Mechanism Of Signal Propagation Research Articles

Pharmacological mechanisms of interhemispheric signal propagation: a TMS-EEG study.

Interhemispheric connections across the corpus callosum have a predominantly inhibitory effect. Previous electrophysiology studies imply that local inhibitory circuits are responsible for inducing transcallosal inhibition, likely through inhibitory GABAB-mediated neurotransmission. We investigated the neurochemical mechanisms involved in interhemispheric connectivity by measuring transcranial magnetic stimulation (TMS)-induced interhemispheric signal propagation (ISP) in the motor cortex and dorsolateral prefrontal cortex (DLPFC) with electroencephalography (EEG) recordings under the pharmacological effects of baclofen, L-DOPA, dextromethorphan, and rivastigmine. We hypothesized that for both stimulated regions, GABAB receptor agonist baclofen would decrease ISP when compared against baseline while drugs that target other neurotransmitter systems (dopaminergic, acetylcholinergic, and glutamatergic systems) would have no effect on ISP. Twelve right-handed healthy volunteers completed this study and underwent TMS across five sessions in a randomized order. In the motor cortex, participants showed a significant decrease in ISP under baclofen, but not in the other drug conditions. There were no drug-induced changes in ISP in the DLPFC and baseline ISP did not differ across experimental sessions for both brain regions. Together, our results suggest that the inhibitory effects observed with interhemispheric signal transmission are mediated by a population of interneurons involving GABAB receptor neurotransmission. Inhibitory mechanisms of ISP may be more salient for motor-related functions in the motor cortex than for cognitive control in the DLPFC. These findings are a fundamental step in advancing our understanding of interhemispheric connectivity and may be used to identify treatments for disorders in which transcallosal transmission is dysfunctional.

Towards Debris Information Analysis and Abstraction for Wi-Fi Radar Edge in Collapsed Structures

Structural collapses are widespread, owing to a surge in climatic changes, earthquakes, and terrorism. Therefore, there are some technological rescue methods in practice that involve sensors, radars, cameras, microphones, and robots. However, deployment of these techniques faces at least one issue amongst cost, availability, and technical expertise, which limits their application in developing countries. So, there is a dire need for a low-cost and easy deployable rescue method. Recently, we witnessed an increasing trend of using Wi-Fi radios as sensing modality for various applications, including breathing detection and localization, thus leading to device-free communication. Based on this, we may envisage having a Wi-Fi rescue solution. However, Wi-Fi signals cannot easily penetrate through collapsed structures due to the multilayered obstacle scenario. So, in this study, we focus our research on the proper information analysis and abstraction of debris and also present the possible methodology to have better coverage for Wi-Fi signals using Wi-Fi radar edge. We define two objectives of this work; 1) debris information analysis and 2) the Wi-Fi signal propagation mechanism, respectively. We achieve our first goal by conducting site surveys of earthquake-hit areas that enable us to analyze the causes and types of structural collapses followed by debris concept selection model. We employ a bijective soft set approach to accurately select the debris based on the complexity and nature of structural engineering followed. Moreover, we use the Wi-Fi Halow radar edge for wireless signal propagation and perform extensive simulations at low power. Finally, we compare both methods and discuss prospects.

Ligand binding domain interface: A tipping point for pharmacological agents binding with GluN1/2A subunit containing NMDA receptors

N-methyl D-aspartate (NMDA) receptors play a crucial role in normal brain function, pathogenesis of neurodegenerative and psychiatric disorders. Functional tetra-heteromeric NMDA receptor contains two obligatory GluN1 subunits and two identical or different non-GluN1 subunits that evolve from six different genes including four GluN2 (A-D) and two GluN3 (A-B) subunits. Since NMDA receptors confer varied physiological properties and spatiotemporal distributions in the brain, pharmacological agents that target NMDA receptors with specific GluN2 subunits have significant potential for therapeutic applications. In the present work, by using electrophysiology techniques, we have studied the role of ligand binding domain (LBD) interactions in determining the effect of well-characterized pharmacological agents including agonists, competitive antagonists, channel blockers and an allosteric modulator. Remarkably, point mutations at the distal end (site-II&III) of GluN1 LBD interface increased memantine potency up to sevenfold when co-expressed with wild type GluN2A receptors but exhibit no effect on Mg2+ activity. Conversely, mutations at the proximal end (site-I) of the LBD interface did not affect the memantine but altered Zn2+ and Mg2+ potency towards opposite directions. These results indicate that GluN1/2A LBD interface interactions play a key role in determining channel function. Further, subtle changes in LBD interaction can be readily translated to the downstream extracellular vestibule of channel pore to adopt a conformation that may affect memantine, Zn2+ and Mg2+ binding. Further studies on NMDA receptor LBD to transmembrane domain signal propagation mechanisms will help develop GluN2 subunit selective biomolecules that can be used for the treatment of neurological and psychiatric disorders.

Structure of the insulin receptor-insulin complex by single-particle cryo-EM analysis.

SummaryThe insulin receptor (IR) is a dimeric protein that plays a crucial role in controlling glucose homeostasis, regulating lipid, protein and carbohydrate metabolism, and modulating brain neurotransmitter levels1,2. IR dysfunctions have been associated with many diseases, including diabetes, cancer, and Alzheimer’s1,3,4. The primary sequence has been known since the 1980s5, and is composed of an extracellular portion (ectodomain, ECD), a single transmembrane helix and an intracellular tyrosine kinase domain. Insulin binding to the dimeric ECD triggers kinase domain auto-phosphorylation and subsequent activation of downstream signaling molecules. Biochemical and mutagenesis data have identified two putative insulin binding sites (S1 and S2)6. While insulin bound to an ECD fragment containing S1 and the apo ectodomain have been characterized structurally7,8, details of insulin binding to the full receptor and the signal propagation mechanism are still not understood. Here we report single particle cryoEM reconstructions for the 1:2 (4.3 Å) and 1:1 (7.4 Å) IR ECD dimer:Insulin complexes. The symmetric 4.3 Å structure shows two insulin molecules per dimer, each bound between the Leucine-rich sub domain L1 of one monomer and the first fibronectin-like domain (FnIII-1) of the other monomer, and making extensive interactions with the α subunit C-terminal helix (α-CT helix). The 7.4 Å structure has only one similarly bound insulin per receptor dimer. The structures confirm the S1 binding interactions and define the full S2 binding site. These insulin receptor states suggest that recruitment of the α-CT helix upon binding of the first insulin changes the relative sub domain orientations and triggers downstream signal propagation.

Mathematical model of a communication channel in urban environment

This article discusses the mechanism of signal propagation in urban environment and for the development of a three-dimensional communication channel model.

A Comprehensive Analysis of 5G Heterogeneous Cellular Systems Operating Over $\kappa$ – $\mu$ Shadowed Fading Channels

Emerging cellular technologies such as those proposed for use in 5G communications will accommodate a wide range of usage scenarios with diverse link requirements. This will include the necessity to operate over a versatile set of wireless channels ranging from indoor to outdoor, from line-of-sight (LOS) to non-LOS, and from circularly symmetric scattering to environments which promote the clustering of scattered multipath waves. Unfortunately, many of the conventional fading models adopted in the literature to develop network models lack the flexibility to account for such disparate signal propagation mechanisms. To bridge the gap between theory and practical channels, we consider $\kappa$-$\mu$ shadowed fading, which contains as special cases, the majority of the linear fading models proposed in the open literature, including Rayleigh, Rician, Nakagami-m, Nakagami-q, One-sided Gaussian, $\kappa$-$\mu$, $\eta$-$\mu$, and Rician shadowed to name but a few. In particular, we apply an orthogonal expansion to represent the $\kappa$-$\mu$ shadowed fading distribution as a simplified series expression. Then using the series expressions with stochastic geometry, we propose an analytic framework to evaluate the average of an arbitrary function of the SINR over $\kappa$-$\mu$ shadowed fading channels. Using the proposed method, we evaluate the spectral efficiency, moments of the SINR, bit error probability and outage probability of a $K$-tier HetNet with $K$ classes of BSs, differing in terms of the transmit power, BS density, shadowing characteristics and small-scale fading. Building upon these results, we provide important new insights into the network performance of these emerging wireless applications while considering a diverse range of fading conditions and link qualities.

Mechanism of signal propagation in Physarum polycephalum

Complex behaviors are typically associated with animals, but the capacity to integrate information and function as a coordinated individual is also a ubiquitous but poorly understood feature of organisms such as slime molds and fungi. Plasmodial slime molds grow as networks and use flexible, undifferentiated body plans to forage for food. How an individual communicates across its network remains a puzzle, but Physarum polycephalum has emerged as a novel model used to explore emergent dynamics. Within P. polycephalum, cytoplasm is shuttled in a peristaltic wave driven by cross-sectional contractions of tubes. We first track P. polycephalum's response to a localized nutrient stimulus and observe a front of increased contraction. The front propagates with a velocity comparable to the flow-driven dispersion of particles. We build a mathematical model based on these data and in the aggregate experiments and model identify the mechanism of signal propagation across a body: The nutrient stimulus triggers the release of a signaling molecule. The molecule is advected by fluid flows but simultaneously hijacks flow generation by causing local increases in contraction amplitude as it travels. The molecule is initiating a feedback loop to enable its own movement. This mechanism explains previously puzzling phenomena, including the adaptation of the peristaltic wave to organism size and P. polycephalum's ability to find the shortest route between food sources. A simple feedback seems to give rise to P. polycephalum's complex behaviors, and the same mechanism is likely to function in the thousands of additional species with similar behaviors.

VLF radio wave anomalies associated with the 2010 Ms 7.1 Yushu earthquake

The VLF radio signals recorded both from the ground based VLF radio wave monitoring network and the DEMETER satellite are investigated during the 2010Ms 7.1 Yushu earthquake. The ground-based observations show that the disturbance intensity of VLF wave’s amplitude relative to the background gets an enhancement over 22% at 11.9kHz, 27% at 12.6kHz and 62% at 14.9kHz VLF radio wave along the path from Novosibirsk - TH one day before the main shock, as compared to the maximum 20% observed during non-earthquake time. The space based observations indicate that there is a decrease of the signal to noise ratio (SNR) for the power spectral density data of 14.9kHz VLF radio signal at electric field four days before the main shock, with disturbance intensity exceeding the background by over 5% as compared to the maximum 3% observed during non-earthquake time. The geoelectric field observations in the epicenter region also show that a sharp enhancement from ∼340 to 430mV/km simultaneously appeared at two monitors 14days before main shock. The comparative analysis from the ground and space based observations during the earthquake and non-earthquake time provides us convincible evidence that there exits seismic anomalies from the VLF radio wave propagation before the 2010 Ms 7.1 Yushu earthquake. The possible mechanism for VLF radio signal propagation anomaly during 2010 Yushu earthquake maybe related to the change of the geoelectric field nearby the earthquake zone.

The Die Is Cast: Precision Electrophilic Modifications Contribute to Cellular Decision Making.

This perspective sets out to critically evaluate the scope of reactive electrophilic small molecules as unique chemical signal carriers in biological information transfer cascades. We consider these electrophilic cues as a new volatile cellular currency and compare them to canonical signaling circulation such as phosphate in terms of chemical properties, biological specificity, sufficiency, and necessity. The fact that nonenzymatic redox sensing properties are found in proteins undertaking varied cellular tasks suggests that electrophile signaling is a moonlighting phenomenon manifested within a privileged set of sensor proteins. The latest interrogations into these on-target electrophilic responses set forth a new horizon in the molecular mechanism of redox signal propagation wherein direct low-occupancy electrophilic modifications on a single sensor target are biologically sufficient to drive functional redox responses with precision timing. We detail how the various mechanisms through which redox signals function could contribute to their interesting phenotypic responses, including hormesis.

Signaling States of a Short Blue-Light Photoreceptor Protein PpSB1-LOV Revealed from Crystal Structures and Solution NMR Spectroscopy

Light–Oxygen–Voltage (LOV) domains represent the photo-responsive domains of various blue-light photoreceptor proteins and are widely distributed in plants, algae, fungi, and bacteria. Here, we report the dark-state crystal structure of PpSB1-LOV, a slow-reverting short LOV protein from Pseudomonas putida that is remarkably different from our previously published “fully light-adapted” structure [1]. A direct comparison of the two structures provides insight into the light-activated signaling mechanism. Major structural differences involve a~11Å movement of the C terminus in helix Jα, ~4Å movement of Hβ–Iβ loop, disruption of hydrogen bonds in the dimer interface, and a~29° rotation of chain-B relative to chain-A as compared to the light-state dimer. Both crystal structures and solution NMR data are suggestive of the key roles of a conserved glutamine Q116 and the N-cap region consisting of A′α–Aβ loop and the A′α helix in controlling the light-activated conformational changes. The activation mechanism proposed here for the PpSB1-LOV supports a rotary switch mechanism and provides insights into the signal propagation mechanism in naturally existing and artificial LOV-based, two-component systems and regulators.

Comparison of Empirical Path Loss Propagation Models with Building Penetration Path Loss Model

Path loss Propagation models plays a fundamental role in planning and designing of mobile radio communication link. In this paper a building penetration path loss model was developed using AUTOCAD. The model involved the combination of three mechanisms of signal propagation; refraction, reflection and diffraction. The signal penetration through building wall was modelled as refraction using Fresnel Refraction Coefficient and the signal propagation through the roof was modelled as diffraction using the principle of knife-edge diffraction. The developed building penetration path loss model was compared with some empirical path loss models namely, Log distance path loss, Okumura, HATA and COST-231 models and the results showed that the models compared accurately with the existing path loss models. Hence, it can be stated that the developed building penetration path loss model can be used to accurately predict signal attenuation in buildings located in an urban environment.

A stochastic mechanism for signal propagation in the brain: Force of rapid random fluctuations in membrane potentials of individual neurons

There are two functionally important factors in signal propagation in a brain structural network: the very first synaptic delay–a time delay about 1ms–from the moment when signals originate to the moment when observation on the signal propagation can begin; and rapid random fluctuations in membrane potentials of every individual neuron in the network at a timescale of microseconds. We provide a stochastic analysis of signal propagation in a general setting. The analysis shows that the two factors together result in a stochastic mechanism for the signal propagation as described below. A brain structural network is not a rigid circuit rather a very flexible framework that guides signals to propagate but does not guarantee success of the signal propagation. In such a framework, with the very first synaptic delay, rapid random fluctuations in every individual neuron in the network cause an “alter-and-concentrate effect” that almost surely forces signals to successfully propagate. By the stochastic mechanism we provide analytic evidence for the existence of a force behind signal propagation in a brain structural network caused by rapid random fluctuations in every individual neuron in the network at a timescale of microseconds with a time delay of 1ms.

The feasibility of coherent energy transfer in microtubules.

It was once purported that biological systems were far too 'warm and wet' to support quantum phenomena mainly owing to thermal effects disrupting quantum coherence. However, recent experimental results and theoretical analyses have shown that thermal energy may assist, rather than disrupt, quantum coherent transport, especially in the 'dry' hydrophobic interiors of biomolecules. Specifically, evidence has been accumulating for the necessary involvement of quantum coherent energy transfer between uniquely arranged chromophores in light harvesting photosynthetic complexes. The 'tubulin' subunit proteins, which comprise microtubules, also possess a distinct architecture of chromophores, namely aromatic amino acids, including tryptophan. The geometry and dipolar properties of these aromatics are similar to those found in photosynthetic units indicating that tubulin may support coherent energy transfer. Tubulin aggregated into microtubule geometric lattices may support such energy transfer, which could be important for biological signalling and communication essential to living processes. Here, we perform a computational investigation of energy transfer between chromophoric amino acids in tubulin via dipole excitations coupled to the surrounding thermal environment. We present the spatial structure and energetic properties of the tryptophan residues in the microtubule constituent protein tubulin. Plausibility arguments for the conditions favouring a quantum mechanism of signal propagation along a microtubule are provided. Overall, we find that coherent energy transfer in tubulin and microtubules is biologically feasible.

On-Chip Photonic Interconnects: A Computer Architect's Perspective

As the number of cores on a chip continues to climb, architects will need to address both bandwidth and power consumption issues related to the interconnection network. Electrical interconnects are not likely to scale well to a large number of processors for energy efficiency reasons, and the problem is compounded by the fact that there is a fixed total power budget for a die, dictated by the amount of heat that can be dissipated without special (and expensive) cooling and packaging techniques. Thus, there is a need to seek alternatives to electrical signaling for on-chip interconnection applications. Photonics, which has a fundamentally different mechanism of signal propagation, offers the potential to not only overcome the drawbacks of electrical signaling, but also enable the architect to build energy efficient, scalable systems. The purpose of this book is to introduce computer architects to the possibilities and challenges of working with photons and designing on-chip photonic interconnection networks. Table of Contents: List of Figures / List of Tables / List of Acronyms / Acknowledgments / Introduction / Photonic Interconnect Basics / Link Construction / On-Chip Photonic Networks / Challenges / Other Developments / Summary and Conclusion / Bibliography / Authors' Biographies

Computational model of Ca2+ wave propagation in human retinal pigment epithelium

AbstractPurpose Ca2+ signaling is relevant to most biological functions. In retinal pigment epithelium (RPE) a significant Ca2+ wave is produced by mechanical stimulation. To understand this process in detail, we modeled Ca2+ wave propagation in ARPE‐19 cells.Methods Mechanically induced Ca2+ wave was recorded from ARPE‐19 cells by Ca2+ imaging. Based on the measurements, a mathematical model was constructed. The model assessed Ca2+ wave propagation by assuming that cells were experiencing different conditions depending on their location with respect to the stimulation site.Results The model describes Ca2+ metabolism after stimulation as follows: 1) Cells near the stimulus site are likely to conduct Ca2+ through plasma membrane stretch‐sensitive Ca2+ channels and gap junctions. 2) The extracellular ligand and inositol 1,4,5‐trisphosphate (IP3) diffusion through gap junctions mediate the signal in all locations of the monolayer, ligand concentration decreasing with distance. 3) The kinase activity targeted to IP3 receptor defines the sensitivity of the cell to the ligand. The model predicts suramin drug effects on P2Y2 receptors suggesting that suramin accelerates the phosphorylation rate of the receptors by enhancing their desensitization.Conclusion Our model is the first mathematical model of Ca2+ signaling in ARPE‐19 cells. The model enables the analysis of the Ca2+ signal propagation mechanisms, and predicts new pathways of suramin drug effects.

Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation

BackgroundFormation of asymmetric kinase dimers is required for wt-EGFR activation upon ligand stimulation. The role of receptor dimerization in oncogenic EGFRvIII mutant activation is not completely understood and the molecular details of EGFRvIII interactions within homo-dimers and hetero-dimers are not elucidated yet.FindingsBy employing mutations that disrupt the asymmetric kinase dimer interface in EGFRvIII, we demonstrate that the mechanism of oncogenic EGFRvIII mutant activation is similar to that of the full-length wild-type EGFR. Surprisingly, the monomeric EGFRvIII lacks autophosphorylation and the formation of asymmetric kinase dimers is indispensable for oncogenic kinase activation. In addition, we show that ERBB3 can act as an activator of EGFRvIII by forming asymmetric kinase dimer in a ligand-independent manner. Interestingly, we found that the formation of asymmetric kinase dimer is dispensable for ERBB3 phosphorylation by the activated EGFR kinase as well as the ERBB2 kinase thus revealing a novel model for receptor function.ConclusionsLateral signaling is a novel mechanism of signal propagation via ERBB3 upon activation by EGFR/ERBB2 kinase even in the absence of their ability to form asymmetric kinase dimers.

Optical stimulation and imaging of functional brain circuitry in a segmented laminar flow chamber

Microfluidic technology is emerging as a useful tool for the study of brain slices, offering precise delivery of chemical factors along with robust oxygen and nutrient transport. However, continued reliance upon electrode-based physiological recording poses inherent limitations in terms of physical access, as well as the number of sites that can be sampled simultaneously. In the present study, we combine a microfluidic laminar flow chamber with fast voltage-sensitive dye imaging and laser photostimulation via caged glutamate to map neural network activity across large cortical regions in living brain slices. We find that the closed microfluidic chamber results in greatly improved signal-to-noise performance for optical measurements of neural signaling. These optical tools are also leveraged to characterize laminar flow interfaces within the device, demonstrating a functional boundary width of less than 100 μm. Finally, we utilize this integrated platform to investigate the mechanism of signal propagation for spontaneous neural activity in the developing mouse hippocampus. Through the use of localized Ca(2+) depletion, we provide evidence for Ca(2+)-dependent synaptic transmission.

Negative Coupling as a Mechanism for Signal Propagation between C2 Domains of Synaptotagmin I

Synaptotagmin I (Syt I) is a vesicle-localized protein implicated in sensing the calcium influx that triggers fast synchronous release of neurotransmitter. How Syt I utilizes its two C2 domains to integrate signals and mediate neurotransmission has continued to be a controversial area of research, though prevalent hypotheses favor independent function. Using differential scanning calorimetry and fluorescence lifetime spectroscopy in a thermodynamic denaturation approach, we tested an alternative hypothesis in which both domains interact to cooperatively disseminate binding information. The free energy of stability was determined for C2A, C2B, and C2AB constructs by globally fitting both methods to a two-state model of unfolding. By comparing the additive free energies of C2A and C2B with C2AB, we identified a negative coupling interaction between the C2 domains of Syt I. This interaction not only provides a mechanistic means for propagating signals, but also a possible means for coordinating the molecular events of neurotransmission.

Modeling and simulation of ion channels.

Modeling and simulation of ion channels.

Non-targeted effects of ionising radiation and radiotherapy

Modern radiobiology is undergoing rapid change due to new discoveries contradicting the target concept which is currently used to predict dose-response relationships. Thus relatively recently discovered radiation-induced bystander effects (RIBEs), that include additional death, mutation and radio-adaptation in non-irradiated cells, change our understanding of the target concept and broadens its boundaries. This can be significant from a radioprotection point of view and also has the potential to reassess radiation damage models currently used in radiotherapy. This article reviews briefly the general concepts of RIBEs such as the proposed underlying mechanisms of signal induction and propagation, experimental approaches and biological end points used to investigate these phenomena. It also summarises several mathematical models currently proposed in an attempt to quantify RIBE. The main emphasis of this article is to review and highlight the potential impact of the bystander phenomena in radiotherapy.