Nonlinear Signal Amplification Research Articles

Generation of Giant Amplitude Pulses in a Klystron Chaos Auto-Oscillator

The presented experimental results demonstrate that microwave pulses of giant amplitude are generated in a klystron generator operating in the self-excited mode of chaotic oscillations. The auto-oscillator is assembled using a noisetron scheme that contains two five-cavity floating-drift klystrons serially connected in a ring, one of which operates in the mode of linear signal amplification (the linear klystron) and the other works in the mode of nonlinear signal amplification (the nonlinear klystron). It is established that, at a certain value of the beam current of a nonlinear klystron, intermittency of chaos–chaos type is realized in the auto-oscillation system in the form of chaotic sequences of microwave pulses of giant amplitude formed over the chaotic amplitude background. This type of intermittency is caused by the amplitude bistability of the nonlinear floating-drift klystron.

Circulating Tumor Cell Detection and Capture by Photoacoustic Flow Cytometry in Vivo and ex Vivo.

Despite progress in detecting circulating tumor cells (CTCs), existing assays still have low sensitivity (1–10 CTC/mL) due to the small volume of blood samples (5–10 mL). Consequently, they can miss up to 103–104 CTCs, resulting in the development of barely treatable metastasis. Here we analyze a new concept of in vivo CTC detection with enhanced sensitivity (up to 102–103 times) by the examination of the entire blood volume in vivo (5 L in adults). We focus on in vivo photoacoustic (PA) flow cytometry (PAFC) of CTCs using label-free or targeted detection, photoswitchable nanoparticles with ultrasharp PA resonances, magnetic trapping with fiber-magnetic-PA probes, optical clearance, real-time spectral identification, nonlinear signal amplification, and the integration with PAFC in vitro. We demonstrate PAFC’s capability to detect rare leukemia, squamous carcinoma, melanoma, and bulk and stem breast CTCs and its clusters in preclinical animal models in blood, lymph, bone, and cerebrospinal fluid, as well as the release of CTCs from primary tumors triggered by palpation, biopsy or surgery, increasing the risk of metastasis. CTC lifetime as a balance between intravasation and extravasation rates was in the range of 0.5–4 h depending on a CTC metastatic potential. We introduced theranostics of CTCs as an integration of nanobubble-enhanced PA diagnosis, photothermal therapy, and feedback through CTC counting. In vivo data were verified with in vitro PAFC demonstrating a higher sensitivity (1 CTC/40 mL) and throughput (up to 10 mL/min) than conventional assays. Further developments include detection of circulating cancer-associated microparticles, and super-resolution PAFC beyond the diffraction and spectral limits.

Fleeing heat and light

Fleeing heat and light

Bidirectional temperature-sensing by a single thermosensory neuron in C. elegans

Humans and other animals can sense temperature changes as small as 0.1 degree C. How animals achieve such exquisite sensitivity is poorly understood. By recording from the C. elegans thermosensory neurons AFD in vivo, we found that cooling closes and warming opens ion channels. We found that AFD thermosensitivity, which exceeds that of most biological processes by many orders of magnitude, is achieved by nonlinear signal amplification. Mutations in genes encoding subunits of a cyclic guanosine monophosphate (cGMP)-gated ion channel (tax-4 and tax-2) and transmembrane guanylate cyclases (gcy-8, gcy-18 and gcy-23) eliminated both cooling- and warming-activated thermoreceptor currents, indicating that a cGMP-mediated pathway links variations in temperature to changes in ionic currents. The resemblance of C. elegans thermosensation to vertebrate photosensation and the sequence similarity between TAX-4 and TAX-2 and subunits of the rod phototransduction channel raise the possibility that nematode thermosensation and vertebrate vision are linked by conserved evolution.

Stochastic modelling for gradient sensing by chemotactic cells

Chemotaxis, the process by which cells move toward attractant molecules, operates in a range of biological processes including immunity, neuronal patterning, and morphogenesis. Dictyostelium discoideum cells display a strong chemotactic response to cyclic adenosine 3',5'-monophosphate (cAMP), which binds to a cell surface receptor. Each Dictyostelium has ca. 80000 cAMP receptors, and can transduce shallow spatial chemoattractant gradients into strongly localized intracellular responses in spite of large statistical fluctuation of receptor occupancy even in the case of very low cAMP concentration. In this study, we develop a stochastic model for gradient sensing by chemotactic cells. We simulate the binding of cAMP molecules to receptors by a Monte-Carlo method in order to account for statistical fluctuation of receptor occupancy and treat intracellular signal processing by a diffusion–translocation model, which includes the production of second-messenger molecules and positive feedback mechanisms mediated by effector molecules. Our simulation results show that the fluctuation of second-messenger concentration is much smaller than that of receptor occupancy, and that a shallow chemoattractant gradient are transduced into a large second-messenger concentration gradient through nonlinear signal amplification.

Switching between cortical and subcortical sensorimotor pathways

It is well known that the reaction times of visually guided saccades exhibit a bimodal distribution. Those with extremely short reaction times are termed 'express saccades'. In their case, visual input appears to be transformed into motor output via a 'short-loop', brainstem-mediated pathway. In contrast, those with longer reaction times are called 'regular saccades'. The latter are presumably executed via a cortically mediated, 'long-loop' sensorimotor pathway. The 'gate' that switches signal flow between the short and long loop is thought to be located in between the superficial and deeper layers of the superior colliculus (SC). Nonlinear signal amplification mechanisms, which operate in local circuits of the deeper SC layers may underlie this gating function, with switching of the gate regulated in a context-dependent manner by inputs from the cerebral cortex and basal ganglia.

Local Excitatory Network and NMDA Receptor Activation Generate a Synchronous and Bursting Command from the Superior Colliculus

The generation of bursting spike activity in the deeper layers of the superior colliculus (SC) is a critical determinant of decision making in the initiation of orienting behaviors, such as saccades. The bursting activity exhibits a typical threshold effect that may arise from a nonlinear signal amplification process in the deeper layers of the SC. We used whole-cell patch-clamp recordings in rat SC slices to investigate the neuronal mechanism underlying the generation of such bursting activity. We found that (1) neurons in the intermediate gray layer [stratum griseum intermediale (SGI)] produce a prolonged bursting response when released from GABA(A) receptor-mediated inhibition, (2) this GABA(A) inhibition may partially arise from inhibitory interneurons within the SGI that are driven synaptically by glutamatergic excitatory inputs to the SC, (3) the bursting is not the result of the intrinsic membrane properties of individual SC neurons but is instead produced by local circuits within the SGI, (4) the bursting is mediated by activation of NMDA receptors, and (5) the bursting can be synchronous among SGI neurons. These results suggest that activation of a local excitatory network within the deeper layers of the SC and NMDA receptor-dependent synaptic transmission after release from GABA(A) inhibition are fundamental mechanisms that may explain the nonlinear signal amplification process in the deeper layers of the SC.

Nonlinear signal amplification in a 2D system operating in static and oscillatory regimes

We study the spectral response of a nonlinear system of coupled oscillator equations representing the overdamped two-junction (dc) superconducting quantum interference device (SQUID) loop; this system admits of static or oscillatory solutions for the autonomous case. In the presence of a weak time-dependent sinusoidal target signal and noise we find, in the regime of oscillatory or “running” solutions, an enhancement of the response (characterized by an output signal-to-noise ratio at the drive frequency) as a function of the intrinsic device parameters as well as externally controlled bias parameters that determine the nature of the long-time solutions. Modeling the device via a derived input-output transfer characteristic yields results in good agreement with recent experiments. This work offers a technique whereby the response of nonlinear devices with similar response characteristics may be optimized without directly adjusting the system noise.

Long-latency reflexes and motor control: [formula omitted] (NIH Clinical Center, Bldg. 10, Rm. 5N226, Bethesda, MD 20892, U.S.A.)

It is well known that the reaction times of visually guided saccades exhibit a bimodal distribution. Those with extremely short reaction times are termed ‘express saccades’. In their case, visual input appears to be transformed into motor output via a ‘short-loop’, brainstem-mediated pathway. In contrast, those with longer reaction times are called ‘regular saccades’. The latter are presumably executed via a cortically mediated, ‘long-loop’ sensorimotor pathway. The ‘gate’ that switches signal flow between the short and long loop is thought to be located in between the superficial and deeper layers of the superior colliculus (SC). Nonlinear signal amplification mechanisms, which operate in local circuits of the deeper SC layers may underlie this gating function, with switching of the gate regulated in a context-dependent manner by inputs from the cerebral cortex and basal ganglia.