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151.
Jayme Salsman Jordan Pinder Brenda Tse Dale Corkery Graham Dellaire 《Experimental cell research》2013
The promyelocytic leukemia protein (PML) is a tumor suppressor protein that regulates a variety of important cellular processes, including gene expression, DNA repair and cell fate decisions. Integral to its function is the ability of PML to form nuclear bodies (NBs) that serve as hubs for the interaction and modification of over 90 cellular proteins. There are seven canonical isoforms of PML, which encode diverse C-termini generated by alternative pre-mRNA splicing. Recruitment of specific cellular proteins to PML NBs is mediated by protein–protein interactions with individual PML isoforms. Using a yeast two-hybrid screen employing peptide sequences unique to PML isoform I (PML-I), we identified an interaction with the eukaryotic initiation factor 3 subunit K (eIF3K), and in the process identified a novel eIF3K isoform, which we term eIF3K-2. We further demonstrate that eIF3K and PML interact both in vitro via pull-down assays, as well as in vivo within human cells by co-immunoprecipitation and co-immunofluorescence. In addition, eIF3K isoform 2 (eIF3K-2) colocalizes to PML bodies, particularly those enriched in PML-I, while eIF3K isoform 1 associates poorly with PML NBs. Thus, we report eIF3K as the first known subunit of the eIF3 translation pre-initiation complex to interact directly with the PML protein, and provide data implicating alternative splicing of both PML and eIF3K as a possible regulatory mechanism for eIF3K localization at PML NBs. 相似文献
152.
Lewis D. Pennington Douglas A. Whittington Michael D. Bartberger Steven R. Jordan Holger Monenschein Thomas T. Nguyen Bryant H. Yang Qiufen M. Xue Filisaty Vounatsos Robert C. Wahl Kui Chen Stephen Wood Martin Citron Vinod F. Patel Stephen A. Hitchcock Wenge Zhong 《Bioorganic & medicinal chemistry letters》2013,23(15):4459-4464
We describe a systematic study of how macrocyclization in the P1–P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. 相似文献
153.
Kevin Lewellyn Dobroslawa Bialonska Melissa J. Loria Stephen W. White Kenneth J. Sufka Jordan K. Zjawiony 《Bioorganic & medicinal chemistry》2013,21(22):7083-7090
Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki’s as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety–depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model. 相似文献
154.
Tommy Fang Jean-Luc Watson Jordan Goodman Christian O. Dimkpa Nicole Martineau Siddhartha Das Joan E. McLean David W. Britt Anne J. Anderson 《Microbiological research》2013,168(2):91-98
Doping of ZnO nanoparticles (NPs) is being used to increase their commercialization in the optical and semiconductor fields. This paper addresses whether doping with Al alters how ZnO NPs at nonlethal levels modifies the metabolism of soil-borne pseudomonads which are beneficial in performing bioremediation or promoting plant growth. The differences in X-ray diffraction (XRD) patterns, observed between commercial ZnO and Al-doped ZnO NPs indicated the aluminum was present as Al NPs. Both particles aggregated in the bacterial growth medium and formed colloids of different surface charges. They had similar effects on bacterial metabolism: rapid, dose-dependent loss in light output indicative of temporary toxicity in a biosensor constructed in Pseudomonas putida KT2440; increased production of a fluorescent pyoverdine-type siderophore, and decreased levels of indole acetic acid and phenazines in Pseudomonas chlororaphis O6. Solubilization of Zn and Al from the NPs contributed to these responses to different extents. These findings indicate that Al-doping of the ZnO NPs did not reduce the ability of the NPs to alter bacterial metabolism in ways that could influence performance of the pseudomonads in their soil environment. 相似文献
155.
The response regulator/histidine kinase pair LiaRS of Bacillus subtilis, together with its membrane‐bound inhibitor protein LiaF, constitutes an envelope stress‐sensing module that is conserved in Firmicutes bacteria. LiaR positively autoregulates the expression of the liaIH‐liaGFSR operon from a strictly LiaR‐dependent promoter (PliaI). A comprehensive perturbation analysis revealed that the functionality of the LiaFSR system is very susceptible to alterations of its protein composition and amounts. A genetic analysis indicates a LiaF:LiaS:LiaR ratio of 18:4:1. An excess of LiaS over LiaR was subsequently verified by quantitative Western analysis. This stoichiometry, which is crucial to maintain a functional Lia system, differs from any other two‐component system studied to date, in which the response regulator is present in excess over the histidine kinase. Moreover, we demonstrate that LiaS is a bifunctional histidine kinase that acts as a phosphatase on LiaR in the absence of a suitable stimulus. An increased amount of LiaR – both in the presence and in the absence of LiaS – leads to a strong induction of PliaI activity due to phosphorylation of the response regulator by acetyl phosphate. Our data demonstrate that LiaRS, in contrast to other two‐component systems, is non‐robust with regard to perturbations of its stoichiometry. 相似文献
156.
The impact of man-made earthen barriers on the physical structure of New England tidal marshes (USA)
In New England salt marshes, man-made earthen barriers, or berms, are generally historic, small-scale (average height = 0.71 m ± 0.12 SE; average length = 166 m ± 41 SE) tidal restrictions which originated from past agricultural, industrial, and environmental practices. The orientation and size depends primarily on the original purpose of the barrier, but this study examines the effects of berms oriented parallel to the incoming tide such that some landward portion of the marsh receives a different tidal signal than the seaward portion. Our hypotheses considered the impacts of the altered hydrology on pore water chemistry and edaphic characteristics. The results indicate that the effect of berms on salt marsh physical structure varies significantly by site. Where the tidal flooding frequency is restricted and drainage is poor, the landward marsh shows pool development, high salinity and sulfide concentrations, and low vegetation cover. In contrast, where tidal flooding is inhibited but the marsh soils are well-drained, salinity and sulfide concentrations decrease and accelerated decomposition results in subsidence and reduced soil organic matter. Given these findings, impacts from berms may impair salt marsh function and resilience to invasive plants and sea level rise. 相似文献
157.
Jeffrey M Skerker Dacia Leon Morgan N Price Jordan S Mar Daniel R Tarjan Kelly M Wetmore Adam M Deutschbauer Jason K Baumohl Stefan Bauer Ana B Ibáñez Valerie D Mitchell Cindy H Wu Ping Hu Terry Hazen Adam P Arkin 《Molecular systems biology》2013,9(1)
The efficient production of biofuels from cellulosic feedstocks will require the efficient fermentation of the sugars in hydrolyzed plant material. Unfortunately, plant hydrolysates also contain many compounds that inhibit microbial growth and fermentation. We used DNA‐barcoded mutant libraries to identify genes that are important for hydrolysate tolerance in both Zymomonas mobilis (44 genes) and Saccharomyces cerevisiae (99 genes). Overexpression of a Z. mobilis tolerance gene of unknown function (ZMO1875) improved its specific ethanol productivity 2.4‐fold in the presence of miscanthus hydrolysate. However, a mixture of 37 hydrolysate‐derived inhibitors was not sufficient to explain the fitness profile of plant hydrolysate. To deconstruct the fitness profile of hydrolysate, we profiled the 37 inhibitors against a library of Z. mobilis mutants and we modeled fitness in hydrolysate as a mixture of fitness in its components. By examining outliers in this model, we identified methylglyoxal as a previously unknown component of hydrolysate. Our work provides a general strategy to dissect how microbes respond to a complex chemical stress and should enable further engineering of hydrolysate tolerance. 相似文献
158.
Morgan N Price Adam M Deutschbauer Jeffrey M Skerker Kelly M Wetmore Troy Ruths Jordan S Mar Jennifer V Kuehl Wenjun Shao Adam P Arkin 《Molecular systems biology》2013,9(1)
Gene regulation in bacteria is usually described as an adaptive response to an environmental change so that genes are expressed when they are required. We instead propose that most genes are under indirect control: their expression responds to signal(s) that are not directly related to the genes’ function. Indirect control should perform poorly in artificial conditions, and we show that gene regulation is often maladaptive in the laboratory. In Shewanella oneidensis MR‐1, 24% of genes are detrimental to fitness in some conditions, and detrimental genes tend to be highly expressed instead of being repressed when not needed. In diverse bacteria, there is little correlation between when genes are important for optimal growth or fitness and when those genes are upregulated. Two common types of indirect control are constitutive expression and regulation by growth rate; these occur for genes with diverse functions and often seem to be suboptimal. Because genes that have closely related functions can have dissimilar expression patterns, regulation may be suboptimal in the wild as well as in the laboratory. 相似文献
159.
Sebastian Ullrich Phillip Bremer Christine Neumann-Grutzeck Helge Otto Christoph Rüther Cay Uwe von Seydewitz Gerd Peter Meyer Keihan Ahmadi-Simab Joachim R?ther Barbara Hogan Wolfgang Schwenk Roman Fischbach J?rg Caselitz Jochen Puttfarcken Susanne Huggett Petra Tiedeken Jordan Pober Nancy C. Kirkiles-Smith Friedrich Hagenmüller 《PloS one》2013,8(2)
Objectives
Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli (STEC/EHEC) is one of the most common causes of Haemolytic Uraemic Syndrome (HUS) related to infectious haemorrhagic colitis. Nearly all recommendations on clinical management of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first to be caused by the serotype O104:H4. This EHEC strain was found to carry genetic features of Entero Aggregative E. coli (EAEC) and extended spectrum β lactamase (ESBL). We report symptoms and complications in patients at one of the most affected centres of the 2011 EHEC O104 outbreak in Northern Germany.Methods
The courses of patients admitted to our hospital due to bloody diarrhoea with suspected EHEC O104 infection were recorded prospectively. These data include the patients’ histories, clinical findings, and complications.Results
EHEC O104 infection was confirmed in 61 patients (female = 37; mean age: 44±2 years). The frequency of HUS was 59% (36/61) in our cohort. An enteric colonisation with co-pathogens was found in 57%. Thirty-one (51%) patients were treated with plasma-separation/plasmapheresis, 16 (26%) with haemodialysis, and 7 (11%) with Eculizumab. Patients receiving antibiotic treatment (n = 37; 61%) experienced no apparent change in their clinical course. Twenty-six (43%) patients suffered from neurological symptoms. One 83-year-old patient died due to comorbidities after HUS was successfully treated.Conclusions
EHEC O104:H4 infections differ markedly from earlier reports on O157:H7 induced enterocolitis in regard to epidemiology, symptomatology, and frequency of complications. We recommend a standard of practice for clinical monitoring and support the renaming of EHEC O104:H4 syndrome as “EAHEC disease”. 相似文献160.
Marcus May Sandor Batkai Alexander A. Zoerner Dimitrios Tsikas Jens Jordan Stefan Engeli 《PloS one》2013,8(4)
Microdialysis sampling of lipophilic molecules in human tissues is challenging because protein binding and adhesion to the membrane limit recovery. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) forms complexes with hydrophobic molecules thereby improving microdialysis recovery of lipophilic molecules in vitro and in rodents. We tested the approach in human subjects. First, we determined HP-ß-CD influences on metabolite stability, delivery, and recovery in vitro. Then, we evaluated HP-ß-CD as microdialysis perfusion fluid supplement in 20 healthy volunteers. We placed 20 kDa microdialysis catheters in subcutaneous abdominal adipose tissue and in the vastus lateralis muscle. We perfused catheters with lactate free Ringer solution with or without 10% HP-ß-CD at flow rates of 0.3–2.0 µl/min. We assessed tissue metabolites, ultrafiltration effects, and blood flow. In both tissues, metabolite concentrations with Ringer+HP-ß-CD perfusate were equal or higher compared to Ringer alone. Addition of HP-ß-CD increased dialysate volume by 10%. Adverse local or systemic reactions to HP-ß-CD did not occur and analytical methods were not disturbed. HP-ß-CD addition allowed to measure interstitial anandamide concentrations, a highly lipophilic endogenous molecule. Our findings suggest that HP-ß-CD is a suitable supplement in clinical microdialysis to enhance recovery of lipophilic molecules from human interstitial fluid. 相似文献