Different efflux rates may determine the cellular accumulation of various bis(guanylhydrazones).
Ontology highlight
ABSTRACT:
SUBMITTER: Alhonen-Hongisto L
PROVIDER: S-EPMC1144031 | biostudies-other | 1984 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Cancer is believed to be a result of accumulated mutations. However, this concept has not been fully confirmed owing to the impossibility of tracking down the ancestral somatic cell. We sought to verify the concept by exploring the correlation between cancer risk and mutation accumulation among different tissues. We hypothesized that the detected mutations through bulk tumor sequencing are commonly shared in majority, if not all, of tumor cells and are therefore largely a reflection of the mutations accumulated in the ancestral cell that gives rise to tumor. We collected a comprehensive list of mutation frequencies revealed by bulk tumor sequencing, and investigated its correlation with cancer risk to mirror the correlation between mutation accumulation and cancer risk. This revealed an approximate 1:1 relationship between mutation frequency and cancer risk in 41 different cancer types based on the sequencing data of 5,542 patients. The correlation strongly suggests that variation in cancer risk among tissues is mainly attributable to distinct mutation accumulation rates. Moreover, the correlation establishes a baseline to evaluate the effect of non-mutagenic carcinogens on cancer risk. Finally, our mathematic modeling provides a reasonable explanation to reinforce that cancer risk is predominantly determined by the first rate-limiting mutation.
| S-EPMC4726417 | biostudies-literature
Project description:Protein synthesis is costly and the proteome size is constrained. Using a genome-scale computational model of proteome allocation together with absolute proteomics data sets from many growth environments, we determine how these fundamental limitations constrain growth and fitness in Escherichia coli. First, we show that the observed variation in growth rates across environments is largely determined by the expression of protein not utilized for growth in a given environment. We then elucidate the overall transcriptional regulatory logic that underlies the expression of unused protein. We systematically classify the unused proteome into segments devoted to environmental readiness and stress resistance functions. While expression of these proteome segments incurs a fitness cost of decreased growth in a fixed environment, they provide fitness benefits in a changing environment. Thus, the systems biology of the prokaryotic proteome can be quantitatively understood based on resource allocation to growth, environmental readiness, and stress resistance functions.
2018-08-01 | GSE72020 | GEO
Project description:Cu(+)-ATPases play a key role in bacterial Cu(+) homeostasis by participating in Cu(+) detoxification and cuproprotein assembly. Characterization of Archaeoglobus fulgidus CopA, a model protein within the subfamily of P(1B-1) type ATPases, has provided structural and mechanistic details on this group of transporters. Atomic resolution structures of cytoplasmic regulatory metal binding domains (MBDs) and catalytic actuator, phosphorylation, and nucleotide binding domains are available. These, in combination with whole protein structures resulting from cryo-electron microscopy analyses, have enabled the initial modeling of these transporters. Invariant residues in helixes 6, 7 and 8 form two transmembrane metal binding sites (TM-MBSs). These bind Cu(+) with high affinity in a trigonal planar geometry. The cytoplasmic Cu(+) chaperone CopZ transfers the metal directly to the TM-MBSs; however, loading both of the TM-MBSs requires binding of nucleotides to the enzyme. In agreement with the classical transport mechanism of P-type ATPases, occupancy of both transmembrane sites by cytoplasmic Cu(+) is a requirement for enzyme phosphorylation and subsequent transport into the periplasmic or extracellular milieus. Recent transport studies have shown that all Cu(+)-ATPases drive cytoplasmic Cu(+) efflux, albeit with quite different transport rates in tune with their various physiological roles. Archetypical Cu(+)-efflux pumps responsible for Cu(+) tolerance, like the Escherichia coli CopA, have turnover rates ten times higher than those involved in cuproprotein assembly (or alternative functions). This explains the incapability of the latter group to significantly contribute to the metal efflux required for survival in high copper environments.
| S-EPMC3092005 | biostudies-literature
Project description:Biochar-different rates Raw sequence reads
| PRJNA1015743 | ENA
Project description:Currently existing theories predict that because deleterious mutations accumulate at a higher rate, selfing populations suffer from more intense genetic degradation relative to outcrossing populations. This prediction may not always be true when we consider a potential difference in deleterious mutation rate between selfers and outcrossers. By analyzing the evolutionary stability of selfing and outcrossing in an infinite population, we found that the genome-wide deleterious mutation rate would be lower in selfing than in outcrossing organisms. When this difference in mutation rate was included in simulations, we found that in a small population, mutations accumulated more slowly under selfing rather than outcrossing. This result suggests that under frequent and intense bottlenecks, a selfing population may have a lower risk of genetic extinction than an outcrossing population.
| S-EPMC3308984 | biostudies-literature
Project description:Gram-negative infections are increasingly difficult to treat because of their impermeable outer membranes (OM) and efflux pumps which maintain a low intracellular accumulation of antibiotics within cells. Historically, measurement of accumulation of drugs or dyes within Gram-negative cells has concentrated on analyzing whole bacterial populations. Here, we have developed a method to measure the intracellular accumulation of ethidium bromide, a fluorescent DNA intercalating dye, in single cells using flow cytometry. Bacterial cells were stained with SYTOTM 84 to easily separate cells from background cell debris. Ethidium bromide fluorescence was then measured within the SYTOTM 84 positive population to measure accumulation. In S. Typhimurium SL1344, ethidium bromide accumulation was low, however, in a number of efflux mutants, accumulation of ethidium bromide increased more than twofold, comparable to previous whole population analysis of accumulation. We demonstrate simultaneous measurement of ethidium bromide accumulation and GFP allowing quantification of gene expression or other facets of phenotype in single cells. In addition, we show here that this assay can be adapted for use with efflux inhibitors, with both Gram-negative and Gram-positive bacteria, and with other fluorescent substrates with different fluorescence spectra.
| S-EPMC6787898 | biostudies-literature
Project description:The heterogeneity in mammalian cells signaling response is largely a result of pre-existing cell-to-cell variability. It is unknown whether cell-to-cell variability rises from biochemical stochastic fluctuations or distinct cellular states. Here, we utilize calcium response to adenosine trisphosphate as a model for investigating the structure of heterogeneity within a population of cells and analyze whether distinct cellular response states coexist. We use a functional definition of cellular state that is based on a mechanistic dynamical systems model of calcium signaling. Using Bayesian parameter inference, we obtain high confidence parameter value distributions for several hundred cells, each fitted individually. Clustering the inferred parameter distributions revealed three major distinct cellular states within the population. The existence of distinct cellular states raises the possibility that the observed variability in response is a result of structured heterogeneity between cells. The inferred parameter distribution predicts, and experiments confirm that variability in IP3R response explains the majority of calcium heterogeneity. Our work shows how mechanistic models and single-cell parameter fitting can uncover hidden population structure and demonstrate the need for parameter inference at the single-cell level.
| S-EPMC5199124 | biostudies-literature
Project description:Interleukin-32 (IL-32) is a pro-inflammatory cytokine and its effects in various inflammatory diseases have been investigated. However, the role of IL-32 on atherosclerosis, an inflammatory disease, remains unknown. The present study examined the use of IL-32?, the most abundant transcript of IL-32, in the treatment of oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages for 24 h, which simulates a foam cell formation model. The effect of IL-32? (20, 50 and 100 ng/ml) on lipid deposition in the macrophages was analyzed using Oil Red O staining, while the cholesterol efflux on apolipoprotein A-I was also measured. The mRNA and protein expression levels of peroxisome proliferator-activated receptor ? (PPAR?), liver X receptor ? (LXR?), ATP-binding cassette transporter A1 (ABCA1) and ABCG1 were quantified by reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The results indicated that IL-32? exposure enhanced the lipid deposition and attenuated the cholesterol efflux from ox-LDL-stimulated THP-1 macrophages in a dose-dependent manner. Furthermore, the expression levels of ABCA1, LXR? and PPAR? were dose-dependently decreased by IL-32? at the mRNA and protein levels. Addition of the PPAR? agonist 15d-PGJ2 or overexpression of PPAR? in THP-1 macrophages abrogated the IL-32?-mediated inhibition of cholesterol efflux and reversed the IL-32?-mediated downregulation of ABCA1 and LXR?. In conclusion, IL-32? enhances lipid accumulation and inhibits cholesterol efflux from ox-LDL-exposed THP-1 macrophages by regulating the PPAR?-LXR?-ABCA1 pathway.
| S-EPMC5526182 | biostudies-literature
Project description:It has been reported that low cell-cholesterol efflux capacity (CEC) of HDL is an independent risk factor for CVD. To better understand CEC regulation, we measured ABCA1- and scavenger receptor class B type I (SR-BI)-dependent cell-cholesterol efflux, HDL anti-oxidative capacity, HDL particles, lipids, and inflammatory- and oxidative-stress markers in 122 subjects with elevated plasma levels of triglyceride (TG), serum amyloid A (SAA), fibrinogen, myeloperoxidase (MPO), or β-sitosterol and in 146 controls. In controls, there were strong positive correlations between ABCA1-dependent cholesterol efflux and small preβ-1 concentrations (R2 = 0.317) and SR-BI-dependent cholesterol efflux and large (α-1 + α-2) HDL particle concentrations (R2 = 0.774). In high-TG patients, both the concentration and the functionality (preβ-1 concentration-normalized ABCA1 efflux) of preβ-1 particles were significantly elevated compared with controls; however, though the concentration of large particles was significantly decreased, their functionality (large HDL concentration-normalized SR-BI efflux) was significantly elevated. High levels of SAA or MPO were not associated with decreased functionality of either the small (preβ-1) or the large (α-1 + α-2) HDL particles. HDL anti-oxidative capacity was negatively influenced by high plasma β-sitosterol levels, but not by the concentrations of HDL particles, TG, SAA, fibrinogen, or MPO. Our data demonstrate that under certain conditions CEC is influenced not only by quantitative (concentration), but also by qualitative (functional) properties of HDL particles.
| S-EPMC5454514 | biostudies-literature
Project description:Pore-forming toxins (PFTs) form multimeric trans-membrane pores in cell membranes that differ in pore channel diameter (PCD). Cellular resistance to large PFTs (>20 nm PCD) was shown to rely on Ca2+ influx activated membrane repair mechanisms. Small PFTs (<2 nm PCD) were shown to exhibit a high cytotoxic activity, but host cell response and membrane repair mechanisms are less well studied. We used monocytic immune cell lines to investigate the cellular resistance and host membrane repair mechanisms to small PFTs lysenin (Eisenia fetida) and aerolysin (Aeromonas hydrophila). Lysenin, but not aerolysin, is shown to induce Ca2+ influx from the extracellular space and to activate Ca2+ dependent membrane repair mechanisms. Moreover, lysenin binds to U937 cells with higher efficiency as compared to THP-1 cells, which is in line with a high sensitivity of U937 cells to lysenin. In contrast, aerolysin equally binds to U937 or THP-1 cells, but in different plasma membrane areas. Increased aerolysin induced cell death of U937 cells, as compared to THP-1 cells, is suggested to be a consequence of cap-like aerolysin binding. We conclude that host cell resistance to small PFTs attack comprises binding efficiency, pore localization, and capability to induce Ca2+ dependent membrane repair mechanisms.
| S-EPMC7914786 | biostudies-literature