Contributors:Maeike Zijlmans, Julia Jacobs, Rina Zelmann, François Dubeau, Jean Gotman
The relation between seizure frequency per month and number of channels with (A) ripples (>1/min), (B) fast ripples (>1/min), and (C) more than 20 fast ripples per minute. There were no patients with 0 channels with ripples (>1/min; A), but there were patients with 0 channels with fast ripples (>1 or >20/min; B and C). The seizure frequency was shown on a logarithmic scale, because of the distribution. As indicated in the text, there was no correlation between seizure frequency per month and the number of channels with more than 1 ripple or fast ripple per minute, but there was a positive correlation between seizure frequency and more than 20 fast ripples per minute.
... This table shows the correlation coefficients Rho for different alternative comparisons: seizure frequency (seizures/month) compared to the number and percentage of channels with ripples, fast ripples, spikes and ripples and fast ripples without spikes (first two lines), seizure frequency compared to number of channels with higher rates of ripples and fast ripples (>5, >10 and >20, lines 3–5) and number of seizure-days/month compared to channels with ripples and fast ripples. All comparisons were done for all patients, all patients with temporal lobe epilepsy and all patients with unilateral mesiotemporal seizure onset.
Contributors:Maeike Zijlmans, Julia Jacobs, Yusuf U. Kahn, Rina Zelmann, François Dubeau, Jean Gotman
Channels with potential muscle artefacts were excluded from the analysis. This was done by reviewing the SEEG at normal time scale with a filter of 80Hz together with the available epidural, ECG and EMG channels. Muscle artifact can be recognized as a simultaneous high frequency artifact over channels that are potentially outside of the brain, like channels LS6-7 and above, LC5-6 and above and RS5-6 and above in this example. Another clue could be obtained by filtering at lower frequencies as well. If still in doubt, the signal was reviewed at a timescale showing all samples. Muscle artifact shows a less sinusoid shape than HFOs and the frequency spectrum shows relatively more frequencies (Otsubo et al., 2008). Whenever there was doubt, the channel was excluded.
... High frequencyoscillations
RANKL-induces Ca2+ oscillations and transient cation currents in RAW 264.7 cells. RAW 264.7 cells were cultured with or without RANKL (30ng/ml) or GST-RANKL (20ng/ml) for 18h and intracellular Ca2+ concentration ([Ca2+]i) and membrane currents were recorded. (A) Spontaneous Ca2+ oscillations in six cells treated with RANKL for 18h were reversibly inhibited by an application of ruthenium red (5μM RR), an inhibitor of TRPV channels. Traces shown in the panel were obtained from six independent cells. (B) Average frequency of [Ca2+]i oscillations (times per 10min) before (control; n=10) and after application of ruthenium red (RR, 5μM; n=10). Each column indicates mean±SEM. Number of cells studied is indicated in parentheses. **PFrequency (times per 1min) of transient inward currents (only counting those with an amplitudes of more than 2pA/pF) before and after application of ruthenium red (RR, 10μM). Each column indicates mean±SEM from number of cells (n) studied. **P<0.01.
... Inhibition of RANKL-induced Ca2+ oscillations by tetracycline-inducible shRNA silencing targeted to store-operated Ca2+ entry associated proteins in RAW264.7/teton/shStim1 or/shOrai1 cells. (A) and (B) RAW264.7/teton/shStim1 (A) or/shOrai1 (B) cells were incubated for 24h in the absence (a) or presence (b) of tetracycline (1μg/ml) and then treated with RANKL (30ng/ml) for 18h, and [Ca2+]i was measured. The changes in [Ca2+]i shown in each graph were simultaneously recorded from four or five cells. Expression of Stim1 (A) or Orai1 (B) protein was reduced in tetracycline treated (tetracycline +) cells as compared to untreated (tetracycline −) cells.
... Effects of PLC inhibitor, U73122, on RANKL-induced [Ca2+]i oscillations and transiently activated cation currents in RAW 264.7/teton/shRNA/TRPV2 cells. Cells treated with RANKL for 18h in the absence of tetracycline were exposed to a phosphlipase C inhibitor, U73343 and its inactive analogue (U73122). (A) Effects of U73343 (10μM) and U73122 (10μM) on Ca2+ oscillations. Recordings were obtained from four cells. (B) Frequency of [Ca2+]i oscillations (times per 10min) before (control; n=12) and 10min after treatment with U73343 (n=5) or U73122 (n=10). Each column indicates mean±SEM. Number of cells studied is indicated in parentheses. **PFrequency (times per 1min) of the transiently activated inward currents (only counting those with amplitude of more than 2pA/pF), before and 15min after treatment with U73343 or U73122. Each column indicates mean±SEM from number of cells (n) studied. **P<0.01.
... Calcium oscillations... Inhibition of RANKL-induced transient activation of cation currents by TRPV2 silencing in RAW 264.7/teton/shTRPV2 cells. RAW 264.7/teton/shTRPV2 cells were cultured with RANKL (30ng/ml) for 18h in the absence (A) or presence (B) of tetracycline (1μg/ml) or doxycycline (10ng/ml) and whole-cell currents (at a membrane potential of −60mV) were recorded using the whole-cell configuration of patch-clamp technique. (C) Frequency (times per 1min) of the transiently activated inward currents (only counting those with amplitudes of more than 2pA/pF) was determined in cells treated with (tetracycline +, closed columns) or without tetracycline (tetracycline −, open columns). Each column indicates mean±SEM. Number of cells studied is indicated in parentheses. **P<0.01.
... Inhibition of RANKL-induced Ca2+ oscillations by tetracycline-inducible shRNA silencing targeted to TRPV2 in RAW264.7/teton/shTRPV2 cells. RAW264.7/teton/shTRPV2 cells were incubated for 24h in the absence (A) or presence (B) of tetracycline (1μg/ml) or doxycycline (10ng/ml) and then treated with RANKL (30ng/ml) for 18h, and their [Ca2+]i was measured. Changes in [Ca2+]i shown in each graph were simultaneously recorded from four cells. (C) Expression of TRPV2 protein was reduced in tetracycline treated (tetracycline +) cells as compared to untreated (tetracycline −) cells. (D) Mean frequency of [Ca2+]i oscillations in cells before (0h) and 18h or 48h after RANKL-treatment in the presence (tetracycline +, closed columns) or absence (tetracycline −, open columns) of tetracycline. Each column indicates mean±SEM. Number of cells studied is indicated in parentheses. **P<0.01.
Contributors:Cheemeng Tan, Faisal Reza, Lingchong You
Critical frequency for the one-stage gene circuit. (A) The amplitude of output oscillations decreased with fin. fc was calculated as the intersection between the “average noise level” curve and the “oscillation amplitude” curve. (B) Calculations of fout for varying fin using stochastic simulations. (C) Fraction of stochastic simulations that generated correct fout (i.e., where fout=fin).
... Analysis of frequency signals with noise. (A) A one-stage gene circuit where the output protein P is controlled by a transcription activator, A. (B) An oscillatory input signal can generate an output signal with oscillations compounded with noise. The mean and standard deviation of the output signal of the linearized model can be analytically computed. Here, we define the mean value as the oscillatory component and the standard deviation as the noise component. Alternatively, the stochastic simulations of the output signal for the nonlinear system can be analyzed by the FFT method to obtain its dominant frequency (see Methods for more details).
... Transmission of a multiplexed signal. (A) A multiplexed input signal. (B) The corresponding output signal computed by stochastic simulation. (C) Power spectra of the input signal. (D) Power spectra of the output signal. Power spectra of the output signal indicate that all three frequencies were transmitted with complete fidelity. Even though power spectra decreased when the input frequency increased, they were still at least 10-fold higher than the power spectra of background noise. Three frequencies (0.005/min, 0.0067/min, and 0.01/min) were multiplexed in a composite signal with an amplitude of five molecules for each input frequency.
Contributors:Jingjing Wang, Da Chen, Yan Xu, Weihui Liu
The resonant frequencies (fs and fp) of the FBAR before and after the immobilization of artificial antigens on the sensing Au surface.
... The dependence of parameter kobs on the MAb concentrations. The experimental points (mean values from five measurements) represent results of fitting of the time-dependent frequency profiles.
... The frequency spectrum of the FBAR oscillator after the PBS was injected into the testing channel.
... (a) The circuit diagrams and (b) an assembled circuitry of the FBAR oscillator.
... The typical time-dependent frequency profiles when the pure parathion MAb solution and the mixed solution of parathion and MAb were respectively injected into the testing channel. (a) working in PBS; (b) injection of the solution; (c) injection of glycine–HCl buffer; (d) another injection of PBS.
Contributors:Simone Guadagna, Christoffer Bundgaard, Nanna Hovelsø, Christiane Volbracht, Paul T. Francis, Jan Egebjerg, Florence Sotty
Effect of MK-801 (0.05 and 0.2mg/kg i.p.) and memantine (2.5 and 10mg/kg s.c.) on the peak frequency of pedunculopontine-induced hippocampal theta in anesthetized mice. Changes in theta peak frequency following vehicle (0.9% NaCl), MK-801 (a) and memantine (b) were compared to the frequency before drug administration. Data are represented as mean±SEM, and were analyzed by a two-way ANOVA followed by Bonferoni post-hoc analysis. * p<0.05.
... Effect of vehicle, MK-801 (0.05 and 0.2mg/kg i.p.) and memantine (2.5 and 10mg/kg s.c.) on spontaneous oscillatory activity in anesthetized mice. Power spectra showing the effect of vehicle (0.9% NaCl) (a), MK-801 (0.05 and 0.2mg/kg i.p., b and c, respectively), and memantine (2.5 and 10mg/kg s.c., d and e, respectively) on frequencies between 0 and 20 (Hz) (left panel) and on frequencies between 20 and 60Hz (right panel). The power spectrum between 0 and 80Hz was analyzed on a 5s period immediately preceding the onset of stimulation. Power spectral analysis was performed for each animal before (average over a 15min period preceding the injection) and after drug administration (average over a 15min period starting 45min after injection). For each animal, the power within each frequency band (resolution of 0.24Hz) was further normalized to the total power between 0 and 80Hz. Average (mean±SEM) power spectra for all animals in each group are represented before (gray lines) and following drug treatment (black lines).
... Effect of vehicle, MK-801 (0.05 and 0.2mg/kg i.p.) and memantine (2.5 and 10mg/kg s.c.) on hippocampal oscillatory activity during stimulation of the pedunculopontine nucleus in anesthetized mice. Power spectra showing the effect of vehicle (0.9% NaCl) (a), MK-801 (0.05 and 0.2mg/kg i.p., b and c, respectively), and memantine (2.5 and 10mg/kg s.c., d and e, respectively) on frequencies between 0 and 20 (Hz) (left panel) and on frequencies between 20 and 60Hz (right panel). The power spectrum between 0 and 80Hz was analyzed for each animal before (average over a 15min period preceding the injection) and after drug administration (average over a 15min period starting 45min after injection). For each animal, the power within each frequency band (resolution of 0.24Hz) was further normalized to the total power between 0 and 80Hz. Average (mean±SEM) power spectra for all animals in each group are represented before (gray lines) and following drug treatment (black lines).
Effect of parameters on robust signal transfer to p-AKT in the presence of noise. For each plot, three values of the parameter are chosen based on the nominal condition. The input insulin oscillation is same as Fig. 7. (A) Effect of PTEN. PTEN is kept at 0.5, 1.0 and 1.5. (B) Effect of negative feedback parameter, Kd. Increasing strength of negative feedback leads to attenuation of output amplitude. (C) Effect of receptor activation rates. Increasing active receptor levels can lead to suppression of the signal due to saturation of the receptors. Note that all the profiles are normalized to the mean levels during the oscillations.
... Response of pathway outputs to different cycle periods in insulin stimulus. Four outputs are plotted here. (A) Surface p-IR, (B) p-IRS1 (Y), (C) p-IRS1 (S) and (D) p-AKT. Insulin levels are subjected to a cycle, modeled as a single square waveform. The duration of the waveform is varied and the resulting cycle in the output is measured. DT stands for duration of half of the cycle. For most cycle durations, the cycle is faithfully transmitted down the pathway, but for a duration of less than 20min, the cycle is no longer transmitted. This is seen as a flat curve where the level of the output remains stable at the pre-cycle steady state. Therefore, any oscillations with a frequency greater than 0.05min−1 (or period less than 20min) will be cut-off by the pathway (for the current waveform). All the results in this section are generated by numerical integration of the ODEs. (For interpretation of the references to color in the text, the reader is referred to the web version of the article.)
... Signal propagation in the pathway under noisy stimulus. (A) Insulin stimulus oscillations with time. Random normal noise is added to the main signal. The pathway is first allowed to reach steady state for insulin concentration of 10−9M. At 300min, the levels of insulin are subjected to oscillations with ω=0.01 and amplitude=0.9. (B) p-IR oscillations with time. (C) p-IRS1 (Y) and (S) oscillations with time (D) p-AKT oscillations with time. The output values are normalized to the mean value during the oscillations. The signal is propagated with high fidelity even in the presence of noise. The effect of noise is dominant during the down half of the cycle when the levels of molecules are low.
... Signal propagation in the pathway without noise. (A) Insulin stimulus oscillations with time. The pathway is first allowed to reach steady state for insulin concentration of 10−9M. At 300min, the levels of insulin are subjected to oscillations with ω=0.01 and amplitude of 0.9. (B) p-IR oscillations with time. (C) p-IRS1 (Y) and (S) oscillations with time (D) p-AKT oscillations with time. In general, the signal is transmitted with attenuation down the pathway for molecules directly upstream of p-AKT. The amplitude is not damped significantly for p-IRS1 (S). For this figure, each output is normalized to the mean value of the oscillations.
... Parametric dependence of signal transfer efficiency to p-AKT. (A) Influence of input amplitude on output oscillations. The amplitude of the input is kept at three levels 0.9, 0.7 and 0.5 for the nominal conditions. For low frequencies, we see a flat response, with a fixed but lower amplitude in the p-AKT output. For frequency higher than 0.1, the amplitude falls down linearly to negligible values. All parameters and initial concentrations are kept at the nominal values and PTP is kept at 1. The numbers indicated in the flat region represent the ratio of output amplitude to input amplitude. (B) Influence of input frequency on the output amplitude of p-AKT in the entire parameter space. The input amplitude is kept constant at 0.9. The value of σ of 0.5 is selected for the analysis. PTP levels are kept at 1. In general, frequency values greater that 0.5 (log scale) show very low output amplitude. GSA is performed in the region highlighted by the rectangle. Parameter variations have the most effect at lower frequencies. Inset: Histogram of output distribution. The Y-axis denotes the number of samples out of 105. (C) First order Sobol’ indices showing influence of different parameters on the output amplitude when input amplitude is kept constant at 0.9 and a frequency of 0.01min−1. The value of σ of 0.5 is selected for the analysis. (D) Second order Sobol’ indices.
Contributors:Wiljan Smaal, Charlotte Kjellander, Yongbin Jeong, Ashutosh Tripathi, Bas van der Putten, Antonio Facchetti, Henry Yan, Jordan Quinn, John Anthony, Kris Myny, Wim Dehaene, Gerwin Gelinck
Fig. S2. Power dissipation of 19-stage ring oscillators as a function of frequency. Frequency was measured at 10V operating voltage for 36 ring oscillators having different WN:WP channel width and different [PFBT]/[PT] ratio’s.
... (a) Micrograph of inkjet printed ring oscillators. (b) Stage delays of 19-stage complementary ring oscillators as a function of supply voltage VDD for different ratio’s of transistor widths of p-type (WP) and n-type (WN) transistors. The gold electrodes were modified using a 40/60 [PFBT]/[PT] SAM. Inset: oscillatory signal of 1:4, measured at a supply voltage of 20V with frequency of 2.6kHz.
Impact of pulse vaccination on disease dynamics and number needed to vaccinate for a moderately transmissible (R0 of 5) endemic disease with durable immunity following infection or immunization. (a) Annual attack rates and cumulative cases averted are shown for lower vaccine efficacies. At higher VE, no cases occur within the 20-year time horizon. The annual attack rate in the absence of vaccination is shown by the grey shaded area. (b) The ratio of NNV using a static versus dynamic approach was calculated annually, starting one year after the introduction of the vaccine pulse (at time=0) into the model population. Observed oscillations in the NNVs/NNVd ratio correspond to periodic outbreaks occurring in the vaccinated population with lower assumed VE.
Frequency of polymorphisms in HIV-1 subtype B IN sequences derived from clinical specimens. Consensus sequences of IN from HIV-1 subtype B are shown at the top. The polymorphism frequency (%) in the HIV-1 IN region among ART-naïve and ART-experienced individuals infected with HIV-1 are shown (GenBank Accession Nos: LC022131 to LC022730). HIV-1 carrying Q148H/R or N155H were classified as a subgroup of ART-experienced. The frequency values are presented only for mutations displaying a frequency >0.5%.
... Clinical course and drug resistance profile of two patients exhibiting RAL treatment failure. (A and B) The treatment histories and clinical courses of case 1 (A) and 2 (B). The triangles indicate the time points for deep sequencing-based HIV-1 genotyping assays (GenBank Accession No. DRA003039). The virologic responses represented by plasma HIV-1 viral load (solid line with circle) and CD4+ T lymphocyte counts (dotted line with diamond). Abbreviations of drugs used: FTC, emtricitabine; d4T, stavudine; 3TC, lamivudine; ABC, abacavir; TDF, tenofovir; EFV, efavirenz; ETR, etravirine; RPV, rilpivirine; RAL, raltegravir; DTG, dolutegravir; DRVr, ritonavir-boosted darunavir; MVC, maraviroc. (A) None of the nucleotide reverse transcriptase inhibitor (NRTI) and/or protease inhibitor (PI) associated INSTI resistance mutations was observed at baseline (time point #1). CCR5 (R5) tropic virus was dominant based on the HIV-1 coreceptor tropism assay (geno2pheno, http://coreceptor.geno2pheno.org/) at time point #4. (B) The minor PI resistance mutation M46I/L and the NRTI revertant mutation T215S were observed at baseline (time point #5). (C and D) The HIV-1 genotyping data analyzed by deep-sequencing in panels C and D correspond to the two cases shown in panels A and B, respectively. The frequencies (%) of the INSTI resistance-associated mutations were analyzed using viral RNA from plasma. Briefly, near full-length HIV-1 genome divided into four fragments were amplified, purified and validated by Qubit Fluorometer (Life technologies) and Agilent 2100 Bioanalyzer (Agilent Technologies). PCR amplicons were subjected to tagmentation and to DNA denaturation, and were sequenced on the Illumina MiSeq (paired end 250bp sequencing read). A minimum coverage was 1000 per nucleotide position ensured to identify a minor variant present. The INSTI resistance-associated mutations reported by the International AIDS Society-USA (Wensing et al., 2014) are shown in bold. The frequency (%) of each mutation is represented only for the mutations displaying a frequency >3%.