Cancer cell proliferation is inhibited by specific modulation frequencies

BACKGROUND: There is clinical evidence that very low and safe levels of amplitude-modulated electromagnetic fields administered via an intrabuccal spoon-shaped probe may elicit therapeutic responses in patients with cancer. However, there is no known mechanism explaining the anti-proliferative effect of very low intensity electromagnetic fields. METHODS: To understand the mechanism of this novel approach, hepatocellular carcinoma (HCC) cells were exposed to 27.12 MHz radiofrequency electromagnetic fields using in vitro exposure systems designed to replicate in vivo conditions. Cancer cells were exposed to tumour-specific modulation frequencies, previously identified by biofeedback methods in patients with a diagnosis of cancer. Control modulation frequencies consisted of randomly chosen modulation frequencies within the same 100 Hz-21 kHz range as cancer-specific frequencies. RESULTS: The growth of HCC and breast cancer cells was significantly decreased by HCC-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of HCC cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, HCC-specific modulation frequencies disrupted the mitotic spindle. CONCLUSION: These findings uncover a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology. British Journal of Cancer (2012) 106, 307-313. doi:10.1038/bjc.2011.523 www.bjcancer.com Published online 1 December 2011 (C) 2012 Cancer Research UK

Exploring nu signals in dark matter detectors

We investigate standard and non-standard solar neutrino signals in direct dark matter detection experiments. It is well known that even without new physics, scattering of solar neutrinos on nuclei or electrons is an irreducible background for direct dark matter searches, once these experiments reach the ton scale. Here, we entertain the possibility that neutrino interactions are enhanced by new physics, such as new light force carriers (for instance a "dark photon") or neutrino magnetic moments. We consider models with only the three standard neutrino flavors, as well as scenarios with extra sterile neutrinos. We find that low-energy neutrino-electron and neutrino-nucleus scattering rates can be enhanced by several orders of magnitude, potentially enough to explain the event excesses observed in CoGeNT and CRESST. We also investigate temporal modulation in these neutrino signals, which can arise from geometric effects, oscillation physics, non-standard neutrino energy loss, and direction-dependent detection efficiencies. We emphasize that, in addition to providing potential explanations for existing signals, models featuring new physics in the neutrino sector can also be very relevant to future dark matter searches, where, on the one hand, they can be probed and constrained, but on the other hand, their signatures could also be confused with dark matter signals.

Novel materials for direct X-ray detectors based on semiconducting organic polymers

Conventional inorganic materials for x-ray radiation sensors suffer from several drawbacks, including their inability to cover large curved areas, me- chanical sti ffness, lack of tissue-equivalence and toxicity. Semiconducting organic polymers represent an alternative and have been employed as di- rect photoconversion material in organic diodes. In contrast to inorganic detector materials, polymers allow low-cost and large area fabrication by sol- vent based methods. In addition their processing is compliant with fexible low-temperature substrates. Flexible and large-area detectors are needed for dosimetry in medical radiotherapy and security applications. The objective of my thesis is to achieve optimized organic polymer diodes for fexible, di- rect x-ray detectors. To this end polymer diodes based on two different semi- conducting polymers, polyvinylcarbazole (PVK) and poly(9,9-dioctyluorene) (PFO) have been fabricated. The diodes show state-of-the-art rectifying be- haviour and hole transport mobilities comparable to reference materials. In order to improve the X-ray stopping power, high-Z nanoparticle Bi2O3 or WO3 where added to realize a polymer-nanoparticle composite with opti- mized properities. X-ray detector characterization resulted in sensitivties of up to 14 uC/Gy/cm2 for PVK when diodes were operated in reverse. Addition of nanoparticles could further improve the performance and a maximum sensitivy of 19 uC/Gy/cm2 was obtained for the PFO diodes. Compared to the pure PFO diode this corresponds to a five-fold increase and thus highlights the potentiality of nanoparticles for polymer detector design. In- terestingly the pure polymer diodes showed an order of magnitude increase in sensitivity when operated in forward regime. The increase was attributed to a different detection mechanism based on the modulation of the diodes conductivity.

Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers

The experiment investigated the impact of sleep restriction on pain perception and related evoked potential correlates (laser-evoked potentials, LEPs). Ten healthy subjects with good sleep quality were investigated in the morning twice, once after habitual sleep and once after partial sleep restriction. Additionally, we studied the impact of attentional focussing on pain and LEPs by directing attention to (intensity discrimination) or away from the stimulus (mental arithmetic). Laser stimuli directed to the hand dorsum were rated as 30% more painful after sleep restriction (49+/-7 mm) than after a night of habitual sleep (38+/-7 mm). A significant interaction between attentional focus and sleep condition suggested that attentional focusing was less distinctive under sleep restriction. Intensity discrimination was preserved. In contrast, the amplitude of the early parasylvian N1 of LEPs was significantly smaller after a night of partial sleep restriction (-36%, p<0.05). Likewise, the amplitude of the vertex N2-P2 was significantly reduced (-34%, p<0.01); also attentional modulation of the N2-P2 was reduced. Thus, objective (LEPs) and subjective (pain ratings) parameters of nociceptive processing were differentially modulated by partial sleep restriction. We propose, that sleep reduction leads to an impairment of activation in the ascending pathway (leading to reduced LEPs). In contradistinction, pain perception was boosted, which we attribute to lack of pain control distinct from classical descending inhibition, and thus not affecting the projection pathway. Sleep-restricted subjects exhibit reduced attentional modulation of pain stimuli and may thus have difficulties to readily attend to or disengage from pain.

Cortical and subcortical correlates of electroencephalographic alpha rhythm modulation

Neural correlates of electroencephalographic (EEG) alpha rhythm are poorly understood. Here, we related EEG alpha rhythm in awake humans to blood-oxygen-level-dependent (BOLD) signal change determined by functional magnetic resonance imaging (fMRI). Topographical EEG was recorded simultaneously with fMRI during an open versus closed eyes and an auditory stimulation versus silence condition. EEG was separated into spatial components of maximal temporal independence using independent component analysis. Alpha component amplitudes and stimulus conditions served as general linear model regressors of the fMRI signal time course. In both paradigms, EEG alpha component amplitudes were associated with BOLD signal decreases in occipital areas, but not in thalamus, when a standard BOLD response curve (maximum effect at approximately 6 s) was assumed. The part of the alpha regressor independent of the protocol condition, however, revealed significant positive thalamic and mesencephalic correlations with a mean time delay of approximately 2.5 s between EEG and BOLD signals. The inverse relationship between EEG alpha amplitude and BOLD signals in primary and secondary visual areas suggests that widespread thalamocortical synchronization is associated with decreased brain metabolism. While the temporal relationship of this association is consistent with metabolic changes occurring simultaneously with changes in the alpha rhythm, sites in the medial thalamus and in the anterior midbrain were found to correlate with short time lag. Assuming a canonical hemodynamic response function, this finding is indicative of activity preceding the actual EEG change by some seconds.

Asymptotic Description of Flutter Amplitude Saturation by Nonlinear Friction Forces

The computation of the non-linear vibration dynamics of an aerodynamically unstable bladed-disk is a formidable numerical task, even for the simplified case of aerodynamic forces assumed to be linear. The nonlinear friction forces effectively couple dif- ferent travelling waves modes and, in order to properly elucidate the dynamics of the system, large time simulations are typically required to reach a final, saturated state. Despite of all the above complications, the output of the system (in the friction microslip regime) is basically a superposition of the linear aeroelastic un- stable travelling waves, which exhibit a slow time modulation that is much longer than the elastic oscillation period. This slow time modulation is due to both, the small aerodynamic effects and the small nonlinear friction forces, and it is crucial to deter- mine the final amplitude of the flutter vibration. In this presenta- tion we apply asymptotic techniques to obtain a new simplified model that captures the slow time dynamics of the amplitudes of the travelling waves. The resulting asymptotic model is very re- duced and extremely cheap to simulate, and it has the advantage that it gives precise information about the characteristics of the nonlinear friction models that actually play a role in the satura- tion of the vibration amplitude.

Asymptotic Description of Flutter Amplitude Saturation by Nonlinear Friction Forces

The computation of the non-linear vibration dynamics of an aerodynamically unstable bladed-disk is a formidable numerical task, even for the simplified case of aerodynamic forces assumed to be linear. The nonlinear friction forces effectively couple dif- ferent travelling waves modes and, in order to properly elucidate the dynamics of the system, large time simulations are typically required to reach a final, saturated state. Despite of all the above complications, the output of the system (in the friction microslip regime) is basically a superposition of the linear aeroelastic un- stable travelling waves, which exhibit a slow time modulation that is much longer than the elastic oscillation period. This slow time modulation is due to both, the small aerodynamic effects and the small nonlinear friction forces, and it is crucial to deter- mine the final amplitude of the flutter vibration. In this presenta- tion we apply asymptotic techniques to obtain a new simplified model that captures the slow time dynamics of the amplitudes of the travelling waves. The resulting asymptotic model is very re- duced and extremely cheap to simulate, and it has the advantage that it gives precise information about the characteristics of the nonlinear friction models that actually play a role in the satura- tion of the vibration amplitude.

High data rate modulation of high power 1060-nm DBR tapered lasers with separate contacts

Direct optical modulation at 2.5 Gb/s with amplitude of more than 0.5 W has been demonstrated in single longitudinal mode distributed Bragg reflector tapered lasers emitting at 1060 nm with separated injection of the ridge waveguide and tapered sections. The modulating signal of ~110 mA peak to peak was applied to the ridge waveguide section, yielding a high modulation efficiency of ~5 W/A. The large-signal frequency response of the experimental set-up was limited by the bandwidth of the electrical amplifier rather than by the internal dynamics of the laser, indicating that higher bit rates could be achieved with improved driving electronics.

Integrable high order UWB pulse photonic generator based on cross phase modulation in a SOA-MZI

We propose and experimentally demonstrate a potentially integrable optical scheme to generate high order UWB pulses. The technique is based on exploiting the cross phase modulation generated in an InGaAsP Mach-Zehnder interferometer containing integrated semiconductor optical amplifiers, and is also adaptable to different pulse modulation formats through an optical processing unit which allows to control of the amplitude, polarity and time delay of the generated taps.

Modulation of N-methyl-d-aspartate receptor function by glycine transport

The recent discovery of glycine transporters in both the central nervous system and the periphery suggests that glycine transport may be critical to N-methyl-d-aspartate receptor (NMDAR) function by controlling glycine concentration at the NMDAR modulatory glycine site. Data obtained from whole-cell patch–clamp recordings of hippocampal pyramidal neurons, in vitro, demonstrated that exogenous glycine and glycine transporter type 1 (GLYT1) antagonist selectively enhanced the amplitude of the NMDA component of a glutamatergic excitatory postsynaptic current. The effect was blocked by 2-amino-5-phosphonovaleric acid and 7-chloro-kynurenic acid but not by strychnine. Thus, the glycine-binding site was not saturated under the control conditions. Furthermore, GLYT1 antagonist enhanced NMDAR function during perfusion with medium containing 10 μM glycine, a concentration similar to that in the cerebrospinal fluid in vivo, thereby supporting the hypothesis that the GLYT1 maintains subsaturating concentration of glycine at synaptically activated NMDAR. The enhancement of NMDAR function by specific GLYT1 antagonism may be a feasible target for therapeutic agents directed toward diseases related to hypofunction of NMDAR.

Presynaptic modulation of cortical synaptic activity by calcineurin.

Synaptic plasticity is modulated by Ca(2+)-induced alterations in the balance between phosphorylation and dephosphorylation. Recent evidence suggests that calcineurin, the Ca(2+)-calmodulin-dependent phosphatase (2B), modulates the activity of postsynaptic glutamate receptors. However, in rat cortex, calcineurin is enriched mainly in presynaptic, not postsynaptic, fractions. To determine if calcineurin modulates glutamatergic neurotransmission through a presynaptic mechanism, we used whole-cell patch clamp experiments to test effects of two specific calcineurin inhibitors, cyclosporin A (CsA) and FK506, on synaptic activity in fetal rat cortical neurons. The rate of spontaneous action-potential firing was markedly increased by either CsA or FK506 but was unaffected by rapamycin, a structural analog of FK506 which has no effect on calcineurin. In voltage-clamp experiments, CsA increased the rate but not the amplitude of glutamate receptor-mediated, excitatory postsynaptic currents, suggesting an increased rate of glutamate release. CsA had no effect on the amplitude of currents evoked by brief bath application of selective glutamate receptor agonists, providing further evidence for a pre- rather than postsynaptic site of action. In conclusion, these data indicate that calcineurin modulates glutamatergic neurotransmission in rat cortical neurons through a presynaptic mechanism.

Neurosecretory habituation in PC12 cells: modulation during parallel habituation.

PC12 cells habituate during repetitive stimulation with acetylcholine, bradykinin, or high potassium. Interspersing these stimulants did not affect the rate of habituation of the others, but it could modulate the amplitude of the norepinephrine secretion each could achieve. Stimulation with acetylcholine inhibited norepinephrine secretion caused by high potassium and bradykinin stimulation, while high potassium had no effect on acetylcholine or bradykinin, and bradykinin increased secretion caused by acetylcholine. Changes in norepinephrine secretion resulting from any of these stimulants correlated with changes in internal calcium levels. Cyclic AMP-, protein kinase C-, and calmodulin-dependent second messenger pathways all modulated norepinephrine secretion caused by acetylcholine and high potassium and showed a distinct hierarchy in their effectiveness. These data demonstrate that different receptor pathways can change the norepinephrine response of one another while not changing the levels of the molecules responsible for habituation.

Matlab scripts for modeled obliquity amplitude modulations

The start of the Mesozoic Era is marked by roughly five million years (myr) of Earth system upheavals, including unstable biotic recovery, repeated global warming, ocean anoxia, and perturbations in the global carbon cycle. Intervals between crises were comparably hospitable to life. The causes of these upheavals are unknown, but are thought to be linked to recurrent Siberian volcanism. Here, two marine sedimentary successions at Chaohu and Daxiakou, South China are evaluated for paleoclimate change from astronomical forcing. In these sections, gamma-ray variations indicative of terrestrial weathering reveal enhanced obliquity cycling over prolonged intervals, characterized by a periodicity of 32.8 kiloyear and strong 1.2 myr modulations. This suggests a 22-hour length-of-day and 1.2 myr interaction between the orbital inclinations of Earth and Mars. The 1.2 myr obliquity modulation cycles in these sections are compared with Early Triassic records of global sea-level, temperature, redox and biotic evolution. The evidence collectively suggests that long-term astronomical forcing was involved in the repeated climatic and biotic upheavals that took place throughout the Early Triassic.

Attentional modulation of oscillatory activity in human visual cortex

The effects of attentional modulation on activity within the human visual cortex were investigated using magnetoencephalography. Chromatic sinusoidal stimuli were used to evoke activity from the occipital cortex, with attention directed either toward or away from the stimulus using a bar-orientation judgment task. For five observers, global magnetic field power was plotted as a function of time from stimulus onset. The major peak of each function occurred at about 120 ms latency and was well modeled by a current dipole near the calcarine sulcus. Independent component analysis (ICA) on the non-averaged data for each observer also revealed one component of calcarine origin, the location of which matched that of the dipolar source determined from the averaged data. For two observers, ICA revealed a second component near the parieto-occipital sulcus. Although no effects of attention were evident using standard averaging procedures, time-varying spectral analyses of single trials revealed that the main effect of attention was to alter the level of oscillatory activity. Most notably, a sustained increase in alpha-band (7-12 Hz) activity of both calcarine and parieto-occipital origin was evident. In addition, calcarine activity in the range of 13-21 Hz was enhanced, while calcarine activity in the range of 5-6 Hz was reduced. Our results are consistent with the hypothesis that attentional modulation affects neural processing within the calcarine and parieto-occipital cortex by altering the amplitude of alpha-band activity and other natural brain rhythms. © 2003 Elsevier Inc. All rights reserved.

The role of local luminance amplitude in the interpretation of shape-from-shading in textured surfaces

Luminance changes within a scene are ambiguous; they can indicate reflectance changes, shadows, or shading due to surface undulations. How does vision distinguish between these possibilities? When a surface painted with an albedo texture is shaded, the change in local mean luminance (LM) is accompanied by a similar modulation of the local luminance amplitude (AM) of the texture. This relationship does not necessarily hold for reflectance changes or for shading of a relief texture. Here we concentrate on the role of AM in shape-from-shading. Observers were presented with a noise texture onto which sinusoidal LM and AM signals were superimposed, and were asked to indicate which of two marked locations was closer to them. Shape-from-shading was enhanced when LM and AM co-varied (in-phase), and was disrupted when they were out-of-phase. The perceptual differences between cue types (in-phase vs out-of-phase) were enhanced when the two cues were present at different orientations within a single image. Similar results were found with a haptic matching task. We conclude that vision can use AM to disambiguate luminance changes. LM and AM have a positive relationship for rendered, undulating, albedo textures, and we assess the degree to which this relationship holds in natural images. [Supported by EPSRC grants to AJS and MAG].