral meristems, which are determinate structures that generate four different types of floral organs before terminating. The precise organization of the flower in whorls, each defined by the identity and number of organs it contains, is controlled by a multi-layered network involving numerous transcriptional regulators. In particular, the AGAMOUS (AG) MADS domain-containing transcription factor plays a major role in controlling floral determinacy in Arabidopsis thaliana in addition to specifying reproductive organ identity. This study aims to characterize the genetic interactions between the ULTRAPETALA1 (ULT1) and LEAFY (LFY) transcriptional regulators during flower morphogenesis, with a focus on AG regulation. Genetic and molecular approaches were used to address the question of redundancy and reciprocal interdependency for the establishment of flower meristem initiation, identity and termination. In particular, the effects of loss of both ULT1 and LFY function were determined by analysing flower developmental phenotypes of double-mutant plants. The dependency of each factor on the other for activating developmental genes was also investigated in gain-of-function experiments. The ULT1 and LFY pathways, while both activating AG expression in the centre of the flower meristem, functioned independently in floral meristem determinacy. Ectopic transcriptional activation by ULT1 of AG and AP3, another gene encoding a MADS domain-containing flower architect, did not depend on LFY function. Similarly, LFY did not require ULT1 function to ectopically determine floral fate. The results indicate that the ULT1 and LFY pathways act separately in regulating identity and determinacy at the floral meristem. In particular, they independently

  5. Coronary Flow Reserve Predicts Cardiopulmonary Fitness in Patients with Coronary Artery Disease Independently of Systolic and Diastolic Function

    DEFF Research Database (Denmark)

    Snoer, Martin; Olsen, Rasmus Huan; Monk-Hansen, Tea

    2014-01-01

    Aims Despite revascularization and optimal medical treatment, patients with coronary artery disease (CAD) have reduced exercise capacity. In the absence of coronary artery stenosis, coronary flow reserve (CFR) is a measure of coronary microvascular function, and a marker of future poor outcome...... early (E) and late (A) inflow velocities, and tissue Doppler diastolic (e′) and systolic (s′) velocities. Peak coronary flow velocity (CFV) was measured in the LAD using pulse-wave Doppler. CFR was calculated as the ratio between peak CFV at rest and during vasodilator stress. Median CFR was 2.22 (1....... Conclusions Coronary flow reserve measured noninvasively predicts cardiopulmonary fitness independently of resting systolic and diastolic function in CAD patients, indicating that cardiac output during maximal exercise is dependent on the ability of the coronary circulation to adapt to the higher metabolic...

  6. Association of quality of life of carers with quality of life and functional independence of stroke survivors

    Directory of Open Access Journals (Sweden)

    Deepak Ganjiwale

    2016-01-01

    Full Text Available Background: Stroke has a great impact not only on patients′ but also on their caregivers′ lives. Carers may experience high levels of burden that can result in deterioration of their health status, social life, and well-being. Association between quality of life (QOL of carers and that of stroke survivors in Indian setting is not much researched. Aims and Settings: To find out QOL and mental health of caregivers of individuals with stroke visiting Physiotherapy Department of Tertiary Care Center in Western India. Design and Methodology: A cross-sectional survey to find QOL and mental health of caregiver of stroke survivors, self-administered screening instrument WHO-QOL BREF, functional independence measurement (FIM scale, and BRIEF COPE were used for data collection on adult populations. Statistical Analysis Used: The statistical analysis was performed by descriptive analysis and correlation. Result: Fifty-four stroke patients and their caregivers (all adults were included in the study. Average FIM score was 83.75 (18.46 while median was 90 (25. FIM score of patients did not much affect QOL of caregivers. Discussion: Analysis of QOL data showed that QOL of caregivers was good in all domains, but patient′s QOL was good only in social relations. There was no correlation found in QOL of carers and stroke survivors. Nine percent of change in caregivers social relationship scores can be attributed to patients′ sphincter scores. Conclusion: QOL of carers and stroke survivors may be independent. Stroke patients in the study required a moderate assistance for their functional independence which does not seem to affect the caregivers QOL significantly.

  7. Functional Reserve: Experience Participating in Instrumental Activities of Daily Living is Associated with Gender and Functional Independence in Mild Cognitive Impairment.

    Science.gov (United States)

    Berezuk, Courtney; Zakzanis, Konstantine K; Ramirez, Joel; Ruocco, Anthony C; Edwards, Jodi D; Callahan, Brandy L; Black, Sandra E

    2017-01-01

    Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer's disease may be explained by gender differences in IADL involvement. We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve. We cross-sectionally examined men (n = 502) and women (n = 340) with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women. Gender was associated with total FAQ (p experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p experience was the most important single variable (4.8% explained, p experience accounted for 6.6% of the variance in FAQ score in men (p experience was not statistically significant. A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment.

  8. Relationship between lower-limb muscle strength and functional independence among elderly people according to frailty criteria: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Fernanda Sotello Batista

    Full Text Available CONTEXT AND OBJECTIVE: Muscle strength and functional independence are considered to be determinants of frailty levels among elderly people. The aim here was to compare lower-limb muscle strength (LLMS with functional independence in relation to sex, age and number of frailty criteria, and to ascertain the influence of these variables on elderly outpatients' independence.DESIGN AND SETTING: Quantitative cross-sectional study, in a tertiary hospital.METHODS: The study was conducted on 150 elderly outpatients of both sexes who were in a cognitive condition allowing oral communication, between October 2005 and October 2007. The following instruments were used: five-times sit-to-stand test (FTSST, Functional Independence Measurement (FIM and Lawton's Instrumental Activities of Daily Living Scale (IADL. Descriptive, comparative, multivariate, univariate and Cronbach alpha analyses were performed.RESULTS: The mean time taken in the FTSST was 21.7 seconds; the mean score for FIM was 82.2 and for IADL was 21.2; 44.7% of the subjects presented 1-2 frailty criteria and 55.3% > 3 criteria. There was a significant association between LLMS and functional independence in relation to the number of frailty criteria, without homogeneity regarding sex and age. Functional independence showed significant influence from sex and LLMS.CONCLUSION: Elderly individuals with 1 or 2 frailty criteria presented greater independence in all FTSST scores. The subjects with higher LLMS presented better functional independence.

  9. Patients Undergoing Subacute Physical Rehabilitation following an Acute Hospital Admission Demonstrated Improvement in Cognitive Functional Task Independence

    Directory of Open Access Journals (Sweden)

    Steven M. McPhail

    2014-01-01

    Full Text Available Objective. This study investigated cognitive functioning among older adults with physical debility not attributable to an acute injury or neurological condition who were receiving subacute inpatient physical rehabilitation. Design. A cohort investigation with assessments at admission and discharge. Setting. Three geriatric rehabilitation hospital wards. Participants. Consecutive rehabilitation admissions (n=814 following acute hospitalization (study criteria excluded orthopaedic, neurological, or amputation admissions. Intervention. Usual rehabilitation care. Measurements. The Functional Independence Measure (FIM Cognitive and Motor items. Results. A total of 704 (86.5% participants (mean age = 76.5 years completed both assessments. Significant improvement in FIM Cognitive items (Z-score range 3.93–8.74, all P<0.001 and FIM Cognitive total score (Z-score = 9.12, P<0.001 occurred, in addition to improvement in FIM Motor performance. A moderate positive correlation existed between change in Motor and Cognitive scores (Spearman’s rho = 0.41. Generalized linear modelling indicated that better cognition at admission (coefficient = 0.398, P<0.001 and younger age (coefficient = −0.280, P<0.001 were predictive of improvement in Motor performance. Younger age (coefficient = −0.049, P<0.001 was predictive of improvement in FIM Cognitive score. Conclusions. Improvement in cognitive functioning was observed in addition to motor function improvement among this population. Causal links cannot be drawn without further research.

  10. The independent influence of concussive and sub-concussive impacts on soccer players' neurophysiological and neuropsychological function.

    Science.gov (United States)

    Moore, R Davis; Lepine, Julien; Ellemberg, Dave

    2017-02-01

    Accumulating research demonstrates that repetitive sub-concussive impacts can alter the structure, function and connectivity of the brain. However, the functional significance of these alterations as well as the independent contribution of concussive and sub-concussive impacts to neurophysiological and neuropsychological health are unclear. Accordingly, we compared the neurophysiological and neuropsychological function of contact athletes with (concussion group) and without (sub-concussion group) a history of concussion, to non-contact athletes. We evaluated event-related brain potentials (ERPs) elicited during an oddball task and performance on a targeted battery of neuropsychological tasks. Athletes in the sub-concussion and concussion groups exhibited similar amplitude reductions in the ERP indices of attentional resource allocation (P3b) and attentional orienting (P3a) relative to non-contact athletes. However, only athletes in the concussion group exhibited reduced amplitude in the ERP index of perceptual attention (N1). Athletes in the sub-concussion and concussion groups also exhibited deficits in memory recall relative to non-contact athletes, but athletes in the concussion group also exhibited significantly more recall errors than athletes in the sub-concussion group. Additionally, only athletes in the concussion group exhibited response delays during the oddball task. The current findings suggest that sub-concussive impacts are associated with alterations in the neurophysiological and neuropsychological indices of essential cognitive functions, albeit to a lesser degree than the combination of sub-concussive and concussive impacts.

  11. TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice.

    Science.gov (United States)

    Vlantis, Katerina; Polykratis, Apostolos; Welz, Patrick-Simon; van Loo, Geert; Pasparakis, Manolis; Wullaert, Andy

    2016-06-01

    The gut microbiota modulates host susceptibility to intestinal inflammation, but the cell types and the signalling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here, we investigated the function of intestinal epithelial toll-like receptor (TLR) responses in the dextran sodium sulfate (DSS)-induced mouse model of colitis. We applied an in vivo genetic approach allowing intestinal epithelial cell (IEC)-specific deletion of the critical TLR signalling adaptors, MyD88 and/or TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as the downstream ubiquitin ligase TRAF6 in order to reveal the IEC-intrinsic function of these TLR signalling molecules during DSS colitis. Mice lacking TRAF6 in IECs showed exacerbated DSS-induced inflammatory responses that ensued in the development of chronic colon inflammation. Antibiotic pretreatment abolished the increased DSS susceptibility of these mice, showing that epithelial TRAF6 signalling pathways prevent the gut microbiota from driving excessive colitis. However, in contrast to epithelial TRAF6 deletion, blocking epithelial TLR signalling by simultaneous deletion of MyD88 and TRIF specifically in IECs did not affect DSS-induced colitis severity. This in vivo functional comparison between TRAF6 and MyD88/TRIF deletion in IECs shows that the colitis-protecting effects of epithelial TRAF6 signalling are not triggered by TLRs. Intestinal epithelial TRAF6-dependent but MyD88/TRIF-independent and, thus, TLR-independent signalling pathways are critical for preventing propagation of DSS-induced colon inflammation by the gut microbiota. Moreover, our experiments using mice with dual MyD88/TRIF deletion in IECs unequivocally show that the gut microbiota trigger non-epithelial TLRs rather than epithelial TLRs to restrict DSS colitis severity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  12. Functional limitations and somatic diseases are independent predictors for incident depressive disorders in seniors: Findings from a nationwide longitudinal study.

    Science.gov (United States)

    Yang, Ya-Ting; Wang, Yao-Hsien; Chiu, Hsien-Tsai; Wu, Chia-Rong; Handa, Yujiro; Liao, Yin-Lin; Hsu, Yi-Hsin Elsa

    2015-01-01

    Few nationwide comprehensive studies analyzed the factors leading to the onset of depression in correlation with medical disease and other related factors concerning geriatric depression. This study examined medical diseases with other factors which lead to depression among the elderly. This Taiwan-based longitudinal study examined a collection of 1467 seniors aged over 65. Subjects who fit this criteria were initially interviewed in 2003, and then four years later. Independent variables included baseline demographics, chronic medical illnesses, and the change of subjects' self-perceived health status, functional limitations including ADL, IADL and mobility limitation factors. The dependent variable was the symptoms of incident depression, as ascertained by the ten-item questionnaire during the later session. The logistic regression analyses were used to examine some of the predictors related to depressive disorders. The findings showed that heart conditions (adjusted OR=1.55, 95% CI: 1.12-2.15, p=0.008) and joint disorders (adjusted OR=1.51, 95% CI: 1.09-2.09, p=0.013), as well as functional limitations, particularly IADL (adjusted OR=1.81, 95% CI: 1.24-2.65, p=0.002) and ADL (adjusted OR=1.77, 95% CI: 1.27-2.47, p=0.001) were independently associated with the onset of depression among the elderly population. These findings indicated that when classifying symptoms of depression in geriatric patients with several underlying medical diseases, keen attention should be directed to the type of medical disorders and the functional deterioration in terms of daily activities and autonomic capabilities. Copyright © 2015. Published by Elsevier Ireland Ltd.

  13. Establishing score equivalence of the Functional Independence Measure motor scale and the Barthel Index, utilising the International Classification of Functioning, Disability and Health and Rasch measurement theory.

    Science.gov (United States)

    Prodinger, Birgit; O'Connor, Rory J; Stucki, Gerold; Tennant, Alan

    2017-05-16

    Two widely used outcome measures to assess functioning in neurological rehabilitation are the Functional Independence Measure (FIM™) and the Barthel Index. The current study aims to establish the equivalence of the total score of the FIM™ motor scale and the Barthel Index through the application of the International Classification of Functioning, Disability and Health, and Rasch measurement theory. Secondary analysis of a large sample of patients with stroke, spinal cord injury, and multiple sclerosis, undergoing rehabilitation was conducted. All patients were assessed at the same time on both the FIM™ and the Barthel Index. The International Classification of Functioning, Disability and Health Linking Rules were used to establish conceptual coherency between the 2 scales, and the Rasch measurement model to establish an exchange of the total scores. Using the FIM™ motor scale, items from both scales linked to the International Classification of Functioning, Disability and Health d4 Mobility or d5 Self-care chapters. Their co-calibration satisfied the assumptions of the Rasch model for each of 3 diagnostic groups. A ceiling effect was observed for the Barthel Index when contrasted against the FIM™ motor scale. Having a Rasch interval metric to transform scores between the FIM™ motor scale and Barthel Index is valuable for monitoring functioning, meta-analysis, quality audits and hospital benchmarking.

  14. A group independent component analysis of covert verb generation in children: a functional magnetic resonance imaging study.

    Science.gov (United States)

    Karunanayaka, Prasanna; Schmithorst, Vincent J; Vannest, Jennifer; Szaflarski, Jerzy P; Plante, Elena; Holland, Scott K

    2010-05-15

    Semantic language skills are an integral part of early childhood language development. The semantic association between verbs and nouns constitutes an important building block for the construction of sentences. In this large-scale functional magnetic resonance imaging (fMRI) study, involving 336 subjects between the ages of 5 and 18 years, we investigated the neural correlates of covert verb generation in children. Using group independent component analysis (ICA), seven task-related components were identified including the mid-superior temporal gyrus, the most posterior aspect of the superior temporal gyrus, the parahippocampal gyrus, the inferior frontal gyrus, the angular gyrus, and medial aspect of the parietal lobule (precuneus/posterior cingulate). A highly left-lateralized component was found including the medial temporal gyrus, the frontal gyrus, the inferior frontal gyrus, and the angular gyrus. The associated independent component (IC) time courses were analyzed to investigate developmental changes in the neural elements supporting covert verb generation. Observed age effects may either reflect specific local neuroplastic changes in the neural substrates supporting language or a more global transformation of neuroplasticity in the developing brain. The results are analyzed and presented in the framework of two theoretical models for neurocognitive brain development. In this context, group ICA of fMRI data from our large sample of children aged 5-18 years provides strong evidence in support of the regionally weighted model for cognitive neurodevelopment of language networks.

  15. A γ-Secretase Independent Role for Presenilin in Calcium Homeostasis Impacts Mitochondrial Function and Morphology in Caenorhabditis elegans.

    Science.gov (United States)

    Sarasija, Shaarika; Norman, Kenneth R

    2015-12-01

    Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) ∼20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, γ-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.

  16. Independence of elderly patients with arterial hypertension in fulfilling their needs, in the aspect of functional assessment and quality of life (QoL)

    NARCIS (Netherlands)

    Muszalik, Marta; Dijkstra, Ate; Kedziora-Kornatowska, Kornelia; Zielinska-Wieczkowska, Halina; Kornatowski, Tomasz

    2011-01-01

    Functional efficiency is the ability to be independent in fulfilling the basic needs of everyday life. Independence in meeting these needs is important to maintain a good quality of life (QoL). Chronic diseases affecting elderly people may, to some extent, limit fulfilling numerous needs, however,

  17. Preliminary investigation of sequence-independent DNA binding proteins in rat skeletal muscle sarcoplasmic reticulum and their function

    Institute of Scientific and Technical Information of China (English)

    赵文; 姜志胜; 倪菊华; 陈光慧; 刘乃奎; 汤健; 贾弘褆; 唐朝枢

    2000-01-01

    To observe the binding of plasmid DNA to non-nuclear DNA binding proteins in sar-coplasmic reticulum (SR) and the effects of this binding on SR function, sarcoplasmic reticulum proteins in rat skeletal muscle were isolated by differential centrifuge and sucrose density-gradient centrifuge. The results showed that there are two sequence-independent DNA binding proteins in SR proteins, the molecular weights of which are 83 and 58 ku, respectively. Ca2+ uptake and release of SR were remarkably promoted by the binding of plasmid DNA to DNA binding proteins in SR, the mechanism is probably through increasing of Ca2+-ATPase activity in SR and changing of character of Ca2+ release channel ryanodine receptors induced by the binding. These results suggest that there exist DNA binding proteins in SR and its binding to DNA may affect Ca2+ transport of SR.

  18. Preliminary investigation of sequence-independent DNA binding proteins in rat skeletal muscle sarcoplasmic reticulum and their function

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    To observe the binding of plasmid DNA to non-nuclear DNA binding proteins in sarcoplasmic reticulum (SR) and the effects of this binding on SR function, sarcoplasmic reticulum proteins in rat skeletal muscle were isolated by differential centrifuge and sucrose density-gradient centrifuge. The results showed that there are two sequence-independent DNA binding proteins in SR proteins, the molecular weights of which are 83 and 58 ku, respectively. Ca2+ uptake and release of SR were remarkably promoted by the binding of plasmid DNA to DNA binding proteins in SR, the mechanism is probably through increasing of Ca2+-ATPase activity in SR and changing of character of Ca2+ release channel ryanodine receptors induced by the binding. These results suggest that there exist DNA binding proteins in SR and its binding to DNA may affect Ca2+ transport of SR.

  19. Metacognition moderates the relationship between dysfunctional self-appraisal and social functioning in prolonged schizophrenia independent of psychopathology.

    Science.gov (United States)

    James, Alison V; Hasson-Ohayon, Ilanit; Vohs, Jenifer; Minor, Kyle S; Leonhardt, Bethany L; Buck, Kelly D; George, Sunita; Lysaker, Paul H

    2016-08-01

    Both dysfunctional self-appraisal and metacognitive deficits, or impairments in the ability to form complex and integrated ideas about oneself and others, may contribute to social deficits in schizophrenia. Little is known, however, about how they interact with each other. In this study, we examined the hypothesis that both higher metacognition and more positive self-appraisal are necessary for increased social functioning. Concurrent assessments of self-appraisal, metacognition, and social functioning were gathered from 66 adults with schizophrenia in a non-acute phase of disorder. Three forms of self-appraisal were used: self-esteem, hope and self-efficacy. Metacognition was assessed using the Metacognitive Assessment Scale-Abbreviated, and social functioning with the Quality of Life Scale. Measures of psychopathology, neurocognition and social cognition were also gathered for use as potential covariates. A single index of self-appraisal was generated from subjecting the assessments of self-appraisal to a principal components analysis. Linear regression analyses revealed that after controlling for severity of psychopathology, metacognition moderated the effect of the self-appraisal factor score upon social functioning. A median split of metacognition and the self-appraisal index yielded four groups. ANCOVA analyses revealed that participants with higher levels of metacognition and more positive self-appraisal had greater capacities for social relatedness than all other participants, regardless of levels of positive and negative symptoms. Correlational analyses revealed that metacognition but not self-appraisal was related to the frequencies of social contact independent of the effects of psychopathology. Assessments of social cognition and neurocognition were not significantly linked with social dysfunction. Greater social functioning is made possible by a combination of both more positive self-appraisals and greater metacognitive capacity. Individuals with

  20. Meixner Class of Non-commutative Generalized Stochastic Processes with Freely Independent Values II. The Generating Function

    Science.gov (United States)

    Bożejko, Marek; Lytvynov, Eugene

    2011-03-01

    Let T be an underlying space with a non-atomic measure σ on it. In [ Comm. Math. Phys. 292, 99-129 (2009)] the Meixner class of non-commutative generalized stochastic processes with freely independent values, {ω=(ω(t))_{tin T}} , was characterized through the continuity of the corresponding orthogonal polynomials. In this paper, we derive a generating function for these orthogonal polynomials. The first question we have to answer is: What should serve as a generating function for a system of polynomials of infinitely many non-commuting variables? We construct a class of operator-valued functions {Z=(Z(t))_{tin T}} such that Z( t) commutes with ω( s) for any {s,tin T}. Then a generating function can be understood as {G(Z,ω)=sum_{n=0}^infty int_{T^n}P^{(n)}(ω(t_1),dots,ω(t_n))Z(t_1)dots Z(t_n)} {σ(dt_1) dots σ(dt_n)} , where {P^{(n)}(ω(t_1),dots,ω(t_n))} is (the kernel of the) n th orthogonal polynomial. We derive an explicit form of G( Z, ω), which has a resolvent form and resembles the generating function in the classical case, albeit it involves integrals of non-commuting operators. We finally discuss a related problem of the action of the annihilation operators {partial_t,t in T} . In contrast to the classical case, we prove that the operators ∂ t related to the free Gaussian and Poisson processes have a property of globality. This result is genuinely infinite-dimensional, since in one dimension one loses the notion of globality.

  1. The H-Function and Probability Density Functions of Certain Algebraic Combinations of Independent Random Variables with H-Function Probability Distribution

    Science.gov (United States)

    1981-05-01

    involving modified Bessel function and Fox’s H- function," Rivista di Matematica della Universita di Parma. Italie, (3) 2, 109-113 (1973). function...Ciencias Matematicas , A(2) 14, 105-111 (1971-72). 100. Dahiya, R. S., "ultiple integrals and the transformations involving H- functions and Tchebichef...transform," R di Matematica della Universita di Parma. Italie, 5, 159- 164 (1964). 117. Gupta, R. K., and S. D. Sharma, "Some infinite integrals involv- ing

  2. A novel bipartite nuclear localization signal guides BPM1 protein to nucleolus suggesting its Cullin3 independent function.

    Directory of Open Access Journals (Sweden)

    Dunja Leljak Levanić

    Full Text Available BPM1 belongs to the MATH-BTB family of proteins, which act as substrate-binding adaptors for the Cullin3-based E3 ubiquitin ligase. MATH-BTB proteins associate with Cullin3 via the BTB domain and with the substrate protein via the MATH domain. Few BPM1-interacting proteins with different functions are recognized, however, specific roles of BPM1, depending on its cellular localization have not been studied so far. Here, we found a novel bipartite nuclear localization signal at the C-terminus of the BPM1 protein, responsible for its nuclear and nucleolar localization and sufficient to drive the green fluorescent protein and cytoplasmic BPM4 protein into the nucleus. Co-localization analysis in live Nicotiana tabacum BY2 cells indicates a Cullin3 independent function since BPM1 localization is predominantly nucleolar and thus devoid of Cullin3. Treatment of BY2 cells with the proteasome inhibitor MG132 blocks BPM1 and Cullin3 degradation, suggesting turnover of both proteins through the ubiquitin-proteasome pathway. Possible roles of BPM1 in relation to its in vivo localization are discussed.

  3. The relationship between aortic stiffness and cardiac function in patients with obstructive sleep apnea, independently from systemic hypertension.

    Science.gov (United States)

    Tavil, Yusuf; Kanbay, Asiye; Sen, Nihat; Ulukavak Ciftçi, Tansu; Abaci, Adnan; Yalçin, M Ridvan; Köktürk, Oğuz; Cengel, Atiye

    2007-04-01

    We sought to evaluate aortic function and its relationship with left ventricular (LV) function in patients with obstructive sleep apnea syndrome (OSAS), with or without systemic hypertension. A total of 29 patients with OSAS, 28 patients with systemic hypertension without OSAS, and 19 patients having both disorders were chosen as a study group, and 29 participants without these two disorders were taken as the control group; none of the patients had a history of cardiac disease. All of them underwent echocardiography and polysomnography. Aortic strain and distensibility were calculated from the aortic diameters measured by echocardiography and blood pressure obtained by cuff-sphygmomanometer. Cardiac functions were determined using echocardiography comprising standard 2-dimensional and conventional Doppler and Doppler tissue imaging. Aortic strain (mean +/- SD; 6.1 +/- 2.7% vs 6.4 +/- 2.4%, 4.7 +/- 1.8%, and 13.7 +/- 4.5%, P < .001, respectively) and distensibility (mean +/- SD 2.8 +/- 1.6 vs 2.5 +/- 0.9, 1.7 +/- 0.7, and 6.2 +/- 3.2 10(-6) cm(2) dyn(-1)P < .001, respectively) were significantly decreased in the patient groups (OSAS, hypertensive, and OSAS and hypertensive) compared with the control group. LV long-axis and diastolic functions were also impaired in the study group. There were good correlations between the aortic stiffness and LV function parameters. In a multivariate analysis, aortic strain was the parameter found to be most strongly associated both with the Doppler tissue imaging mean peak early/late diastolic velocity ratio and the LV mitral lateral annular plane systolic excursion. Aortic stiffness parameters (aortic strain and distensibility), LV systolic long-axis function indicators (mitral lateral annular plane systolic excursion, peak systolic myocardial velocity at lateral annulus, peak systolic myocardial velocity at septal annulus), and Doppler tissue imaging-derived LV diastolic indices were found abnormal in patients with OSAS

  4. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function.

    Directory of Open Access Journals (Sweden)

    Alexandra Vaccaro

    2017-01-01

    Full Text Available Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0 and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1 clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila.

  5. Independent Associations of Organized Physical Activity and Weight Status with Children’s Cognitive Functioning: A Matched-Pairs Design

    Science.gov (United States)

    Tkacz, Joseph P.; Tomporowski, Phillip D.; Bustamante, Eduardo E.

    2015-01-01

    Purpose This study tested whether participation in organized physical activity (active vs. inactive) or weight status (normal weight vs. overweight or obese) independently relate to hildren’s cognition, using a matched-pairs design. Design and Methods Normal weight, active children (8–11 yrs, 5th–75th percentile BMI) were recruited from extracurricular physical activity programs while normal weight inactive (5th–75th percentile BMI) and overweight inactive children (BMI ≥85th percentile) were recruited from local Augusta, Georgia area schools. Measures included the Cognitive Assessment System, anthropometrics, and parent- and self-report of physical activity. Paired t-tests compared cognition scores between matched groups of normal weight active vs. normal weight inactive (N=24 pairs), normal weight inactive vs. overweight inactive (N=21 pairs), and normal weight active vs. overweight inactive children (N=16 pairs). Children in each comparison were matched for race, gender, age, and socioeconomic status. Results Normal weight active children had higher Planning (M±SD=109±11 vs. 100±11, p=.011) and Attention scores (108±11 vs. 100±11, p=013) than overweight inactive children. Normal weight inactive children had higher Attention scores than overweight inactive children (105±13 vs. 93±12, p=008). When compared to normal weight inactive children, normal weight active children had higher Planning (113±10 vs. 102±13, p=008) and marginally higher Attention scores (111±11 vs. 104±12, p=06). Conclusion Findings suggest independent associations of children’s weight status with selective attention, and physical activity with higher-order processes of executive function. PMID:26252198

  6. Independent Associations of Organized Physical Activity and Weight Status with Children's Cognitive Functioning: A Matched-Pairs Design.

    Science.gov (United States)

    Davis, Catherine L; Tkacz, Joseph P; Tomporowski, Phillip D; Bustamante, Eduardo E

    2015-11-01

    This study tested whether participation in organized physical activity (active vs. inactive) or weight status (normal weight vs. overweight or obese) independently relate to children's cognition, using a matched-pairs design. Normal weight, active children (8-11 yrs, 5th-75th percentile BMI) were recruited from extracurricular physical activity programs while normal weight inactive (5th-75th percentile BMI) and overweight inactive children (BMI ≥85th percentile) were recruited from local Augusta, Georgia area schools. Measures included the Cognitive Assessment System, anthropometrics, and parent- and self-report of physical activity. Paired t tests compared cognition scores between matched groups of normal weight active vs. normal weight inactive (N = 24 pairs), normal weight inactive vs. overweight inactive (N = 21 pairs), and normal weight active vs. overweight inactive children (N = 16 pairs). Children in each comparison were matched for race, gender, age, and socioeconomic status. Normal weight active children had higher Planning (M± SD = 109 ± 11 vs. 100 ± 11, p = .011) and Attention scores (108 ± 11 vs. 100 ± 11, p = .013) than overweight inactive children. Normal weight inactive children had higher Attention scores than overweight inactive children (105 ± 13 vs. 93 ± 12, p = .008). When compared with normal weight inactive children, normal weight active children had higher Planning (113 ± 10 vs. 102 ± 13, p = .008) and marginally higher Attention scores (111 ± 11 vs. 104 ± 12, p = .06). Findings suggest independent associations of children's weight status with selective attention, and physical activity with higher-order processes of executive function.

  7. Increase of posterior connectivity in aging within the Ventral Attention Network: A functional connectivity analysis using independent component analysis.

    Science.gov (United States)

    Deslauriers, Johnathan; Ansado, Jennyfer; Marrelec, Guillaume; Provost, Jean-Sébastien; Joanette, Yves

    2017-02-15

    Multiple studies have found neurofunctional changes in normal aging in a context of selective attention. Furthermore, many articles report intrahemispheric alteration in functional networks. However, little is known about age-related changes within the Ventral Attention Network (VAN), which underlies selective attention. The aim of this study is to examine age-related changes within the VAN, focusing on connectivity between its regions. Here we report our findings on the analysis of 27 participants' (13 younger and 14 older healthy adults) BOLD signals as well as their performance on a letter-matching task. We identified the VAN independently for both groups using spatial independent component analysis. Three main findings emerged: First, younger adults were faster and more accurate on the task. Second, older adults had greater connectivity among posterior regions (right temporoparietal junction, right superior parietal lobule, right middle temporal gyrus and left cerebellum crus I) than younger adults but lower connectivity among anterior regions (right anterior insula, right medial superior frontal gyrus and right middle frontal gyrus). Older adults also had more connectivity between anterior and posterior regions than younger adults. Finally, correlations between connectivity and response time on the task showed a trend toward connectivity in posterior regions for the older group and in anterior regions for the younger group. Thus, this study shows that intrahemispheric neurofunctional changes in aging also affect the VAN. The results suggest that, in contexts of selective attention, posterior regions increased in importance for older adults, while anterior regions had reduced centrality. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Drosophila Clock Is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of Its Circadian Function

    Science.gov (United States)

    Issa, Abdul-Raouf; Seugnet, Laurent; Klarsfeld, André

    2017-01-01

    Circadian clocks control many self-sustained rhythms in physiology and behavior with approximately 24-hour periodicity. In many organisms, oxidative stress and aging negatively impact the circadian system and sleep. Conversely, loss of the clock decreases resistance to oxidative stress, and may reduce lifespan and speed up brain aging and neurodegeneration. Here we examined the effects of clock disruptions on locomotor aging and longevity in Drosophila. We found that lifespan was similarly reduced in three arrhythmic mutants (ClkAR, cyc0 and tim0) and in wild-type flies under constant light, which stops the clock. In contrast, ClkAR mutants showed significantly faster age-related locomotor deficits (as monitored by startle-induced climbing) than cyc0 and tim0, or than control flies under constant light. Reactive oxygen species accumulated more with age in ClkAR mutant brains, but this did not appear to contribute to the accelerated locomotor decline of the mutant. Clk, but not Cyc, inactivation by RNA interference in the pigment-dispersing factor (PDF)-expressing central pacemaker neurons led to similar loss of climbing performance as ClkAR. Conversely, restoring Clk function in these cells was sufficient to rescue the ClkAR locomotor phenotype, independently of behavioral rhythmicity. Accelerated locomotor decline of the ClkAR mutant required expression of the PDF receptor and correlated to an apparent loss of dopaminergic neurons in the posterior protocerebral lateral 1 (PPL1) clusters. This neuronal loss was rescued when the ClkAR mutation was placed in an apoptosis-deficient background. Impairing dopamine synthesis in a single pair of PPL1 neurons that innervate the mushroom bodies accelerated locomotor decline in otherwise wild-type flies. Our results therefore reveal a novel circadian-independent requirement for Clk in brain circadian neurons to maintain a subset of dopaminergic cells and avoid premature locomotor aging in Drosophila. PMID:28072817

  9. The cellular chaperone hsc70 is specifically recruited to reovirus viral factories independently of its chaperone function.

    Science.gov (United States)

    Kaufer, Susanne; Coffey, Caroline M; Parker, John S L

    2012-01-01

    Mammalian orthoreoviruses replicate and assemble in the cytosol of infected cells. A viral nonstructural protein, μNS, forms large inclusion-like structures called viral factories (VFs) in which assembling viral particles can be identified. Here we examined the localization of the cellular chaperone Hsc70 and found that it colocalizes with VFs in infected cells and also with viral factory-like structures (VFLs) formed by ectopically expressed μNS. Small interfering RNA (siRNA)-mediated knockdown of Hsc70 did not affect the formation or maintenance of VFLs. We further showed that dominant negative mutants of Hsc70 were also recruited to VFLs, indicating that Hsc70 recruitment to VFLs is independent of the chaperone function. In support of this finding, μNS was immunoprecipitated with wild-type Hsc70, with a dominant negative mutant of Hsc70, and with the minimal substrate-binding site of Hsc70 (amino acids 395 to 540). We identified a minimal region of μNS between amino acids 222 and 271 that was sufficient for the interaction with Hsc70. This region of μNS has not been assigned any function previously. However, neither point mutants with alterations in this region nor the complete deletion of this domain abrogated the μNS-Hsc70 interaction, indicating that a second portion of μNS also interacts with Hsc70. Taken together, these findings suggest a specific chaperone function for Hsc70 within viral factories, the sites of reovirus replication and assembly in cells.

  10. Transient receptor potential mucolipin 1 (TRPML1) and two-pore channels are functionally independent organellar ion channels.

    Science.gov (United States)

    Yamaguchi, Soichiro; Jha, Archana; Li, Qin; Soyombo, Abigail A; Dickinson, George D; Churamani, Dev; Brailoiu, Eugen; Patel, Sandip; Muallem, Shmuel

    2011-07-01

    NAADP is a potent second messenger that mobilizes Ca(2+) from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca(2+) release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca(2+)-permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near complete colocalization with TPC2 and partial colocalization with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1(V432P) channel function or TRPML1(V432P)-mediated Ca(2+) influx. Whereas overexpression of TPCs enhanced NAADP-mediated Ca(2+) signals, overexpression of TRPML1 did not, and the dominant negative TRPML1(D471K) was without affect on endogenous NAADP-mediated Ca(2+) signals. Furthermore, the single channel properties of NAADP-activated TPC2delN were not affected by TRPML1. Finally, NAADP-evoked Ca(2+) oscillations in pancreatic acinar cells were identical in wild-type and TRPML1(-/-) cells. We conclude that although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP.

  11. Human Enterovirus Nonstructural Protein 2CATPase Functions as Both an RNA Helicase and ATP-Independent RNA Chaperone.

    Directory of Open Access Journals (Sweden)

    Hongjie Xia

    2015-07-01

    Full Text Available RNA helicases and chaperones are the two major classes of RNA remodeling proteins, which function to remodel RNA structures and/or RNA-protein interactions, and are required for all aspects of RNA metabolism. Although some virus-encoded RNA helicases/chaperones have been predicted or identified, their RNA remodeling activities in vitro and functions in the viral life cycle remain largely elusive. Enteroviruses are a large group of positive-stranded RNA viruses in the Picornaviridae family, which includes numerous important human pathogens. Herein, we report that the nonstructural protein 2CATPase of enterovirus 71 (EV71, which is the major causative pathogen of hand-foot-and-mouth disease and has been regarded as the most important neurotropic enterovirus after poliovirus eradication, functions not only as an RNA helicase that 3'-to-5' unwinds RNA helices in an adenosine triphosphate (ATP-dependent manner, but also as an RNA chaperone that destabilizes helices bidirectionally and facilitates strand annealing and complex RNA structure formation independently of ATP. We also determined that the helicase activity is based on the EV71 2CATPase middle domain, whereas the C-terminus is indispensable for its RNA chaperoning activity. By promoting RNA template recycling, 2CATPase facilitated EV71 RNA synthesis in vitro; when 2CATPase helicase activity was impaired, EV71 RNA replication and virion production were mostly abolished in cells, indicating that 2CATPase-mediated RNA remodeling plays a critical role in the enteroviral life cycle. Furthermore, the RNA helicase and chaperoning activities of 2CATPase are also conserved in coxsackie A virus 16 (CAV16, another important enterovirus. Altogether, our findings are the first to demonstrate the RNA helicase and chaperoning activities associated with enterovirus 2CATPase, and our study provides both in vitro and cellular evidence for their potential roles during viral RNA replication. These findings

  12. SmD1 Modulates the miRNA Pathway Independently of Its Pre-mRNA Splicing Function.

    Directory of Open Access Journals (Sweden)

    Xiao-Peng Xiong

    2015-08-01

    Full Text Available microRNAs (miRNAs are a class of endogenous regulatory RNAs that play a key role in myriad biological processes. Upon transcription, primary miRNA transcripts are sequentially processed by Drosha and Dicer ribonucleases into ~22-24 nt miRNAs. Subsequently, miRNAs are incorporated into the RNA-induced silencing complexes (RISCs that contain Argonaute (AGO family proteins and guide RISC to target RNAs via complementary base pairing, leading to post-transcriptional gene silencing by a combination of translation inhibition and mRNA destabilization. Select pre-mRNA splicing factors have been implicated in small RNA-mediated gene silencing pathways in fission yeast, worms, flies and mammals, but the underlying molecular mechanisms are not well understood. Here, we show that SmD1, a core component of the Drosophila small nuclear ribonucleoprotein particle (snRNP implicated in splicing, is required for miRNA biogenesis and function. SmD1 interacts with both the microprocessor component Pasha and pri-miRNAs, and is indispensable for optimal miRNA biogenesis. Depletion of SmD1 impairs the assembly and function of the miRISC without significantly affecting the expression of major canonical miRNA pathway components. Moreover, SmD1 physically and functionally associates with components of the miRISC, including AGO1 and GW182. Notably, miRNA defects resulting from SmD1 silencing can be uncoupled from defects in pre-mRNA splicing, and the miRNA and splicing machineries are physically and functionally distinct entities. Finally, photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP analysis identifies numerous SmD1-binding events across the transcriptome and reveals direct SmD1-miRNA interactions. Our study suggests that SmD1 plays a direct role in miRNA-mediated gene silencing independently of its pre-mRNA splicing activity and indicates that the dual roles of splicing factors in post-transcriptional gene regulation may be

  13. SmD1 Modulates the miRNA Pathway Independently of Its Pre-mRNA Splicing Function.

    Directory of Open Access Journals (Sweden)

    Xiao-Peng Xiong

    2015-08-01

    Full Text Available microRNAs (miRNAs are a class of endogenous regulatory RNAs that play a key role in myriad biological processes. Upon transcription, primary miRNA transcripts are sequentially processed by Drosha and Dicer ribonucleases into ~22-24 nt miRNAs. Subsequently, miRNAs are incorporated into the RNA-induced silencing complexes (RISCs that contain Argonaute (AGO family proteins and guide RISC to target RNAs via complementary base pairing, leading to post-transcriptional gene silencing by a combination of translation inhibition and mRNA destabilization. Select pre-mRNA splicing factors have been implicated in small RNA-mediated gene silencing pathways in fission yeast, worms, flies and mammals, but the underlying molecular mechanisms are not well understood. Here, we show that SmD1, a core component of the Drosophila small nuclear ribonucleoprotein particle (snRNP implicated in splicing, is required for miRNA biogenesis and function. SmD1 interacts with both the microprocessor component Pasha and pri-miRNAs, and is indispensable for optimal miRNA biogenesis. Depletion of SmD1 impairs the assembly and function of the miRISC without significantly affecting the expression of major canonical miRNA pathway components. Moreover, SmD1 physically and functionally associates with components of the miRISC, including AGO1 and GW182. Notably, miRNA defects resulting from SmD1 silencing can be uncoupled from defects in pre-mRNA splicing, and the miRNA and splicing machineries are physically and functionally distinct entities. Finally, photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP analysis identifies numerous SmD1-binding events across the transcriptome and reveals direct SmD1-miRNA interactions. Our study suggests that SmD1 plays a direct role in miRNA-mediated gene silencing independently of its pre-mRNA splicing activity and indicates that the dual roles of splicing factors in post-transcriptional gene regulation may be

  14. Peter Pan functions independently of its role in ribosome biogenesis during early eye and craniofacial cartilage development in Xenopus laevis.

    Science.gov (United States)

    Bugner, Verena; Tecza, Aleksandra; Gessert, Susanne; Kühl, Michael

    2011-06-01

    The Xenopus oocyte possesses a large maternal store of ribosomes, thereby uncoupling early development from the de novo ribosome biosynthesis required for cell growth. Brix domain-containing proteins, such as Peter Pan (PPan), are essential for eukaryotic ribosome biogenesis. In this study, we demonstrate that PPan is expressed maternally as well as in the eye and cranial neural crest cells (NCCs) during early Xenopus laevis development. Depletion of PPan and interference with rRNA processing using antisense morpholino oligonucleotides resulted in eye and cranial cartilage malformations. Loss of PPan, but not interference with rRNA processing, led to an early downregulation of specific marker genes of the eye, including Rx1 and Pax6, and of NCCs, such as Twist, Slug and FoxD3. We found that PPan protein is localized in the nucleoli and mitochondria and that loss of PPan results in increased apoptosis. These findings indicate a novel function of PPan that is independent of its role in ribosome biogenesis.

  15. APOBEC3G is a single-stranded DNA cytidine deaminase and functions independently of HIV reverse transcriptase

    Science.gov (United States)

    Suspène, Rodolphe; Sommer, Peter; Henry, Michel; Ferris, Stéphane; Guétard, Denise; Pochet, Sylvie; Chester, Ann; Navaratnam, Naveenan; Wain-Hobson, Simon; Vartanian, Jean-Pierre

    2004-01-01

    In the absence of the viral vif gene, human immunodeficiency virus (HIV) may be restricted by the APOBEC3G gene on chromosome 22. The role of the HIV Vif protein is to exclude host cell APOBEC3G from the budding virion. As APOBEC3G shows sequence homology to cytidine deaminases, it is presumed that in the absence of Vif, cytidine residues in the cDNA are deaminated yielding uracil. It is not known if additional proteins mediate APOBEC3G function or if deamination occurs in concert with reverse transcription. This report describes an in vitro assay showing that Baculovirus derived APOBEC3G alone extensively deaminates cDNA independently of reverse transcriptase. It reproduces the dinucleotide context typical of G → A hypermutants derived from a Δvif virus. By using an RNaseH– form of reverse transcriptase, it was shown that the cDNA has to be free of its RNA template to allow deamination. APOBEC3G deamination of dC or dCTP was not detected. In short, APOBEC3G is a single-stranded DNA cytidine deaminase capable of restricting retroviral replication. PMID:15121899

  16. Su(dx) E3 ubiquitin ligase-dependent and -independent functions of polychaetoid, the Drosophila ZO-1 homologue.

    Science.gov (United States)

    Djiane, Alexandre; Shimizu, Hideyuki; Wilkin, Marian; Mazleyrat, Sabine; Jennings, Martin D; Avis, Johanna; Bray, Sarah; Baron, Martin

    2011-01-10

    Zona occludens (ZO) proteins are molecular scaffolds localized to cell junctions, which regulate epithelial integrity in mammals. Using newly generated null alleles, we demonstrate that polychaetoid (pyd), the unique Drosophila melanogaster ZO homologue, regulates accumulation of adherens junction-localized receptors, such as Notch, although it is dispensable for epithelial polarization. Pyd positively regulates Notch signaling during sensory organ development but acts negatively on Notch to restrict the ovary germline stem cell niche. In both contexts, we identify a core antagonistic interaction between Pyd and the WW domain E3 ubiquitin ligase Su(dx). Pyd binds Su(dx) directly, in part through a noncanonical WW-binding motif. Pyd also restricts epithelial wing cell numbers to control adult wing shape, a function associated with the FERM protein Expanded and independent of Su(dx). As both Su(dx) and Expanded regulate trafficking, we propose that a conserved role of ZO proteins is to coordinate receptor trafficking and signaling with junctional organization.

  17. EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

    Energy Technology Data Exchange (ETDEWEB)

    Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Sun, Jianmin [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Jögi, Annika [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Neumann, Drorit [Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Rönnstrand, Lars [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Påhlman, Sven, E-mail: sven.pahlman@med.lu.se [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel)

    2014-02-28

    Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα{sup +}) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

  18. Functional Diversity of Human Mitochondrial J-proteins Is Independent of Their Association with the Inner Membrane Presequence Translocase.

    Science.gov (United States)

    Sinha, Devanjan; Srivastava, Shubhi; D'Silva, Patrick

    2016-08-12

    Mitochondrial J-proteins play a critical role in governing Hsp70 activity and, hence, are essential for organellar protein translocation and folding. In contrast to yeast, which has a single J-protein Pam18, humans involve two J-proteins, DnaJC15 and DnaJC19, associated with contrasting cellular phenotype, to transport proteins into the mitochondria. Mutation in DnaJC19 results in dilated cardiomyopathy and ataxia syndrome, whereas expression of DnaJC15 regulates the response of cancer cells to chemotherapy. In the present study we have comparatively assessed the biochemical properties of the J-protein paralogs in relation to their association with the import channel. Both DnaJC15 and DnaJC19 formed two distinct subcomplexes with Magmas at the import channel. Knockdown analysis suggested an essential role for Magmas and DnaJC19 in organellar protein translocation and mitochondria biogenesis, whereas DnaJC15 had dispensable supportive function. The J-proteins were found to have equal affinity for Magmas and could stimulate mitochondrial Hsp70 ATPase activity by equivalent levels. Interestingly, we observed that DnaJC15 exhibits bifunctional properties. At the translocation channel, it involves conserved interactions and mechanism to translocate the precursors into mitochondria. In addition to protein transport, DnaJC15 also showed a dual role in yeast where its expression elicited enhanced sensitivity of cells to cisplatin that required the presence of a functional J-domain. The amount of DnaJC15 expressed in the cell was directly proportional to the sensitivity of cells. Our analysis indicates that the differential cellular phenotype displayed by human mitochondrial J-proteins is independent of their activity and association with Magmas at the translocation channel.

  19. Bold-Independent Computational Entropy Assesses Functional Donut-Like Structures in Brain fMRI Images

    Science.gov (United States)

    Peters, James F.; Ramanna, Sheela; Tozzi, Arturo; İnan, Ebubekir

    2017-01-01

    We introduce a novel method for the measurement of information level in fMRI (functional Magnetic Resonance Imaging) neural data sets, based on image subdivision in small polygons equipped with different entropic content. We show how this method, called maximal nucleus clustering (MNC), is a novel, fast and inexpensive image-analysis technique, independent from the standard blood-oxygen-level dependent signals. MNC facilitates the objective detection of hidden temporal patterns of entropy/information in zones of fMRI images generally not taken into account by the subjective standpoint of the observer. This approach befits the geometric character of fMRIs. The main purpose of this study is to provide a computable framework for fMRI that not only facilitates analyses, but also provides an easily decipherable visualization of structures. This framework commands attention because it is easily implemented using conventional software systems. In order to evaluate the potential applications of MNC, we looked for the presence of a fourth dimension's distinctive hallmarks in a temporal sequence of 2D images taken during spontaneous brain activity. Indeed, recent findings suggest that several brain activities, such as mind-wandering and memory retrieval, might take place in the functional space of a four dimensional hypersphere, which is a double donut-like structure undetectable in the usual three dimensions. We found that the Rényi entropy is higher in MNC areas than in the surrounding ones, and that these temporal patterns closely resemble the trajectories predicted by the possible presence of a hypersphere in the brain. PMID:28203153

  20. Equating activities of daily living outcome measures: the Functional Independence Measure and the Korean version of Modified Barthel Index.

    Science.gov (United States)

    Hong, Ickpyo; Woo, Hee-Soon; Shim, Sunhwa; Li, Chih-Ying; Yoonjeong, Lim; Velozo, Craig A

    2016-12-08

    To create a crosswalk between the Functional Independence Measure (FIM) motor items and the Korean version of the Modified Barthel Index (K-MBI). Korean community-dwelling adult patients (n = 276) completed the FIM and K-MBI on the same day in outpatient rehabilitation hospitals. We used a single group design with the Rasch common person equating and conducted a factor analysis of the co-calibrated item pool using the two measures. Rasch analysis was used to investigate the psychometrics of the equated test items in the identified factor structure(s). The correlation between FIM raw scores and converted K-MBI scores was examined. Three measurement constructs were identified: self-care, mobility, involuntary movement. The equated test items in the three constructs demonstrated good person separation reliability (r = 0.94-0.96) and good internal consistency (Cronbach's alpha =0.93-0.97). The three crosswalks between the FIM raw scores and converted K-MBI scores demonstrated good correlations (r = 0.91-0.93, all p test items demonstrating good psychometrics. The crosswalks would address the incomparable scoring systems between the FIM motor items and K-MBI. Implications for Rehabilitation The three crosswalk tables (scoring tables) would allow clinicians to compare or translate a patient's motor scores between the FIM and K-MBI. The crosswalk tables would allow health-care administrators to track patients' functional status across various rehabilitation facilities that exclusively use the FIM or K-MBI.

  1. Plasma soluble urokinase-type plasminogen activator receptor level is independently associated with coronary microvascular function in patients with non-obstructive coronary artery disease

    DEFF Research Database (Denmark)

    Mekonnen, Girum; Corban, Michel T; Hung, Olivia Y;

    2015-01-01

    , medications profiles and hs-CRP, suPAR remained an independent predictor of CFR (B = -0.30, p = 0.04), indicating an independent association between suPAR level and coronary microvascular function. CONCLUSIONS: In this cross-sectional study, plasma suPAR level was an independent predictor of coronary......BACKGROUND: Soluble urokinase-type plasminogen activator receptor (suPAR) is a novel biomarker released from leukocytes and endothelial cells that has been associated with atherosclerotic cardiovascular disease. We hypothesized that plasma suPAR level is an independent predictor of coronary...... microvascular function. METHODS: Coronary blood flow velocity and plasma suPAR levels were evaluated in patients with non-obstructive coronary artery disease. Coronary flow reserve (CFR) was calculated as the ratio of hyperemic to basal average peak blood flow velocity and coronary microvascular dysfunction...

  2. [Fear of falling and the relationship with the measure of functional independence and quality of life in post-Cerebral Vascular Accident (Stroke) victims].

    Science.gov (United States)

    Monteiro, Raquel Buarque Caminha; Laurentino, Glória Elizabeth Carneiro; Melo, Priscilla Gonçalves de; Cabral, Dinalva Lacerda; Correa, João Carlos Ferrari; Teixeira-Salmela, Luci Fuscaldi

    2013-07-01

    The aim of this cross-sectional study was to evaluate the fear of falling of 52 chronic post-stroke individuals and to assess its relationship with measures of functional independence and quality of life (QOL). Fear of falling was assessed by the Brazilian version of Falls Efficacy Scale International (FES-I-BRAZIL) and functional independence by the Functional Independence Measure (FIM) and QOL by the Stroke Specific Quality of Life (SSQOL) scale. Spearman's correlation coefficients were calculated to verify the associations between FES-I-BRAZIL and the other instruments, and the Mann-Whitney U test to compare groups with low and high fall concerns. There was a predominance of individuals with high concerns regarding falling, higher QOL, and independence. FES-I-BRAZIL was statistically associated with FIM and SSQOL. Significant relationships were also found between FES-I-Brazil with FIM transfer and locomotion sub-scales, as well as with the following SSQOL energy, family role, language, mobility, mood, self-care, and upper extremity function domains. Thus, fear of falling may contribute to reduced functional independence and QOL in post-stroke individuals and should be included in the evaluation process of these patients to ensure greater benefits during rehabilitation.

  3. Theory of Mind Is Impaired in Mild to Moderate Huntington’s Disease Independently from Global Cognitive Functioning

    Science.gov (United States)

    Lagravinese, Giovanna; Avanzino, Laura; Raffo De Ferrari, Alessia; Marchese, Roberta; Serrati, Carlo; Mandich, Paola; Abbruzzese, Giovanni; Pelosin, Elisa

    2017-01-01

    Affective “Theory of Mind” (ToM) is the specific ability to represent own and others’ emotional states and feelings. Previous studies examined affective ToM ability in patients with Huntington’s disease (HD), using the “Reading the Mind in the Eyes test” (RMET). Results were consistent in showing difficulties in inferring complex mental states from photographs of people even in the early stage of HD. However, there has been no agreement as to whether or not cognitive impairments in HD population might have contributed to poor performance on the RMET test. The aim of the present study was to assess whether the affective ToM ability was impaired in the mild to moderate stages of HD, and whether there was an association between compromised ToM ability and the presence of cognitive impairment. We evaluated ToM by means of RMET and global cognitive functioning by means of the MoCA questionnaire in 15 HD patients and 15 healthy subjects (HS). Both groups were matched for age and level of education. Our study showed that the ability to judge a person’s mental states from a picture of their eyes was impaired in HD patients compared to normal population. Indeed, HD subjects gave the 34% of correct responses on RMET, whereas healthy control subjects’ percentage of correct responses was 71%. Furthermore, this impairment was not correlated with global cognitive functioning except for the visuospatial task. These results show that RMET might represent a valid instrument to assess affective ToM ability in HD patients in the mild to moderate stages of the disease, independently from their cognitive status. Since it is known that HD patients, in addition to motor symptoms, suffer from cognitive deficits, including memory and executive impairments, it is important to have an instrument, which is not influenced by cognitive abilities. It is possible therefore to use RMET to assess important aspects of HD patients such as their ability to recognize others’ emotions

  4. Phosphatidylinositol 3-phosphate-dependent and -independent functions of p40phox in activation of the neutrophil NADPH oxidase.

    Science.gov (United States)

    Bissonnette, Sarah A; Glazier, Christina M; Stewart, Mary Q; Brown, Glenn E; Ellson, Chris D; Yaffe, Michael B

    2008-01-25

    In response to bacterial infection, the neutrophil NADPH oxidase assembles on phagolysosomes to catalyze the transfer of electrons from NADPH to oxygen, forming superoxide and downstream reactive oxygen species (ROS). The active oxidase is composed of a membrane-bound cytochrome together with three cytosolic phox proteins, p40(phox), p47(phox), and p67(phox), and the small GTPase Rac2, and is regulated through a process involving protein kinase C, MAPK, and phosphatidylinositol 3-kinase. The role of p40(phox) remains less well defined than those of p47(phox) and p67(phox). We investigated the biological role of p40(phox) in differentiated PLB-985 neutrophils, and we show that depletion of endogenous p40(phox) using lentiviral short hairpin RNA reduces ROS production and impairs bacterial killing under conditions where p67(phox) levels remain constant. Biochemical studies using a cytosol-reconstituted permeabilized human neutrophil cores system that recapitulates intracellular oxidase activation revealed that depletion of p40(phox) reduces both the maximal rate and total amount of ROS produced without altering the K(M) value of the oxidase for NADPH. Using a series of mutants, p47PX-p40(phox) chimeras, and deletion constructs, we found that the p40(phox) PX domain has phosphatidylinositol 3-phosphate (PtdIns(3)P)-dependent and -independent functions. Translocation of p67(phox) requires the PX domain but not 3-phosphoinositide binding. Activation of the oxidase by p40(phox), however, requires both PtdIns(3)P binding and an Src homology 3 (SH3) domain competent to bind to poly-Pro ligands. Mutations that disrupt the closed auto-inhibited form of full-length p40(phox) can increase oxidase activity approximately 2.5-fold above that of wild-type p40(phox) but maintain the requirement for PX and SH3 domain function. We present a model where p40(phox) translocates p67(phox) to the region of the cytochrome and subsequently switches the oxidase to an activated state

  5. Promoting physical activity for elders with compromised function: the Lifestyle Interventions and Independence for Elders (LIFE Study physical activity intervention

    Directory of Open Access Journals (Sweden)

    Rejeski WJ

    2013-09-01

    Full Text Available W Jack Rejeski,1 Robert Axtell,2 Roger Fielding,3 Jeffrey Katula,1 Abby C King,4 Todd M Manini,5 Anthony P Marsh,1 Marco Pahor,5 Alvito Rego,6 Catrine Tudor-Locke,7 Mark Newman,8 Michael P Walkup,9 Michael E Miller9  On behalf of the LIFE Study Investigator Group 1Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, 2Exercise Science Department, Southern Connecticut State University, New Haven, CT, 3Nutrtion, Exercise Physiology, and Sarcopenia Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 4Department of Health Research and Policy and Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Palo Alto, CA, 5Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL, 6Department of Internal Medicine, Northwestern School of Medicine, Chicago, IL, 7Pennington Biomedical Research Center, Baton Rouge, LA, 8Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, 9Department of Biostatistical Sciences, Division of Public Health Sciences, School of Medicine, Wake Forest University, Winston-Salem, NC, USA Abstract: The Lifestyle Interventions and Independence for Elders (LIFE Study is a Phase III randomized controlled clinical trial (Clinicaltrials.gov identifier: NCT01072500 that will provide definitive evidence regarding the effect of physical activity (PA on major mobility disability in older adults (70–89 years old who have compromised physical function. This paper describes the methods employed in the delivery of the LIFE Study PA intervention, providing insight into how we promoted adherence and monitored the fidelity of treatment. Data are presented on participants' motives and self-perceptions at the onset of the trial along with accelerometry data on patterns of PA during exercise training. Prior to the onset of training, 31.4% of

  6. Comparison of the sensitivity to change of the Functional Independence Measure with the Assessment of Motor and Process Skills within different rehabilitation populations.

    Science.gov (United States)

    Choo, Silvana X; Stratford, Paul; Richardson, Julie; Bosch, Jackie; Pettit, Susan M; Ansley, Barbara J; Harris, Jocelyn E

    2017-09-10

    To determine whether there was a difference in the sensitivity to change of the subscales of the Functional Independence Measure and the Assessment of Motor and Process Skills within three different post-acute inpatient rehabilitation populations. We conducted retrospective chart review of patients consecutively admitted to inpatient rehabilitation units, with both admission and discharge Functional Independence Measure and Assessment of Motor and Process Skills scores. A total of 276 participants were included and categorized into diagnostic groups (orthopedic, oncology, and geriatric). Within group, sensitivity to change was evaluated for the subscales of each measure by calculating the difference in standardized response means (SRM) and 95% confidence intervals (CI). The Functional Independence Measure motor subscale was more sensitive to change than the Assessment of Motor and Process Skills in the orthopedic and geriatric groups (SRMdifference = 1.53 [95% CI 0.93, 2.3] and 0.65 [95% CI 0.3, 1.02], respectively) but not in the oncology group (SRMdifference = 0.42 [95% CI -0.2, 1.04]). For the cognitive subscales, the Assessment of Motor and Process Skills was more sensitive to change than the Functional Independence Measure in all three groups (SRMdifference = 0.38 [95% CI 004, 0.74], 0.65 [95% CI 0.45, 0.90], and 1.15 [95% CI 0.77, 1.69] for orthopedic, geriatric, and oncology, respectively). The Functional Independence Measure is a mandated measure for all rehabilitation units in Canada. As the cognitive subscale of the Assessment of Motor and Process Skills is more sensitive to change than the Functional Independence Measure, we recommend also administering the Assessment of Motor and Process Skills to better detect changes in the cognitive aspect of function. Implications for rehabilitation When deciding between the Functional Independence Measure or the Assessment of Motor and Process Skills, it is important to consider whether patients

  7. Estudo da independência funcional, motricidade e inserção escolar de crianças com Paralisia Cerebral Study of functional independence, motor skills and school integration of children with Cerebral Palsy

    Directory of Open Access Journals (Sweden)

    Geovana Sôffa Rézio

    2012-12-01

    Full Text Available A Paralisia Cerebral (PC é uma condição clínica que gera alta prevalência de sequelas funcionais. As crianças com este diagnóstico podem apresentar diversos problemas nas atividades funcionais e no controle dos movimentos voluntários. O objetivo deste trabalho foi analisar o nível de independência funcional, motricidade e inserção escolar de crianças com PC. A amostra foi composta por 14 crianças com idade entre um a 11 anos que frequentam regularmente o Setor Clínico da Associação Pestalozzi de Goiânia, seus respectivos pais e/ou responsáveis e professores do ensino escolar. Os resultados mostraram que quanto maior o nível de independência funcional e melhor o desempenho na função motora grossa das crianças com Paralisia Cerebral, menor é a assistência fornecida pelos cuidadores e menos adaptações são necessárias para que essas crianças realizem as tarefas do ensino escolar. É importante uma parceria entre os profissionais da saúde com os professores, através de orientações e contribuições, no que for necessário para a inclusão escolar das crianças com deficiência.Cerebral Palsy is a medical condition that causes high prevalence of functional sequelae. For this reason, children with this diagnosis can present several problems in functional activities related to controlling voluntary movements. The aim of this study was to examine the level of functional independence, motor skills and school integration of children with cerebral palsy. The sample consisted of 14 children aged one to 11 years attending regularly the Clinical Sector of the Pestalozzi Association−Goiânia Unit, their parents and/or guardians and school teachers. The results showed that the higher the level of functional independence and the better their performance in gross motor function of these children with cerebral palsy, the lower the assistance provided by caregivers and fewer the adjustments needed for these children to perform

  8. 对独立学院复变函数教学的探索%The Exploration of Independent Institute for Teaching in Functions of Complex Variable

    Institute of Scientific and Technical Information of China (English)

    赵新暖; 周丽莉

    2011-01-01

    This paper explore the teaching in function of complex variable in independent institute combined with the author's teaching practice.%本文主要结合作者的教学实践,对独立学院复变函数教学进行了探索.

  9. Kinome-wide functional screen identifies role of PLK1 in hormone-independent, ER-positive breast cancer.

    Science.gov (United States)

    Bhola, Neil E; Jansen, Valerie M; Bafna, Sangeeta; Giltnane, Jennifer M; Balko, Justin M; Estrada, Mónica V; Meszoely, Ingrid; Mayer, Ingrid; Abramson, Vandana; Ye, Fei; Sanders, Melinda; Dugger, Teresa C; Allen, Eliezer V; Arteaga, Carlos L

    2015-01-15

    Estrogen receptor (ER) α-positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER(+) breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER(+) human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy.

  10. Field Dependence-Independence as Visuospatial and Executive Functioning in Working Memory: Implications for Instructional Systems Design and Research

    Science.gov (United States)

    Rittschof, Kent A.

    2010-01-01

    Field dependence-independence (FDI) has long been conceptualized and discussed as a cognitive style relevant to numerous educational approaches and outcomes. However, the FDI construct is most often measured as a cognitive ability, as opposed to a style, using instruments such as the Group-Embedded Figures test (GEFT) or the Hidden Figures Test…

  11. Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Narizhneva, Natalia V; Tararova, Natalia D; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G; Purmal, Andrei A; Gudkov, Andrei V; Gurova, Katerina V

    2009-12-15

    In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization.

  12. The Impact of Multiple Concussions on Emotional Distress, Post-Concussive Symptoms, and Neurocognitive Functioning in Active Duty United States Marines Independent of Combat Exposure or Emotional Distress

    Science.gov (United States)

    Lathan, Corinna E.; Bleiberg, Joseph; Tsao, Jack W.

    2014-01-01

    Abstract Controversy exists as to whether the lingering effects of concussion on emotional, physical, and cognitive symptoms is because of the effects of brain trauma or purely to emotional factors such as post-traumatic stress disorder or depression. This study examines the independent effects of concussion on persistent symptoms. The Defense Automated Neurobehavioral Assessment, a clinical decision support tool, was used to assess neurobehavioral functioning in 646 United States Marines, all of whom were fit for duty. Marines were assessed for concussion history, post-concussive symptoms, emotional distress, neurocognitive functioning, and deployment history. Results showed that a recent concussion or ever having experienced a concussion was associated with an increase in emotional distress, but not with persistent post-concussive symptoms (PPCS) or neurocognitive functioning. Having had multiple lifetime concussions, however, was associated with greater emotional distress, PPCS, and reduced neurocognitive functioning that needs attention and rapid discrimination, but not for memory-based tasks. These results are independent of deployment history, combat exposure, and symptoms of post-traumatic stress disorder and depression. Results supported earlier findings that a previous concussion is not generally associated with post-concussive symptoms independent of covariates. In contrast with other studies that failed to find a unique contribution for concussion to PPCS, however, evidence of recent and multiple concussion was seen across a range of emotional distress, post-concussive symptoms, and neurocognitive functioning in this study population. Results are discussed in terms of implications for assessing concussion on return from combat. PMID:25003552

  13. Linear Independence of T-Spline Blending Functions%T样条调配函数线性无关性的判定算法

    Institute of Scientific and Technical Information of China (English)

    王爱增; 赵罡

    2011-01-01

    Aimed at the open question whether T-spline blending functions are linear independence or not, this paper proposes a linear independence determining algorithm for T-spline blending functions. First, based on the property of T-spline blending functions, by converting T-splines to B-splines, this paper gives a proof of the necessary and sufficient condition for the linear independence of T-spline blending functions. The sufficient condition for the linear independence of T-spline blending functions has been also proved, which makes us easier to determine the linear independence of some special cases. Then combined two conditions mentioned above, an algorithm for determining the linear independence of T-spline blending functions has been given. Some examples are given to verify the effectiveness of the algorithm.%针对T样条调配函数的公开问题——T样条曲面表达式中的调配函数是否具有线性无关性,提出一种T样条调配函数线性无关性的验证算法.首先分析了T样条调配函数的数学性质,给出T样条调配函数线性无关的充要条件和充分条件,通过充分条件可以较容易地对一些特殊的T样条调配函数的线性无关性进行判定;然后结合充要条件和充分条件给出一种T样条调配函数线性无关性的验证算法.最后通过实例验证了该算法的有效性.文中结果对于开展T样条造型算法方面的研究有重要意义.

  14. Functional Independence Measure in Iran: A Confirmatory Factor Analysis and Evaluation of Ceiling and Floor Effects in Traumatic Brain Injury Patients

    Directory of Open Access Journals (Sweden)

    Rezaei

    2015-12-01

    Full Text Available Background The functional independence measure (FIM is one of the most important assessment instruments for motor and cognitive dependence in rehabilitation medicine; however, there is little data about its confirmatory factor analysis (CFA and ceiling/floor effects from other countries and also in Iranian patients. Objectives The aim of this study was to evaluate a two-factor model (motor and cognitive independence as latent variables and ceiling/floor effects for FIM in Iranian patients with traumatic brain injuries (TBI. Patients and Methods In this cross-sectional study, 185 subacute TBI patients were selected from emergency and neurosurgery departments of Poursina Hospital (the largest trauma hospital in northern Iran, Rasht using the consecutive sampling method and were assessed for functional independence. Results The results of this study showed that the floor effect was not observed; however, ceiling effects were observed for the FIM total score and its subscales. The confirmatory factor analysis showed that the chi-square/df ratio was 2.8 for the two-factor structure and the fit indices for this structural model including root mean square error of approximation (RMSEA = 0.099, normed fit index (NFI = 0.96, tucker lewis index (TLI = 0.97, comparative fit index (CFI = 0.97 were close to standard indices. Conclusions Although ceiling effects should be considered for rehabilitation targets, the two-factor model of FIM (motor and cognitive independence has an eligible fitness for Iranian patients with TBI.

  15. Arabidopsis CALCINEURIN B-LIKE10 Functions Independently of the SOS Pathway during Reproductive Development in Saline Conditions.

    Science.gov (United States)

    Monihan, Shea M; Magness, Courtney A; Yadegari, Ramin; Smith, Steven E; Schumaker, Karen S

    2016-05-01

    The accumulation of sodium in soil (saline conditions) negatively affects plant growth and development. The Salt Overly Sensitive (SOS) pathway in Arabidopsis (Arabidopsis thaliana) functions to remove sodium from the cytosol during vegetative development preventing its accumulation to toxic levels. In this pathway, the SOS3 and CALCINEURIN B-LIKE10 (CBL10) calcium sensors interact with the SOS2 protein kinase to activate sodium/proton exchange at the plasma membrane (SOS1) or vacuolar membrane. To determine if the same pathway functions during reproductive development in response to salt, fertility was analyzed in wild type and the SOS pathway mutants grown in saline conditions. In response to salt, CBL10 functions early in reproductive development before fertilization, while SOS1 functions mostly after fertilization when seed development begins. Neither SOS2 nor SOS3 function in reproductive development in response to salt. Loss of CBL10 function resulted in reduced anther dehiscence, shortened stamen filaments, and aborted pollen development. In addition, cbl10 mutant pistils could not sustain the growth of wild-type pollen tubes. These results suggest that CBL10 is critical for reproductive development in the presence of salt and that it functions in different pathways during vegetative and reproductive development.

  16. [The relation between health-related quality of life and pain, depression, anxiety, and functional independence in persons with chronic physical disability].

    Science.gov (United States)

    Tarsuslu, Tülay; Yümin, Eylem Tütün; Oztürk, Asuman; Yümin, Murat

    2010-01-01

    This study was designed to investigate the relation between health- related quality of life and pain, depression, anxiety, and functional independence. The study included 82 healthy subjects aged 38.18+/-11.06 and 89 physically disabled subjects aged 37.72+/-16.40. Physical and social characteristics of the subjects such as age, height, length, weight, gender, occupational and marital status, and level of education were recorded. Visual Analogue Scale, Beck Depression Inventory, Beck Anxiety Inventory, Nottingham Health Profile, and Functional Independence Measure were used to evaluate pain, depression, anxiety, quality of life, and functional independence, respectively. Compared to healthy individuals, chronically disabled subjects had higher pain, depression and anxiety and lower quality of life scores. Between-group comparison showed that there was a significant difference in pain, depression, anxiety levels and health-related quality of life (pdisabled individuals indicated a negative correlation between pain, depression, anxiety and quality of life (pdisabled individuals, there is a strong correlation between pain, depression, anxiety, and quality of life. These results should be considered carefully when planning assessment and rehabilitation programs for individuals with chronic disabilities.

  17. Central bank Financial Independence

    OpenAIRE

    J.Ramon Martinez-Resano

    2004-01-01

    Central bank independence is a multifaceted institutional design. The financial component has been seldom analysed. This paper intends to set a comprehensive conceptual background for central bank financial independence. Quite often central banks are modelled as robot like maximizers of some goal. This perspective neglects the fact that central bank functions are inevitably deployed on its balance sheet and have effects on its income statement. A financially independent central bank exhibits ...

  18. Comparative Analysis of Benzoxazinoid Biosynthesis in Monocots and Dicots: Independent Recruitment of Stabilization and Activation Functions[W][OA

    Science.gov (United States)

    Dick, Regina; Rattei, Thomas; Haslbeck, Martin; Schwab, Wilfried; Gierl, Alfons; Frey, Monika

    2012-01-01

    Benzoxazinoids represent preformed protective and allelophatic compounds that are found in a multitude of species of the family Poaceae (Gramineae) and occur sporadically in single species of phylogenetically unrelated dicots. Stabilization by glucosylation and activation by hydrolysis is essential for the function of these plant defense compounds. We isolated and functionally characterized from the dicot larkspur (Consolida orientalis) the benzoxazinoid-specific UDP-glucosyltransferase and β-glucosidase that catalyze the enzymatic functions required to avoid autotoxicity and allow activation upon challenge by herbivore and pathogen attack. A phylogenetic comparison of these enzymes with their counterparts in the grasses indicates convergent evolution by repeated recruitment from homologous but not orthologous genes. The data reveal a great evolutionary flexibility in recruitment of these essential functions of secondary plant metabolism. PMID:22415274

  19. Pericardial- Rather than Intramyocardial Fat Is Independently Associated with Left Ventricular Systolic Heart Function in Metabolically Healthy Humans.

    Directory of Open Access Journals (Sweden)

    Peter Wolf

    Full Text Available Obesity is a major risk factor to develop heart failure, in part due to possible lipotoxic effects of increased intramyocardial (MYCL and/or local or paracrine effects of pericardial (PERI lipid accumulation. Recent evidence suggests that MYCL is highly dynamic and might rather be a surrogate marker for disturbed energy metabolism than the underlying cause of cardiac dysfunction. On the other hand, PERI might contribute directly by mechanic and paracrine effects. Therefore, we hypothesized that PERI rather than MYCL is associated with myocardial function.To avoid potential confounding of metabolic disease 31 metabolically healthy subjects (age: 29±10yrs; BMI: 23±3kg/m2 were investigated using 1H-magnetic resonance spectroscopy and imaging. MYCL and PERI, as well as systolic and diastolic left ventricular heart function were assessed. Additionally, anthropometric data and parameters of glucose and lipid metabolism were analyzed. Correlation analysis was performed using Pearson's correlation coefficient. Linear regression model was used to show individual effects of PERI and MYCL on myocardial functional parameters.Correlation analysis with parameters of systolic heart function revealed significant associations for PERI (Stroke Volume (SV: R = -0.513 p = 0.001; CardiacIndex (CI: R = -0.442 p = 0.014, but not for MYCL (SV: R = -0.233; p = 0.207; CI: R = -0.130; p = 0.484. No significant correlations were found for E/A ratio as a parameter of diastolic heart function. In multiple regression analysis CI was negatively predicted by PERI, whereas no impact of MYCL was observed in direct comparison.Cardiac fat depots impact left ventricular heart function in a metabolically healthy population. Direct comparison of different lipid stores revealed that PERI is a more important predictor than MYCL for altered myocardial function.

  20. Functional independence measure evaluation in individuals with stroke disability Avaliação da medida de independência funcional de indivíduos com seqüelas de acidente vascular encefálico (AVE

    Directory of Open Access Journals (Sweden)

    Simone Nunes Ávila

    2008-12-01

    Full Text Available Introduction: The stroke is characterized by a lesion that strikes one of the vessels that irrigates the cerebral region. People who have suffered a stroke present functional loss, showing difficulties in locomotion and self-care. Objective: To evaluate the functional independence mesure of individuals with stroke’s sequalae during the realization of their routinal activities, submitted to physical therapy in a hospital phase (considered acute phase and in an outpatient phase (considered chronic phase. Materials and Methods: In the period between March 2007 and May 2008, 26 patients have been evaluated, 12 in the hospitalar phase and 14 in the outpatient phase, with ages between 44 and 80. Patients were from both genders and presented sequalae of stroke. The data was collected using the Functional Independence Measure (FIM instrument. Results: On the hospitalar group, a significant difference has been noticed between the initial score and the final score (p=0,011. The items “self-care”, “locomotion” and “communication” were the ones that presented the highest evolution. On the outpatient group, there were no significant differences between scores of both evaluations (p>0,10. Conclusions: In the hospitalar phase, patients who have suffered a stroke presented a faster recovery in the first weeks. On the other hand, those patients in the outpatient phase have remained stable.Introdução: O acidente vascular encefálico (AVE é caracterizado por uma lesão que acomete um dos vasos que irrigam a região cerebral. Pessoas que sofrem AVE apresentam perda funcional, manifestando dificuldades na locomoção e no cuidado pessoal. Objetivo: O objetivo deste estudo foi avaliar a evolução da capacidade de independência funcional de indivíduos com seqüela de AVE na realização de atividades da vida diária, submetidos a tratamento fisioterapêutico na fase hospitalar (considerada fase aguda e na fase ambulatorial (considerada fase cr

  1. Accounting for Independent Schools.

    Science.gov (United States)

    Sonenstein, Burton

    The diversity of independent schools in size, function, and mode of operation has resulted in a considerable variety of accounting principles and practices. This lack of uniformity has tended to make understanding, evaluation, and comparison of independent schools' financial statements a difficult and sometimes impossible task. This manual has…

  2. Independence of Internal Auditors.

    Science.gov (United States)

    Montondon, Lucille; Meixner, Wilda F.

    1993-01-01

    A survey of 288 college and university auditors investigated patterns in their appointment, reporting, and supervisory practices as indicators of independence and objectivity. Results indicate a weakness in the positioning of internal auditing within institutions, possibly compromising auditor independence. Because the auditing function is…

  3. Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density

    DEFF Research Database (Denmark)

    Andersen, Alina Joukainen; Windschiegl, Barbara; Ilbasmis-Tamer, Sibel

    2013-01-01

    Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)1000 (PEG1000), PEG1500 and PEG4000 with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube...... eliminated. Our observations address the difficulty in making carbon nanotubes more compatible with innate immunity through covalent PEG functionalization as well as double PEGylation strategies. From the Clinical EditorComplement-mediated toxicity is a major limiting factor in certain nanomedicine...... applications. This study clarifies that PEGylation of carbon nanotubes is unlikely to address this complication....

  4. Fundamental Evaluation of Adaptation and Human Capabilities in a Condition Using a System to Give a User an Artificial Oculomotor Function to Control Directions of Both Eyes Independently

    Directory of Open Access Journals (Sweden)

    Fumio Mizuno

    2011-10-01

    Full Text Available To investigate flexible adaptation of visual system, we developed a system to provide a user an artificial oculomotor function to control directions of both eyes. The system named “Virtual Chameleon” consists of two CCD cameras independently controlled and a head-mounted display. The user can control each tracking directions of two cameras with sensors set to both hands so that the user can get independent arbitrary view fields for both eyes. We performed fundamental experiments to evaluate capability to evaluate adaptation to use of Virtual Chameleon and effects on the user's capabilities. Eleven healthy volunteers with normal and corrected-to-normal vision participated in the experiments. The experiments were tests to find out each position of targets put in both side of a subject. In the experiments, a condition using Virtual Chameleon and a condition without it was adopted. We obtained accuracy rates and time intervals to find out target positions as experimental results. The experiments showed all of volunteers became able to actively control independent visual axes and correctly understood two different views by using Virtual Chameleon, even though two independent view fields yielded binocular rivalry to volunteers and binocular rivalry reduced human capabilities compared to cases without Virtual Chameleon.

  5. Independence among People with Disabilities: II. Personal Independence Profile.

    Science.gov (United States)

    Nosek, Margaret A.; And Others

    1992-01-01

    Developed Personal Independence Profile (PIP) as an instrument to measure aspects of independence beyond physical and cognitive functioning in people with diverse disabilities. PIP was tested for reliability and validity with 185 subjects from 10 independent living centers. Findings suggest that the Personal Independence Profile measures the…

  6. Light quantity and photosystem function mediate host susceptibility to turnip mosaic virus via a salicylic acid-independent mechanism

    Science.gov (United States)

    Evidence going as far back as the early part of the 20th century suggests that both light and chloroplast function may play key roles in host susceptibility to viruses. Despite the long history of such work, confirmation of these phenomena and a determination of the underlying mechanisms remain elu...

  7. Complement activation by PEG-functionalized multi-walled carbon nanotubes is independent of PEG molecular mass and surface density

    DEFF Research Database (Denmark)

    Andersen, Alina Joukainen; Windschiegl, Barbara; Ilbasmis-Tamer, Sibel

    2013-01-01

    Carboxylated (4%) multi-walled carbon nanotubes were covalently functionalized with poly(ethylene glycol)1000 (PEG1000), PEG1500 and PEG4000 with a PEG loading of approximately 11% in all cases. PEG loading generated non-uniform and heterogeneous higher surface structures and increased nanotube...

  8. Depressive and conduct disorder symptoms in youth living with HIV: the independent and interactive roles of coping and neuropsychological functioning.

    Science.gov (United States)

    Salama, Christina; Morris, Mary; Armistead, Lisa; Koenig, Linda J; Demas, Penelope; Ferdon, Corinne; Bachanas, Pamela

    2013-01-01

    Emerging research suggests the importance of psychosocial characteristics (e.g., coping and social support) for positive adaptation among youth with behaviorally acquired HIV. However, little is known about how these traits interact with cognitive abilities to impact emotional and behavioral adjustment. This study examined whether coping skills and executive functioning interact in their association with psychological adjustment in HIV-positive youth. Data from Project Adolescents Living with HIV/AIDS (ALPHA), a study to examine psychosocial, behavioral and neuropsychological functioning of youth with behaviorally acquired HIV, were used. Fifty-nine participants, aged 14-23, diagnosed with HIV prior to age 20 and receiving care in one of two HIV clinics in Atlanta or New York City, were recruited, consented and enrolled. Participants completed measures of depressive symptoms (Beck Depression Inventory), conduct disorder (Adolescent Symptom Index), and use of positive and negative coping strategies (Kidcope). The Wisconsin Card Sorting Test (WCST) assessed abstract reasoning (categories completed) and cognitive inflexibility (perseverative errors). In this sample of HIV-positive youth, depressive symptoms were best predicted by an interactive combination of negative coping skills and poor neuropsychological functioning. Neuropsychological functioning (cognitive inflexibility) and negative coping skills were directly associated with conduct disorder symptoms. Results highlight the importance of including neuropsychological assessment in the evaluation of HIV-positive youth, particularly those with emotional or behavioral problems.

  9. Metformin Improves Endothelial Function and Reduces Blood Pressure in Diabetic Spontaneously Hypertensive Rats Independent from Glycemia Control : Comparison to Vildagliptin

    NARCIS (Netherlands)

    Hamidi Shishavan, Mahdi; Henning, Robert H; van Buiten, Azuwerus; Goris, Maaike; Deelman, Leo E; Buikema, Hendrik

    2017-01-01

    Metformin confers vascular benefits beyond glycemia control, possibly via pleiotropic effects on endothelial function. In type-1-diabetes-mellitus (T1DM-)patients metformin improved flow-mediated dilation but also increased prostaglandin(PG)-F2α, a known endothelial-contracting factor. To explain

  10. Independent and Combined Effects of Exercise and Vitamin D on Muscle Morphology, Function and Falls in the Elderly

    Directory of Open Access Journals (Sweden)

    Robin M. Daly

    2010-09-01

    Full Text Available Regular exercise, particularly progressive resistance training (PRT, is recognized as one of the most effective strategies to prevent age-related muscle loss (sarcopenia, but its effects on muscle function are mixed. However, emerging data indicates that high velocity PRT (fast concentric muscle contractions is more effective for improving functional outcomes than traditional PRT. In terms of falls prevention, high-challenging balance training programs appear to be most effective. There is also compelling evidence that supplemental vitamin D is an effective therapeutic option for falls prevention. The findings from a recent meta-analysis revealed that supplemental vitamin D at a dose of at least 700–1,000 IU/d or an achieved serum 25(OHD level of at least 60 nmol/L was associated with reduced falls risk among older individuals. Based on these findings, it is possible that the combination of exercise and vitamin D could have a synergistic effect on muscle morphology and function, particularly since both interventions have been shown to have beneficial effects on type II “fast twitch” muscle fibers and systemic inflammation, which have both been linked to losses in muscle mass and function. Unfortunately however, the findings from the limited number of factorial 2 × 2 design RCTs indicate that additional vitamin D does not enhance the effects of exercise on measures of muscle morphology, function or falls risk. However, none of these trials were adequately powered to detect a “synergistic” effect between the two treatment strategies, but it is likely that if an exercise-by-vitamin D interaction does exist, it may be limited to situations when vitamin D deficiency/insufficiency is corrected. Further targeted research in “high risk” groups is still needed to address this question, and evaluate whether there is a threshold level of serum 25(OHD to maximize the effects of exercise on muscle and falls risk.

  11. Lysine Methylation of Progesterone Receptor at Activation Function 1 Regulates both Ligand-independent Activity and Ligand Sensitivity of the Receptor*

    Science.gov (United States)

    Chung, Hwa Hwa; Sze, Siu Kwan; Woo, Amanda Rui En; Sun, Yang; Sim, Kae Hwan; Dong, Xue Ming; Lin, Valerie C-L.

    2014-01-01

    Progesterone receptor (PR) exists in two isoforms, PRA and PRB, and both contain activation functions AF-1 and AF-2. It is believed that AF-1 is primarily responsible for the ligand-independent activity, whereas AF-2 mediates ligand-dependent PR activation. Although more than a dozen post-translational modifications of PR have been reported, no post-translational modification on AF-1 or AF-2 has been reported. Using LC-MS/MS-based proteomic analysis, this study revealed AF-1 monomethylation at Lys-464. Mutational analysis revealed the remarkable importance of Lys-464 in regulating PR activity. Single point mutation K464Q or K464A led to ligand-independent PR gel upshift similar to the ligand-induced gel upshift. This upshift was associated with increases in both ligand-dependent and ligand-independent PR phosphorylation and PR activity due to the hyperactivation of AF-1. In contrast, mutation of Lys-464 to the bulkier phenylalanine to mimic the effect of methylation caused a drastic decrease in PR activity. Importantly, PR-K464Q also showed heightened ligand sensitivity, and this was associated with increases in its functional interaction with transcription co-regulators NCoR1 and SRC-1. These results suggest that monomethylation of PR at Lys-464 probably has a repressive effect on AF-1 activity and ligand sensitivity. PMID:24415758

  12. Lysine methylation of progesterone receptor at activation function 1 regulates both ligand-independent activity and ligand sensitivity of the receptor.

    Science.gov (United States)

    Chung, Hwa Hwa; Sze, Siu Kwan; Woo, Amanda Rui En; Sun, Yang; Sim, Kae Hwan; Dong, Xue Ming; Lin, Valerie C-L

    2014-02-28

    Progesterone receptor (PR) exists in two isoforms, PRA and PRB, and both contain activation functions AF-1 and AF-2. It is believed that AF-1 is primarily responsible for the ligand-independent activity, whereas AF-2 mediates ligand-dependent PR activation. Although more than a dozen post-translational modifications of PR have been reported, no post-translational modification on AF-1 or AF-2 has been reported. Using LC-MS/MS-based proteomic analysis, this study revealed AF-1 monomethylation at Lys-464. Mutational analysis revealed the remarkable importance of Lys-464 in regulating PR activity. Single point mutation K464Q or K464A led to ligand-independent PR gel upshift similar to the ligand-induced gel upshift. This upshift was associated with increases in both ligand-dependent and ligand-independent PR phosphorylation and PR activity due to the hyperactivation of AF-1. In contrast, mutation of Lys-464 to the bulkier phenylalanine to mimic the effect of methylation caused a drastic decrease in PR activity. Importantly, PR-K464Q also showed heightened ligand sensitivity, and this was associated with increases in its functional interaction with transcription co-regulators NCoR1 and SRC-1. These results suggest that monomethylation of PR at Lys-464 probably has a repressive effect on AF-1 activity and ligand sensitivity.

  13. Independent and interactive effects of blood pressure and cardiac function on brain volume and white matter hyperintensities in heart failure.

    Science.gov (United States)

    Alosco, Michael L; Brickman, Adam M; Spitznagel, Mary Beth; Griffith, Erica Y; Narkhede, Atul; Raz, Naftali; Cohen, Ronald; Sweet, Lawrence H; Hughes, Joel; Rosneck, Jim; Gunstad, John

    2013-01-01

    Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated. Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume. Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (P cardiac index exacerbated WMH (P = .048). Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume, and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations. Copyright © 2013 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  14. The Drosophila PRR GNBP3 assembles effector complexes involved in antifungal defenses independently of its Toll-pathway activation function.

    Science.gov (United States)

    Matskevich, Alexey A; Quintin, Jessica; Ferrandon, Dominique

    2010-05-01

    The Drosophila Toll-signaling pathway controls the systemic antifungal host response. Gram-negative binding protein 3 (GNBP3), a member of the beta-glucan recognition protein family senses fungal infections and activates this pathway. A second detection system perceives the activity of proteolytic fungal virulence factors and redundantly activates Toll. GNBP3(hades) mutant flies succumb more rapidly to Candida albicans and to entomopathogenic fungal infections than WT flies, despite normal triggering of the Toll pathway via the virulence detection system. These observations suggest that GNBP3 triggers antifungal defenses that are not dependent on activation of the Toll pathway. Here, we show that GNBP3 agglutinates fungal cells. Furthermore, it can activate melanization in a Toll-independent manner. Melanization is likely to be an essential defense against some fungal infections given that the entomopathogenic fungus Beauveria bassiana inhibits the activity of the main melanization enzymes, the phenol oxidases. Finally, we show that GNBP3 assembles "attack complexes", which comprise phenoloxidase and the necrotic serpin. We propose that Drosophila GNBP3 targets fungi immediately at the inception of the infection by bringing effector molecules in direct contact with the invading microorganisms.

  15. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

    Science.gov (United States)

    Schiebler, Mark; Brown, Karen; Hegyi, Krisztina; Newton, Sandra M; Renna, Maurizio; Hepburn, Lucy; Klapholz, Catherine; Coulter, Sarah; Obregón-Henao, Andres; Henao Tamayo, Marcela; Basaraba, Randall; Kampmann, Beate; Henry, Katherine M; Burgon, Joseph; Renshaw, Stephen A; Fleming, Angeleen; Kay, Robert R; Anderson, Karen E; Hawkins, Phillip T; Ordway, Diane J; Rubinsztein, David C; Floto, Rodrigo Andres

    2015-02-01

    Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection.

  16. Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion

    Science.gov (United States)

    Schiebler, Mark; Brown, Karen; Hegyi, Krisztina; Newton, Sandra M; Renna, Maurizio; Hepburn, Lucy; Klapholz, Catherine; Coulter, Sarah; Obregón-Henao, Andres; Henao Tamayo, Marcela; Basaraba, Randall; Kampmann, Beate; Henry, Katherine M; Burgon, Joseph; Renshaw, Stephen A; Fleming, Angeleen; Kay, Robert R; Anderson, Karen E; Hawkins, Phillip T; Ordway, Diane J; Rubinsztein, David C; Floto, Rodrigo Andres

    2015-01-01

    Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection. PMID:25535254

  17. Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels*

    OpenAIRE

    2011-01-01

    NAADP is a potent second messenger that mobilizes Ca2+ from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca2+ release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca2+-permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near com...

  18. Exercise training and antioxidant supplementation independently improve cognitive function in adult male and female GFAP-APOE mice

    Directory of Open Access Journals (Sweden)

    Kiran Chaudhari

    2014-09-01

    Conclusion: Exercise was the most effective treatment at improving cognitive function in both genotypes and sex, while antioxidants seemed to be effective only in the APOE4. In young adult mice only non-spatial learning and memory were improved. The combination of the two treatments did not yield further improvement in cognition, and there was no antagonistic action of the antioxidant supplementation on the beneficial effects of exercise.

  19. Strength and independence of associations between ghrelin, leptin, adiponectin and insulin in stimulating basic functions to energy metabolism

    OpenAIRE

    Hoda A. Nour; Amel L. El Sawaf; Samia M. Elewa; Yosria El Sayed

    2014-01-01

    Background: The effect of diet composition on the fat regulating hormones and its possible interaction with insulin is necessary to fully understand the mechanisms by which the body controls feed intake. Objective: The objective of this work was to evaluate the relationship between ghrelin, leptin, adiponectin and insulin with respect to diet composition. Fasting and refeeding represent a natural challenge for stimulating basic functions to energy metabolism. Methods: The present study ...

  20. Use of a structured functional evaluation process for independent medical evaluations of claimants presenting with disabling mental illness: rationale and design for a multi-center reliability study.

    Science.gov (United States)

    Bachmann, Monica; de Boer, Wout; Schandelmaier, Stefan; Leibold, Andrea; Marelli, Renato; Jeger, Joerg; Hoffmann-Richter, Ulrike; Mager, Ralph; Schaad, Heinz; Zumbrunn, Thomas; Vogel, Nicole; Bänziger, Oskar; Busse, Jason W; Fischer, Katrin; Kunz, Regina

    2016-07-29

    Work capacity evaluations by independent medical experts are widely used to inform insurers whether injured or ill workers are capable of engaging in competitive employment. In many countries, evaluation processes lack a clearly structured approach, standardized instruments, and an explicit focus on claimants' functional abilities. Evaluation of subjective complaints, such as mental illness, present additional challenges in the determination of work capacity. We have therefore developed a process for functional evaluation of claimants with mental disorders which complements usual psychiatric evaluation. Here we report the design of a study to measure the reliability of our approach in determining work capacity among patients with mental illness applying for disability benefits. We will conduct a multi-center reliability study, in which 20 psychiatrists trained in our functional evaluation process will assess 30 claimants presenting with mental illness for eligibility to receive disability benefits [Reliability of Functional Evaluation in Psychiatry, RELY-study]. The functional evaluation process entails a five-step structured interview and a reporting instrument (Instrument of Functional Assessment in Psychiatry [IFAP]) to document the severity of work-related functional limitations. We will videotape all evaluations which will be viewed by three psychiatrists who will independently rate claimants' functional limitations. Our primary outcome measure is the evaluation of claimant's work capacity as a percentage (0 to 100 %), and our secondary outcomes are the 12 mental functions and 13 functional capacities assessed by the IFAP-instrument. Inter-rater reliability of four psychiatric experts will be explored using multilevel models to estimate the intraclass correlation coefficient (ICC). Additional analyses include subgroups according to mental disorder, the typicality of claimants, and claimant perceived fairness of the assessment process. We hypothesize that a

  1. The influence of age on health valuations: the older olds prefer functional independence while the younger olds prefer less morbidity

    Directory of Open Access Journals (Sweden)

    Hofman CS

    2015-07-01

    Full Text Available Cynthia S Hofman,1,2 Peter Makai,1 Han Boter,3 Bianca M Buurman,4 Anton J de Craen,5 Marcel GM Olde Rikkert,1 Rogier Donders,2 René JF Melis1 1Department of Geriatric Medicine, Radboud University Medical Center, Nijmegen, the Netherlands; 2Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands; 3Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands; 4Department of Internal Medicine, Section of Geriatric Medicine, Academic Medical Center, Amsterdam, the Netherlands; 5Department of Gerontology and Geriatrics, Leiden University Medical Centre, Leiden, the Netherlands Background: To assess the effectiveness of geriatric interventions, The Older Persons and Informal Caregivers Survey – Composite Endpoint (TOPICS-CEP has been developed based on health valuations of older persons and informal caregivers. This study explored the influence of the raters’ age on the preference weights of TOPICS-CEP’s components.Methods: A vignette study was conducted with 200 raters (mean age ± standard deviation: 72.5±11.8 years; 66.5% female. Profiles of older persons were used to obtain the preference weights for all TOPICS-CEP components: morbidity, functional limitations, emotional wellbeing, pain experience, cognitive functioning, social functioning, self-perceived health, and self-perceived quality of life. The raters assessed the general wellbeing of these vignettes on a 0–10 scale. Mixed linear regression analysis with interaction terms was used to explore the effects of raters’ age on the preference weights.Results: Interaction effects between age and the TOPICS-CEP components showed that older raters gave significantly (P<0.05 more weight to functional limitations and social functioning and less to morbidities and pain experience, compared to younger raters.Conclusion: Researchers examining effectiveness in elderly care need to consider the

  2. Independent specialisation of myosin II paralogues in muscle vs. non-muscle functions during early animal evolution: a ctenophore perspective

    Directory of Open Access Journals (Sweden)

    Dayraud Cyrielle

    2012-07-01

    expression of the other paralogue, PpiMHCIIb1, was the result of neofunctionalisation within the ctenophore lineage, making independent origin of ctenophore muscle cells a likely option.

  3. Independent Directors

    DEFF Research Database (Denmark)

    Ringe, Wolf-Georg

    2013-01-01

    This paper re-evaluates the corporate governance concept of ‘board independence’ against the disappointing experiences during the 2007-08 financial crisis. Independent or outside directors had long been seen as an essential tool to improve the monitoring role of the board. Yet the crisis revealed...... that they did not prevent firms' excessive risk taking; further, these directors sometimes showed serious deficits in understanding the business they were supposed to control, and remained passive in addressing structural problems. A closer look reveals that under the surface of seemingly unanimous consensus...... about board independence in Western jurisdictions, a surprising disharmony prevails about the justification, extent and purpose of independence requirements. These considerations lead me to question the benefits of the current system. Instead, this paper proposes a new, ‘functional’ concept of board...

  4. HDAC3 as a molecular chaperone for shuttling phosphorylated TR2 to PML: a novel deacetylase activity-independent function of HDAC3.

    Directory of Open Access Journals (Sweden)

    Pawan Gupta

    Full Text Available TR2 is an orphan nuclear receptor specifically expressed in early embryos (Wei and Hsu, 1994, and a transcription factor for transcriptional regulation of important genes in stem cells including the gate keeper Oct4 (Park et al. 2007. TR2 is known to function as an activator (Wei et al. 2000, or a repressor (Chinpaisal et al., 1998, Gupta et al. 2007. Due to the lack of specific ligands, mechanisms triggering its activator or repressor function have remained puzzling for decades. Recently, we found that all-trans retinoic acid (atRA triggers the activation of extracellular-signal-regulated kinase 2 (ERK2, which phosphorylates TR2 and stimulates its partitioning to promyelocytic leukemia (PML nuclear bodies, thereby converting the activator function of TR2 into repression (Gupta et al. 2008; Park et al. 2007. Recruitment of TR2 to PML is a crucial step in the conversion of TR2 from an activator to a repressor. However, it is unclear how phosphorylated TR2 is recruited to PML, an essential step in converting TR2 from an activator to a repressor. In the present study, we use both in vitro and in vivo systems to address the problem of recruiting TR2 to PML nuclear bodies. First, we identify histone deacetylase 3 (HDAC3 as an effector molecule. HDAC3 is known to interact with TR2 (Franco et al. 2001 and this interaction is enhanced by the atRA-stimulated phosphorylation of TR2 at Thr-210 (Gupta et al. 2008. Secondly, in this study, we also find that the carrier function of HDAC3 is independent of its deacetylase activity. Thirdly, we find another novel activity of atRA that stimulates nuclear enrichment of HDAC3 to form nuclear complex with PML, which is ERK2 independent. This is the first report identifying a deacetylase-independent function for HDAC3, which serves as a specific carrier molecule that targets a specifically phosphorylated protein to PML NBs. This is also the first study delineating how protein recruitment to PML nuclear bodies occurs

  5. Characterizations of Linear Independence and Stability of the Shifts of a Univariate Refinable Function in Terms of Its Refinement Mask

    Science.gov (United States)

    1992-09-01

    decompositions of L2(IR) via the idea of multiresolution as originated in [Ma] and [Me]; see also [CW2], [JM2] and the references therein. The definition...acterization of the orthogonality property of the shifts. In the first part of the section we show how Result 5.1 can be explained via the result of Theorem...Strang and G. Fix, A Fourier analysis of the finite element variational method. C.I.M.E. II Ciclo 1971, in Constructive Aspects of Functional Analysis ed. G. Gey- monat 1973, 793-840. 16

  6. Multiple independent analyses reveal only transcription factors as an enriched functional class associated with microRNAs

    Directory of Open Access Journals (Sweden)

    Croft Larry

    2012-07-01

    Full Text Available Abstract Background Transcription factors (TFs have long been known to be principally activators of transcription in eukaryotes and prokaryotes. The growing awareness of the ubiquity of microRNAs (miRNAs as suppressive regulators in eukaryotes, suggests the possibility of a mutual, preferential, self-regulatory connectivity between miRNAs and TFs. Here we investigate the connectivity from TFs and miRNAs to other genes and each other using text mining, TF promoter binding site and 6 different miRNA binding site prediction methods. Results In the first approach text mining of PubMed abstracts reveal statistically significant associations between miRNAs and both TFs and signal transduction gene classes. Secondly, prediction of miRNA targets in human and mouse 3’UTRs show enrichment only for TFs but not consistently across prediction methods for signal transduction or other gene classes. Furthermore, a random sample of 986 TarBase entries was scored for experimental evidence by manual inspection of the original papers, and enrichment for TFs was observed to increase with score. Low-scoring TarBase entries, where experimental evidence is anticorrelated miRNA:mRNA expression with predicted miRNA targets, appear not to select for real miRNA targets to any degree. Our manually validated text-mining results also suggests that miRNAs may be activated by more TFs than other classes of genes, as 7% of miRNA:TF co-occurrences in the literature were TFs activating miRNAs. This was confirmed when thirdly, we found enrichment for predicted, conserved TF binding sites in miRNA and TF genes compared to other gene classes. Conclusions We see enrichment of connections between miRNAs and TFs using several independent methods, suggestive of a network of mutual activating and suppressive regulation. We have also built regulatory networks (containing 2- and 3-loop motifs for mouse and human using predicted miRNA and TF binding sites and we have developed a web server

  7. BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

    Directory of Open Access Journals (Sweden)

    Finnson Kenneth

    2010-02-01

    Full Text Available Abstract Background Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. Results The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. Conclusion The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has

  8. Less is more: Independent loss-of-function OCIMENE SYNTHASE alleles parallel pollination syndrome diversification in monkeyflowers (Mimulus).

    Science.gov (United States)

    Peng, Foen; Byers, Kelsey J R P; Bradshaw, Harvey D

    2017-07-19

    Pollinator-mediated selection on flower phenotypes (e.g., shape, color, scent) is key to understanding the adaptive radiation of angiosperms, many of which have evolved specialized relationships with a particular guild of animal pollinators (e.g., birds, bats, moths, bees). E-β-Ocimene, a monoterpene produced by OCIMENE SYNTHASE (OS) in Mimulus lewisii, is a floral scent important in attracting the species' bumblebee pollinators. The taxa closely related to M. lewisii have evolved several different pollination syndromes, including hummingbird pollination and self pollination (autogamy). We are interested in how floral scent variation contributed to species diversification in this clade. We analyzed variation in E-β-ocimene emission within this Mimulus clade and explored its molecular basis through a combination of DNA sequencing, reverse transcriptase PCR, and enzyme functional analysis in vitro. We found that none of the taxa, other than M. lewisii, emitted E-β-ocimene from flowers. But the molecular basis underlying loss of E-β-ocimene emission is unique in each taxon, including deletion, missense, or frameshift mutations in the OS gene, and potential posttranscriptional downregulation. The molecular evidence suggests that parallel loss-of-function in OS is the best explanation for the observed pattern of E-β-ocimene emission, likely as the result of natural selection. © 2017 Botanical Society of America.

  9. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.

    Science.gov (United States)

    Crow, A R; Song, S; Semple, J W; Freedman, J; Lazarus, A H

    2001-12-01

    Although the mechanism of action of intravenous immunoglobulin (IVIg) in treating antibody-dependent thrombocytopenia remains unclear, most studies have suggested that IVIg blocks the function of Fc receptors in the reticuloendothelial system (RES) and/or the protective effect may be due to the presence of variable region-reactive (anti-idiotype) antibodies within IVIg. We evaluated the effect of IVIg on platelet counts in a murine model of passively induced immune thrombocytopenia (PIT). Although IVIg was unable to neutralize the binding of two platelet-specific monoclonal antibodies to their target antigens either in vivo or in vitro, it was able to prevent PIT as well as ameliorate pre-established PIT mediated by these antibodies. IVIg adsorbed against the antibody used to induce thrombocytopenia or endogenous murine immunoglobulin also protected against PIT, indicating that antibodies with anti-idiotype activity present in IVIg are not necessary for its effective treatment of PIT. IVIg significantly blocked the ability of the RES to clear antibody-sensitized red blood cells. F(ab')2 fragments of IVIg, which are unable to block the RES but retain the idiotypic regions, were ineffective at protecting mice from PIT. Our data suggest that IVIg exerts its rapid effect by inhibiting RES function and that anti-idiotype interactions are not required.

  10. Plant Functional Diversity Can Be Independent of Species Diversity: Observations Based on the Impact of 4-Yrs of Nitrogen and Phosphorus Additions in an Alpine Meadow.

    Science.gov (United States)

    Li, Wei; Cheng, Ji-Min; Yu, Kai-Liang; Epstein, Howard E; Guo, Liang; Jing, Guang-Hua; Zhao, Jie; Du, Guo-Zhen

    2015-01-01

    Past studies have widely documented the decrease in species diversity in response to addition of nutrients, however functional diversity is often independent from species diversity. In this study, we conducted a field experiment to examine the effect of nitrogen and phosphorus fertilization ((NH4)2 HPO4) at 0, 15, 30 and 60 g m-2 yr-1 (F0, F15, F30 and F60) after 4 years of continuous fertilization on functional diversity and species diversity, and its relationship with productivity in an alpine meadow community on the Tibetan Plateau. To this purpose, three community-weighted mean trait values (specific leaf area, SLA; mature plant height, MPH; and seed size, SS) for 30 common species in each fertilization level were determined; three components of functional diversity (functional richness, FRic; functional evenness, FEve; and Rao's index of quadratic entropy, FRao) were quantified. Our results showed that: (i) species diversity sharply decreased, but functional diversity remained stable with fertilization; (ii) community-weighted mean traits (SLA and MPH) had a significant increase along the fertilization level; (iii) aboveground biomass was not correlated with functional diversity, but it was significantly correlated with species diversity and MPH. Our results suggest that decreases in species diversity due to fertilization do not result in corresponding changes in functional diversity. Functional identity of species may be more important than functional diversity in influencing aboveground productivity in this alpine meadow community, and our results also support the mass ratio hypothesis; that is, the traits of the dominant species influenced the community biomass production.

  11. A Transmembrane Domain GGxxG Motif in CD4 Contributes to Its Lck-Independent Function but Does Not Mediate CD4 Dimerization.

    Directory of Open Access Journals (Sweden)

    Heather L Parrish

    Full Text Available CD4 interactions with class II major histocompatibility complex (MHC molecules are essential for CD4+ T cell development, activation, and effector functions. While its association with p56lck (Lck, a Src kinase, is important for these functions CD4 also has an Lck-independent role in TCR signaling that is incompletely understood. Here, we identify a conserved GGxxG motif in the CD4 transmembrane domain that is related to the previously described GxxxG motifs of other proteins and predicted to form a flat glycine patch in a transmembrane helix. In other proteins, these patches have been reported to mediate dimerization of transmembrane domains. Here we show that introducing bulky side-chains into this patch (GGxxG to GVxxL impairs the Lck-independent role of CD4 in T cell activation upon TCR engagement of agonist and weak agonist stimulation. However, using Forster's Resonance Energy Transfer (FRET, we saw no evidence that these mutations decreased CD4 dimerization either in the unliganded state or upon engagement of pMHC concomitantly with the TCR. This suggests that the CD4 transmembrane domain is either mediating interactions with an unidentified partner, or mediating some other function such as membrane domain localization that is important for its role in T cell activation.

  12. Functional activity and white matter microstructure reveal the independent effects of age of acquisition and proficiency on second-language learning.

    Science.gov (United States)

    Nichols, Emily S; Joanisse, Marc F

    2016-12-01

    Two key factors govern how bilingual speakers neurally maintain two languages: the speakers' second language age of acquisition (AoA) and their subsequent proficiency. However, the relative roles of these two factors have been difficult to disentangle given that the two can be closely correlated, and most prior studies have examined the two factors in isolation. Here, we combine functional magnetic resonance imaging with diffusion tensor imaging to identify specific brain areas that are independently modulated by AoA and proficiency in second language speakers. First-language Mandarin Chinese speakers who are second language speakers of English were scanned as they performed a picture-word matching task in either language. In the same session we also acquired diffusion-weighted scans to assess white matter microstructure, along with behavioural measures of language proficiency prior to entering the scanner. Results reveal gray- and white-matter networks involving both the left and right hemisphere that independently vary as a function of a second-language speaker's AoA and proficiency, focused on the superior temporal gyrus, middle and inferior frontal gyrus, parahippocampal gyrus, and the basal ganglia. These results indicate that proficiency and AoA explain separate functional and structural networks in the bilingual brain, which we interpret as suggesting distinct types of plasticity for age-dependent effects (i.e., AoA) versus experience and/or predisposition (i.e., proficiency).

  13. Multi-Day Recordings of Wearable Sensors Are Valid and Sensitive Measures of Function and Independence in Human Spinal Cord Injury.

    Science.gov (United States)

    Brogioli, Michael; Popp, Werner L; Schneider, Sophie; Albisser, Urs; Brust, Anne K; Frotzler, Angela; Gassert, Roger; Curt, Armin; Starkey, Michelle L

    2017-03-15

    Wearable sensor assessment tools have proven to be reliable in measuring function in normal and impaired movement disorders during well-defined assessment protocols. While such assessments can provide valid and sensitive measures of upper limb activity in spinal cord injury (SCI), no assessment tool has yet been introduced into unsupervised daily recordings to complement clinical assessments during rehabilitation. The objective of this study was to measure the overall amount of upper-limb activity in subjects with acute SCI using wearable sensors and relate this to lesion characteristics, independence, and function. The overall amount of upper extremity activity counts, measures of wheeling (speed and distance), and limb-use laterality were measured in 30 in-patients with an acute cervical or thoracic SCI three months after injury. The findings were related to the international standards for neurological classification of SCI, the spinal cord independence measure, and the upper extremity motor scores of the Graded and Redefined Assessment of Strength, Sensibility, and Prehension. Overall upper extremity activity counts were successfully recorded in all patients and correlated with the neurological level of injury and independence. Clinical measures of proximal muscle strength were related to overall activity count and peak velocity of wheeling. Compared with paraplegics, tetraplegics showed significantly lower activity counts and increased limb-use laterality. This is the first cross-sectional study showing the feasibility and clinical value of sensor recordings during unsupervised daily activities in rehabilitation. The strong relationship between sensor-based measures and clinical outcomes supports the application of such technology to assess and track changes in function during rehabilitation and in clinical trials.

  14. Analysis of C. elegans NR2E nuclear receptors defines three conserved clades and ligand-independent functions

    Directory of Open Access Journals (Sweden)

    Weber Katherine P

    2012-06-01

    Full Text Available Abstract Background The nuclear receptors (NRs are an important class of transcription factors that are conserved across animal phyla. Canonical NRs consist of a DNA-binding domain (DBD and ligand-binding domain (LBD. While most animals have 20–40 NRs, nematodes of the genus Caenorhabditis have experienced a spectacular proliferation and divergence of NR genes. The LBDs of evolutionarily-conserved Caenorhabditis NRs have diverged sharply from their Drosophila and vertebrate orthologs, while the DBDs have been strongly conserved. The NR2E family of NRs play critical roles in development, especially in the nervous system. In this study, we explore the phylogenetics and function of the NR2E family of Caenorhabditis elegans, using an in vivo assay to test LBD function. Results Phylogenetic analysis reveals that the NR2E family of NRs consists of three broadly-conserved clades of orthologous NRs. In C. elegans, these clades are defined by nhr-67, fax-1 and nhr-239. The vertebrate orthologs of nhr-67 and fax-1 are Tlx and PNR, respectively. While the nhr-239 clade includes orthologs in insects (Hr83, an echinoderm, and a hemichordate, the gene appears to have been lost from vertebrate lineages. The C. elegans and C. briggsae nhr-239 genes have an apparently-truncated and highly-diverged LBD region. An additional C. elegans NR2E gene, nhr-111, appears to be a recently-evolved paralog of fax-1; it is present in C. elegans, but not C. briggsae or other animals with completely-sequenced genomes. Analysis of the relatively unstudied nhr-111 and nhr-239 genes demonstrates that they are both expressed—nhr-111 very broadly and nhr-239 in a small subset of neurons. Analysis of the FAX-1 LBD in an in vivo assay revealed that it is not required for at least some developmental functions. Conclusions Our analysis supports three conserved clades of NR2E receptors, only two of which are represented in vertebrates, indicating three ancestral NR2E genes in the

  15. Choosing Independence

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Milo Djukanovic, Prime Minister of Montenegro, won a key referendum May 21 when voters in his tiny, mountainous nation endorsed a plan to split from Serbia and become an independent state. This marked a final step in the breakup of the former Yugoslavia formed by six republics.

  16. Functional independence: A comparison of the changes during neurorehabilitation between patients with non-traumatic subarachnoid hemorrhage and intracerebral hemorrhage or acute ischemic stroke

    DEFF Research Database (Denmark)

    Stabel, Henriette Holm; Pedersen, Asger Roer; Johnsen, Søren Paaske

    2017-01-01

    Objective To compare the changes in functional independence measured by the FIM after specialized neurorehabilitation between patients with nontraumatic subarachnoid hemorrhage (SAH) and patients with intracerebral hemorrhage (ICH) or acute ischemic stroke (AIS). Design Historical cohort study......) comprised patients with a first-time nontraumatic SAH (n=212) and age-matched patients with a first-time ICH/AIS (n=448). Interventions Not applicable. Main Outcome Measures Crude and adjusted comparisons of FIM (total and item by item) measured at baseline and at discharge. Results Patients...

  17. A Coding System with Independent Annotations of Gesture Forms and Functions during Verbal Communication: Development of a Database of Speech and GEsture (DoSaGE).

    Science.gov (United States)

    Kong, Anthony Pak-Hin; Law, Sam-Po; Kwan, Connie Ching-Yin; Lai, Christy; Lam, Vivian

    2015-03-01

    Gestures are commonly used together with spoken language in human communication. One major limitation of gesture investigations in the existing literature lies in the fact that the coding of forms and functions of gestures has not been clearly differentiated. This paper first described a recently developed Database of Speech and GEsture (DoSaGE) based on independent annotation of gesture forms and functions among 119 neurologically unimpaired right-handed native speakers of Cantonese (divided into three age and two education levels), and presented findings of an investigation examining how gesture use was related to age and linguistic performance. Consideration of these two factors, for which normative data are currently very limited or lacking in the literature, is relevant and necessary when one evaluates gesture employment among individuals with and without language impairment. Three speech tasks, including monologue of a personally important event, sequential description, and story-telling, were used for elicitation. The EUDICO Linguistic ANnotator (ELAN) software was used to independently annotate each participant's linguistic information of the transcript, forms of gestures used, and the function for each gesture. About one-third of the subjects did not use any co-verbal gestures. While the majority of gestures were non-content-carrying, which functioned mainly for reinforcing speech intonation or controlling speech flow, the content-carrying ones were used to enhance speech content. Furthermore, individuals who are younger or linguistically more proficient tended to use fewer gestures, suggesting that normal speakers gesture differently as a function of age and linguistic performance.

  18. Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.

    Directory of Open Access Journals (Sweden)

    Martin F Dietrich

    Full Text Available BACKGROUND: The low-density lipoprotein (LDL receptor gene family is a highly conserved group of membrane receptors with diverse functions in developmental processes, lipoprotein trafficking, and cell signaling. The low-density lipoprotein (LDL receptor-related protein 1b (LRP1B was reported to be deleted in several types of human malignancies, including non-small cell lung cancer. Our group has previously reported that a distal extracellular truncation of murine Lrp1b that is predicted to secrete the entire intact extracellular domain (ECD is fully viable with no apparent phenotype. METHODS AND PRINCIPAL FINDINGS: Here, we have used a gene targeting approach to create two mouse lines carrying internally rearranged exons of Lrp1b that are predicted to truncate the protein closer to the N-terminus and to prevent normal trafficking through the secretary pathway. Both mutations result in early embryonic lethality, but, as expected from the restricted expression pattern of LRP1b in vivo, loss of Lrp1b does not cause cellular lethality as homozygous Lrp1b-deficient blastocysts can be propagated normally in culture. This is similar to findings for another LDL receptor family member, Lrp4. We provide in vitro evidence that Lrp4 undergoes regulated intramembraneous processing through metalloproteases and gamma-secretase cleavage. We further demonstrate negative regulation of the Wnt signaling pathway by the soluble extracellular domain. CONCLUSIONS AND SIGNIFICANCE: Our results underline a crucial role for Lrp1b in development. The expression in mice of truncated alleles of Lrp1b and Lrp4 with deletions of the transmembrane and intracellular domains leads to release of the extracellular domain into the extracellular space, which is sufficient to confer viability. In contrast, null mutations are embryonically (Lrp1b or perinatally (Lrp4 lethal. These findings suggest that the extracellular domains of both proteins may function as a scavenger for

  19. Post-exercise contractility, diastolic function, and pressure: Operator-independent sensor-based intelligent monitoring for heart failure telemedicine

    Directory of Open Access Journals (Sweden)

    Giannoni Massimo

    2009-05-01

    Full Text Available Abstract Background New sensors for intelligent remote monitoring of the heart should be developed. Recently, a cutaneous force-frequency relation recording system has been validated based on heart sound amplitude and timing variations at increasing heart rates. Aim To assess sensor-based post-exercise contractility, diastolic function and pressure in normal and diseased hearts as a model of a wireless telemedicine system. Methods We enrolled 150 patients and 22 controls referred for exercise-stress echocardiography, age 55 ± 18 years. The sensor was attached in the precordial region by an ECG electrode. Stress and recovery contractility were derived by first heart sound amplitude vibration changes; diastolic times were acquired continuously. Systemic pressure changes were quantitatively documented by second heart sound recording. Results Interpretable sensor recordings were obtained in all patients (feasibility = 100%. Post-exercise contractility overshoot (defined as increase > 10% of recovery contractility vs exercise value was more frequent in patients than controls (27% vs 8%, p 1 in 20 patients and in none of the controls (p 1 in only 3 patients (p Conclusion Post-exercise contractility, diastolic time and pressure changes can be continuously measured by a cutaneous sensor. Heart disease affects not only exercise systolic performance, but also post-exercise recovery, diastolic time intervals and blood pressure changes – in our study, all of these were monitored by a non-invasive wearable sensor.

  20. Variation in Chronic Nicotinamide Treatment after Traumatic Brain Injury Can Alter Components of Functional Recovery Independent of Histological Damage

    Directory of Open Access Journals (Sweden)

    Michael R Hoane

    2008-01-01

    Full Text Available Previously, we have shown that the window of opportunity for nicotinamide (NAM therapy (50 mg/kg following cortical contusion injuries (CCI extended to 4–8 hrs post-CCI when administered over a six day post-CCI interval. The purpose of the present study was to determine if a more chronic NAM treatment protocol administered following CCI would extend the current window of opportunity for effective treatment onset. Groups of rats received either unilateral CCI's or sham procedures. Initiation of NAM therapy (50 mg/kg, ip began at either 15-min, 4-hrs, 8-hrs or 24-hrs post-injury. All groups received daily systemic treatments for 12 days post-CCI at 24 hr intervals. Behavioral assessments were conducted for 28 days post injury and included: vibrissae forelimb placing, bilateral tactile adhesive removal, forelimb asymmetry task and locomotor placing testing. Behavioral analysis on both the tactile removal and locomotor placing tests showed that all NAM-treated groups facilitated recovery of function compared to saline treatment. However, on the vibrissae-forelimb placing and forelimb asymmetry tests only the 4-hr and 8-hr NAM-treated groups were significantly different from the saline-treated group. The lesion analysis showed that treatment with NAM out to 8 hrs post-CCI significantly reduced the size of the injury cavity. The window of opportunity for NAM treatment is task-dependent and in some situations can extend to 24 hrs post-CCI. These results suggest that a long term treatment regimen of 50 mg/kg of NAM starting at the clinically relevant time points may prove efficacious in human TBI.

  1. Independent preferences

    DEFF Research Database (Denmark)

    Vind, Karl

    1991-01-01

    A simple mathematical result characterizing a subset of a product set is proved and used to obtain additive representations of preferences. The additivity consequences of independence assumptions are obtained for preferences which are not total or transitive. This means that most of the economic...... theory based on additive preferences - expected utility, discounted utility - has been generalized to preferences which are not total or transitive. Other economic applications of the theorem are given...

  2. A phosphatase-independent gain-of-function mutation in PTEN triggers aberrant cell growth in astrocytes through an autocrine IGF-1 loop.

    Science.gov (United States)

    Fernández, S; Genis, L; Torres-Alemán, I

    2014-08-07

    Loss-of-function mutations in the phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome10) contribute to aberrant cell growth in part through upregulation of the mitogenic IGF-1/PI3K/Akt pathway. In turn, this pathway exerts a homeostatic feedback over PTEN. Using mutagenesis analysis to explore a possible impact of this mutual control on astrocyte growth, we found that truncation of the C-terminal region of PTEN (Δ51) associates with a marked increase in NFκB activity, a transcription factor overactivated in astrocyte tumors. Whereas mutations of PTEN are considered to lead to a loss-of-function, PTENΔ51, a truncation that comprises a region frequently mutated in human gliomas, displayed a neomorphic (gain-of-function) activity that was independent of its phosphatase activity. This gain-of-function of PTENΔ51 includes stimulation of IGF-1 synthesis through protein kinase A activation of the IGF-1 promoter. Increased IGF-1 originates an autocrine loop that activates Akt and NFκB. Constitutive activation of NFκB in PTENΔ51-expressing astrocytes leads to aberrant cell growth; astrocytes expressing this mutant PTEN generate colonies in vitro and tumors in vivo. Mutations converting a tumor suppressor such as PTEN into a tumor promoter through a gain-of-function involving IGF-1 production may further our understanding of the role played by this growth factor in glioma growth and help us define druggable targets for personalized therapy.

  3. Decoding the encoding of functional brain networks: An fMRI classification comparison of non-negative matrix factorization (NMF), independent component analysis (ICA), and sparse coding algorithms.

    Science.gov (United States)

    Xie, Jianwen; Douglas, Pamela K; Wu, Ying Nian; Brody, Arthur L; Anderson, Ariana E

    2017-04-15

    Brain networks in fMRI are typically identified using spatial independent component analysis (ICA), yet other mathematical constraints provide alternate biologically-plausible frameworks for generating brain networks. Non-negative matrix factorization (NMF) would suppress negative BOLD signal by enforcing positivity. Spatial sparse coding algorithms (L1 Regularized Learning and K-SVD) would impose local specialization and a discouragement of multitasking, where the total observed activity in a single voxel originates from a restricted number of possible brain networks. The assumptions of independence, positivity, and sparsity to encode task-related brain networks are compared; the resulting brain networks within scan for different constraints are used as basis functions to encode observed functional activity. These encodings are then decoded using machine learning, by using the time series weights to predict within scan whether a subject is viewing a video, listening to an audio cue, or at rest, in 304 fMRI scans from 51 subjects. The sparse coding algorithm of L1 Regularized Learning outperformed 4 variations of ICA (pcoding algorithms. Holding constant the effect of the extraction algorithm, encodings using sparser spatial networks (containing more zero-valued voxels) had higher classification accuracy (pcoding algorithms suggests that algorithms which enforce sparsity, discourage multitasking, and promote local specialization may capture better the underlying source processes than those which allow inexhaustible local processes such as ICA. Negative BOLD signal may capture task-related activations. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. The Arabidopsis downy mildew resistance gene, RPP13-Nd, functions independently of NDR1 and EDS1 and does not require the accumulation of salicylic acid.

    Science.gov (United States)

    Bittner-Eddy, P D; Beynon, J L

    2001-03-01

    RPP13-Nd-mediated resistance prevents parasitism by five isolates of Peronospora parasitica (At) in a transgenic Arabidopsis. Columbia background. We tested the effect of a number of known disease resistance mutations on the RPP13-Nd function and found that resistance remained unaltered in plants carrying mutations in either EDS1 or NDR1 and in double ndr1-1/eds1-2 mutant lines. Furthermore, we found that pbs2, pad4-1, npr1-1, and rps5-1, which compromise resistance to a number of P. parasitica (At) isolates, had no affect on RPP13-Nd function. In addition, RPP13-Nd-mediated resistance remained unchanged in a background of salicylic acid depletion (nahG). We conclude that RPP13-Nd is the first Arabidopsis R gene product reported to act via a novel signaling pathway that is independent of salicylic acid-mediated responses and is completely independent of NDR1 and EDS1.

  5. The P-type ATPase CATP-1 is a novel regulator of C. elegans developmental timing that acts independently of its predicted pump function.

    Science.gov (United States)

    Ruaud, Anne-Françoise; Bessereau, Jean-Louis

    2007-03-01

    During postembryonic stages, metazoans synchronize the development of a large number of cells, tissues and organs by mechanisms that remain largely unknown. In Caenorhabditis elegans larvae, an invariant cell lineage is tightly coordinated with four successive molts, thus defining a genetically tractable system to analyze the mechanisms underlying developmental synchronization. Illegitimate activation of nicotinic acetylcholine receptors (nAChRs) by the nicotinic agonist dimethylphenylpiperazinium (DMPP) during the second larval stage (L2) of C. elegans causes a lethal heterochronic phenotype. DMPP exposure delays cell division and differentiation without affecting the molt cycle, hence resulting in deadly exposure of a defective cuticle to the surrounding environment. In a screen for DMPP-resistant mutants, we identified catp-1 as a gene coding for a predicted cation-transporting P-type ATPase expressed in the epidermis. Larval development was specifically slowed down at the L2 stage in catp-1 mutants compared with wild-type animals and was not further delayed after exposure to DMPP. We demonstrate that CATP-1 interacts with the insulin/IGF and Ras-MAPK pathways to control several postembryonic developmental events. Interestingly, these developmental functions can be fulfilled independently of the predicted cation-transporter activity of CATP-1, as pump-dead engineered variants of CATP-1 can rescue most catp-1-mutant defects. These results obtained in vivo provide further evidence for the recently proposed pump-independent scaffolding functions of P-type ATPases in the modulation of intracellular signaling.

  6. Higher Cognitive Function in Elderly Individuals with Previous Cataract Surgery: Cross-Sectional Association Independent of Visual Acuity in the HEIJO-KYO Cohort.

    Science.gov (United States)

    Miyata, Kimie; Obayashi, Kenji; Saeki, Keigo; Tone, Nobuhiro; Tanaka, Kunihiko; Nishi, Tomo; Morikawa, Masayuki; Kurumatani, Norio; Ogata, Nahoko

    2016-06-01

    Cataract surgery improves visual acuity and drastically increases the capacity for light reception to the retina. Although previous studies suggested that both light exposure and visual acuity were associated with cognitive function, the relationships between cataract surgery, visual acuity, and cognitive function have not been evaluated in large populations. In this cross-sectional study, we measured cognitive function using the Mini-Mental State Examination and best-corrected visual acuity in pseudophakic (previous cataract surgery) and phakic (no previous cataract surgery) elderly individuals. Of 945 participants (mean age 71.7 years), 166 (17.6%) had pseudophakia and 317 (33.5%) had impaired cognitive function (score ≤26). The pseudophakic group showed significantly better visual acuity than the phakic group (p = 0.003) and lower age-adjusted odds ratio (ORs) for cognitive impairment (OR 0.66; p = 0.038). Consistently, in multivariate logistic regression models, after adjusting for confounding factors, including visual acuity and socioeconomic status, ORs for cognitive impairment were significantly lower in the pseudophakic group than in the phakic group (OR 0.64; 95% confidence interval 0.43-0.96; p = 0.031). This association remained significant in sensitivity analysis, excluding participants with low cognitive score ≤23 (n = 36). In conclusion, in a general elderly population, prevalence of cognitive impairment was significantly lower in pseudophakic individuals independently of visual acuity. The association was also independent of several major causes of cognitive impairment such as aging, gender, obesity, socioeconomic status, hypertension, diabetes, sleep disturbances, depressive symptoms, and physical inactivity.

  7. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus.

    Science.gov (United States)

    Zeng, Chenjie; Guo, Xingyi; Long, Jirong; Kuchenbaecker, Karoline B; Droit, Arnaud; Michailidou, Kyriaki; Ghoussaini, Maya; Kar, Siddhartha; Freeman, Adam; Hopper, John L; Milne, Roger L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Agata, Simona; Ahmed, Shahana; Aittomäki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arason, Adalgeir; Arndt, Volker; Arun, Banu K; Arver, Brita; Bacot, Francois; Barrowdale, Daniel; Baynes, Caroline; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Blot, William J; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Borresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Broeks, Annegien; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Cai, Qiuyin; Caldes, Trinidad; Campbell, Ian; Carpenter, Jane; Chang-Claude, Jenny; Choi, Ji-Yeob; Claes, Kathleen B M; Clarke, Christine; Cox, Angela; Cross, Simon S; Czene, Kamila; Daly, Mary B; de la Hoya, Miguel; De Leeneer, Kim; Devilee, Peter; Diez, Orland; Domchek, Susan M; Doody, Michele; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Dwek, Miriam; Dworniczak, Bernd; Egan, Kathleen; Eilber, Ursula; Einbeigi, Zakaria; Ejlertsen, Bent; Ellis, Steve; Frost, Debra; Lalloo, Fiona; Fasching, Peter A; Figueroa, Jonine; Flyger, Henrik; Friedlander, Michael; Friedman, Eitan; Gambino, Gaetana; Gao, Yu-Tang; Garber, Judy; García-Closas, Montserrat; Gehrig, Andrea; Damiola, Francesca; Lesueur, Fabienne; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Giles, Graham G; Godwin, Andrew K; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Guénel, Pascal; Haeberle, Lothar; Haiman, Christopher A; Hallberg, Emily; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Hartikainen, Jaana M; Hartman, Mikael; Hassan, Norhashimah; Healey, Sue; Hogervorst, Frans B L; Verhoef, Senno; Hendricks, Carolyn B; Hillemanns, Peter; Hollestelle, Antoinette; Hulick, Peter J; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Ito, Hidemi; Jakubowska, Anna; Janavicius, Ramunas; Jaworska-Bieniek, Katarzyna; Jensen, Uffe Birk; John, Esther M; Joly Beauparlant, Charles; Jones, Michael; Kabisch, Maria; Kang, Daehee; Karlan, Beth Y; Kauppila, Saila; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Knight, Julia A; Konstantopoulou, Irene; Kraft, Peter; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Le Marchand, Loic; Lee, Chuen Neng; Lee, Min Hyuk; Lester, Jenny; Li, Jingmei; Liljegren, Annelie; Lindblom, Annika; Lophatananon, Artitaya; Lubinski, Jan; Mai, Phuong L; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Matsuo, Keitaro; McGuffog, Lesley; Meindl, Alfons; Menegaux, Florence; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Newcomb, Polly A; Nord, Silje; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olswold, Curtis; Osorio, Ana; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Peeters, Stephanie; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Presneau, Nadege; Radice, Paolo; Rahman, Nazneen; Ramus, Susan J; Rashid, Muhammad Usman; Rennert, Gad; Rhiem, Kerstin; Rudolph, Anja; Salani, Ritu; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Marjanka K; Schmutzler, Rita K; Schoemaker, Minouk J; Schürmann, Peter; Seynaeve, Caroline; Shen, Chen-Yang; Shrubsole, Martha J; Shu, Xiao-Ou; Sigurdson, Alice; Singer, Christian F; Slager, Susan; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Swerdlow, Anthony; Szabo, Csilla I; Tchatchou, Sandrine; Teixeira, Manuel R; Teo, Soo H; Terry, Mary Beth; Tessier, Daniel C; Teulé, Alex; Thomassen, Mads; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tung, Nadine; Turnbull, Clare; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Ven den Berg, David; Vijai, Joseph; Wang-Gohrke, Shan; Weitzel, Jeffrey N; Whittemore, Alice S; Winqvist, Robert; Wong, Tien Y; Wu, Anna H; Yannoukakos, Drakoulis; Yu, Jyh-Cherng; Pharoah, Paul D P; Hall, Per; Chenevix-Trench, Georgia; Dunning, Alison M; Simard, Jacques; Couch, Fergus J; Antoniou, Antonis C; Easton, Douglas F; Zheng, Wei

    2016-06-21

    Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/ ), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 × 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 × 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 × 10(-4)) identified in the general populations, and rs113824616 (P = 7 × 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby

  8. Are Independent Fiscal Institutions Really Independent?

    Directory of Open Access Journals (Sweden)

    Slawomir Franek

    2015-08-01

    Full Text Available In the last decade the number of independent fiscal institutions (known also as fiscal councils has tripled. They play an important oversight role over fiscal policy-making in democratic societies, especially as they seek to restore public finance stability in the wake of the recent financial crisis. Although common functions of such institutions include a role in analysis of fiscal policy, forecasting, monitoring compliance with fiscal rules or costing of spending proposals, their roles, resources and structures vary considerably across countries. The aim of the article is to determine the degree of independence of such institutions based on the analysis of the independence index of independent fiscal institutions. The analysis of this index values may be useful to determine the relations between the degree of independence of fiscal councils and fiscal performance of particular countries. The data used to calculate the index values will be derived from European Commission and IMF, which collect sets of information about characteristics of activity of fiscal councils.

  9. Probabilistic conditional independence structures

    CERN Document Server

    Studeny, Milan

    2005-01-01

    Probabilistic Conditional Independence Structures provides the mathematical description of probabilistic conditional independence structures; the author uses non-graphical methods of their description, and takes an algebraic approach.The monograph presents the methods of structural imsets and supermodular functions, and deals with independence implication and equivalence of structural imsets.Motivation, mathematical foundations and areas of application are included, and a rough overview of graphical methods is also given.In particular, the author has been careful to use suitable terminology, and presents the work so that it will be understood by both statisticians, and by researchers in artificial intelligence.The necessary elementary mathematical notions are recalled in an appendix.

  10. Activation of the DNA Damage Response Is a Conserved Function of HIV-1 and HIV-2 Vpr That Is Independent of SLX4 Recruitment

    Directory of Open Access Journals (Sweden)

    Oliver I. Fregoso

    2016-09-01

    Full Text Available There has been extraordinary progress in understanding the roles of lentiviral accessory proteins in antagonizing host antiviral defense proteins. However, the precise primary function of the accessory gene Vpr remains elusive. Here we suggest that engagement with the DNA damage response is an important function of primate lentiviral Vpr proteins because of its conserved function among diverse lentiviral lineages. In contrast, we show that, for HIV-1, HIV-2, and related Vpr isolates and orthologs, there is a lack of correlation between DNA damage response activation and interaction with the host SLX4 protein complex of structure specific endonucleases; some Vpr proteins are able to interact with SLX4, but the majority are not. Using the clustered regularly interspaced short palindromic repeat (CRISPR/Cas9 method to knock out SLX4, we formally showed that HIV-1 and HIV-2 Vpr orthologs can still activate the DNA damage response and cell cycle arrest in the absence of SLX4. Together, our data suggest that activation of the DNA damage response, but not SLX4 interaction, is conserved and therefore indicative of an important function of Vpr. Our data also indicate that Vpr activates the DNA damage response through an SLX4-independent mechanism that remains uncharacterized.

  11. RNA Helicase DDX5 Inhibits Reprogramming to Pluripotency by miRNA-Based Repression of RYBP and its PRC1-Dependent and -Independent Functions.

    Science.gov (United States)

    Li, Huanhuan; Lai, Ping; Jia, Jinping; Song, Yawei; Xia, Qing; Huang, Kaimeng; He, Na; Ping, Wangfang; Chen, Jiayu; Yang, Zhongzhou; Li, Jiao; Yao, Mingze; Dong, Xiaotao; Zhao, Jicheng; Hou, Chunhui; Esteban, Miguel A; Gao, Shaorong; Pei, Duanqing; Hutchins, Andrew P; Yao, Hongjie

    2017-04-06

    RNA-binding proteins (RBPs), in addition to their functions in cellular homeostasis, play important roles in lineage specification and maintaining cellular identity. Despite their diverse and essential functions, which touch on nearly all aspects of RNA metabolism, the roles of RBPs in somatic cell reprogramming are poorly understood. Here we show that the DEAD-box RBP DDX5 inhibits reprogramming by repressing the expression and function of the non-canonical polycomb complex 1 (PRC1) subunit RYBP. Disrupting Ddx5 expression improves the efficiency of iPSC generation and impedes processing of miR-125b, leading to Rybp upregulation and suppression of lineage-specific genes via RYBP-dependent ubiquitination of H2AK119. Furthermore, RYBP is required for PRC1-independent recruitment of OCT4 to the promoter of Kdm2b, a histone demethylase gene that promotes reprogramming by reactivating endogenous pluripotency genes. Together, these results reveal important functions of DDX5 in regulating reprogramming and highlight the importance of a Ddx5-miR125b-Rybp axis in controlling cell fate.

  12. Central angiotensin-(1-7) improves vagal function independent of blood pressure in hypertensive (mRen2)27 rats.

    Science.gov (United States)

    Nautiyal, Manisha; Shaltout, Hossam A; de Lima, Daniel C; do Nascimento, Kenia; Chappell, Mark C; Diz, Debra I

    2012-11-01

    Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1-7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1-7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide

  13. Promoting Function, Independence, and Mobility

    Science.gov (United States)

    ... Health Insurance and Medicare Disability Insurance Life and Long-Term Care Insurance Financial Resources d Advanced Care Needs Pressure ... This information-packed book explores options in health, technology, attendant services, employment, travel, sports, relationships, sexuality and parenting. ... Find an MS Care Provider The Partners in MS Care program recognizes ...

  14. High Nutritional-Related Risk on Admission Predicts Less Improvement of Functional Independence Measure in Geriatric Stroke Patients: A Retrospective Cohort Study.

    Science.gov (United States)

    Kokura, Yoji; Maeda, Keisuke; Wakabayashi, Hidetaka; Nishioka, Shinta; Higashi, Sotaro

    2016-06-01

    The aim of the present study was to establish whether high nutritional-related risk on admission predicts less improvement of Functional Independence Measure (FIM) in geriatric stroke patients. We performed a retrospective cohort study of patients admitted for stroke at 5 major hospitals in the Noto district of Japan from July 2009 to June 2013. Patients were divided into 2 groups according to Geriatric Nutritional Risk Index (GNRI) at admission. Patient characteristics were compared between the low GNRI (nutritional status using GNRI and activities of daily living using the FIM. A total of 540 participants (mean age, 80 years; interquartile range, 75-85 years) were included in the present study. Patients were admitted because of cerebral infarction (394 patients), intracerebral hemorrhage (123 patients), and subarachnoid hemorrhage (23 patients). Univariate analysis of FIM gain demonstrated significant differences between groups. Multivariate analysis of FIM gain adjusting for confounding factors demonstrated age (β = -.139; 95% confidence interval [CI] = -.629 to -.140), cerebral infarction (β = -.264; 95% CI = -12.956 to -6.729), National Institutes of Health Stroke Scale (β = -.180; 95% CI = -.688 to -.248), and GNRI score (β = .089; 95% CI = .010-.347) as independent factors associated with FIM gain (P nutritional status is a predictor of lower FIM improvement in geriatric stroke patients. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Androgen receptor gene CAG repeat polymorphism independently influences recovery of male sexual function after testosterone replacement therapy in postsurgical hypogonadotropic hypogonadism.

    Science.gov (United States)

    Tirabassi, Giacomo; Delli Muti, Nicola; Corona, Giovanni; Maggi, Mario; Balercia, Giancarlo

    2014-05-01

    Few and contradictory studies have evaluated the possible influence of androgen receptor (AR) gene CAG repeat polymorphism on male sexual function. In this study we evaluated the role of AR gene CAG repeat polymorphism in the recovery of sexual function after testosterone replacement therapy (TRT) in men affected by postsurgical hypogonadotropic hypogonadism, a condition which is often associated with hypopituitarism and in which the sexual benefits of TRT must be distinguished from those of pituitary-function replacement therapies. Fifteen men affected by postsurgical hypogonadotropic hypogonadism were retrospectively assessed before and after TRT. Main outcome measures included sexual parameters as assessed by the International Index of Erectile Function questionnaire, levels of pituitary dependent hormones (total testosterone, free T3, free T4, cortisol, insulin-like growth factor-1 [IGF-1], prolactin), and results of genetic analysis (AR gene CAG repeat number). Plasma concentrations of free T3, free T4, cortisol, and prolactin did not vary significantly between the two phases, while testosterone and IGF-1 increased significantly after TRT. A significant improvement in all sexual parameters studied was found. The number of CAG triplets was negatively and significantly correlated with changes in all the sexual parameters, while opposite correlations were found between changes in sexual parameters and changes in testosterone levels; no correlation of change in IGF1 with change in sexual parameters was reported. On multiple linear regression analysis, after correction for changes in testosterone, nearly all the associations between the number of CAG triplets and changes in sexual parameters were confirmed. Shorter length AR gene CAG repeat number is associated with the recovery of sexual function after TRT in postsurgical male hypogonadotropic hypogonadism, independently of the effects of concomitant pituitary-replacement therapies. © 2014 International Society

  16. A Rad53 independent function of Rad9 becomes crucial for genome maintenance in the absence of the Recq helicase Sgs1.

    Directory of Open Access Journals (Sweden)

    Ida Nielsen

    Full Text Available The conserved family of RecQ DNA helicases consists of caretaker tumour suppressors, that defend genome integrity by acting on several pathways of DNA repair that maintain genome stability. In budding yeast, Sgs1 is the sole RecQ helicase and it has been implicated in checkpoint responses, replisome stability and dissolution of double Holliday junctions during homologous recombination. In this study we investigate a possible genetic interaction between SGS1 and RAD9 in the cellular response to methyl methane sulphonate (MMS induced damage and compare this with the genetic interaction between SGS1 and RAD24. The Rad9 protein, an adaptor for effector kinase activation, plays well-characterized roles in the DNA damage checkpoint response, whereas Rad24 is characterized as a sensor protein also in the DNA damage checkpoint response. Here we unveil novel insights into the cellular response to MMS-induced damage. Specifically, we show a strong synergistic functionality between SGS1 and RAD9 for recovery from MMS induced damage and for suppression of gross chromosomal rearrangements, which is not the case for SGS1 and RAD24. Intriguingly, it is a Rad53 independent function of Rad9, which becomes crucial for genome maintenance in the absence of Sgs1. Despite this, our dissection of the MMS checkpoint response reveals parallel, but unequal pathways for Rad53 activation and highlights significant differences between MMS- and hydroxyurea (HU-induced checkpoint responses with relation to the requirement of the Sgs1 interacting partner Topoisomerase III (Top3. Thus, whereas earlier studies have documented a Top3-independent role of Sgs1 for an HU-induced checkpoint response, we show here that upon MMS treatment, Sgs1 and Top3 together define a minor but parallel pathway to that of Rad9.

  17. C1 metabolism and the Calvin cycle function simultaneously and independently during HCHO metabolism and detoxification in Arabidopsis thaliana treated with HCHO solutions.

    Science.gov (United States)

    Song, Zhong-Bang; Xiao, Su-Qin; You, Lan; Wang, Sha-Sha; Tan, Hao; Li, Kun-Zhi; Chen, Li-Mei

    2013-08-01

    Formaldehyde (HCHO) is suggested to be detoxified through one-carbon (C1) metabolism or assimilated by the Calvin cycle in plants. To further understand the function of the Calvin cycle and C1 metabolism in HCHO metabolism in plants, HCHO elimination and metabolism by Arabidopsis thaliana in HCHO solutions was investigated in this study. Results verified that Arabidopsis could completely eliminate aqueous HCHO from the HCHO solutions. Carbon-13 nuclear magnetic resonance ((13)C-NMR) analysis showed that H(13)CHO absorbed by Arabidopsis was first oxidized to H(13)COOH. Subsequently, a clear increase in [U-(13)C]Gluc peaks accompanied by a strong enhancement in peaks of [2-(13)C]Ser and [3-(13)C]Ser appeared in Arabidopsis. Pretreatment with cyclosporin A or L-carnitine, which might inhibit the transport of (13)C-enriched compounds into chloroplasts and mitochondria, caused a remarkable decline in yields of both [U-(13)C]Gluc and [3-(13)C]Ser in H(13)CHO-treated Arabidopsis. These results suggested that both the Calvin cycle and the C1 metabolism functioned simultaneously during HCHO detoxification. Moreover, both functioned more quickly under high H(13)CHO stress than low H(13)CHO stress. When a photorespiration mutant was treated in 6 mm H(13)CHO solution, formation of [U-(13)C]Gluc and [2-(13)C]Ser was completely inhibited, but generation of [3-(13)C]Ser was not significantly affected. This evidence suggested that the Calvin cycle and C1 metabolism functioned independently in Arabidopsis during HCHO metabolism.

  18. Independent Losses of Function in a Polyphenol Oxidase in Rice: Differentiation in Grain Discoloration between Subspecies and the Role of Positive Selection under Domestication[W

    Science.gov (United States)

    Yu, Yanchun; Tang, Tian; Qian, Qian; Wang, Yonghong; Yan, Meixian; Zeng, Dali; Han, Bin; Wu, Chung-I; Shi, Suhua; Li, Jiayang

    2008-01-01

    Asian rice (Oryza sativa) cultivars originated from wild rice and can be divided into two subspecies by several criteria, one of which is the phenol reaction (PHR) phenotype. Grains of indica cultivars turn brown in a phenol solution that accelerates a similar process that occurs during prolonged storage. By contrast, the grains of japonica do not discolor. This distinction may reflect the divergent domestication of these two subspecies. The PHR is controlled by a single gene, Phr1; here, we report the cloning of Phr1, which encodes a polyphenol oxidase. The Phr1 gene is indeed responsible for the PHR phenotype, as transformation with a functional Phr1 can complement a PHR negative cultivar. Phr1 is defective in all japonica lines but functional in nearly all indica and wild strains. Phylogenetic analysis showed that the defects in Phr1 arose independently three times. The multiple recent origins and rapid spread of phr1 in japonica suggest the action of positive selection, which is further supported by several population genetic tests. This case may hence represent an example of artificial selection driving the differentiation among domesticated varieties. PMID:19033526

  19. Independent and Combined Association of Muscle Strength and Cardiorespiratory Fitness in Youth With Insulin Resistance and β-Cell Function in Young Adulthood

    DEFF Research Database (Denmark)

    Grøntved, Anders; Ried-Larsen, Mathias; Ekelund, Ulf

    2013-01-01

    OBJECTIVETo examine the independent and combined association of isometric muscle strength of the abdomen and back and cardiorespiratory fitness (CRF) in youth with indices of glucose metabolism in young adulthood among boys and girls from the European Youth Heart Study.RESEARCH DESIGN AND METHODSWe.......RESULTSFor each 1-SD difference in isometric muscle strength (0.16 N/kg) in youth, fasting insulin, HOMA-IR, and HOMA-B in young adulthood changed with -11.3% (95% CI, -17.0 to -5.2), -12.2% (-18.2 to -5.7), and -8.9% (-14.4 to -3.0), respectively, in young adulthood after adjustment for CRF and personal...... ergometer test. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) and β-cell function (homeostasis model assessment of β-cell function [HOMA-B]) were estimated from fasting serum insulin and glucose that were obtained in youth and at follow-up in young adulthood...

  20. Murine Herc6 Plays a Critical Role in Protein ISGylation In Vivo and Has an ISGylation-Independent Function in Seminal Vesicles.

    Science.gov (United States)

    Arimoto, Kei-ichiro; Hishiki, Takayuki; Kiyonari, Hiroshi; Abe, Takaya; Cheng, Chuyi; Yan, Ming; Fan, Jun-Bao; Futakuchi, Mitsuru; Tsuda, Hiroyuki; Murakami, Yoshiki; Suzuki, Hideyuki; Zhang, Dong-Er; Shimotohno, Kunitada

    2015-05-01

    ISG15 conjugation (ISGylation) to proteins is a multistep process involving interferon (IFN)-inducible UBE1L (E1), UbcH8 (E2), and ISG15 E3 ligases (E3s). Studies performed over the past several years have shown that ISGylation plays a pivotal role in the host antiviral response against certain viruses. Recent in vitro studies revealed that human Herc5 and mouse Herc6 are major ISG15 E3 ligases, respectively. However, the global function of Herc5/6 proteins in vivo still remains unclear. Here, we report generation and initial characterization of Herc6 knockout mice. Substantial reductions of ISGylation were observed in Herc6-deficient cells after polyinosinic-polycytidylic acid double-stranded RNA injection of mice or IFN treatment of cells. On the other hand, Herc6-deficient cells and wild-type (WT) cells had similar responses to IFN stimulation, Sendai virus (Z strain) infection, and vesicular stomatitis virus infection. These results indicate that Herc6 does not play a critical role in antiviral defense of these viral infections in mice. Interestingly, male Herc6-deficient mice showed seminal vesicle hypertrophy. No such problem was detected in WT and ISG15 activating enzyme Ube1L-deficient mice. These results suggest that in addition to promoting protein ISGylation, Herc6 has a novel and protein ISGylation-independent function in the male reproductive system.

  1. Independence in appearance

    DEFF Research Database (Denmark)

    Warming-Rasmussen, Bent; Quick, Reiner; Liempd, Dennis van

    2011-01-01

    article presents research contributions to the question whether the auditor is to continue to provide both audit and non-audit services (NAS) to an audit client. Research results show that this double function for the same audit client is a problem for stakeholders' confidence in auditor independence...

  2. Bi-functional prodrugs of 5-aminolevulinic acid and butyric acid increase erythropoiesis in anemic mice in an erythropoietin-independent manner.

    Science.gov (United States)

    Rephaeli, Ada; Tarasenko, Nataly; Fibach, Eitan; Rozic, Gabriela; Lubin, Ido; Lipovetsky, Julia; Furman, Svetlana; Malik, Zvi; Nudelman, Abraham

    2016-08-25

    Anemia is a major cause of morbidity and mortality worldwide resulting from a wide variety of pathological conditions. In severe cases it is treated by blood transfusions or injection of erythroid stimulating agents, e.g., erythropoietin (Epo), which can be associated with serious adverse effects. Therefore, there is a need to develop new treatment modalities. We recently reported that treatment of erythroleukemic cells with the novel the bi-functional prodrugs of 5-aminolevulinic acid (ALA) and butyric acid (BA), AN233 and AN908, enhanced hemoglobin (Hb) synthesis to a substantially higher level than did ALA and BA individually or their mixture. Herein, we describe that these prodrugs when given orally to mice induced histone deacetylase inhibition in the kidneys, bone marrow and spleen, thus, indicating good penetrability to the tissues. In mice where anemia was chemically induced, treatment with the prodrugs increased the Hb, the number of red blood cells (RBCs) and the percentage of reticulocytes to normal levels. The prodrugs had no adverse effects even after repeated treatment at 100-200mg/kg for 50days. The lack of increased levels of Epo in the blood of mice that were treated with the prodrugs suggests that AN233 and AN908 affected the Hb and RBC levels in an Epo-independent manner. Taken together with our previous studies, we propose that the prodrugs increase globin expression by BA inhibition of histone deacetylase and elevation heme synthesis by ALA. These results support an Epo-independent approach for treating anemia with these prodrugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Peroxisome proliferator-activated receptors (PPARs-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice

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    Wakutsu Masaki

    2010-09-01

    Full Text Available Abstract Background Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. Methods Mice were fed a diet containing 30 en% beef tallow (B diet for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet. Each group was further divided into two groups which were administered PPARα and γ antagonists or vehicle once a day for three weeks. Results The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. Conclusion These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway-independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils.

  4. Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition.

    Science.gov (United States)

    Kelly, Mairead; Trudel, Stephanie; Brouillard, Franck; Bouillaud, Frederick; Colas, Julien; Nguyen-Khoa, Thao; Ollero, Mario; Edelman, Aleksander; Fritsch, Janine

    2010-04-01

    Two highly potent and selective cystic fibrosis (CF) transmembrane regulator (CFTR) inhibitors have been identified by high-throughput screening: the thiazolidinone CFTR(inh)-172 [3-[(3-trifluoromethyl)phenyl]-5-[(4-carboxyphenyl)methylene]- 2-thioxo-4-thiazolidinone] and the glycine hydrazide GlyH-101 [N-(2-naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide]. Inhibition of the CFTR chloride channel by these compounds has been suggested to be of pharmacological interest in the treatment of secretory diarrheas and polycystic kidney disease. In addition, functional inhibition of CFTR by CFTR(inh)-172 has been proposed to be sufficient to mimic the CF inflammatory profile. In the present study, we investigated the effects of the two compounds on reactive oxygen species (ROS) production and mitochondrial membrane potential in several cell lines: the CFTR-deficient human lung epithelial IB3-1 (expressing the heterozygous F508del/W1282X mutation), the isogenic CFTR-corrected C38, and HeLa and A549 as non-CFTR-expressing controls. Both inhibitors were able to induce a rapid increase in ROS levels and depolarize mitochondria in the four cell types, suggesting that these effects are independent of CFTR inhibition. In HeLa cells, these events were associated with a decrease in the rate of oxygen consumption, with GlyH-101 demonstrating a higher potency than CFTR(inh)-172. The impact of CFTR inhibitors on inflammatory parameters was also tested in HeLa cells. CFTR(inh)-172, but not GlyH-101, induced nuclear translocation of nuclear factor-kappaB (NF-kappaB). CFTR(inh)-172 slightly decreased interleukin-8 secretion, whereas GlyH-101 induced a slight increase. These results support the conclusion that CFTR inhibitors may exert nonspecific effects regarding ROS production, mitochondrial failure, and activation of the NF-kappaB signaling pathway, independently of CFTR inhibition.

  5. Niemann-Pick C1 Functions Independently of Niemann-Pick C2 in the Initial Stage of Retrograde Transport of Membrane-impermeable Lysosomal Cargo*

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    Goldman, Stephen D. B.; Krise, Jeffrey P.

    2010-01-01

    The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [3H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo. PMID:20007703

  6. Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo.

    Science.gov (United States)

    Goldman, Stephen D B; Krise, Jeffrey P

    2010-02-12

    The rare neurodegenerative disease Niemann-Pick Type C (NPC) results from mutations in either NPC1 or NPC2, which are membrane-bound and soluble lysosomal proteins, respectively. Previous studies have shown that mutations in either protein result in biochemically indistinguishable phenotypes, most notably the hyper-accumulation of cholesterol and other cargo in lysosomes. We comparatively evaluated the kinetics of [(3)H]dextran release from lysosomes of wild type, NPC1, NPC2, and NPC1/NPC2 pseudo-double mutant cells and found significant differences between all cell types examined. Specifically, NPC1 or NPC2 mutant fibroblasts treated with NPC1 or NPC2 siRNA (to create NPC1/NPC2 pseudo-double mutants) secreted dextran less efficiently than did either NPC1 or NPC2 single mutant cell lines, suggesting that the two proteins may work independently of one another in the egress of membrane-impermeable lysosomal cargo. To investigate the basis for these differences, we examined the role of NPC1 and NPC2 in the retrograde fusion of lysosomes with late endosomes to create so-called hybrid organelles, which is believed to be the initial step in the egress of cargo from lysosomes. We show here that cells with mutated NPC1 have significantly reduced rates of late endosome/lysosome fusion relative to wild type cells, whereas cells with mutations in NPC2 have rates that are similar to those observed in wild type cells. Instead of being involved in hybrid organelle formation, we show that NPC2 is required for efficient membrane fission events from nascent hybrid organelles, which is thought to be required for the reformation of lysosomes and the release of lysosomal cargo-containing membrane vesicles. Collectively, these results suggest that NPC1 and NPC2 can function independently of one another in the egress of certain membrane-impermeable lysosomal cargo.

  7. RNA Polymerase V Functions in Arabidopsis Interphase Heterochromatin Organization Independently of the 24-nt siRNA-Directed DNA Methylation Pathway

    Institute of Scientific and Technical Information of China (English)

    Olga Pontes; Pedro Costa-Nunes; Paul Vithayathil; Craig S.Pikaard

    2009-01-01

    In Arabidopsis,pericentromeric repeats,retroelements,and silenced rRNA genes are assembled into heterochromatin within nuclear structures known as chromocenters.The mechanisms governing higher-order heterochromatin organization are poorly understood but 24-nt small interfering RNAs (siRNAs) are known to play key roles in heterochromatin formation.Nuclear RNA polymerase IV (Pol IV),RNA-DEPENDENT RNA POLYMERASE 2 (RDR2),and DICER-LIKE 3 (DCL3) are required for biogenesis of 24-nt siRNAs that associate with ARGONAUTE 4 (AGO4).Nuclear RNA polymerase V (Pol V) collaborates with DRD1 (DEFICIENT IN RNA-DEPENDENT DNA METHYLATION 1) to generate transcripts at heterochromatic loci that are hypothesized to bind to siRNA-AGO4 complexes and subsequently recruit the de-novo DNA methylation and/or histone modifying machinery.Here,we report that decondensation of the major pericentromeric repeats and depletion of the heterochromatic mark histone H3 lysine 9 dimethylation at chromocenters occurs specifically in pol V and drd1 mutants.Disruption of pericentromeric repeats condensation is coincident with transcriptional reactivation of specific classes of pericentromeric 180-bp repeats.We further demonstrate that Pol V functions independently of Pol IV,RDR2,and DCL3-mediated siRNA production to affect interphase heterochromatin organization,possibly by involving RNAs that recruit structural or chromatin-modifying proteins.

  8. Podocyturia parallels proximal tubule dysfunction in type 2 diabetes mellitus patients independently of albuminuria and renal function decline: A cross-sectional study.

    Science.gov (United States)

    Petrica, Ligia; Vlad, Mihaela; Vlad, Adrian; Gluhovschi, Gheorghe; Gadalean, Florica; Dumitrascu, Victor; Popescu, Roxana; Gluhovschi, Cristina; Matusz, Petru; Velciov, Silvia; Bob, Flaviu; Ursoniu, Sorin; Vlad, Daliborca

    2017-09-01

    Detection of podocytes in the urine of patients with type 2 diabetes may indicate severe injury to the podocytes. In the course of type 2 diabetes the proximal tubule is involved in urinary albumin processing. We studied the significance of podocyturia in relation with proximal tubule dysfunction in type 2 diabetes. A total of 86 patients with type 2 diabetes (34-normoalbuminuria; 30-microalbuminuria; 22-macroalbuminuria) and 28 healthy subjects were enrolled in the study and assessed concerning urinary podocytes, podocyte-associated molecules, and biomarkers of proximal tubule dysfunction. Urinary podocytes were examined in cell cultures by utilizing monoclonal antibodies against podocalyxin and synaptopodin. Podocytes were detected in the urine of 10% of the healthy controls, 24% of the normoalbuminuric, 40% of the microalbuminuric, and 82% of the macroalbuminuric patients. In multivariate logistic regression analysis, urinary podocytes correlated with urinary albumin:creatinine ratio (p=0.006), urinary nephrin/creat (p=0.001), urinary vascular endothelial growth factor/creat (p=0.001), urinary kidney injury molecule-1/creat (p=0.003), cystatin C (p=0.001), urinary advanced glycation end-products (p=0.002), eGFR (p=0.001). In patients with type 2 diabetes podocyturia parallels proximal tubule dysfunction independently of albuminuria and renal function decline. Advanced glycation end-products may impact the podocytes and the proximal tubule. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Physical exercise and functional fitness in independently living vs institutionalized elderly women: a comparison of 60- to 79-year-old city dwellers.

    Science.gov (United States)

    Furtado, Hélio L; Sousa, Nelson; Simão, Roberto; Pereira, Fabio Dutra; Vilaça-Alves, José

    2015-01-01

    To compare functional fitness (FF) levels among independent-living (IL) and day care (DC) elderly women of different age groups and to analyze changes in FF after 8 months of participation in an exercise program intervention for the IL elderly women. A total of 674 elderly women were divided into four IL groups with age in the range of 60-64 years (IL60-64, n=149), 65-69 years (IL65-69, n=138), 70-74 years (IL70-74, n=135), and 75-79 years (IL75-79, n=83), and four DC groups with age in the range of 60-64 years (DC60-64, n=35), 65-69 years (DC65-69, n=34), 70-74 years (DC70-74, n=47), and 75-79 years (DC75-79, n=53). The intervention consisted of a multimodal exercise training, 3 days per week for 8 months. Senior Fitness Test battery performances were obtained at baseline and after 8-month intervention. Significant differences were identified between all IL groups and DC groups in all FF tests (Pelderly women. The multimodal training was effective in improving all FF components related to daily living activities, in all age groups. In contrast, institutionalized elderly showed a clear tendency to worsen their FF over the time.

  10. Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors.

    Science.gov (United States)

    Gillis, Joanna L; Selth, Luke A; Centenera, Margaret M; Townley, Scott L; Sun, Shihua; Plymate, Stephen R; Tilley, Wayne D; Butler, Lisa M

    2013-05-01

    The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.

  11. Excess pressure integral predicts cardiovascular events independent of other risk factors in the conduit artery functional evaluation substudy of Anglo-Scandinavian Cardiac Outcomes Trial.

    Science.gov (United States)

    Davies, Justin E; Lacy, Peter; Tillin, Therese; Collier, David; Cruickshank, J Kennedy; Francis, Darrel P; Malaweera, Anura; Mayet, Jamil; Stanton, Alice; Williams, Bryan; Parker, Kim H; McG Thom, Simon A; Hughes, Alun D

    2014-07-01

    Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.

  12. JAK2 inhibitor combined with DC-activated AFP-specific T-cells enhances tantitumor function in a Fas/FasL signal-independent pathway

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    Liu Y

    2016-07-01

    Full Text Available Yang Liu,1 Yue-ru Wang,2 Guang-hui Ding,1 Ting-song Yang,1 Le Yao,1 Jie Hua,1 Zhi-gang He,1 Ming-ping Qian1 1Department of Hepatobiliary Surgery, Shanghai 10th People’s Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of China; 2Department of Infection, Shanghai First People’s Hospital Affiliated to Jiaotong University, Shanghai, People’s Republic of China Objective: Combination therapy for cancer is more effective than using only standard chemo- or radiotherapy. Our previous results showed that dendritic cell-activated α-fetoprotein (AFP-specific T-cells inhibit tumor in vitro and in vivo. In this study, we focused on antitumor function of CD8+ T-cells combined with or without JAK2 inhibitor. Methods: Proliferation and cell cycle were analyzed by CCK-8 and flow cytometry. Western blot was used to analyze the expression level of related protein and signaling pathway. Results: We demonstrated reduced viability and induction of apoptosis of tumor cells with combination treatment. Intriguingly, cell cycle was blocked at the G1 phase by using AFP-specific CD8+ T-cells combined with JAK2 inhibitor (AG490. Furthermore, an enhanced expression of BAX but no influence on Fas/FasL was detected from the tumor cells. Conclusion: These results indicate a Fas/FasL-independent pathway for cellular apoptosis in cancer therapies with the treatment of AFP-specific CD8+ T-cells combined with JAK2 inhibitor. Keywords: AFP-specific CD8+ T-cells, JAK2 inhibitor, Fas/FasL signal, antitumor, apoptosis 

  13. Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations

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    McMillan, Brian J.; Zimmerman, Brandon; Egan, Emily D.; Lofgren, Michael; Xu, Xiang; Hesser, Anthony; Blacklow, Stephen C.

    2017-03-17

    Protein O-fucosyltransferase-1 (POFUT1), which transfers fucose residues to acceptor sites on serine and threonine residues of epidermal growth factor-like repeats of recipient proteins, is essential for Notch signal transduction in mammals. Here, we examine the consequences of POFUT1 loss on the oncogenic signaling associated with certain leukemia-associated mutations of human Notch1, report the structures of human POFUT1 in free and GDP-fucose bound states, and assess the effects of Dowling-Degos mutations on human POFUT1 function. CRISPR-mediated knockout of POFUT1 in U2OS cells suppresses both normal Notch1 signaling, and the ligand-independent signaling associated with leukemogenic mutations of Notch1. Normal and oncogenic signaling are rescued by wild-type POFUT1 but rescue is impaired by an active-site R240A mutation. The overall structure of the human enzyme closely resembles that of the Caenorhabditis elegans protein, with an overall backbone RMSD of 0.93 Å, despite primary sequence identity of only 39% in the mature protein. GDP-fucose binding to the human enzyme induces limited backbone conformational movement, though the side chains of R43 and D244 reorient to make direct contact with the fucose moiety in the complex. The reported Dowling-Degos mutations of POFUT1, except for M262T, fail to rescue Notch1 signaling efficiently in the CRISPR-engineered POFUT1-/- background. Together, these studies identify POFUT1 as a potential target for cancers driven by Notch1 mutations and provide a structural roadmap for its inhibition.

  14. Two components of the new ESPEN diagnostic criteria for malnutrition are independent predictors of lung function in hospitalized patients with chronic obstructive pulmonary disease (COPD).

    Science.gov (United States)

    Ingadottir, Arora Ros; Beck, Anne Marie; Baldwin, Christine; Weekes, C Elizabeth; Geirsdottir, Olof Gudny; Ramel, Alfons; Gislason, Thorarinn; Gunnarsdottir, Ingibjorg

    2017-06-08

    Low fat free mass index (FFMI) is a component of the ESPEN diagnosis criteria of malnutrition, that only when accompanied with weight loss is considered to be a determinant of malnutrition. Our aims were to assess the prevalence of malnutrition in patients with chronic obstructive pulmonary disease (COPD) applying the ESPEN criteria, and to examine the ability of different components of the criteria to predict COPD severity, length of stay (LOS), hospital readmissions within 30 days and mortality. Subjects were COPD patients (n = 121) admitted to Landspitali University Hospital from March 2015 to March 2016. Patients were screened for nutritional risk using Icelandic screening tool (ISS) and NRS-2002. Body composition was measured by bioelectrical impedance analysis (BIA). Lung function was measured by spirometry. The prevalence of malnutrition according to the ESPEN criteria was 21%. The association between nutritional assessment, applying different components of the ESPEN criteria, and COPD severity was highly significant, with the highest risk being associated with low FFMI OR (95% CI) 4.77 (2.03, 11.20; p 7 days in subjects with low FFMI (OR 2.46 95% CI 0.92, 6.59; p = 0.074) and increased risk of 6 and 9 months' mortality (OR 2.72 95% CI 0.88, 8.39, P = 0.082 and OR 2.72 95% CI 0.94, 7.87, P = 0.065, respectively) in subjects diagnosed as malnourished by the ESPEN criteria. This study describes the prevalence of malnutrition in hospitalized COPD patients using the ESPEN criteria from 2015. Our findings suggest that FFMI could be used independently of weight loss for the diagnosis of malnutrition in COPD patients, although there remain some problems associated with its measurement in the clinical setting. Copyright © 2017 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  15. A Comparison between Two Instruments for Assessing Dependency in Daily Activities: Agreement of the Northwick Park Dependency Score with the Functional Independence Measure

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    Siv Svensson

    2012-01-01

    Full Text Available Background. There is a need for tools to assess dependency among persons with severe impairments. Objectives. The aim was to compare the Functional Independence Measure (FIM and the Northwick Park Dependency Score (NPDS, in a sample from in-patient rehabilitation. Material and Methods. Data from 115 persons (20 to 65 years of age with neurological impairments was gathered. Analyses were made of sensitivity, specificity, positive predictive value, and negative predictive value. Agreement of the scales was assessed with kappa and concordance with Goodman-Kruskal’s gamma. Scale structures were explored using the Rank-Transformable Pattern of Agreement (RTPA. Content validation was performed. Results. The sensitivity of the NPDS as compared to FIM varied between 0.53 (feeding and 1.0 (mobility and specificity between 0.64 (mobility and 1.0 (bladder. The positive predictive value varied from 0.62 (mobility to 1.0 (bladder, and the negative predictive value varied from 0.48 (bowel to 1.0 (mobility. Agreement between the scales was moderate to good (four items and excellent (three items. Concordance was good, with a gamma of −.856, an asymptotic error (ase of .025, and P<.000. The parallel reliability between the FIM and the NPDS showed a tendency for NPDS to be more sensitive (having more categories when dependency is high. Conclusion. FIM and NPDS complement each other. NPDS can be used as a measure for severely injured patients who are sensitive when there is a high need of nursing time.

  16. Telomerase inhibition targets clonogenic multiple myeloma cells through telomere length-dependent and independent mechanisms.

    Directory of Open Access Journals (Sweden)

    Sarah K Brennan

    Full Text Available BACKGROUND: Plasma cells constitute the majority of tumor cells in multiple myeloma (MM but lack the potential for sustained clonogenic growth. In contrast, clonotypic B cells can engraft and recapitulate disease in immunodeficient mice suggesting they serve as the MM cancer stem cell (CSC. These tumor initiating B cells also share functional features with normal stem cells such as drug resistance and self-renewal potential. Therefore, the cellular processes that regulate normal stem cells may serve as therapeutic targets in MM. Telomerase activity is required for the maintenance of normal adult stem cells, and we examined the activity of the telomerase inhibitor imetelstat against MM CSC. Moreover, we carried out both long and short-term inhibition studies to examine telomere length-dependent and independent activities. METHODOLOGY/PRINCIPAL FINDINGS: Human MM CSC were isolated from cell lines and primary clinical specimens and treated with imetelstat, a specific inhibitor of the reverse transcriptase activity of telomerase. Two weeks of exposure to imetelstat resulted in a significant reduction in telomere length and the inhibition of clonogenic MM growth both in vitro and in vivo. In addition to these relatively long-term effects, 72 hours of imetelstat treatment inhibited clonogenic growth that was associated with MM CSC differentiation based on expression of the plasma cell antigen CD138 and the stem cell marker aldehyde dehydrogenase. Short-term treatment of MM CSC also decreased the expression of genes typically expressed by stem cells (OCT3/4, SOX2, NANOG, and BMI1 as revealed by quantitative real-time PCR. CONCLUSIONS: Telomerase activity regulates the clonogenic growth of MM CSC. Moreover, reductions in MM growth following both long and short-term telomerase inhibition suggest that it impacts CSC through telomere length-dependent and independent mechanisms.

  17. Physical exercise and functional fitness in independently living vs institutionalized elderly women: a comparison of 60- to 79-year-old city dwellers

    Science.gov (United States)

    Furtado, Hélio L; Sousa, Nelson; Simão, Roberto; Pereira, Fabio Dutra; Vilaça-Alves, José

    2015-01-01

    Purpose To compare functional fitness (FF) levels among independent-living (IL) and day care (DC) elderly women of different age groups and to analyze changes in FF after 8 months of participation in an exercise program intervention for the IL elderly women. Materials and methods A total of 674 elderly women were divided into four IL groups with age in the range of 60–64 years (IL60–64, n=149), 65–69 years (IL65–69, n=138), 70–74 years (IL70–74, n=135), and 75–79 years (IL75–79, n=83), and four DC groups with age in the range of 60–64 years (DC60–64, n=35), 65–69 years (DC65–69, n=34), 70–74 years (DC70–74, n=47), and 75–79 years (DC75–79, n=53). The intervention consisted of a multimodal exercise training, 3 days per week for 8 months. Senior Fitness Test battery performances were obtained at baseline and after 8-month intervention. Results Significant differences were identified between all IL groups and DC groups in all FF tests (P<0.001), except between IL70–74 and DC70–74 in the chair sit-and-reach. Analysis of covariance (ANCOVA) identified significant improvements in all FF tests between pre- and posttests in the IL groups (P<0.001), except in the chair sit-and-reach for the IL70–74. ANCOVA also showed a significant declining performance in all FF tests for DC groups (P<0.001), except in the chair sit-and-reach for the DC70–74 and DC75–79. Conclusion IL women are more fit than institutionalized DC elderly women. The multimodal training was effective in improving all FF components related to daily living activities, in all age groups. In contrast, institutionalized elderly showed a clear tendency to worsen their FF over the time. PMID:25941443

  18. Measurement of decline of functioning in persons with amyotrophic lateral sclerosis: responsiveness and possible applications of the Functional Independence Measure, Barthel Index, Rehabilitation Activities Profile and Frenchay Activities Index.

    Science.gov (United States)

    De Groot, Imelda J M; Post, Marcel W M; Van Heuveln, Tineke; Van Den Berg, Leonard H; Lindeman, Eline

    2006-09-01

    It is important not only to monitor the functional change during the course of ALS, but also to determine whether or not the available help is sufficient. This study was performed to determine which generic assessment instrument is most appropriate. A multicentre cohort of patients with ALS was followed for one year. At baseline, six months, and 1 year four instruments were used: Functional Independence Measure (FIM), Rehabilitation Activities Profile (RAP), Barthel Index (BI), and Frenchay Activities Index (FAI). The responsiveness of the measures was examined using effect sizes and standardized response mean statistics. Seventy-three patients at baseline, 63 after six months and 43 after one year were assessed. If calculated on the group that completed all three assessments, the FIM, BI, and RAP showed moderate effect sizes and standardized response means over a period of six months and large effect sizes over 12 months. Based on their responsiveness FIM, BI, and RAP can be used to evaluate limitations in activities and care needs of persons with ALS and to evaluate treatment results in trials. The FIM was the most responsive instrument, although the BI might be easier to use in clinical practice.

  19. Kinome wide functional screen identifies role of Polo-like kinase 1 (PLK1) in hormone-independent, ER-positive breast cancer

    Science.gov (United States)

    Bhola, Neil; Jansen, Valerie M.; Bafna, Sangeeta; Giltnane, Jennifer M.; Balko, Justin M.; Estrada, Mónica V.; Meszoely, Ingrid; Mayer, Ingrid; Abramson, Vandana; Ye, Fei; Sanders, Melinda; Dugger, Teresa C.; Van Allen, Eliezer; Arteaga, Carlos L.

    2014-01-01

    Estrogen receptor α (ER)-positive breast cancers initially respond to antiestrogens but eventually become estrogen-independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki67 score in primary ER+ breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacological inhibition of PLK1 with volasertib, a small molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared to parental MCF7 cells. Further, JUNB and BCL2L1 (which encodes anti-apoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER+ human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy. PMID:25480943

  20. Tiotropium improves lung function, exacerbation rate, and asthma control, independent of baseline characteristics including age, degree of airway obstruction, and allergic status

    DEFF Research Database (Denmark)

    Kerstjens, Huib A M; Moroni-Zentgraf, Petra; Tashkin, Donald P

    2016-01-01

    exacerbations and asthma worsening, and improved asthma symptom control, independent of a broad range of baseline characteristics, as add-on to ICS plus LABAs in patients with severe symptomatic asthma. TRIAL REGISTRY: ClinicalTrials.gov; numbers NCT00772538 and NCT00776984 URL: www.clinicaltrials.gov....

  1. Change in body fat mass is independently associated with executive functions in older women: a secondary analysis of a 12-month randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Elizabeth Dao

    Full Text Available OBJECTIVES: To investigate the independent contribution of change in sub-total body fat and lean mass to cognitive performance, specifically the executive processes of selective attention and conflict resolution, in community-dwelling older women. METHODS: This secondary analysis included 114 women aged 65 to 75 years old. Participants were randomly allocated to once-weekly resistance training, twice-weekly resistance training, or twice-weekly balance and tone training. The primary outcome measure was the executive processes of selective attention and conflict resolution as assessed by the Stroop Test. Sub-total body fat and lean mass were measured by dual-energy x-ray absorptiometry (DXA to determine the independent association of change in both sub-total body fat and sub-total body lean mass with Stroop Test performance at trial completion. RESULTS: A multiple linear regression model showed reductions in sub-total body fat mass to be independently associated with better performance on the Stroop Test at trial completion after accounting for baseline Stroop performance, age, baseline global cognitive state, baseline number of comorbidities, baseline depression, and experimental group. The total variance explained was 39.5%; change in sub-total body fat mass explained 3.9% of the variance. Change in sub-total body lean mass was not independently associated with Stroop Test performance (P>0.05. CONCLUSION: Our findings suggest that reductions in sub-total body fat mass - not sub-total lean mass - is associated with better performance of selective attention and conflict resolution.

  2. Long-term adherence to exercise: the relationship with functional fitness and personal motivation among community-dwelling independent-living older women

    Directory of Open Access Journals (Sweden)

    Philipe de Souto BarretoI

    2011-03-01

    Full Text Available OBJECTIVE: The aim of this study were to examine the relationships between functional fitness, self-esteem, aesthetic body care and long-term adherence to dance, and to identify other characteristics related to dance adherence in the elderly. METHODS: Seventeen women, aged 59-86 years-old, who practised a type of dance labeled "bodily expression". RESULTS: Functional fitness was correlated to dance adherence and was the only factor related to this variable in a linear regression analysis. Self-esteem and aesthetic body care seemed to play an indirect role on adherence. Functional fitness, specially upper-body flexibility and lower-body muscular function, and interest in dance (qualitative data were related to long-term adherence to dance. CONCLUSIONS: Functional fitness and interest in exercising were the main aspects related to participants' long-term adherence to dance.

  3. Neuromuscular adaptations predict functional disability independently of clinical pain and psychological factors in patients with chronic non-specific low back pain.

    Science.gov (United States)

    Dubois, Jean-Daniel; Abboud, Jacques; St-Pierre, Charles; Piché, Mathieu; Descarreaux, Martin

    2014-08-01

    Patients with chronic low back pain exhibit characteristics such as clinical pain, psychological symptoms and neuromuscular adaptations. The purpose of this study was to determine the independent contribution of clinical pain, psychological factors and neuromuscular adaptations to disability in patients with chronic low back pain. Clinical pain intensity, pain catastrophizing, fear-avoidance beliefs, anxiety, neuromuscular adaptations to chronic pain and neuromuscular responses to experimental pain were assessed in 52 patients with chronic low back pain. Lumbar muscle electromyographic activity was assessed during a flexion-extension task (flexion relaxation phenomenon) to assess both chronic neuromuscular adaptations and neuromuscular responses to experimental pain during the task. Multiple regressions showed that independent predictors of disability included neuromuscular adaptations to chronic pain (β=0.25, p=0.006, sr(2)=0.06), neuromuscular responses to experimental pain (β=-0.24, p=0.011, sr(2)=0.05), clinical pain intensity (β=0.28, p=0.002, sr(2)=0.08) and psychological factors (β=0.58, ppain intensity and psychological factors, and contribute to inter-individual differences in patients' disability. This suggests that disability, in chronic low back pain patients, is determined by a combination of factors, including clinical pain, psychological factors and neuromuscular adaptations. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Zebrafish colgate/hdac1 functions in the non-canonical Wnt pathway during axial extension and in Wnt-independent branchiomotor neuron migration.

    Science.gov (United States)

    Nambiar, Roopa M; Ignatius, Myron S; Henion, Paul D

    2007-01-01

    Vertebrate gastrulation involves the coordinated movements of populations of cells. These movements include cellular rearrangements in which cells polarize along their medio-lateral axes leading to cell intercalations that result in elongation of the body axis. Molecular analysis of this process has implicated the non-canonical Wnt/Frizzled signaling pathway that is similar to the planar cell polarity pathway (PCP) in Drosophila. Here we describe a zebrafish mutant, colgate (col), which displays defects in the extension of the body axis and the migration of branchiomotor neurons. Activation of the non-canonical Wnt/PCP pathway in these mutant embryos by overexpressing DeltaNdishevelled, rho kinase2 and van gogh-like protein 2 (vangl2) rescues the extension defects suggesting that col acts as a positive regulator of the non-canonical Wnt/PCP pathway. Further, we show that col normally regulates the caudal migration of nVII facial hindbrain branchiomotor neurons and that the mutant phenotype can be rescued by misexpression of vangl2 independent of the Wnt/PCP pathway. We cloned the col locus and found that it encodes histone deacetylase1 (hdac1). Our previous results and studies by others have implicated hdac1 in repressing the canonical Wnt pathway. Here, we demonstrate novel roles for zebrafish hdac1 in activating non-canonical Wnt/PCP signaling underlying axial extension and in promoting Wnt-independent caudal migration of a subset of hindbrain branchiomotor neurons.

  5. Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21(WAF1/Cip1)-dependent mechanism independent of functional p53.

    Science.gov (United States)

    Fecteau, Jessie-F; Corral, Laura G; Ghia, Emanuela M; Gaidarova, Svetlana; Futalan, Diahnn; Bharati, Ila Sri; Cathers, Brian; Schwaederlé, Maria; Cui, Bing; Lopez-Girona, Antonia; Messmer, Davorka; Kipps, Thomas J

    2014-09-04

    Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin-4 and -10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor, p21(WAF1/Cip1) (p21). Silencing p21 with small interfering RNA impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon, a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3. We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells were also induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a cereblon/p21-dependent but p53-independent manner, at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL.

  6. Lenalidomide inhibits the proliferation of CLL cells via a cereblon/p21WAF1/Cip1-dependent mechanism independent of functional p53

    Science.gov (United States)

    Fecteau, Jessie-F.; Corral, Laura G.; Ghia, Emanuela M.; Gaidarova, Svetlana; Futalan, Diahnn; Bharati, Ila Sri; Cathers, Brian; Schwaederlé, Maria; Cui, Bing; Lopez-Girona, Antonia; Messmer, Davorka

    2014-01-01

    Lenalidomide has demonstrated clinical activity in patients with chronic lymphocytic leukemia (CLL), even though it is not cytotoxic for primary CLL cells in vitro. We examined the direct effect of lenalidomide on CLL-cell proliferation induced by CD154-expressing accessory cells in media containing interleukin-4 and -10. Treatment with lenalidomide significantly inhibited CLL-cell proliferation, an effect that was associated with the p53-independent upregulation of the cyclin-dependent kinase inhibitor, p21WAF1/Cip1 (p21). Silencing p21 with small interfering RNA impaired the capacity of lenalidomide to inhibit CLL-cell proliferation. Silencing cereblon, a known molecular target of lenalidomide, impaired the capacity of lenalidomide to induce expression of p21, inhibit CD154-induced CLL-cell proliferation, or enhance the degradation of Ikaros family zinc finger proteins 1 and 3. We isolated CLL cells from the blood of patients before and after short-term treatment with low-dose lenalidomide (5 mg per day) and found the leukemia cells were also induced to express p21 in vivo. These results indicate that lenalidomide can directly inhibit proliferation of CLL cells in a cereblon/p21-dependent but p53-independent manner, at concentrations achievable in vivo, potentially contributing to the capacity of this drug to inhibit disease-progression in patients with CLL. PMID:24990888

  7. ZmCPK1, a calcium-independent kinase member of the Zea mays CDPK gene family, functions as a negative regulator in cold stress signalling.

    Science.gov (United States)

    Weckwerth, Philipp; Ehlert, Britta; Romeis, Tina

    2015-03-01

    Calcium-dependent protein kinases (CDPKs) have been shown to play important roles in plant environmental stress signal transduction. We report on the identification of ZmCPK1 as a member of the maize (Zea mays) CDPK gene family involved in the regulation of the maize cold stress response. Based upon in silico analysis of the Z. mays cv. B73 genome, we identified that the maize CDPK gene family consists of 39 members. Two CDPK members were selected whose gene expression was either increased (Zmcpk1) or decreased (Zmcpk25) in response to cold exposure. Biochemical analysis demonstrated that ZmCPK1 displays calcium-independent protein kinase activity. The C-terminal calcium-binding domain of ZmCPK1 was sufficient to mediate calcium independency of a previously calcium-dependent enzyme in chimeric ZmCPK25-CPK1 proteins. Furthermore, co-transfection of maize mesophyll protoplasts with active full-length ZmCPK1 suppressed the expression of a cold-induced marker gene, Zmerf3 (ZmCOI6.21). In accordance, heterologous overexpression of ZmCPK1 in Arabidopsis thaliana yielded plants with altered acclimation-induced frost tolerance. Our results identify ZmCPK1 as a negative regulator of cold stress signalling in maize.

  8. Long-term adherence to exercise: the relationship with functional fitness and personal motivation among community-dwelling independent-living older women

    OpenAIRE

    Philipe de Souto BarretoI; Jose Carlos Jaenes Sanchez

    2011-01-01

    OBJECTIVE: The aim of this study were to examine the relationships between functional fitness, self-esteem, aesthetic body care and long-term adherence to dance, and to identify other characteristics related to dance adherence in the elderly. METHODS: Seventeen women, aged 59-86 years-old, who practised a type of dance labeled "bodily expression". RESULTS: Functional fitness was correlated to dance adherence and was the only factor related to this variable in a linear regression analysis. Sel...

  9. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes

    DEFF Research Database (Denmark)

    Klausen, Klaus; Borch-Johnsen, Knut; Feldt-Rasmussen, Bo

    2004-01-01

    BACKGROUND: The aim of this study was to assess the level of urinary albumin excretion (microalbuminuria), which is associated with increased risk of coronary heart disease and death, in the population. Microalbuminuria has been suggested as an atherosclerotic risk factor. However, the lower cutoff...... excretion above the upper quartile, ie, 4.8 microg/min, was associated with increased risk of coronary heart disease (RR, 2.0; 95% CI, 1.4 to 3.0; Pdiabetes mellitus, hypertension, and plasma...... lipids. Lower levels of urinary albumin excretion were not associated with increased risk. CONCLUSIONS: Microalbuminuria, defined as urinary albumin excretion >4.8 microg/min (corresponding to approximately 6.4 microg/min during daytime), is a strong and independent determinant of coronary heart disease...

  10. Introduction to algebraic independence theory

    CERN Document Server

    Philippon, Patrice

    2001-01-01

    In the last five years there has been very significant progress in the development of transcendence theory. A new approach to the arithmetic properties of values of modular forms and theta-functions was found. The solution of the Mahler-Manin problem on values of modular function j(tau) and algebraic independence of numbers pi and e^(pi) are most impressive results of this breakthrough. The book presents these and other results on algebraic independence of numbers and further, a detailed exposition of methods created in last the 25 years, during which commutative algebra and algebraic geometry exerted strong catalytic influence on the development of the subject.

  11. Frame independent cosmological perturbations

    Energy Technology Data Exchange (ETDEWEB)

    Prokopec, Tomislav; Weenink, Jan, E-mail: t.prokopec@uu.nl, E-mail: j.g.weenink@uu.nl [Institute for Theoretical Physics and Spinoza Institute, Utrecht University, Leuvenlaan 4, 3585 CE Utrecht (Netherlands)

    2013-09-01

    We compute the third order gauge invariant action for scalar-graviton interactions in the Jordan frame. We demonstrate that the gauge invariant action for scalar and tensor perturbations on one physical hypersurface only differs from that on another physical hypersurface via terms proportional to the equation of motion and boundary terms, such that the evolution of non-Gaussianity may be called unique. Moreover, we demonstrate that the gauge invariant curvature perturbation and graviton on uniform field hypersurfaces in the Jordan frame are equal to their counterparts in the Einstein frame. These frame independent perturbations are therefore particularly useful in relating results in different frames at the perturbative level. On the other hand, the field perturbation and graviton on uniform curvature hypersurfaces in the Jordan and Einstein frame are non-linearly related, as are their corresponding actions and n-point functions.

  12. Left ventricular dyssynchrony assessed by gated SPECT phase analysis is an independent predictor of death in patients with advanced coronary artery disease and reduced left ventricular function not undergoing cardiac resynchronization therapy

    Energy Technology Data Exchange (ETDEWEB)

    Uebleis, Christopher; Hellweger, Stefan; Lehner, Sebastian; Haug, Alexander; Bartenstein, Peter; Cumming, Paul; Hacker, Marcus [Ludwig-Maximilians University, Department of Nuclear Medicine, Munich (Germany); Laubender, Ruediger Paul [Ludwig-Maximilians University, Institute of Medical Informatics, Biometry, and Epidemiology (IBE), Munich (Germany); Becker, Alexander [Ludwig-Maximilians University, Medical Department I, Munich (Germany); Sohn, Hae-Young [Ludwig-Maximilians University, Medical Department Innenstadt, Munich (Germany); Van Kriekinge, Serge D.; Slomka, Piotr J. [Cedars-Sinai Medical Center, Los Angeles, CA (United States); UCLA, David Geffen School of Medicine, Los Angeles, CA (United States)

    2012-10-15

    Left ventricular (LV) mechanical dyssynchrony (LVMD) was assessed by gated single-photon emission CT myocardial perfusion imaging (MPI) as an independent predictor of death from any cause in patients with known coronary artery disease (CAD) and reduced LV function. Between 2001 and 2010, 135 patients (64 {+-} 11 years of age, 84 % men) with known CAD, reduced LV ejection fraction (LVEF, 38 {+-} 15 %) and without an implanted cardiac resynchronization therapy device underwent gated MPI at rest. LV functional evaluation, which included phase analysis, was conducted to identify patients with LVMD. Kaplan-Meier survival curves were calculated for death of any cause during a mean follow-up of 2.0 {+-} 1.7 years. Uni- and multivariate Cox proportional hazards regression models were calculated to identify independent predictors of death from any cause. Of the 135 patients, 30 (22 %) died during follow-up (18 cardiac deaths and 12 deaths from other causes). Kaplan-Meier curves showed a significantly shorter survival time in the patients with severely reduced LVEF (<30 %, n = 45) or with LVMD (n = 81, log-rank test P <0.005). Cox models identified LVMD, LVEF <30 % and a total perfusion deficit at rest of {>=}20 % as independent predictors of death from any cause. While patients with LVEF <30 % in conjunction with LVMD had similar survival times irrespective of whether they had early revascularization or medical therapy, those patients with LVEF {>=}30% and LVMD who underwent revascularization had significantly longer survival. In patients with known CAD and reduced LV function, dyssynchrony of the LV is an independent predictor of death from any cause. (orig.)

  13. Kidney transplantation improves arterial function measured by pulse wave analysis and endothelium-independent dilatation in uraemic patients despite deterioration of glucose metabolism

    DEFF Research Database (Denmark)

    Hornum, Mads; Clausen, Peter; Idorn, Thomas

    2011-01-01

    BACKGROUND: The aim of this study is to investigate the effect of kidney transplantation on arterial function in relation to changes in glucose metabolism. METHODS: Included were 40 kidney recipients (Tx group, age 38 ± 13 years) and 40 patients without known diabetes remaining on the waiting list...... for kidney transplantation (uraemic control group, age 47 ± 11 years). Arterial function was estimated by the pulse wave velocity (PWV) of the carotid-femoral pulse wave, aortic augmentation index (AIX), flow-mediated (FMD) and nitroglycerin-induced vasodilatation (NID) of the brachial artery performed...... before transplantation and after 12 months. PWV recorded sequentially at the carotid and femoral artery is an estimate of arterial stiffness; AIX is an integrated index of vascular and ventricular function. FMD and NID are the dilatory capacities of the brachial artery after increased flow (endothelium...

  14. The Drosophila U2 snRNP protein U2A′ has an essential function that is SNF/U2B″ independent

    OpenAIRE

    Nagengast, Alexis A.; Salz, Helen K.

    2001-01-01

    Recruitment of the U2 snRNP to the pre-mRNA is an essential step in spliceosome assembly. Although the protein components of the U2 snRNP have been identified, their individual contributions to function are poorly defined. In vitro studies with the Drosophila and human proteins suggest that two of the U2 snRNP-specific proteins, U2A′ and U2B″, function exclusively as a dimer. In Drosophila the presence of the U2B″ counterpart, Sans-Fille (SNF), in the U2 snRNP ...

  15. Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons.

    Science.gov (United States)

    Saloman, Jami L; Scheff, Nicole N; Snyder, Lindsey M; Ross, Sarah E; Davis, Brian M; Gold, Michael S

    2016-10-19

    Designer receptors exclusively activated by designer drugs (DREADDs) are an advanced experimental tool that could potentially provide a novel approach to pain management. In particular, expression of an inhibitory (Gi-coupled) DREADD in nociceptors might enable ligand-dependent analgesia. To test this possibility, TRPV1-cre mice were used to restrict expression of Gi-DREADDs to predominantly C-fibers. Whereas baseline heat thresholds in both male and female mice expressing Gi-DREADD were normal, 1 mg/kg clozapine-N-oxide (CNO) produced a significant 3 h increase in heat threshold that returned to baseline by 5 h after injection. Consistent with these behavioral results, CNO decreased action potential firing in isolated sensory neurons from Gi-DREADD mice. Unexpectedly, however, the expression of Gi-DREADD in sensory neurons caused significant changes in voltage-gated Ca(2+) and Na(+) currents in the absence of CNO, as well as an increase in Na(+) channel (NaV1.7) expression. Furthermore, CNO-independent excitatory and inhibitory second-messenger signaling was also altered in these mice, which was associated with a decrease in the analgesic effect of endogenous inhibitory G-protein-coupled receptor activation. These results highlight the potential of this exciting technology, but also its limitations, and that it is essential to identify the underlying mechanisms for any observed behavioral phenotypes. DREADD technology is a powerful tool enabling manipulation of activity and/or transmitter release from targeted cell populations. The purpose of this study was to determine whether inhibitory DREADDs in nociceptive afferents could be used to produce analgesia, and if so, how. DREADD activation produced a ligand-dependent analgesia to heat in vivo and a decrease in neuronal firing at the single-cell level. However, we observed that expression of Gi-DREADD also causes ligand-independent changes in ion channel activity and second-messenger signaling. These findings

  16. The HDL anti-inflammatory function is impaired in myocardial infarction and may predict new cardiac events independent of HDL cholesterol

    NARCIS (Netherlands)

    Dullaart, Robin P. F.; Annema, Wijtske; Tio, Rene A.; Tietge, Uwe J. F.

    2014-01-01

    Background: Intrinsic functional properties of high density lipoproteins (HDL) are considered to be physiologically important for atheroprotection. We compared the HDL anti-inflammatory capacity between patients with acute myocardial infarction (MI) and patients with non-cardiac chest pain, and pros

  17. The HDL anti-inflammatory function is impaired in myocardial infarction and may predict new cardiac events independent of HDL cholesterol

    NARCIS (Netherlands)

    Dullaart, Robin P. F.; Annema, Wijtske; Tio, Rene A.; Tietge, Uwe J. F.

    2014-01-01

    Background: Intrinsic functional properties of high density lipoproteins (HDL) are considered to be physiologically important for atheroprotection. We compared the HDL anti-inflammatory capacity between patients with acute myocardial infarction (MI) and patients with non-cardiac chest pain, and

  18. Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function

    Directory of Open Access Journals (Sweden)

    Bunn Janice Y

    2010-03-01

    Full Text Available Abstract Background Asthma is a chronic inflammatory disease of the airway that is characterized by a Th2-type of immune response with increasing evidence for involvement of Th17 cells. The role of IL-6 in promoting effector T cell subsets suggest that IL-6 may play a functional role in asthma. Classically IL-6 has been viewed as an inflammatory marker, along with TNFα and IL-1β, rather than as regulatory cytokine. Objective To investigate the potential relationship between IL-6 and other proinflammatory cytokines, Th2/Th17 cytokines and lung function in allergic asthma, and thus evaluate the potential role of IL-6 in this disease. Methods Cytokine levels in induced sputum and lung function were measured in 16 healthy control and 18 mild-moderate allergic asthmatic subjects. Results The levels of the proinflammatory biomarkers TNFα and IL-1β were not different between the control and asthmatic group. In contrast, IL-6 levels were specifically elevated in asthmatic subjects compared with healthy controls (p S = 0.53, p Conclusions In mild-moderate asthma, IL-6 dissociates from other proinflammatory biomarkers, but correlates with IL-13 levels. Furthermore, IL-6 may contribute to impaired lung function in allergic asthma.

  19. Short-axis epicardial volume change is a measure of cardiac left ventricular short-axis function, which is independent of myocardial wall thickness.

    Science.gov (United States)

    Ugander, Martin; Carlsson, Marcus; Arheden, Håkan

    2010-02-01

    Fractional shortening (FS) by echocardiography is considered to represent the short-axis contribution to the stroke volume (SV), also called short-axis function. However, FS is mathematically coupled to the amount of myocardium, since it rearranges during atrioventricular plane displacement (AVPD). The SV is the sum of the volumes generated by 1) reduction in outer volume of the heart, and 2) inner AVPD. The long-axis contribution to the SV is generated by AVPD, and thus the short-axis contribution is the remaining outer volume change of the heart, which should be unrelated to myocardial wall thickness. We hypothesized that both endocardial and midwall shortening indexed to SV are dependent on myocardial wall thickness, whereas epicardial volume change (EVC) indexed to SV is not. Twelve healthy volunteers (normals), 12 athletes, and 12 patients with dilated cardiomyopathy (ejection fraction EVC was defined as SV minus long-axis function. Endocardial and midwall shortening were measured in a midventricular short-axis slice. Endocardial shortening/SV and midwall shortening/SV both varied in relation to end-diastolic myocardial wall thickness (R(2) = 0.16, P = 0.008 and R(2) = 0.14, P = 0.012, respectively), whereas EVC/SV did not (R(2) = 0.00, P = 0.37). FS is dependent on myocardial wall thickness, whereas EVC is not and therefore represents true short-axis function. This is not surprising considering that FS is mainly caused by rearrangement of myocardium secondary to long-axis function. FS is therefore not synonymous with short-axis function.

  20. Functions of Danggui Buxue Tang, a Chinese Herbal Decoction Containing Astragali Radix and Angelicae Sinensis Radix, in Uterus and Liver are Both Estrogen Receptor-Dependent and -Independent

    Directory of Open Access Journals (Sweden)

    Oliver Zierau

    2014-01-01

    Full Text Available Danggui Buxue Tang (DBT, a herbal decoction containing Astragali Radix (AR and Angelicae Sinensis Radix (ASR, has been used in treating menopausal irregularity in women for more than 800 years in China. Pharmacological results showed that DBT exhibited significant estrogenic properties in vitro, which therefore suggested that DBT could activate the nuclear estrogen receptors. Here, we assessed the estrogenic properties of DBT in an ovariectomized in vivo rat model: DBT was applied to the ovariectomized rats for 3 days. The application of DBT did not alter the weight of uterus and liver, as well as the transcript expression of the proliferation markers including the estrogen receptors α and β. However, DBT stimulated the transcript expression of the estrogen responsive genes. In addition, the inductive role of DBT on the expression of members of the aryl hydrocarbon receptor family in uterus and liver of ovariectomized rats was confirmed. These responses of DBT however were clearly distinct from the response pattern detectable here for 17β-estradiol. Therefore, DBT exhibited weak, but significant, estrogenic properties in vivo; however, some of its activities were independent of the estrogen receptor. Thus, DBT could be an exciting Chinese herbal decoction for an alternative treatment of hormone replacement therapy for women in menopause without subsequent estrogenic side effects.

  1. Identification and functional characterization of NifA variants that are independent of GlnB activation in the photosynthetic bacterium Rhodospirillum rubrum

    Science.gov (United States)

    Zou, Xiaoxiao; Zhu, Yu; Pohlmann, Edward L.; Li, Jilun; Zhang, Yaoping; Roberts, Gary P.

    2012-01-01

    The activity of NifA, the transcriptional activator of the nitrogen fixation (nif) gene, is tightly regulated in response to ammonium and oxygen. However, the mechanisms for the regulation of NifA activity are quite different among various nitrogen-fixing bacteria. Unlike the well-studied NifL–NifA regulatory systems in Klebsiella pneumoniae and Azotobacter vinelandii, in Rhodospirillum rubrum NifA is activated by a direct protein–protein interaction with the uridylylated form of GlnB, which in turn causes a conformational change in NifA. We report the identification of several substitutions in the N-terminal GAF domain of R. rubrum NifA that allow NifA to be activated in the absence of GlnB. Presumably these substitutions cause conformational changes in NifA necessary for activation, without interaction with GlnB. We also found that wild-type NifA can be activated in a GlnB-independent manner under certain growth conditions, suggesting that some other effector(s) can also activate NifA. An attempt to use Tn5 mutagenesis to obtain mutants that altered the pool of these presumptive effector(s) failed, though much rarer spontaneous mutations in nifA were detected. This suggests that the necessary alteration of the pool of effector(s) for NifA activation cannot be obtained by knockout mutations. PMID:18757802

  2. Impulse control and underlying functions of the left DLPFC mediate age-related and age-independent individual differences in strategic social behavior.

    Science.gov (United States)

    Steinbeis, Nikolaus; Bernhardt, Boris C; Singer, Tania

    2012-03-01

    Human social exchange is often characterized by conflicts of interest requiring strategic behavior for their resolution. To investigate the development of the cognitive and neural mechanisms underlying strategic behavior, we studied children's decisions while they played two types of economic exchange games with differing demands of strategic behavior. We show an increase of strategic behavior with age, which could not be explained by age-related changes in social preferences but instead by developmental differences in impulsivity and associated brain functions of the left dorsolateral prefrontal cortex (DLPFC). Furthermore, observed differences in cortical thickness of lDLPFC were predictive of differences in impulsivity and strategic behavior irrespective of age. We conclude that egoistic behavior in younger children is not caused by a lack of understanding right or wrong, but by the inability to implement behavioral control when tempted to act selfishly; a function relying on brain regions maturing only late in ontogeny.

  3. ACE inhibition with spirapril improves diastolic function at rest independent of vasodilation during treatment with spirapril in mild to moderate hypertension

    DEFF Research Database (Denmark)

    Petersen, J R; Drabaek, H; Fornitz, Gitte Gleerup;

    1996-01-01

    The effects of the ACE inhibitor spirapril and of hydrochlorothiazide on left ventricular diastolic function were studied. Thirteen patients with mild to moderate essential hypertension completed this randomized, double-blinded, placebo-controlled, crossover study. After a three-week run-in period.......44-1.25), and the drug normalized the A/E-ratio VTI in those patients with elevated values. The hemodynamic variables, left ventricular mass, and end-systolic wall stress were unchanged during all three treatments. There were no significant changes in mean blood pressure during the treatment periods. These results...... indicate that spirapril lowers A/E ratio within four weeks in patients with mild to moderate essential hypertension. It thereby seems able to improve left ventricular diastolic function. The effect is not dependent upon changes in hemodynamic variables, blood pressure, left ventricular mass, or end...

  4. Interpreting measurements of cardiac function using vendor-independent speckle tracking echocardiography in children: a prospective, blinded comparison with catheter-derived measurements.

    Science.gov (United States)

    Goudar, Suma P; Baker, G Hamilton; Chowdhury, Shahryar M; Reid, Kimberly J; Shirali, Girish; Scheurer, Mark A

    2016-12-01

    Adult studies demonstrate that echocardiographic measurements of cardiac function using speckle tracking correlate with invasive measurements, but such data in the pediatric population are sparse. Our aim was to compare speckle-derived measures of cardiac function to measurements routinely obtained by cardiac catheterization in children. Echocardiograms were performed on the day of cardiac catheterization. Using Tomtec 2D Cardiac Performance Analysis, longitudinal strain (LS), longitudinal strain rate (LSR), early diastolic LSR, and ejection fraction (EF) for the right and left ventricle (RV and LV) were calculated via speckle tracking. Global LS and LSR were calculated for the LV. These results were compared to cardiac index, maximum ventricular dp/dt (max dp/dt), ventricular end-diastolic pressure (EDP), and pulmonary capillary wedge pressure (PCWP) obtained by fluid-filled catheters. A blinded observer performed all echo measurements. Fifty studies were performed on 28 patients ages 4 months to 20 years old. Their diagnoses included cardiac transplant (48 studies), repaired AV septal defect (1), and dilated cardiomyopathy (1). RVEDP ranged from 2 to 22 mm Hg (median=6) and PCWP ranged from 6 to 32 mmHg (median 10). LV global LS and LV 2-chamber LSR by speckle-tracking negatively correlated with LV max dp/dt (LV global LS R=-.83, P=.001; LV 2-chamber LSR R=-.69, P=.009). RV LS weakly correlated with max dp/dt (R=.363, P=.002). Early diastolic strain rate did not correlate with EDP in either ventricle. Speckle-derived measurements of function in the LV have stronger correlation than the RV to catheter-derived measures. LV global LS has the strongest correlation with invasive function measures in children. © 2016, Wiley Periodicals, Inc.

  5. Distinct roles of autophagy-dependent and -independent functions of FIP200 revealed by generation and analysis of a mutant knock-in mouse model

    OpenAIRE

    Chen, Song; Wang, Chenran; Yeo, Syn; Liang, Chun-Chi; Okamoto, Takako; Sun, Shaogang; Wen, Jian; Guan, Jun-Lin

    2016-01-01

    Chen et al. generated a FIP200-4A mutant knock-in mouse model and found that specifically blocking FIP200 interaction with Atg13 abolishes autophagy in vivo. Analysis of the new mouse model showed that nonautophagic functions of FIP200 are sufficient to fully support embryogenesis by maintaining a protective role in TNFα-induced apoptosis. However, FIP200-mediated canonical autophagy is required to support neonatal survival and tumor cell growth.

  6. Muscular weakness represents the main limiting factor of walk, functional independence and quality of life of myelopathy patients associated to HTLV-1

    Directory of Open Access Journals (Sweden)

    Renata Costa Caiafa

    2016-04-01

    Full Text Available ABSTRACT HTLV-1-associated myelopathy is a progressive disabling disease associated with gait abnormalities. Objective To identify and quantify the main muscles affected by weakness and spasticity, their impact on gait, functional capacity and on quality of life of HTLV-1-associated myelopathy patients. Method We evaluated lower limbs muscular strength according to the Medical Research Council scale, spasticity according to the modified Ashworth scale, daily activities according to the Barthel Index and quality of life according to the Short-Form Health Survey-36 of 26 HTLV-1-associated myelopathy patients. Results The muscles most affected by weakness included the dorsal flexors and knee flexors. Spasticity predominated in the hip adductor muscles and in plantar flexors. Assistance for locomotion, minimal dependence in daily activities, limitations in functional capacity and physical aspects were the most common findings. Conclusion The impairment of gait, functional dependence and quality of life were predominantly a consequence of intense muscle weakness in HTLV-1-associated myelopathy patients.

  7. Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma.

    Science.gov (United States)

    Filatova, Alina; Seidel, Sascha; Böğürcü, Nuray; Gräf, Sabine; Garvalov, Boyan K; Acker, Till

    2016-10-01

    Hypoxia is a common feature of solid tumors, which controls multiple aspects of cancer progression. One important function of hypoxia and the hypoxia-inducible factors (HIF) is the maintenance of cancer stem-like cells (CSC), a population of tumor cells that possess stem cell-like properties and drives tumor growth. Among the changes promoted by hypoxia is a metabolic shift resulting in acidification of the tumor microenvironment. Here, we show that glioma hypoxia and acidosis functionally cooperate in inducing HIF transcription factors and CSC maintenance. We found that these effects did not involve the classical PHD/VHL pathway for HIF upregulation, but instead involved the stress-induced chaperone protein HSP90. Genetic or pharmacologic inactivation of HSP90 inhibited the increase in HIF levels and abolished the self-renewal and tumorigenic properties of CSCs induced by acidosis. In clinical specimens of glioma, HSP90 was upregulated in the hypoxic niche and was correlated with a CSC phenotype. Our findings highlight the role of tumor acidification within the hypoxic niche in the regulation of HIF and CSC function through HSP90, with implications for therapeutic strategies to target CSC in gliomas and other hypoxic tumors. Cancer Res; 76(19); 5845-56. ©2016 AACR.

  8. Function of the Borrelia burgdorferi FtsH Homolog Is Essential for Viability both In Vitro and In Vivo and Independent of HflK/C

    Directory of Open Access Journals (Sweden)

    Chen-Yi Chu

    2016-04-01

    Full Text Available In many bacteria, the FtsH protease and its modulators, HflK and HflC, form a large protein complex that contributes to both membrane protein quality control and regulation of the cellular response to environmental stress. Both activities are crucial to the Lyme disease pathogen Borrelia burgdorferi, which depends on membrane functions, such as motility, protein transport, and cell signaling, to respond to rapid changes in its environment. Using an inducible system, we demonstrate that FtsH production is essential for both mouse and tick infectivity and for in vitro growth of B. burgdorferi. FtsH depletion in B. burgdorferi cells resulted in membrane deformation and cell death. Overproduction of the protease did not have any detectable adverse effects on B. burgdorferi growth in vitro, suggesting that excess FtsH does not proteolytically overwhelm its substrates. In contrast, we did not observe any phenotype for cells lacking the protease modulators HflK and HflC (ΔHflK/C, although we examined morphology, growth rate, growth under stress conditions, and the complete mouse-tick infectious cycle. Our results demonstrate that FtsH provides an essential function in the life cycle of the obligate pathogen B. burgdorferi but that HflK and HflC do not detectably affect FtsH function.

  9. Cell-free synthesis of functional human epidermal growth factor receptor: Investigation of ligand-independent dimerization in Sf21 microsomal membranes using non-canonical amino acids

    Science.gov (United States)

    Quast, Robert B.; Ballion, Biljana; Stech, Marlitt; Sonnabend, Andrei; Varga, Balázs R.; Wüstenhagen, Doreen A.; Kele, Péter; Schiller, Stefan M.; Kubick, Stefan

    2016-01-01

    Cell-free protein synthesis systems represent versatile tools for the synthesis and modification of human membrane proteins. In particular, eukaryotic cell-free systems provide a promising platform for their structural and functional characterization. Here, we present the cell-free synthesis of functional human epidermal growth factor receptor and its vIII deletion mutant in a microsome-containing system derived from cultured Sf21 cells. We provide evidence for embedment of cell-free synthesized receptors into microsomal membranes and asparagine-linked glycosylation. Using the cricket paralysis virus internal ribosome entry site and a repetitive synthesis approach enrichment of receptors inside the microsomal fractions was facilitated thereby providing analytical amounts of functional protein. Receptor tyrosine kinase activation was demonstrated by monitoring receptor phosphorylation. Furthermore, an orthogonal cell-free translation system that provides the site-directed incorporation of p-azido-L-phenylalanine is characterized and applied to investigate receptor dimerization in the absence of a ligand by photo-affinity cross-linking. Finally, incorporated azides are used to generate stable covalently linked receptor dimers by strain-promoted cycloaddition using a novel linker system. PMID:27670253

  10. The two tryptophans of β2-microglobulin have distinct roles in function and folding and might represent two independent responses to evolutionary pressure

    Directory of Open Access Journals (Sweden)

    Monti Maria

    2011-06-01

    Full Text Available Abstract Background We have recently discovered that the two tryptophans of human β2-microglobulin have distinctive roles within the structure and function of the protein. Deeply buried in the core, Trp95 is essential for folding stability, whereas Trp60, which is solvent-exposed, plays a crucial role in promoting the binding of β2-microglobulin to the heavy chain of the class I major histocompatibility complex (MHCI. We have previously shown that the thermodynamic disadvantage of having Trp60 exposed on the surface is counter-balanced by the perfect fit between it and a cavity within the MHCI heavy chain that contributes significantly to the functional stabilization of the MHCI. Therefore, based on the peculiar differences of the two tryptophans, we have analysed the evolution of β2-microglobulin with respect to these residues. Results Having defined the β2-microglobulin protein family, we performed multiple sequence alignments and analysed the residue conservation in homologous proteins to generate a phylogenetic tree. Our results indicate that Trp60 is highly conserved, whereas some species have a Leu in position 95; the replacement of Trp95 with Leu destabilizes β2-microglobulin by 1 kcal/mol and accelerates the kinetics of unfolding. Both thermodynamic and kinetic data fit with the crystallographic structure of the Trp95Leu variant, which shows how the hydrophobic cavity of the wild-type protein is completely occupied by Trp95, but is only half filled by Leu95. Conclusions We have established that the functional Trp60 has been present within the sequence of β2-microglobulin since the evolutionary appearance of proteins responsible for acquired immunity, whereas the structural Trp95 was selected and stabilized, most likely, for its capacity to fully occupy an internal cavity of the protein thereby creating a better stabilization of its folded state.

  11. Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

    OpenAIRE

    2012-01-01

    Müller glia are the primary glial subtype in the retina and perform a wide range of physiological tasks in support of retinal function, but little is known about the transcriptional network that maintains these cells in their differentiated state. We report that selective deletion of the LIM homeodomain transcription factor Lhx2 from mature Müller glia leads to the induction of reactive retinal gliosis in the absence of injury. Furthermore, Lhx2 expression is also down-regulated in Prph2Rd2/R...

  12. The V499G/Y501H mutation impairs fast motor kinetics of prestin and has significance for defining functional independence of individual prestin subunits.

    Science.gov (United States)

    Homma, Kazuaki; Duan, Chongwen; Zheng, Jing; Cheatham, Mary Ann; Dallos, Peter

    2013-01-25

    Outer hair cells (OHCs) are a mammalian innovation for mechanically amplifying sound energy to overcome the viscous damping of the cochlear partition. Although the voltage-dependent OHC membrane motor, prestin, has been demonstrated to be essential for mammalian cochlear amplification, the molecular mechanism by which prestin converts electrical energy into mechanical displacement/force remains elusive. Identifying mutations that alter the motor function of prestin provides vital information for unraveling the energy transduction mechanism of prestin. We show that the V499G/Y501H mutation does not deprive prestin of its voltage-induced motor activity, but it does significantly impair the fast motor kinetics and voltage operating range. Furthermore, mutagenesis studies suggest that Val-499 is the primary site responsible for these changes. We also show that V499G/Y501H prestin forms heteromers with wild-type prestin and that the fast motor kinetics of wild-type prestin is not affected by heteromer formation with V499G/Y501H prestin. These results suggest that prestin subunits are individually functional within a given multimer.

  13. Use of Two-Body Correlated Basis Functions with van der Waals Interaction to Study the Shape-Independent Approximation for a Large Number of Trapped Interacting Bosons

    Science.gov (United States)

    Lekala, M. L.; Chakrabarti, B.; Das, T. K.; Rampho, G. J.; Sofianos, S. A.; Adam, R. M.; Haldar, S. K.

    2017-01-01

    We study the ground-state and the low-lying excitations of a trapped Bose gas in an isotropic harmonic potential for very small (˜ 3) to very large (˜ 10^7 ) particle numbers. We use the two-body correlated basis functions and the shape-dependent van der Waals interaction in our many-body calculations. We present an exhaustive study of the effect of inter-atomic correlations and the accuracy of the mean-field equations considering a wide range of particle numbers. We calculate the ground-state energy and the one-body density for different values of the van der Waals parameter C6 . We compare our results with those of the modified Gross-Pitaevskii results, the correlated Hartree hypernetted-chain equations (which also utilize the two-body correlated basis functions), as well as of the diffusion Monte Carlo for hard sphere interactions. We observe the effect of the attractive tail of the van der Waals potential in the calculations of the one-body density over the truly repulsive zero-range potential as used in the Gross-Pitaevskii equation and discuss the finite-size effects. We also present the low-lying collective excitations which are well described by a hydrodynamic model in the large particle limit.

  14. Cardiac tamponade as an independent condition affecting the relationship between the plasma B-type natriuretic peptide levels and cardiac function.

    Science.gov (United States)

    Minai, Kosuke; Komukai, Kimiaki; Arase, Satoshi; Nagoshi, Tomohisa; Matsuo, Seiichiro; Ogawa, Kazuo; Kayama, Yosuke; Inada, Keiichi; Tanigawa, Shin-Ichi; Takemoto, Tomoyuki; Sekiyama, Hiroshi; Date, Taro; Ogawa, Takayuki; Taniguchi, Ikuo; Yoshimura, Michihiro

    2013-07-01

    Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24-48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 ± 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 ± 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered.

  15. Development of an efficient in vitro transcription system for bloodstream form Trypanosoma brucei reveals life cycle-independent functionality of class I transcription factor A.

    Science.gov (United States)

    Park, Sung Hee; Nguyen, Tu N; Günzl, Arthur

    2012-01-01

    Trypanosomatid parasites possess extremely divergent transcription factors whose identification typically relied on biochemical, structural and functional analyses because they could not be identified by standard sequence analysis. For example, subunits of the Trypanosoma brucei mediator and class I transcription factor A (CITFA) have no sequence resemblance to putative counterparts in higher eukaryotes. Therefore, homologous in vitro transcription systems have been crucial in evaluating the transcriptional roles of T. brucei proteins but so far such systems have been restricted to the insect-stage, procyclic form (PF) of the parasite. Here, we report the development of a homologous system for the mammalian-infective, bloodstream form (BF) of T. brucei which supports accurately initiated transcription from three different RNA polymerase (pol) I promoters as well as from the RNA pol II-recruiting spliced leader RNA gene promoter. The system is based on a small scale extract preparation procedure which accommodates the low cell densities obtainable in BF culture. BF and PF systems behave surprisingly similar and we show that the CITFA complex purified from procyclic extract is fully functional in the BF system indicating that the transcriptional machinery in general is equivalent in both life cycle stages. A notable difference, however, was observed with the RNA pol I-recruiting GPEET procyclin promoter whose reduced promoter strength and increased sensitivity to manganese ions in the BF system suggests the presence of a specific transcriptional activator in the PF system. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. 12 CFR 323.5 - Appraiser independence.

    Science.gov (United States)

    2010-01-01

    ... appraiser, that appraiser must be independent of the lending, investment, and collection functions and not... appraisal are involved in the lending, investment, or collection functions of the regulated institution, the regulated institution shall take appropriate steps to ensure that the appraisers exercise independent...

  17. Central Bank independence

    Directory of Open Access Journals (Sweden)

    Vasile DEDU

    2012-08-01

    Full Text Available In this paper we present the key aspects regarding central bank’s independence. Most economists consider that the factor which positively influences the efficiency of monetary policy measures is the high independence of the central bank. We determined that the National Bank of Romania (NBR has a high degree of independence. NBR has both goal and instrument independence. We also consider that the hike of NBR’s independence played an important role in the significant disinflation process, as headline inflation dropped inside the targeted band of 3% ± 1 percentage point recently.

  18. Gestational Diabetes Mellitus Worsens the Profile of Cardiometabolic Risk Markers and Decrease Indexes of Beta-Cell Function Independently of Insulin Resistance in Nondiabetic Women with a Parental History of Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Alina Sokup

    2014-01-01

    Full Text Available Background. Women with a history of both parental type 2 diabetes (pt2DM and previous gestational diabetes (pGDM represent a group at high risk of cardiovascular events. We hypothesized that pGDM changes cardiometabolic risk markers levels as well as theirs associations with glucose indices in nondiabetic pt2DM women. Methods. Anthropometric parameters, glucose regulation (OGTT, insulin resistance (HOMA-IR, beta-cell function, lipid levels, parameters of endothelial dysfunction, and inflammation were evaluated in 55 women with pt2DM, 40 with both pt2DM and pGDM 2–24 months postpartum, and 35 controls. Results. Prediabetes was diagnosed more frequently in women with both pt2DM and pGDM in comparison with women with only pt2DM (10 versus 8, P=0.04. The pGDM group had higher LDL-cholesterol, sICAM-1, tPa Ag, fibrinogen, and lower beta-cell function after adjustment for HOMA-IR, in comparison with pt2DM group. In pt2DM group postchallenge glucose correlated independently with hsCRP and in pGDM group fasting glucose with HOMA-IR. Conclusions. pGDM exerts a combined effect on cardiometabolic risk markers in women with pt2DM. In these women higher LDL-cholesterol, fibrinogen, sICAM-1, tPa Ag levels and decreased beta cell function are associated with pGDM independently of HOMA-IR index value. Fasting glucose is an important cardiometabolic risk marker and is independently associated with HOMA-IR.

  19. Gestational diabetes mellitus worsens the profile of cardiometabolic risk markers and decrease indexes of beta-cell function independently of insulin resistance in nondiabetic women with a parental history of type 2 diabetes.

    Science.gov (United States)

    Sokup, Alina; Ruszkowska-Ciastek, Barbara; Walentowicz-Sadłecka, Małgorzata; Grabiec, Marek; Rość, Danuta

    2014-01-01

    Women with a history of both parental type 2 diabetes (pt2DM) and previous gestational diabetes (pGDM) represent a group at high risk of cardiovascular events. We hypothesized that pGDM changes cardiometabolic risk markers levels as well as theirs associations with glucose indices in nondiabetic pt2DM women. Anthropometric parameters, glucose regulation (OGTT), insulin resistance (HOMA-IR), beta-cell function, lipid levels, parameters of endothelial dysfunction, and inflammation were evaluated in 55 women with pt2DM, 40 with both pt2DM and pGDM 2-24 months postpartum, and 35 controls. Prediabetes was diagnosed more frequently in women with both pt2DM and pGDM in comparison with women with only pt2DM (10 versus 8, P = 0.04). The pGDM group had higher LDL-cholesterol, sICAM-1, tPa Ag, fibrinogen, and lower beta-cell function after adjustment for HOMA-IR, in comparison with pt2DM group. In pt2DM group postchallenge glucose correlated independently with hsCRP and in pGDM group fasting glucose with HOMA-IR. pGDM exerts a combined effect on cardiometabolic risk markers in women with pt2DM. In these women higher LDL-cholesterol, fibrinogen, sICAM-1, tPa Ag levels and decreased beta cell function are associated with pGDM independently of HOMA-IR index value. Fasting glucose is an important cardiometabolic risk marker and is independently associated with HOMA-IR.

  20. The cyclase-associated protein FgCap1 has both protein kinase A-dependent and -independent functions during deoxynivalenol production and plant infection in Fusarium graminearum.

    Science.gov (United States)

    Yin, Tao; Zhang, Qiang; Wang, Jianhua; Liu, Huiquan; Wang, Chenfang; Xu, Jin-Rong; Jiang, Cong

    2017-01-31

    Fusarium graminearum is a causal agent of wheat scab and a producer of the trichothecene mycotoxin deoxynivalenol (DON). The expression of trichothecene biosynthesis (TRI) genes and DON production are mainly regulated by the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway and two pathway-specific transcription factors (TRI6 and TRI10). Interestingly, deletion mutants of TRI6 show reduced expression of several components of cAMP signalling, including the FgCAP1 adenylate-binding protein gene that has not been functionally characterized in F. graminearum. In this study, we show that FgCap1 interacts with Fac1 adenylate cyclase and that deletion of FgCAP1 reduces the intracellular cAMP level and PKA activity. The Fgcap1 deletion mutant is defective in vegetative growth, conidiogenesis and plant infection. It also shows significantly reduced DON production and TRI gene expression, which can be suppressed by exogenous cAMP, indicating a PKA-dependent regulation of DON biosynthesis by FgCap1. The wild-type, but not tri6 mutant, shows increased levels of intracellular cAMP and FgCAP1 expression under DON-producing conditions. Furthermore, the promoter of FgCAP1 contains one putative Tri6-binding site that is important for its function during DON biosynthesis, but is dispensable for hyphal growth, conidiogenesis and pathogenesis. In addition, FgCap1 shows an actin-like localization to the cortical patches at the apical region of hyphal tips. Phosphorylation of FgCap1 at S353 was identified by phosphoproteomics analysis. The S353A mutation in FgCAP1 has no effect on its functions during vegetative growth, conidiation and DON production. However, expression of the FgCAP1(S353A) allele fails to complement the defects of the Fgcap1 mutant in plant infection, indicating the importance of the phosphorylation of FgCap1 at S353 during pathogenesis. Taken together, our results suggest that FgCAP1 is involved in the regulation of DON production via cAMP signalling

  1. On the k-independence required by linear probing and minwise independence

    DEFF Research Database (Denmark)

    Pǎtraşcu, Mihai; Thorup, Mikkel

    2016-01-01

    We show that linear probing requires 5-independent hash functions for expected constant-time performance, matching an upper bound of Pagh et al. [2009]. More precisely, we construct a random 4-independent hash function yielding expected logarithmic search time for certain keys. For (1 + ε......)-approximate minwise independence, we show that Ω(lg1 ε)-independent hash functions are required, matching an upper bound of Indyk [2001]. We also show that the very fast 2-independent multiply-shift scheme of Dietzfelbinger [1996] fails badly in both applications....

  2. Characterization of an Arabidopsis-Phytophthora pathosystem: resistance requires a functional PAD2 gene and is independent of salicylic acid, ethylene and jasmonic acid signalling.

    Science.gov (United States)

    Roetschi, A; Si-Ammour, A; Belbahri, L; Mauch, F; Mauch-Mani, B

    2001-11-01

    Arabidopsis accessions were screened with isolates of Phytophthora porri originally isolated from other crucifer species. The described Arabidopsis-Phytophthora pathosystem shows the characteristics of a facultative biotrophic interaction similar to that seen in agronomically important diseases caused by Phytophthora species. In susceptible accessions, extensive colonization of the host tissue occurred and sexual and asexual spores were formed. In incompatible combinations, the plants reacted with a hypersensitive response (HR) and the formation of papillae at the sites of attempted penetration. Defence pathway mutants such as jar1 (jasmonic acid-insensitive), etr1 (ethylene receptor mutant) and ein2 (ethylene-insensitive) remained resistant towards P. porri. However, pad2, a mutant with reduced production of the phytoalexin camalexin, was hyper-susceptible. The accumulation of salicylic acid (SA) and PR1 protein was strongly reduced in pad2. Surprisingly, this lack of SA accumulation does not appear to be the cause of the hyper-susceptibility because interference with SA signalling in nahG plants or sid2 or npr1 mutants had only a minor effect on resistance. In addition, the functional SA analogue benzothiadiazol (BTH) did not induce resistance in susceptible plants including pad2. Similarly, the complete blockage of camalexin biosynthesis in pad3 did not cause susceptibility. Resistance of Arabidopsis against P. porri appears to depend on unknown defence mechanisms that are under the control of PAD2.

  3. MHC multimer-guided and cell culture-independent isolation of functional T cell receptors from single cells facilitates TCR identification for immunotherapy.

    Directory of Open Access Journals (Sweden)

    Georg Dössinger

    Full Text Available Adoptive therapy using T cells redirected to target tumor- or infection-associated antigens is a promising strategy that has curative potential and broad applicability. In order to accelerate the screening process for suitable antigen-specific T cell receptors (TCRs, we developed a new approach circumventing conventional in vitro expansion-based strategies. Direct isolation of paired full-length TCR sequences from non-expanded antigen-specific T cells was achieved by the establishment of a highly sensitive PCR-based T cell receptor single cell analysis method (TCR-SCAN. Using MHC multimer-labeled and single cell-sorted HCMV-specific T cells we demonstrate a high efficacy (approximately 25% and target specificity of TCR-SCAN receptor identification. In combination with MHC-multimer based pre-enrichment steps, we were able to isolate TCRs specific for the oncogenes Her2/neu and WT1 even from very small populations (original precursor frequencies of down to 0.00005% of CD3(+ T cells without any cell culture step involved. Genetic re-expression of isolated receptors demonstrates their functionality and target specificity. We believe that this new strategy of TCR identification may provide broad access to specific TCRs for therapeutically relevant T cell epitopes.

  4. Independent candidates in Mexico

    OpenAIRE

    Campos, Gonzalo Santiago

    2014-01-01

    In this paper we discuss the issue of independent candidates in Mexico, because through the so-called political reform of 2012 was incorporated in the Political Constitution of the Mexican United States the right of citizens to be registered as independent candidates. Also, in September 2013 was carried out a reform of Article 116 of the Political Constitution of the Mexican United States in order to allow independent candidates in each state of the Republic. However, prior to the constitutio...

  5. Gravity Independent Compressor Project

    Data.gov (United States)

    National Aeronautics and Space Administration — We propose to develop and demonstrate a small, gravity independent, vapor compression refrigeration system using a linear motor compressor which effectively...

  6. Efeitos da natação sobre a independência funcional de pacientes com lesão medular Efectos de la natación sobre la independencia funcional de pacientes con lesión medular Effects of swimming on the functional independence of patients with spinal cord injury

    Directory of Open Access Journals (Sweden)

    Maurício Corte Real da Silva

    2005-08-01

    puntaje total. CONCLUSIÓN: La actividad de natación fue efectiva en la mejora de la condición física, trayendo beneficios motores sobre las habilidades funcionales de los participantes del grupo experimental.FUNDAMENTS AND OBJECTIVE: Sports play an important role in the physical rehabilitation of patients with spinal cord injury by broadening the therapeutic alternatives in addition to providing functional independence. The objective of this study is to determining the effects of swimming on the functional capacity of patients with spinal cord injury. METHODS: 16 patients with spinal cord injury were divided into two groups: experimental and control. The assessment of both groups was performed using the Functional Independence Measure (FIM scale before and after the trial, which consisted of swimming sessions performed twice a week during a period of four months. RESULTS: Both groups demonstrated noticeable gains related to body care, transference, overall and motor scores, even though the experimental group presented greater gains in transference, overall motor score and overall score. CONCLUSION: The swimming activity was effective in improving their physical condition, bringing motor benefits on the functional capacity of participants from the experimental group.

  7. Functional independence in patients with chronic kidney disease being treated with haemodialysis¹ Independencia funcional en pacientes con enfermedad renal crónica en tratamiento de hemodiálisis Independência funcional em pacientes com doença renal crônica em tratamento hemodialítico

    Directory of Open Access Journals (Sweden)

    Graziella Allana Serra Alves de Oliveira Oller

    2012-12-01

    Full Text Available PURPOSE: This study has described and analysed the functional independence of the patients served in the haemodialysis services of a countryside town in the State of São Paulo, Brazil, using the Functional Independence Measure (FIM. METHOD: The population considered was that of 214 patients being treated with haemodialysis, assessed in 2011, by means of a social, demographic and clinical report, a Mini-Mental State Examination (MMSE and also the FIM. RESULTS: The mean age of the population under study was 58.01 years, while the mean FIM point score was 118.38 points, showing a level of complete or modified independence within this population. Even though the level of dependence found has been low, this can be highlighted, within the locomotion domain, in the activity of going up and down stairs (10.28%. Age, complications arising from haemodialysis, and comorbidities show a negative correlation with FIM. CONCLUSION: Awareness of the level of functional independence of the patients being subjected to treatment with haemodialysis is essential in order to back up intervention for the improvement of nursing assistance provided to this population.OBJETIVO: este estudio describió y analizó la independencia funcional de los pacientes atendidos en los servicios de hemodiálisis de una ciudad del interior paulista, según la Medida de Independencia Funcional (MIF. MÉTODO: la población fue de 214 pacientes en tratamiento de hemodiálisis, evaluados en 2011, por medio de un cuestionario sociodemográfico y clínico, Mini examen del Estado Mental y MIF. RESULTADOS: la edad Media de la población del estudio fue de 58,01 años y la media de la MIF fue de 118,38 puntos, evidenciando un nivel de independencia completa o modificada de esa población. Mismo habiendo sido bajo el nivel de dependencia encontrado, se destacó en el dominio locomoción, en la actividad ascender y bajar escaleras (10,28%. La edad, complicaciones relacionadas a la hemodiálisis y

  8. Nível de independência funcional e déficit cognitivo em idosos com doença de Alzheimer Nivel de independencia funcional y déficit cognitivo en ancianos con enfermedade de Alzheimer Functional independence level and cognitive deficit in elderly individuals with Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Luana Flávia da Silva Talmelli

    2010-12-01

    Full Text Available Este estudo investigou a influência do nível de independência funcional dos idosos com doença de Alzheimer segundo escores da avaliação cognitiva. A população foi com