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91.
92.
Onur Basak Maaike van de Born Jeroen Korving Joep Beumer Stefan van der Elst Johan H van Es Hans Clevers 《The EMBO journal》2014,33(18):2057-2068
Cycling Lgr5+ stem cells fuel the rapid turnover of the adult intestinal epithelium. The existence of quiescent Lgr5+ cells has been reported, while an alternative quiescent stem cell population is believed to reside at crypt position +4. Here, we generated a novel Ki67RFP knock-in allele that identifies dividing cells. Using Lgr5-GFP;Ki67RFP mice, we isolated crypt stem and progenitor cells with distinct Wnt signaling levels and cell cycle features and generated their molecular signature using microarrays. Stem cell potential of these populations was further characterized using the intestinal organoid culture. We found that Lgr5high stem cells are continuously in cell cycle, while a fraction of Lgr5low progenitors that reside predominantly at +4 position exit the cell cycle. Unlike fast dividing CBCs, Lgr5low Ki67− cells have lost their ability to initiate organoid cultures, are enriched in secretory differentiation factors, and resemble the Dll1 secretory precursors and the label-retaining cells of Winton and colleagues. Our findings support the cycling stem cell hypothesis and highlight the cell cycle heterogeneity of early progenitors during lineage commitment. 相似文献
93.
Nihal Simsek Ozek I. Burak Bal Yildirim Sara Rustu Onur Feride Severcan 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Statins are the most commonly used drugs for the treatment of hypercholesterolemia. Their most frequent side effect is myotoxicity. To date, it remains unclear whether statins preferentially induce myotoxicity in fast- or in slow-twitch muscles. Therefore, we investigated these effects on fast- (extensor digitorum longus; EDL), slow- (soleus; SOL), and mixed-twitch muscles (diaphragm; DIA) in rats by comparing their contractile and molecular structural properties.Methods
Simvastatin-induced functional changes were determined by muscle contraction measurements, and drug-induced molecular changes were investigated using Fourier transform infrared (FTIR) and attenuated total reflectance (ATR) FTIR spectroscopy.Results
With simvastatin administration (30 days, 50 mg/kg), a depression in the force–frequency curves in all muscles was observed, indicating the impairment of muscle contractility; however, the EDL and DIA muscles were affected more severely than the SOL muscle. Spectroscopic findings also showed a decrease in protein, glycogen, nucleic acid, lipid content and an increase in lipid order and lipid dynamics in the simvastatin-treated muscles. The lipid order and dynamics directly affect membrane thickness. Therefore, the kinetics and functions of membrane ion channels were also affected, contributing to the statin-induced impairment of muscle contractility. Furthermore, a reduction in α-helix and β-sheet and an increase in random coil, aggregated and antiparallel β-sheet were observed, indicating the protein denaturation. Spectral studies showed that the extent of molecular structural alterations in the muscles following simvastatin administration was in the order EDL > DIA > SOL.Conclusions
Simvastatin-induced structural and functional alterations are more profound in the fast-twitch than in the slow-twitch muscles.General significance
Myotoxic effects of simvastatin are primarily observed in the fast-twitch muscles. 相似文献94.
95.
Yukio Furukawa Shunsuke Teraguchi Takahisa Ikegami Onur Dagliyan Lin Jin Damien Hall Nikolay V. Dokholyan Keiichi Namba Shizuo Akira Tomohiro Kurosaki Yoshihiro Baba Daron M. Standley 《Journal of molecular biology》2014
Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein–protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2 + concentration. The oligomerization of STIM1, which triggers extracellular Ca2 + influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca2 + concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2 + concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2 + concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca2 + influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2 + loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2 +-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion. 相似文献
96.
While the subject of learning has attracted immense interest from both behavioral and neural scientists, only relatively few investigators have observed single-neuron activity while animals are acquiring an operantly conditioned response, or when that response is extinguished. But even in these cases, observation periods usually encompass only a single stage of learning, i.e. acquisition or extinction, but not both (exceptions include protocols employing reversal learning; see Bingman et al.1 for an example). However, acquisition and extinction entail different learning mechanisms and are therefore expected to be accompanied by different types and/or loci of neural plasticity.Accordingly, we developed a behavioral paradigm which institutes three stages of learning in a single behavioral session and which is well suited for the simultaneous recording of single neurons'' action potentials. Animals are trained on a single-interval forced choice task which requires mapping each of two possible choice responses to the presentation of different novel visual stimuli (acquisition). After having reached a predefined performance criterion, one of the two choice responses is no longer reinforced (extinction). Following a certain decrement in performance level, correct responses are reinforced again (reacquisition). By using a new set of stimuli in every session, animals can undergo the acquisition-extinction-reacquisition process repeatedly. Because all three stages of learning occur in a single behavioral session, the paradigm is ideal for the simultaneous observation of the spiking output of multiple single neurons. We use pigeons as model systems, but the task can easily be adapted to any other species capable of conditioned discrimination learning. 相似文献
97.
Susan Strome William G. Kelly Sevinc Ercan Jason D. Lieb 《Cold Spring Harbor perspectives in biology》2014,6(3)
Dosage compensation, which regulates the expression of genes residing on the sex chromosomes, has provided valuable insights into chromatin-based mechanisms of gene regulation. The nematode Caenorhabditis elegans has adopted various strategies to down-regulate and even nearly silence the X chromosomes. This article discusses the different chromatin-based strategies used in somatic tissues and in the germline to modulate gene expression from the C. elegans X chromosomes and compares these strategies to those used by other organisms to cope with similar X-chromosome dosage differences. 相似文献
98.
Cecilia Conaco Pantelis Tsoulfas Onur Sakarya Amanda Dolan John Werren Kenneth S. Kosik 《PloS one》2016,11(3)
Horizontal gene transfer (HGT) is common between prokaryotes and phagotrophic eukaryotes. In metazoans, the scale and significance of HGT remains largely unexplored but is usually linked to a close association with parasites and endosymbionts. Marine sponges (Porifera), which host many microorganisms in their tissues and lack an isolated germ line, are potential carriers of genes transferred from prokaryotes. In this study, we identified a number of potential horizontally transferred genes within the genome of the sponge, Amphimedon queenslandica. We further identified homologs of some of these genes in other sponges. The transferred genes, most of which possess catalytic activity for carbohydrate or protein metabolism, have assimilated host genome characteristics and are actively expressed. The diversity of functions contributed by the horizontally transferred genes is likely an important factor in the adaptation and evolution of A. queenslandica. These findings highlight the potential importance of HGT on the success of sponges in diverse ecological niches. 相似文献
99.
Zhiling Zhang Camilla A. Nix Utku K. Ercan Jonathan A. Gerstenhaber Suresh G. Joshi Yinghui Zhong 《PloS one》2014,9(1)
Infection and inflammation are common complications that seriously affect the functionality and longevity of implanted medical implants. Systemic administration of antibiotics and anti-inflammatory drugs often cannot achieve sufficient local concentration to be effective, and elicits serious side effects. Local delivery of therapeutics from drug-eluting coatings presents a promising solution. However, hydrophobic and thick coatings are commonly used to ensure sufficient drug loading and sustained release, which may limit tissue integration and tissue device communications. A calcium-mediated drug delivery mechanism was developed and characterized in this study. This novel mechanism allows controlled, sustained release of minocycline, an effective antibiotic and anti-inflammatory drug, from nanoscale thin hydrophilic polyelectrolyte multilayers for over 35 days at physiologically relevant concentrations. pH-responsive minocycline release was observed as the chelation between minocycline and Ca2+ is less stable at acidic pH, enabling ‘smart’ drug delivery in response to infection and/or inflammation-induced tissue acidosis. The release kinetics of minocycline can be controlled by varying initial loading, Ca2+ concentration, and Ca2+ incorporation into different layers, enabling facile development of implant coatings with versatile release kinetics. This drug delivery platform can potentially be used for releasing any drug that has high Ca2+ binding affinity, enabling its use in a variety of biomedical applications. 相似文献
100.
Z S Ercan 《Archives internationales de physiologie et de biochimie》1975,83(4):799-807
The influence of A II and PGE2 on the rise of perfusion pressure induced by periarterial stimulation and NA were studied in the rabbit isolated perfused kidney. Periarterial stimulation produced an increase in perfusion pressure and the venous outflow superfusing the rabbit aortic strip caused the muscle to contract. Both effects were found to be frequency dependent. NA induced similar effect when given into the renal artery. A II and its N-terminal analogs produced equal potentiation to periarterial stimulation without altering the effect of exogenous NA when added to the perfusion medium. DMGIA II which is a competitive inhibitor of A II inhibited the potentiating affect of A II. PGE2 also inhibited the effect of A II without altering the effect of exogenous NA. Addition of aspirin to the perfusion medium caused a potentiation to periarteral stimulation but did not change the effect of NA. A II added to the perfusion fluid containing aspirin still caused potentiation. From these results it was concluded that: (i) A II-induced potentiation to periarterial stimulation is mediated via specific receptors and probably due to facilitation of the release of transmitter from sympathetic nerve ending. (ii) PGE2 inhibited the release of transmitter. The effect of A II and PGE2 seemed to be mediated by independent mechanisms. 相似文献