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151.
152.
Leventhal GE Kouyos R Stadler T Wyl Vv Yerly S Böni J Cellerai C Klimkait T Günthard HF Bonhoeffer S 《PLoS computational biology》2012,8(3):e1002413
Contact structure is believed to have a large impact on epidemic spreading and consequently using networks to model such contact structure continues to gain interest in epidemiology. However, detailed knowledge of the exact contact structure underlying real epidemics is limited. Here we address the question whether the structure of the contact network leaves a detectable genetic fingerprint in the pathogen population. To this end we compare phylogenies generated by disease outbreaks in simulated populations with different types of contact networks. We find that the shape of these phylogenies strongly depends on contact structure. In particular, measures of tree imbalance allow us to quantify to what extent the contact structure underlying an epidemic deviates from a null model contact network and illustrate this in the case of random mixing. Using a phylogeny from the Swiss HIV epidemic, we show that this epidemic has a significantly more unbalanced tree than would be expected from random mixing. 相似文献
153.
Roman Pleskot P?emysl Pejchar Viktor ?ársky Christopher J. Staiger Martin Potocky 《PLoS computational biology》2012,8(11)
The actin cytoskeleton is a dynamic structure that coordinates numerous fundamental processes in eukaryotic cells. Dozens of actin-binding proteins are known to be involved in the regulation of actin filament organization or turnover and many of these are stimulus-response regulators of phospholipid signaling. One of these proteins is the heterodimeric actin-capping protein (CP) which binds the barbed end of actin filaments with high affinity and inhibits both addition and loss of actin monomers at this end. The ability of CP to bind filaments is regulated by signaling phospholipids, which inhibit the activity of CP; however, the exact mechanism of this regulation and the residues on CP responsible for lipid interactions is not fully resolved. Here, we focus on the interaction of CP with two signaling phospholipids, phosphatidic acid (PA) and phosphatidylinositol (4,5)-bisphosphate (PIP2). Using different methods of computational biology such as homology modeling, molecular docking and coarse-grained molecular dynamics, we uncovered specific modes of high affinity interaction between membranes containing PA/phosphatidylcholine (PC) and plant CP, as well as between PIP2/PC and animal CP. In particular, we identified differences in the binding of membrane lipids by animal and plant CP, explaining previously published experimental results. Furthermore, we pinpoint the critical importance of the C-terminal part of plant CPα subunit for CP–membrane interactions. We prepared a GST-fusion protein for the C-terminal domain of plant α subunit and verified this hypothesis with lipid-binding assays in vitro. 相似文献
154.
Local field potentials (LFPs) are widely used to study the function of local networks in the brain. They are also closely correlated with the blood-oxygen-level-dependent signal, the predominant contrast mechanism in functional magnetic resonance imaging. We developed a new laminar cortex model (LCM) to simulate the amplitude and frequency of LFPs. Our model combines the laminar architecture of the cerebral cortex and multiple continuum models to simulate the collective activity of cortical neurons. The five cortical layers (layer I, II/III, IV, V, and VI) are simulated as separate continuum models between which there are synaptic connections. The LCM was used to simulate the dynamics of the visual cortex under different conditions of visual stimulation. LFPs are reported for two kinds of visual stimulation: general visual stimulation and intermittent light stimulation. The power spectra of LFPs were calculated and compared with existing empirical data. The LCM was able to produce spontaneous LFPs exhibiting frequency-inverse (1/ƒ) power spectrum behaviour. Laminar profiles of current source density showed similarities to experimental data. General stimulation enhanced the oscillation of LFPs corresponding to gamma frequencies. During simulated intermittent light stimulation, the LCM captured the fundamental as well as high order harmonics as previously reported. The power spectrum expected with a reduction in layer IV neurons, often observed with focal cortical dysplasias associated with epilepsy was also simulated. 相似文献
155.
Radially arranged cortical microtubules are a prominent feature of guard cells. We observed guard cells expressing GFP-tubulin (GFP-TUA6) with confocal microscopy and found recognizable changes in the appearance of microtubules when stomata open or close (Eisinger et al., 2012). In the present study, analysis of fluorescence distribution showed a dramatic increase in peak intensities of microtubule bundles within guard cells as stomata open. This increase was correlated with an increase in the total fluorescence that could be attributed to polymerized tubulin. Adjacent pavement cells did not show similar changes in peak intensities or integrated fluorescence when stomatal apertures changed. Imaging of RFP-tagged end binding protein 1 (EB1) and YFP-tagged α-tubulin expressed in the same cell revealed that the number of microtubules with growing ends remained constant, although the total amount of polymerized tubulin was higher in open than in closed guard cells. Taken together, these results indicate that the changes in microtubule array organization that are correlated with and required for normal guard cell function are characterized by changes in microtubule clustering or bundling. 相似文献
156.
Hydrolysis of phosphatidylinositol 4,5-bisphosphate mediates calcium-induced inactivation of TRPV6 channels 总被引:2,自引:0,他引:2
TRPV6 is a member of the transient receptor potential superfamily of ion channels that facilitates Ca(2+) absorption in the intestines. These channels display high selectivity for Ca(2+), but in the absence of divalent cations they also conduct monovalent ions. TRPV6 channels have been shown to be inactivated by increased cytoplasmic Ca(2+) concentrations. Here we studied the mechanism of this Ca(2+)-induced inactivation. Monovalent currents through TRPV6 substantially decreased after a 40-s application of Ca(2+), but not Ba(2+). We also show that Ca(2+), but not Ba(2+), influx via TRPV6 induces depletion of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2) or PIP(2)) and the formation of inositol 1,4,5-trisphosphate. Dialysis of DiC(8) PI(4,5)P(2) through the patch pipette inhibited Ca(2+)-dependent inactivation of TRPV6 currents in whole-cell patch clamp experiments. PI(4,5)P(2) also activated TRPV6 currents in excised patches. PI(4)P, the precursor of PI(4,5)P(2), neither activated TRPV6 in excised patches nor had any effect on Ca(2+)-induced inactivation in whole-cell experiments. Conversion of PI(4,5)P(2) to PI(4)P by a rapamycin-inducible PI(4,5)P(2) 5-phosphatase inhibited TRPV6 currents in whole-cell experiments. Inhibiting phosphatidylinositol 4 kinases with wortmannin decreased TRPV6 currents and Ca(2+) entry into TRPV6-expressing cells. We propose that Ca(2+) influx through TRPV6 activates phospholipase C and the resulting depletion of PI(4,5)P(2) contributes to the inactivation of TRPV6. 相似文献
157.
Anna Halmikov Pavla Heringov Jana Kaprkov Francesco P. Intini Giovanni Natile Alina Nemirovski Dan Gibson Viktor Brabec 《Journal of inorganic biochemistry》2008,102(5-6):1077
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes. 相似文献
158.
Kress M Karasek J Ferrer-Montiel AV Scherbakov N Haberberger RV 《Histochemistry and cell biology》2008,130(4):655-667
Transient receptor potential (TRP) channels of the TRPV, TRPA, and TRPM subfamilies play important roles in somatosensation including nociception. While particularly the Thermo TRPs have been extensively investigated in sensory neurons, the relevance of the subclass of "canonical" TRPC channels in primary afferents is yet elusive. In the present study, we investigated the presence and contribution to Ca(2+) transients of TRPC channels in dorsal root ganglion neurons. We found that six of the seven known TRPC subtypes were expressed in lumbar DRG, with TRPC1, C3, and C6 being the most abundant. Microfluorimetric calcium measurements showed Ca(2+) influx induced by oleylacylglycerol (OAG), an activator of the TRPC3/C6/C7 subgroup. Furthermore, OAG induced rises in [Ca(2+)](i) were inhibited by SKF96365, an inhibitor of receptor and store operated calcium channel. OAG induced calcium transients were also inhibited by blockers of diacylglycerol (DAG) lipase, lipoxygenase or cyclooxygenase and, intriguingly, by inhibitors of the capsaicin receptor TRPV1. Notably, SKF96365 did not affect capsaicin-induced calcium transients. Taken together, our findings suggest that TRPC are functionally expressed in subpopulations of DRG neurons. These channels, along with TRPV1, contribute to calcium homeostasis in rat sensory neurons. 相似文献
159.
Prokhorov DA Timchenko AA Uversky VN Khristoforov VS Kihara H Kimura K Kutyshenko VP 《Biochimica et biophysica acta》2008,1784(5):834-842
Aggregation and subsequent development of protein deposition diseases originate from conformational changes in corresponding amyloidogenic proteins. Many proteins unrelated to amyloidoses also fibrillate at the appropriate conditions. These proteins serve as a model for studying the processes of protein misfolding, oligomerization and fibril formation. The accumulated data support the model where protein fibrillogenesis proceeds via the formation of a relatively unfolded amyloidogenic conformation. The urea-induced unfolding of bovine carbonic anhydrase II, BCA II, is characterized by a combination of high-resolution NMR, circular dichroism spectroscopy and small angle X-ray scattering. It is shown that the formation of associates of protein molecules in complex with solvent (water and urea), APS, takes place in the presence of 4-6 M urea. The subsequent increase in urea concentration to 8 M is accompanied by a disruption of APS and leads to a complete unfolding of a protein molecule. Analysis of BCA II self-association in the presence of 4.2 M urea revealed that APS are relatively large mostly beta-structural blocks with the averaged molecular mass of 190-220 kDa. This work also demonstrates some novel NMR-based methodological approaches that provide useful information on protein self-association. 相似文献
160.
Ricci C Pastukh V Leonard J Turrens J Wilson G Schaffer D Schaffer SW 《American journal of physiology. Cell physiology》2008,294(2):C413-C422
Recently, it has become apparent that mitochondrial DNA (mtDNA) damage can rapidly initiate apoptosis independent of mutations, although the mechanism involved remains unclear. To elucidate this mechanism, angiotensin II-mediated apoptosis was studied in cells that were transduced with a lentiviral vector to overexpress the DNA repair enzyme 8-oxoguanine glycosylase or were treated with inhibitors known to block angiotensin II-induced mtDNA damage. Cells exhibiting angiotensin II-induced mtDNA damage showed two phases of superoxide generation, the first derived from NAD(P)H oxidase and the second of mitochondrial origin, whereas cells prevented from experiencing mtDNA damage importantly exhibited only the first phase. Furthermore, cells with mtDNA damage demonstrated impairments in mitochondrial protein expression, cellular respiration, and complex 1 activity before the onset of the second phase of oxidation. After the second phase, the mitochondrial membrane potential collapsed, cytochrome c was released, and the cells underwent apoptosis, all of which were prevented by disrupting mtDNA damage. Collectively, these data reveal a novel mechanism of apoptosis that is initiated when mtDNA damage triggers mitochondrial superoxide generation and ultimately the activation of the mitochondrial permeability transition. This novel mechanism may play an important pathological role. angiotensin II; mitochondrial permeability transition pore; NADPH oxidase 相似文献