965 research outputs found

    Interactions between Transmembrane Helices within Monomers of the Aquaporin AtPIP2;1 Play a Crucial Role in Tetramer Formation

    Get PDF
    Aquaporin (AQP) is a water channel protein found in various subcellular membranes of both prokaryotic and eukaryotic cells. The physiological functions of AQPs have been elucidated in many organisms. However, understanding their biogenesis remains elusive, particularly regarding how they assemble into tetramers. Here, we investigated the amino acid residues involved in the tetramer formation of the Arabidopsis plasma membrane AQP AtPIP2; 1 using extensive amino acid substitution mutagenesis. The mutant proteins V41A/E44A, F51A/L52A, F87A/I91A, F92A/I93A, V95A/Y96A, and H216A/L217A, harboring alanine substitutions in the transmembrane (TM) helices of AtPIP2; 1 polymerized into multiple oligomeric complexes with a variable number of subunits greater than four. Moreover, these mutant proteins failed to traffic to the plasma membrane, instead of accumulating in the endoplasmic reticulum(ER). Structure-based modeling revealed that these residues are largely involved in interactions between TM helices within monomers. These results suggest that inter-TM interactions occurring both within and between monomers play crucial roles in tetramer formation in the AtPIP2; 1 complex. Moreover, the assembly of AtPIP2; 1 tetramers is critical for their trafficking from the ER to the plasma membrane, as well as water permeability.1133Ysciescopu

    The GSK-3Ī²-FBXL21 Axis Contributes to Circadian TCAP Degradation and Skeletal Muscle Function.

    Full text link
    FBXL21 is a clock-controlled E3 ligase modulating circadian periodicity via subcellular-specific CRYPTOCHROME degradation. How FBXL21 regulates tissue-specific circadian physiology and what mechanism operates upstream is poorly understood. Here we report the sarcomere component TCAP as a cytoplasmic substrate of FBXL21. FBXL21 interacts with TCAP in a circadian manner antiphasic to TCAP accumulation in skeletal muscle, and circadian TCAP oscillation is disrupted in Psttm mice with an Fbxl21 hypomorph mutation. GSK-3Ī² phosphorylates FBXL21 and TCAP to activate FBXL21-mediated, phosphodegron-dependent TCAP degradation. GSK-3Ī² inhibition or knockdown diminishes FBXL21-Cul1 complex formation and delays FBXL21-mediated TCAP degradation. Finally, Psttm mice show significant skeletal muscle defects, including impaired fiber size, exercise tolerance, grip strength, and response to glucocorticoid-induced atrophy, in conjunction with cardiac dysfunction. These data highlight a circadian regulatory pathway where a GSK-3Ī²-FBXL21 functional axis controls TCAP degradation via SCF complex formation and regulates skeletal muscle function

    Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib

    Get PDF
    BACKGROUND: Patients with metastatic pancreatic cancer (mPC) often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, Phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and mPC whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300ā€‰mg bid; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; aā€‰ā‰„ā€‰10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was less than 10 points in both arms and there was no significant between-group difference (-2.47; 95% CIā€‰-ā€‰7.27, 2.33; P=0.31). Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CIā€‰-ā€‰8.75, -0.16; P=0.04). There was no difference in TSCMD for olaparib versus placebo for GHS (P=0.25; HR 0.72; 95% CI 0.41, 1.27) or physical functioning (P=0.32; HR 1.38; 95%CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and mPC. CLINCALTRIALS.GOV NUMBER: NCT02184195

    ROR activation by Nobiletin enhances antitumor efficacy via suppression of IĪŗB/NF-ĪŗB signaling in triple-negative breast cancer

    Full text link
    AbstractTriple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOBā€“ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IĪŗBĪ± promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-ĪŗB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-ĪŗB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-ĪŗB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.</jats:p

    Rechargeable-hybrid-seawater fuel cell

    Get PDF
    A novel energy conversion and storage system using seawater as a cathode is proposed herein. This system is an intermediate between a battery and a fuel cell, and is accordingly referred to as a hybrid fuel cell. The circulating seawater in this opencathode system results in a continuous supply of sodium ions, which gives this system superior cycling stability that allows the application of various alternative anodes to sodium metal by compensating for irreversible charge losses. Indeed, hard carbon and Sn-C nanocomposite electrodes were successfully applied as anode materials in this hybrid-seawater fuel cell, yielding highly stable cycling performance and reversible capacities exceeding 110 mAh g-1 and 300 mAh g-1, respectively. &amp;copy; 2014 Nature Publishing Group All rights reservedclose1

    Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders

    Get PDF
    Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0Ā mg/d; maximum dose 20Ā mg/d) or haloperidol (initial dose, 0.75Ā mg/d; maximum dose, 4.5Ā mg/d) for 8Ā weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (pĀ <Ā 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4Ā weeks after commencement of medication (pĀ <Ā 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients

    Three little pieces for computer and relativity

    Full text link
    Numerical relativity has made big strides over the last decade. A number of problems that have plagued the field for years have now been mostly solved. This progress has transformed numerical relativity into a powerful tool to explore fundamental problems in physics and astrophysics, and I present here three representative examples. These "three little pieces" reflect a personal choice and describe work that I am particularly familiar with. However, many more examples could be made.Comment: 42 pages, 11 figures. Plenary talk at "Relativity and Gravitation: 100 Years after Einstein in Prague", June 25 - 29, 2012, Prague, Czech Republic. To appear in the Proceedings (Edition Open Access). Collects results appeared in journal articles [72,73, 122-124
    • ā€¦
    corecore