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101.
102.
GTPases are widespread in directing cytoskeletal rearrangements and affecting cellular organization. How they do so is not well understood. Yeast cells divide by budding, which occurs in two spatially programmed patterns, axial or bipolar [1-3]. Cytoskeletal polarization to form a bud is governed by the Ras-like GTPase, Bud1/Rsr1, in response to cortical landmarks. Bud1 is uniformly distributed on the plasma membrane, so presumably its regulators, Bud5 GTPase exchange factor and Bud2 GTPase activating protein, impart spatial specificity to Bud1 action [4]. We examined the localizations of Bud5 and Bud2. Both Bud1 regulators associate with cortical landmarks designating former division sites. In haploids, Bud5 forms double rings that encircle the mother-bud neck and split upon cytokinesis so that each progeny cell inherits Bud5 at the axial division remnant. Recruitment of Bud5 into these structures depends on known axial landmark components. In cells undergoing bipolar budding, Bud5 associates with multiple sites, in response to the bipolar landmarks. Like Bud5, Bud2 associates with the axial division remnant, but rather than being inherited, Bud2 transiently associates with the remnant in late G1, before condensing into a patch at the incipient bud site. The relative timing of Bud5 and Bud2 localizations suggests that both regulators contribute to the spatially specific control of Bud1 GTPase. 相似文献
103.
Claudia Vieira Anayda Portela Tina Miller Ernestina Coast Tiziana Leone Cicely Marston 《PloS one》2012,7(10)
Background
Improved access to skilled health personnel for childbirth is a priority strategy to improve maternal health. This study investigates interventions to achieve this where traditional birth attendants were providers of childbirth care and asks what has been done and what has worked?Methods and Findings
We systematically reviewed published and unpublished literature, searching 26 databases and contacting experts to find relevant studies. We included references from all time periods and locations. 132 items from 41 countries met our inclusion criteria and are included in an inventory; six were intervention evaluations of high or moderate quality which we further analysed. Four studies report on interventions to deploy midwives closer to communities: two studies in Indonesia reported an increase in use of skilled health personnel; another Indonesian study showed increased uptake of caesarean sections as midwives per population increased; one study in Bangladesh reported decreased risk of maternal death. Two studies report on interventions to address financial barriers: one in Bangladesh reported an increase in use of skilled health personnel where financial barriers for users were addressed and incentives were given to skilled care providers; another in Peru reported that use of emergency obstetric care increased by subsidies for preventive and maternity care, but not by improved quality of care.Conclusions
The interventions had positive outcomes for relevant maternal health indicators. However, three of the studies evaluate the village midwife programme in Indonesia, which limits the generalizability of conclusions. Most studies report on a main intervention, despite other activities, such as community mobilization or partnerships with traditional birth attendants. Many authors note that multiple factors including distance, transport, family preferences/support also need to be addressed. Case studies of interventions in the inventory illustrate how different countries attempted to address these complexities. Few high quality studies that measure effectiveness of interventions exist. 相似文献104.
Barrett SD Bridges AJ Dudley DT Saltiel AR Fergus JH Flamme CM Delaney AM Kaufman M LePage S Leopold WR Przybranowski SA Sebolt-Leopold J Van Becelaere K Doherty AM Kennedy RM Marston D Howard WA Smith Y Warmus JS Tecle H 《Bioorganic & medicinal chemistry letters》2008,18(24):6501-6504
A novel series of benzhydroxamate esters derived from their precursor anthranilic acids have been prepared and have been identified as potent MEK inhibitors. 2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide, CI-1040, was the first MEK inhibitor to demonstrate in vivo activity in preclinical animal models and subsequently became the first MEK inhibitor to enter clinical trial. CI-1040 suffered however from poor exposure due to its poor solubility and rapid clearance, and as a result, development of the compound was terminated. Optimization of the diphenylamine core and modification of the hydroxamate side chain for cell potency, solubility, and exposure with oral delivery resulted in the discovery of the clinical candidate N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide PD 0325901. 相似文献
105.
Kurash JK Lei H Shen Q Marston WL Granda BW Fan H Wall D Li E Gaudet F 《Molecular cell》2008,29(3):392-400
The protein methyltransferase Set7/9 was recently shown to regulate p53 activity in cancer cells. However, the impact of Set7/9 on p53 function in vivo is unclear. To explore these issues, we created a null allele of Set7/9 in mice. Cells from Set7/9 mutant mice fail to methylate p53 K369, are unable to induce p53 downstream targets upon DNA damage, and are predisposed to oncogenic transformation. Importantly, we find that methylation of p53 by Set7/9 is required for the binding of the acetyltransferase Tip60 to p53 and for the subsequent acetylation of p53. We provide the first genetic evidence demonstrating that lysine methylation of p53 by Set7/9 is important for p53 activation in vivo and suggest a mechanistic link between methylation and acetylation of p53 through Tip60. 相似文献
106.
Chunman Li Xiaomin Luo Shan Zhao Gavin KY Siu Yongheng Liang Hsiao Chang Chan Ayano Satoh Sidney SB Yu 《The EMBO journal》2017,36(4):441-457
The transport protein particle (TRAPP) was initially identified as a vesicle tethering factor in yeast and as a guanine nucleotide exchange factor (GEF) for Ypt1/Rab1. In mammals, structures and functions of various TRAPP complexes are beginning to be understood. We found that mammalian TRAPPII was a GEF for both Rab18 and Rab1. Inactivation of TRAPPII‐specific subunits by various methods including siRNA depletion and CRISPR–Cas9‐mediated deletion reduced lipolysis and resulted in aberrantly large lipid droplets. Recruitment of Rab18 onto lipid droplet (LD) surface was defective in TRAPPII‐deleted cells, but the localization of Rab1 on Golgi was not affected. COPI regulates LD homeostasis. We found that the previously documented interaction between TRAPPII and COPI was also required for the recruitment of Rab18 to the LD. We hypothesize that the interaction between COPI and TRAPPII helps bring TRAPPII onto LD surface, and TRAPPII, in turn, activates Rab18 and recruits it on the LD surface to facilitate its functions in LD homeostasis. 相似文献
107.
Background
Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer''s disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.Methods
We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-signal trials, thus mimicking task parameters of human CPTs that use signal and non-signal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a simple reaction-time (RT) task involving only one choice (1CRT task). We hypothesized that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the sensitivity index measure from signal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).Conclusions
C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, consistent with human performance in simple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies. 相似文献108.
Phosphorylation of the calcium ion-regulated thin filaments from vascular smooth muscle. A new regulatory mechanism? 总被引:1,自引:0,他引:1 下载免费PDF全文
The thin filaments of vascular smooth muscle (pig aorta) contain a Ca2+-sensitive regulatory system that resembles troponin-tropomyosin [Marston, Trevett & Walters (1980) Biochem. J. 185, 355-365]. Our thin-filament preparations also contain enzymes that phosphorylate and dephosphorylate a specific protein. Initial rate of phosphorylation was 0.42 +/- 0.10 (95% confidence limits) mumol of Pi/min per g of thin filaments; half-maximal incorporation was obtained in 4 1/2 min, and a maximum of 1.8 +/- 0.1 mumol of Pi/g of thin filaments was incorporated after 40 min (conditions: 1 mM-MgATP, 60 mM-MgATP, 60 mM-KCl, 10 mM-imidazole, pH 7.0, 5 mM-MgCl2, 10 mM-NaN3, 0.5 mM-dithiothreitol, 0.1 mM-CaCl2, 25 degrees C). On gel electrophoresis in polyacrylamide (4-30% gradient)/0.25% sodium dodecyl sulphate gel over 75% of protein-bound phosphate was in a single protein of mol.wt. 21000. On electrophoresis in polyacrylamide (8%)/6 M-urea (pH 8.6) gel the phosphoprotein remained at the origin. Phosphorylation was associated with an increase in the concentration of high-affinity (K congruent to 10(6) M-1) Ca2+-binding sites from 0.8-1.5 to 6.3 mumol of Ca2+/g of thin filaments. Phosphorylation also changed the regulatory properties of the skeletal-muscle myosin-aorta thin-filament MgATPase; maximum activity was unaltered, but the phosphorylated thin filaments required only 0.36 microM-Ca2+ for half-activation compared with 2.7 microM-Ca2+ for unphosphorylated thin filaments. The possible regulatory role of thin-filament phosphorylation is discussed. 相似文献
109.
110.
Robert A Terkeltaub H Ralph Schumacher John D Carter Herbert SB Baraf Robert R Evans Jian Wang Shirletta King-Davis Steven P Weinstein 《Arthritis research & therapy》2013,15(1):R25