Contributors: Maeike Zijlmans, Julia Jacobs, Rina Zelmann, François Dubeau, Jean Gotman

Date: 2009-08-01

High frequency oscillations (HFOs) have been associated with epileptogenicity. In rats, the extent of HFOs (>200Hz) is correlated with seizure frequency. We studied whether the same applies to patients with focal epilepsy. Thirty-nine patients with intracerebral EEG sampled at 2000Hz were studied for interictal ripples (80–250Hz), fast ripples (FR, 250–500Hz) and spikes. Seizure frequency before implantation was compared to numbers of channels with HFOs (>1/min). Analyses were repeated for HFO rates of >5, >10 and >20. Separate analyses were done for 25 patients with temporal lobe epilepsy only and for a selection of similar unilateral temporal channels in 12 patients. No linear correlation or trend was found relating the number of channels with HFOs and seizure frequency. There was a linear positive correlation between the number of channels with more than 20 FRs/min and seizure frequency. The hypothesis that the more tissue generating HFOs, the higher the seizure frequency, was not confirmed, though there might be a correlation for high FR rates....High frequency oscillations (HFOs) have been associated with epileptogenicity. In rats, the extent of HFOs (>200Hz) is correlated with seizure frequency. We studied whether the same applies to patients with focal epilepsy. Thirty-nine patients with intracerebral EEG sampled at 2000Hz were studied for interictal ripples (80–250Hz), fast ripples (FR, 250–500Hz) and spikes. Seizure frequency before implantation was compared to numbers of channels with HFOs (>1/min). Analyses were repeated for HFO rates of >5, >10 and >20. Separate analyses were done for 25 patients with temporal lobe epilepsy only and for a selection of similar unilateral temporal channels in 12 patients. No linear correlation or trend was found relating the number of channels with HFOs and seizure frequency. There was a linear positive correlation between the number of channels with more than 20 FRs/min and seizure frequency. The hypothesis that the more tissue generating HFOs, the higher the seizure frequency, was not confirmed, though there might be a correlation for high FR rates....High frequency oscillations and seizure frequency in patients with focal epilepsy...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. ... High frequency oscillations (HFOs) have been associated with epileptogenicity. In rats, the extent of HFOs (>200Hz) is correlated with seizure frequency. We studied whether the same applies to patients with focal epilepsy. Thirty-nine patients with intracerebral EEG sampled at 2000Hz were studied for interictal ripples (80–250Hz), fast ripples (FR, 250–500Hz) and spikes. Seizure frequency before implantation was compared to numbers of channels with HFOs (>1/min). Analyses were repeated for HFO rates of >5, >10 and >20. Separate analyses were done for 25 patients with temporal lobe epilepsy only and for a selection of similar unilateral temporal channels in 12 patients. No linear correlation or trend was found relating the number of channels with HFOs and seizure frequency. There was a linear positive correlation between the number of channels with more than 20 FRs/min and seizure frequency. The hypothesis that the more tissue generating HFOs, the higher the seizure frequency, was not confirmed, though there might be a correlation for high FR rates.

Contributors: Maeike Zijlmans, Julia Jacobs, Yusuf U. Kahn, Rina Zelmann, François Dubeau, Jean Gotman

Date: 2011-04-01

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. ...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. ...Ictal and interictal high frequency oscillations in patients with focal epilepsy...High frequency oscillations...High frequency oscillations (HFOs) can be recorded with depth electrodes in focal epilepsy patients. They occur during seizures and interictally and seem important in seizure genesis. We investigated whether interictal and ictal HFOs occur in the same regions and how they relate to epileptiform spikes....High frequency oscillations...High frequency oscillations (HFOs) can be recorded with depth electrodes in focal epilepsy patients. They occur during seizures and interictally and seem important in seizure genesis. We investigated whether interictal and ictal HFOs occur in the same regions and how they relate to epileptiform spikes. ... High frequency oscillations (HFOs) can be recorded with depth electrodes in focal epilepsy patients. They occur during seizures and interictally and seem important in seizure genesis. We investigated whether interictal and ictal HFOs occur in the same regions and how they relate to epileptiform spikes.

Contributors: Jingjing Wang, Da Chen, Yan Xu, Weihui Liu

Date: 2014-01-01

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 resona...The frequency spectrum of the FBAR oscillator after the PBS was injected into the testing channel. ...The f...(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. ...A highly sensitive label-free immunosensor based on film bulk acoustic resonator has been developed for the detection of pesticide residues. The film bulk acoustic resonator works at 2GHz as a mass-sensitive transducer for bio-sensing. Artificial antigens were immobilized on the sensing surface of the resonator through self-assembled method to employ a competitive format for the immunoassays. The competitive immunoreactions are observed in real time by measuring the frequency changes of the resonator. The presence of pesticides can be detected according to the diminution of the frequency shift compared with the level without pesticides. The obtained ultra low limit of detection for parathion was as low as 0.08μg/L. The fabricated device was further used to detect trace pesticide residues in vegetable samples. The results show that the proposed immunosensor is a rapid and convenient detection method with a high accuracy comparable to gas chromatography....(a) The circuit diagrams and (b) an assembled circuitry of the FBAR oscillator. ...The frequency spectrum of the FBAR oscillator after the PBS was injected into the testing channel. ...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 standard calibration curves of the FBAR immunosensor for the parathion. ... A highly sensitive label-free immunosensor based on film bulk acoustic resonator has been developed for the detection of pesticide residues. The film bulk acoustic resonator works at 2GHz as a mass-sensitive transducer for bio-sensing. Artificial antigens were immobilized on the sensing surface of the resonator through self-assembled method to employ a competitive format for the immunoassays. The competitive immunoreactions are observed in real time by measuring the frequency changes of the resonator. The presence of pesticides can be detected according to the diminution of the frequency shift compared with the level without pesticides. The obtained ultra low limit of detection for parathion was as low as 0.08μg/L. The fabricated device was further used to detect trace pesticide residues in vegetable samples. The results show that the proposed immunosensor is a rapid and convenient detection method with a high accuracy comparable to gas chromatography.

Contributors: Shibin Mathew, Ipsita Banerjee

Date: 2014-12-04

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.) ...Robustness is a critical feature of signaling pathways ensuring signal propagation with high fidelity in the event of perturbations. Here we present a detailed quantitative analysis of robustness in insulin mediated PI3K/AKT pathway, a critical signaling pathway maintaining self-renewal in human embryonic stem cells. Using global sensitivity analysis, we identified robustness promoting mechanisms that ensure (1) maintenance of a first order or overshoot dynamics of self-renewal molecule, p-AKT and (2) robust transfer of signals from oscillatory insulin stimulus to p-AKT in the presence of noise. Our results indicate that negative feedback controls the robustness to most perturbations. Faithful transfer of signal from the stimulating ligand to p-AKT occurs even in the presence of noise, albeit with signal attenuation and high frequency cut-off. Negative feedback contributes to signal attenuation, while positive regulators upstream of PIP3 contribute to signal amplification. These results establish precise mechanisms to modulate self-renewal molecules like p-AKT....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. ...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. ...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. ...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.) ...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. ... Robustness is a critical feature of signaling pathways ensuring signal propagation with high fidelity in the event of perturbations. Here we present a detailed quantitative analysis of robustness in insulin mediated PI3K/AKT pathway, a critical signaling pathway maintaining self-renewal in human embryonic stem cells. Using global sensitivity analysis, we identified robustness promoting mechanisms that ensure (1) maintenance of a first order or overshoot dynamics of self-renewal molecule, p-AKT and (2) robust transfer of signals from oscillatory insulin stimulus to p-AKT in the presence of noise. Our results indicate that negative feedback controls the robustness to most perturbations. Faithful transfer of signal from the stimulating ligand to p-AKT occurs even in the presence of noise, albeit with signal attenuation and high frequency cut-off. Negative feedback contributes to signal attenuation, while positive regulators upstream of PIP3 contribute to signal amplification. These results establish precise mechanisms to modulate self-renewal molecules like p-AKT.

Contributors: Simone Guadagna, Christoffer Bundgaard, Nanna Hovelsø, Christiane Volbracht, Paul T. Francis, Jan Egebjerg, Florence Sotty

Date: 2012-01-01

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 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). ...Memantine is an uncompetitive, low-affinity NMDA receptor antagonist clinically used for the treatment of cognitive deficits in moderate to severe Alzheimer’s disease. Both neurophysiological and behavioral studies in rodents have suggested a beneficial effect of memantine on synaptic plasticity and learning performances. In the present study, we investigated the effect of memantine on pedonculopontine-elicited theta oscillations in the hippocampus of urethane anesthetized mice, a model shown to be sensitive to several pharmacological agents exhibiting cognitive-enhancing properties. We found that a low dose of memantine potentiated elicited theta power while a high dose was disruptive. The low dose of memantine used was shown to yield an unbound brain concentration well within the range of therapeutic concentrations reported in rodent brain extracellular fluid and human cerebrospinal fluid. For further comparison, the effect of another uncompetitive NMDA receptor antagonist with higher affinity, i.e. MK-801, was also investigated. MK-801 was at a low dose devoid of effect on elicited theta power, while a high dose, within the range of doses reported to induce cognitive deficits in a variety of hippocampal-dependent learning paradigms in mice, was found disruptive on elicited theta waves. Taken together, our results suggest that clinically relevant doses of memantine promote neuronal network synchronization in the hippocampus, which may represent an underlying mechanism for the reported cognitive-enhancing properties in both preclinical and clinical studies....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 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). ... Memantine is an uncompetitive, low-affinity NMDA receptor antagonist clinically used for the treatment of cognitive deficits in moderate to severe Alzheimer’s disease. Both neurophysiological and behavioral studies in rodents have suggested a beneficial effect of memantine on synaptic plasticity and learning performances. In the present study, we investigated the effect of memantine on pedonculopontine-elicited theta oscillations in the hippocampus of urethane anesthetized mice, a model shown to be sensitive to several pharmacological agents exhibiting cognitive-enhancing properties. We found that a low dose of memantine potentiated elicited theta power while a high dose was disruptive. The low dose of memantine used was shown to yield an unbound brain concentration well within the range of therapeutic concentrations reported in rodent brain extracellular fluid and human cerebrospinal fluid. For further comparison, the effect of another uncompetitive NMDA receptor antagonist with higher affinity, i.e. MK-801, was also investigated. MK-801 was at a low dose devoid of effect on elicited theta power, while a high dose, within the range of doses reported to induce cognitive deficits in a variety of hippocampal-dependent learning paradigms in mice, was found disruptive on elicited theta waves. Taken together, our results suggest that clinically relevant doses of memantine promote neuronal network synchronization in the hippocampus, which may represent an underlying mechanism for the reported cognitive-enhancing properties in both preclinical and clinical studies.

Contributors: Wiljan Smaal, Charlotte Kjellander, Yongbin Jeong, Ashutosh Tripathi, Bas van der Putten, Antonio Facchetti, Henry Yan, Jordan Quinn, John Anthony, Kris Myny

Date: 2012-09-01

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. ...Complementary thin-film transistor circuits composed of 6,13-bis(triisopropyl-silylethynyl) pentacene (TIPS–PEN) and a rylene carboxylic diimide derivative for p- and n-channel thin-film transistors (TFTs) were fabricated on flexible foils. The so-called staggered TFT configuration is used, meaning that the semiconductors layers are deposited last. The work-function of the injecting gold electrodes were modified using several self-assembled monolayers (SAMs). For optimized contacts the mobility of the n- and p-channel TFTs was 0.5cm2/Vs and 0.2cm2/Vs, respectively. Strongly degraded performance is obtained when the n-channel material was printed on contacts optimized for the p-channel TFT, and vice versa. This illustrates that for CMOS circuits we need careful work-function engineering to allow proper injection for both electrons and holes. We show for the first time that by using a bimolecular mixture for the SAM we can systematically vary the work function, and demonstrate how this affects the performance of discrete n-type and p-type transistors, as well as CMOS inverters and ring oscillators. Under optimal processing conditions we realized complementary 19-stage ring oscillators with 10μs stage delay operating at 20V....(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. ...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. ... Complementary thin-film transistor circuits composed of 6,13-bis(triisopropyl-silylethynyl) pentacene (TIPS–PEN) and a rylene carboxylic diimide derivative for p- and n-channel thin-film transistors (TFTs) were fabricated on flexible foils. The so-called staggered TFT configuration is used, meaning that the semiconductors layers are deposited last. The work-function of the injecting gold electrodes were modified using several self-assembled monolayers (SAMs). For optimized contacts the mobility of the n- and p-channel TFTs was 0.5cm2/Vs and 0.2cm2/Vs, respectively. Strongly degraded performance is obtained when the n-channel material was printed on contacts optimized for the p-channel TFT, and vice versa. This illustrates that for CMOS circuits we need careful work-function engineering to allow proper injection for both electrons and holes. We show for the first time that by using a bimolecular mixture for the SAM we can systematically vary the work function, and demonstrate how this affects the performance of discrete n-type and p-type transistors, as well as CMOS inverters and ring oscillators. Under optimal processing conditions we realized complementary 19-stage ring oscillators with 10μs stage delay operating at 20V.

Contributors: Julian Antonio Valverde, Adriana Echavarría, Maria Filipa Ribeiro, Luz Amparo Palacio, Jean-Guillaume Eon

Date: 2012-09-30

Ni-K edge EXAFS oscillations in R and k spaces of the NiAlH_Cal. – observed spectrum, -o- simulated spectrum. ...(a) V-K edges EXAFS oscillations in R space, (b) V-K edges EXAFS oscillations in k spaces, (c) Ni-K edges EXAFS oscillations in R space, NiO contributions and (d) Ni-K edges EXAFS oscillations in R space, Ni3V2O8 contributions (V1_1: 3.43, V1_2: 3.44 and V1_3: 4.41Å) of NiAlHV_Cal. – observed spectrum, -o- simulated spectrum. ... Two nickel–aluminum hydrotalcite type precursors were synthesized with molar ratio Ni/Al=3, using hydroxyl and carbonate as compensation anions. These precursors were intercalated by 30% (theoretical) decavanadate anion. The catalysts were obtained after calcination at 550°C and their performance was evaluated in propane oxidative dehydrogenation at 400°C using space velocities of 100, 150, 200 and 400mlg−1min−1 under conditions of oxygen deficiency and oxygen excess. Catalysts derived from nickel–aluminum-hydroxyl precursors attained an excellent performance under oxygen deficiency conditions promoting high propene selectivity and conversion. Under oxygen excess conditions the catalyst was more active but its selectivity was lower. Vanadium-containing catalysts showed improved selectivity under this operation condition. The formation of the hydrotalcite phase in precursors and mixed oxides in the catalysts was evidenced by X-ray diffraction (XRD). Analyses of textural and reduction properties were carried-out with nitrogen adsorption and temperature programmed reduction techniques respectively. Structural studies were performed by X-ray absorption spectroscopy for materials that showed best performance in the oxidative dehydrogenation reaction.

Contributors: Edoardo Paluan

Date: 2016-12-06

The aim of the project is to create an optical interferometer which can detect the acoustic analogue of a supernova explosion. The fingerprint of an acoustic wave propagating from a diapason will be measured. A Michelson Morley interferometer1 will be used, whereby analysis of the interference pattern will allow for the calculation of the frequency of the diapason....frequency 800Hz.txt...In a Michelson interferometer, light from a monochromatic source (S) is divided by a beam splitter (BS), oriented at an angle of 45° to the beam, producing two beams of equal intensity. The transmitted beam (T) travels to mirror M2 where it is reflected back to BS. 50% of the returning beam is then deflected by 90° at the beam splitter and is made to strike the detector (D). The reflected beam travels to mirror M1, where it is reflected. Again, 50% of the beam passes straight through the BS and reaches the detector. The Laser is a He-Ne laser, having a polarized wavelength of 633nm (red). The wave is coherent and monochromatic; since the beam is coherent, light from other sources will not interfere with the interference pattern. Mirrors provide a way for the beam to change its direction of travel, if M1 and M2 are misaligned, the recombination of the beams occurs at a different location in the BS, resulting in the formation of two signals on D which do not form an interference pattern. When working with laser light, a cube beamsplitter (CB) possesses the best combination of optical performance and power handling ,CBs avoid displacing the beam by being perpendicular to the incident beam. To achieve the best possible performance, CBs should be operated with collimated light as convergent or divergent beams will contribute unwanted spherical aberrations to the setup. A piezoelectric was connected to a signal generator and attached to M2. This acted as a test for the apparatus and allowed the mirror to oscillate at various frequencies. The distance travelled by M2 due to excitation of the piezoelectric was a secondary investigation inherent in the project. The detector used allowed the intensity of light hitting it to be recorded. When two or more waves interact with one another an interference pattern is produced. This pattern is a result of the phase difference between the waves. When the waves are in phase constructive interference occurs and the resulting amplitude of the two superimposed waves is a maximum, on a screen, this is seen as a light fringe. When the waves are π out of phase, destructive interference occurs and the resulting amplitude is 0, on a screen this is seen as a dark fringe. ...In a Michelson interferometer, light from a monochromatic source (S) is divided by a beam splitter (BS), oriented at an angle of 45° to the beam, producing two beams of equal intensity. The transmitted beam (T) travels to mirror M2 where it is reflected back to BS. 50% of the returning beam is then deflected by 90° at the beam splitter and is made to strike the detector (D). The reflected beam travels to mirror M1, where it is reflected. Again, 50% of the beam passes straight through the BS and reaches the detector. The Laser is a He-Ne laser, having a polarized wavelength of 633nm (red). The wave is coherent and monochromatic; since the beam is coherent, light from other sources will not interfere with the interference pattern. Mirrors provide a way for the beam to change its direction of travel, if M1 and M2 are misaligned, the recombination of the beams occurs at a different location in the BS, resulting in the formation of two signals on D which do not form an interference pattern. When working with laser light, a cube beamsplitter (CB) possesses the best combination of optical performance and power handling ,CBs avoid displacing the beam by being perpendicular to the incident beam. To achieve the best possible performance, CBs should be operated with collimated light as convergent or divergent beams will contribute unwanted spherical aberrations to the setup. A piezoelectric was connected to a signal generator and attached to M2. This acted as a test for the apparatus and allowed the mirror to oscillate at various frequencies. The distance travelled by M2 due to excitation of the piezoelectric was a secondary investigation inherent in the project. The detector used allowed the intensity of light hitting it to be recorded. When two or more waves interact with one another an interference pattern is produced. This pattern is a result of the phase difference between the waves. When the waves are in phase constructive interference occurs and the resulting amplitude of the two superimposed waves is a maximum, on a screen, this is seen as a light fringe. When the waves are π out of phase, destructive interference occurs and the resulting amplitude is 0, on a screen this is seen as a dark fringe. ... The aim of the project is to create an optical interferometer which can detect the acoustic analogue of a supernova explosion. The fingerprint of an acoustic wave propagating from a diapason will be measured. A Michelson Morley interferometer1 will be used, whereby analysis of the interference pattern will allow for the calculation of the frequency of the diapason.

Contributors: Sandrine Hayette, Kaddour Chabane, Mauricette Michallet, Estelle Michallat, Pascale Cony-Makhoul, Stéphanie Salesse, Véronique Maguer-Satta, Jean-Pierre Magaud, Franck E. Nicolini

Date: 2011-01-01

This report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine. ... This report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine.

Contributors: Rajesh R. Singh, Keyur P. Patel, Mark J. Routbort, Neelima G. Reddy, Bedia A. Barkoh, Brian Handal, Rashmi Kanagal-Shamanna, Wesley O. Greaves, L. Jeffrey Medeiros, Kenneth D. Aldape

Date: 2013-09-01

Inter-run and intrarun sequencing reproducibility. A: A 1:9 dilution of H2122 in HL60 DNA (10% H2122) was sequenced multiple times (n = 14) as a part of multiplexed runs, and the results showed very little variability in the variant frequencies detected for the KRAS and MET mutations, indicating very reproducible mutation detection sensitivity. B: Four heterozygous mutations detected in a 25% (1:3) dilution of DLD1 DNA in H460 DNA showed very little variation in their variant frequencies across five different multiplexed runs. C: A patient sample harboring three mutations was sequenced in 25 different multiplexed runs. Consistent detection of the mutations with minimum variation of the variant frequencies showed a high degree of inter-run sequencing. D: Intrarun reproducibility was tested by using a single patient DNA as a template and preparing 10 different libraries, each with a distinct barcode. The 10 libraries were multiplexed and sequenced on the same IonChip. The results showed consistent detection of mutations with ≥10% variant frequency and coverage ≥250×. Data are given as means ± SE. ...Inter-run and intrarun sequencing reproducibility. A: A 1:9 dilution of H2122 in HL60 DNA (10% H2122) was sequenced multiple times (n = 14) as a part of multiplexed runs, and the results showed very little variability in the variant frequencies detected for the KRAS and MET mutations, indicating very reproducible mutation detection sensitivity. B: Four heterozygous mutations detected in a 25% (1:3) dilution of DLD1 DNA in H460 DNA showed very little variation in their variant frequencies across five different multiplexed runs. C: A patient sample harboring three mutations was sequenced in 25 different multiplexed runs. Consistent detection of the mutations with minimum variation of the variant frequencies showed a high degree of inter-run sequencing. D: Intrarun reproducibility was tested by using a single patient DNA as a template and preparing 10 different libraries, each with a distinct barcode. The 10 libraries were multiplexed and sequenced on the same IonChip. The results showed consistent detection of mutations with ≥10% variant frequency and coverage ≥250×. Data are given as means ± SE. ...Sequencing efficiency on Ion 316 and 318 Chips. Four samples were sequenced as a part of different numbers of multiplexed sample sets on Ion 316 and 318 Chips for comparison. A: Sample 1 was tested as a multiplexed sample with three and seven other samples on Ion 316 and 318 Chips, respectively. B: Samples 2, 3, and 4 were sequenced along with one and five other samples on Ion 316 and 318 Chips, respectively. Manual E-PCR and breaking was used in sample preparation for sequencing on both chips. C and D: Sequencing of the samples was comparable on both the chips as evident by the matching AQ20 reads obtained per sample and the congruence of the mutations detected and their variant frequencies in the background of wild type. ...Transfer of next-generation sequencing technology to a Clinical Laboratory Improvement Amendments–certified laboratory requires vigorous validation. Herein, we validated a next-generation sequencing screen interrogating 740 mutational hotspots in 46 cancer-related genes using the Ion Torrent AmpliSeq cancer panel and Ion Torrent Personal Genome Machine (IT-PGM). Ten nanograms of FFPE DNA was used as template to amplify mutation hotspot regions of 46 genes in 70 solid tumor samples, including 22 archival specimens with known mutations and 48 specimens sequenced in parallel with alternate sequencing platforms. In the archival specimens, the IT-PGM detected expected nucleotide substitutions (n = 29) and four of six insertions/deletions; in parallel, 66 variants were detected. These variants, except a single nucleotide substitution, were confirmed by alternate platforms. Repeated sequencing of progressively diluted DNA from two cancer cell lines with known mutations demonstrated reliable sensitivity at 10% variant frequency for single nucleotide variants with high intrarun and inter-run reproducibility. Manual library preparation yielded relatively superior sequencing performance compared with the automated Ion Torrent OneTouch system. Overall, the IT-PGM platform with the ability to multiplex and simultaneously sequence multiple patient samples using low amounts of FFPE DNA was specific and sensitive for single nucleotide variant mutation analysis and can be incorporated easily into the clinical laboratory for routine testing....Sequencing efficiency on Ion 316 and 318 Chips. Four samples were sequenced as a part of different numbers of multiplexed sample sets on Ion 316 and 318 Chips for comparison. A: Sample 1 was tested as a multiplexed sample with three and seven other samples on Ion 316 and 318 Chips, respectively. B: Samples 2, 3, and 4 were sequenced along with one and five other samples on Ion 316 and 318 Chips, respectively. Manual E-PCR and breaking was used in sample preparation for sequencing on both chips. C and D: Sequencing of the samples was comparable on both the chips as evident by the matching AQ20 reads obtained per sample and the congruence of the mutations detected and their variant frequencies in the background of wild type. ... Transfer of next-generation sequencing technology to a Clinical Laboratory Improvement Amendments–certified laboratory requires vigorous validation. Herein, we validated a next-generation sequencing screen interrogating 740 mutational hotspots in 46 cancer-related genes using the Ion Torrent AmpliSeq cancer panel and Ion Torrent Personal Genome Machine (IT-PGM). Ten nanograms of FFPE DNA was used as template to amplify mutation hotspot regions of 46 genes in 70 solid tumor samples, including 22 archival specimens with known mutations and 48 specimens sequenced in parallel with alternate sequencing platforms. In the archival specimens, the IT-PGM detected expected nucleotide substitutions (n = 29) and four of six insertions/deletions; in parallel, 66 variants were detected. These variants, except a single nucleotide substitution, were confirmed by alternate platforms. Repeated sequencing of progressively diluted DNA from two cancer cell lines with known mutations demonstrated reliable sensitivity at 10% variant frequency for single nucleotide variants with high intrarun and inter-run reproducibility. Manual library preparation yielded relatively superior sequencing performance compared with the automated Ion Torrent OneTouch system. Overall, the IT-PGM platform with the ability to multiplex and simultaneously sequence multiple patient samples using low amounts of FFPE DNA was specific and sensitive for single nucleotide variant mutation analysis and can be incorporated easily into the clinical laboratory for routine testing.