Biased Signaling Research Articles

Robust Frequency-Adaptive Quadrature Phase-Locked-Loops With Lyapunov-Certified Global Stability

This work describes and compares two phase-locked-loop (PLL) algorithms aimed at tracking a biased sinusoidal signal with unknown frequency, amplitude, and phase, with inherent robustness to dc offset. The proposed methods endow quadrature PLLs, renowned for their excellent tracking performance, with frequency-adaptation capability, while providing robust global stability certificates. The large-gain global stability, proved by Lyapunov-like arguments borrowed from adaptive control theory, represents a major benefit when compared to the conventional PLLs, whose convergence instead can be proved only locally by small-signal analysis or small-gain assumptions. In this connection, the proposed algorithms represent the first frequency-adaptive and dc-bias rejecting PLL-type architectures with Lyapunov-certified global stability. When used for signal tracking, the proposed methods are shown to outperform the adaptive observer, especially in noisy conditions. Moreover, they provide more accurate frequency estimates than existent frequency-adaptive PLLs, showing enhanced robustness in facing both phase-noise and measurement perturbations.

Phase Bias Estimation and Imaging for High-Squint Multichannel SAR in Azimuth

High-squint multichannel synthetic aperture radar (SAR) in azimuth can overcome the constraint of minimum antenna area in the traditional single-channel classical SAR system, and thereby it would be much more flexible to achieve high-resolution and wide-swath (HRWS) imaging than broadside SAR. However, for the high-squint multichannel SAR imaging mode, the squint angle causes Doppler centroid varying with the range frequency, which can further result in much more complicated problem of the spectral folding after down-sampled with low PRF. Meanwhile, the Doppler centroid frequency is indispensable for the estimation of phase bias and unambiguous signal reconstruction among received channels. In this paper, the impact of high-squint angle on the aliased Doppler spectrum and Doppler centroid is analyzed in detail. Then, a novel approach to phase bias estimation as well as the underlying signal processing in the case of high-squint multichannel SAR imaging mode in azimuth is proposed. Simulation results validate the effectiveness of the proposed processing flowchart for high-squint multichannel SAR.

FRACTAL PULL-IN MOTION OF ELECTROSTATIC MEMS RESONATORS BY THE VARIATIONAL ITERATION METHOD

The dynamic pull-in instability of a microstructure is a vast research field and its analysis is of great significance for ensuring the effective operation and reliability of micro-electromechanical systems (MEMS). A fractal modification for the traditional MEMS system is suggested to be closer to the real state as a practical application in the air with impurities or humidity. In this paper, we establish a fractal model for a class of electrostatically driven microstructure resonant sensors and find the phenomenon of pull-in instability caused by DC bias voltage and AC excitation voltage. The variational iteration method has been extended to obtain approximate analytical solutions and the pull-in threshold value for the fractal MEMS system. The result obtained from this method shows good agreement with the numerical solution. The simple and efficient operability is demonstrated through theoretical analysis and results comparisons.

Influence of goals on modular brain network organization during working memory.

Top-down control underlies our ability to attend relevant stimuli while ignoring irrelevant, distracting stimuli and is a critical process for prioritizing information in working memory (WM). Prior work has demonstrated that top-down biasing signals modulate sensory-selective cortical areas during WM, and that the large-scale organization of the brain reconfigures due to WM demands alone; however, it is not yet understood how brain networks reconfigure between the processing of relevant versus irrelevant information in the service of WM. Here, we investigated the effects of task goals on brain network organization while participants performed a WM task that required participants to detect repetitions (e.g., 0-back or 1-back) and had varying levels of visual interference (e.g., distracting, irrelevant stimuli). We quantified changes in network modularity-a measure of brain sub-network segregation-that occurred depending on overall WM task difficulty as well as trial-level task goals for each stimulus during the task conditions (e.g., relevant or irrelevant). First, we replicated prior work and found that whole-brain modularity was lower during the more demanding WM task conditions compared to a baseline condition. Further, during the WM conditions with varying task goals, brain modularity was selectively lower during goal-directed processing of task-relevant stimuli to be remembered for WM performance compared to processing of distracting, irrelevant stimuli. Follow-up analyses indicated that this effect of task goals was most pronounced in default mode and visual sub-networks. Finally, we examined the behavioral relevance of these changes in modularity and found that individuals with lower modularity for relevant trials had faster WM task performance. These results suggest that brain networks can dynamically reconfigure to adopt a more integrated organization with greater communication between sub-networks that supports the goal-directed processing of relevant information and guides WM.

Daridorexant: A drug to treat insomnia

In this review, we have explained the drug “Daridorexant” which is been used for the treatment of insomnia. Clinical research has shown, however, that individuals with insomnia have inconsistent reporting of subjective (i.e., self-reported diaries) and objective (i.e., polysomnography) estimations of their sleep characteristics. Idorsia Pharmaceuticals Ltd. is developing daridorexant (Quviviq™), an orally given dual orexin Type 1 and Type 2 (OX1 and OX2) receptor antagonist (DORA), for the treatment of insomnia. Daridorexant was chosen from a pool of medication candidates because it had estimated effect duration of 8 h at a dosage of 25 mg and a half-life designed to minimize residual effects that might impede daytime functioning. Symptoms have been self-reported by approximately 30% of the general population and can cause a wide range of daily impacts such as fatigue, decreased energy, mood changes, and cognitive impairments. We have explained the pharmacokinetics and pharmacodynamics profile of Daridorexant. It preferentially targets orexin neurons and inhibits downstream neuronal pathways that promote wakefulness; however, it does not affect neuronal pathways that induce adverse effects found with positive allosteric gamma-aminobutyric acid-A receptor modulators. In the context of arrestin-mediated pathways, the possibility of biased signaling is being investigated. The drugs used in the orexinergic system are also included in this review.

BDS/QZSS integrated PPPAR time–frequency transfer

Based on BeiDou navigation satellite system (BDS), the Quasi-Zenith satellite system (QZSS) was added to assist in studying the precise point positioning (PPP) time and frequency transfer effect. Ambiguity resolution (AR) is the key to the rapid conversion of the PPP method. Therefore, this paper also used the ionospheric-free combination and the observable-specific signal bias (OSB) product of Wuhan University to test the time–frequency transfer effect of BDS ambiguity-fixed. In this way, BDS PPP, BDS + QZSS PPP, BDS PPP-AR, and global positioning system (GPS) PPP methods were formed. Six stations located in Japan and Australia were selected for experiments. Conclusion: BDS can reach the same level as GPS; when the cut-off angle is greater than 15°, adding QZSS could improve the success rate, accuracy, and frequency stability of the solution of time links effectively; the ambiguity fixed strategy can improve the time transfer accuracy but not the short-term frequency stability.

Cognitive flexibility in post-traumatic stress disorder: Sustained interference associated with altered modulation of cortical oscillatory activity during task-switching

Post-traumatic stress disorder (PTSD) is associated with deficits in cognitive flexibility, with evidence suggesting that these deficits may be a risk factor for the development of core PTSD symptoms. Understanding the neurophysiological substrate of this association could aid the development of effective therapies for PTSD. In this study, we investigated the relationship between post-traumatic stress severity (PTSS) in service members with combat exposure and the modulation of cortical oscillatory activity during a test of cognitive flexibility. Participants were assigned to three groups based on PTSS scores: low (well below a threshold consistent with a diagnosis of PTSD, n = 30), moderate (n = 32), and high (n = 29) symptom severity. Magnetoencephalography data were recorded while participants performed a cued rule-switching task in which two matching rules were repeated or switched across consecutive trials. Participants with high PTSS had longer reaction times for both switch and repeat trials, and showed evidence of sustained residual interference during repeat trials. During the cue-stimulus interval, participants with moderate and high PTSS showed higher relative theta power in switch trials over left dorsolateral prefrontal cortex (DLPFC). After test-stimulus onset, participants with high PTSS showed less suppression of beta band activity, which was present over multiple prefrontal, parietal, and temporal regions in switch trials, but it was confined to ventromedial prefrontal cortex in repeat trials. Higher theta band activity is a marker of effortful voluntary shifting of attention, while lower suppression of beta band activity reflects difficulties with inhibition of competing perceptual information and courses of action. These findings are consistent with a role for altered suppression of beta band activity, which can be due to less effective top-down bias signals exerted by DLPFC, in the etiology of cognitive flexibility deficits in PTSD.

Voltage-modulated surface plasmon resonance biosensors integrated with gold nanohole arrays.

Surface plasmon resonance (SPR) has emerged as one of the most efficient and attractive techniques for optical sensors in biological applications. The traditional approach of an EC (electrochemical)-SPR biosensor to generate SPR is by adopting a prism underneath the sensing substrate, and an angular scan is performed to characterize the reflectivity of target analytes. In this paper, we designed and investigated a novel optical biosensor based on a hybrid plasmonic and electrochemical phenomenon. The SPR was generated from a thin layer of gold nanohole array on a glass substrate. Using C-Reactive Protein (CRP) as the target analyte, we tested our device for different concentrations and observed the optical response under various voltage bias conditions. We observed that SPR response is concentration-dependent and can be modulated by varying DC voltages or AC bias frequencies. For CRP concentrations ranging from 1 to 1000 µg/mL, at the applied voltage of -600 mV, we obtained a limit of detection for this device of 16.5 ng/mL at the resonance peak wavelength of 690 nm. The phenomenon is due to spatial re-distribution of electron concentration at the metal-solution interface. The results suggest that CRP concentration can be determined from the SPR peak wavelength shift by scanning the voltages. The proposed new sensor structure is permissible for various future optoelectronic integration for plasmonic and electrochemical sensing.

Magnetic Particle Imaging of Transplanted Human Islets Using a Machine Learning Algorithm.

Human islet transplantation is a promising therapy to restore normoglycemia for type 1 diabetes (T1D). Despite recent advances, human islet transplantation remains suboptimal due to significant islet graft loss after transplantation. Various immunological and nonimmunological factors contribute to this loss therefore signifying a need for strategies and approaches for visualizing and monitoring transplanted human islet grafts. One such imaging approach is magnetic particle imaging (MPI), an emerging imaging modality that detects the magnetization of iron oxide nanoparticles. MPI is known for its specificity due to its high image contrast and sensitivity. MPI through its noninvasive nature provides the means for monitoring transplanted human islets in real time. Here we summarize an approach to track transplanted human islets using MPI. We label human islet from donors with dextran-coated ferucarbotran iron oxide nanoparticles, transplant the labeled human islet into under the left kidney capsule, and image graft cells using an MPI scanner. We engineer a K-means++, clustering-based unsupervised machine learning algorithm for standardized image segmentation and iron quantification of the MPI, which solves problems with selection bias and indiscriminate signal boundary that accompanies this newer imaging modality. In this chapter, we summarize the methods of this emerging imaging modality of MPI in conjunction with unsupervised machine learning to monitor and visualize islets after transplantation.

Molecular Mechanisms of PTH/PTHrP Class B GPCR Signaling and Pharmacological Implications.

The classical paradigm of G protein-coupled receptor (GPCR) signaling via G proteins is grounded in a view that downstream responses are relatively transient and confined to the cell surface, but this notion has been revised in recent years following the identification of several receptors that engage in sustained signaling responses from subcellular compartments following internalization of the ligand-receptor complex. This phenomenon was initially discovered for the parathyroid hormone (PTH) type 1 receptor (PTH1R), a vital GPCR for maintaining normal calcium and phosphate levels in the body with the paradoxical ability to build or break down bone in response to PTH binding. The diverse biological processes regulated by this receptor are thought to depend on its capacity to mediate diverse modes of cyclic adenosine monophosphate (cAMP) signaling. These include transient signaling at the plasma membrane and sustained signaling from internalized PTH1R within early endosomes mediated by PTH. Here we discuss recent structural, cell signaling, and in vivo studies that unveil potential pharmacological outputs of the spatial versus temporal dimension of PTH1R signaling via cAMP. Notably, the combination of molecular dynamics simulations and elastic network model-based methods revealed how precise modulation of PTH signaling responses is achieved through structure-encoded allosteric coupling within the receptor and between the peptide hormone binding site and the G protein coupling interface. The implications of recent findings are now being explored for addressing key questions on how location bias in receptor signaling contributes to pharmacological functions, and how to drug a difficult target such as the PTH1R toward discovering nonpeptidic small molecule candidates for the treatment of metabolic bone and mineral diseases.

Dual-bias modulation heterodyne Kelvin probe force microscopy in FM mode

The use of a heterodyne detection scheme in Kelvin probe force microscopy (KPFM) is an effective way for enhancing the performance of KPFM. However, this detection scheme generally has difficulty in detecting the first- and second-harmonic electrostatic forces simultaneously. To overcome this problem, we propose dual-bias modulation heterodyne frequency modulation KPFM (DM-hetero-FM KPFM), in which dual AC biases at 2f1±fm are applied between the tip and the sample. DM-hetero-FM KPFM enables us to measure the contact potential difference and capacitance gradient simultaneously at high frequencies (in the MHz range) beyond the bandwidth of phase-lock loop. Moreover, the present method allows us to perform it in the open-loop mode, which is highly desired for performing KPFM on semiconductors or in liquids at high frequencies.

Phosphoproteomic Analysis of Dopamine D2 Receptor Signaling Reveals Interplay of G Protein- and β-Arrestin-Mediated Effects.

Leveraging biased signaling of G protein-coupled receptors has been proposed as a promising strategy for the development of drugs with higher specificity. However, the consequences of selectively targeting G protein- or β-arrestin-mediated signaling on cellular functions are not comprehensively understood. In this study, we utilized phosphoproteomics to gain a systematic overview of signaling induced by the four biased and balanced dopamine D2 receptor (D2R) ligands MS308, BM138, quinpirole, and sulpiride in an in vitro D2R transfection model. Quantification of 14,160 phosphosites revealed a low impact of the partial G protein agonist MS308 on cellular protein phosphorylation, as well as surprising similarities between the balanced agonist quinpirole and the inverse agonist sulpiride. Analysis of the temporal profiles of ligand-induced phosphorylation events showed a transient impact of the G protein-selective agonist MS308, whereas the β-arrestin-preferring agonist BM138 elicited a delayed, but more pronounced response. Functional enrichment analysis of ligand-impacted phosphoproteins and treatment-linked kinases confirmed multiple known functions of D2R signaling while also revealing novel effects, for example of MS308 on sterol regulatory element-binding protein-related gene expression. All raw data were deposited in MassIVE (MSV000089457).

Quantum dynamics of a 4π kink in Josephson junction parallel arrays with large kinetic inductance

We present a theoretical study of the quantum dynamics of two magnetic fluxons trapped in Josephson junction parallel arrays (JJPAs) with large kinetic inductances. The Josephson phase distribution of two trapped magnetic fluxons satisfies a topological constraint, i.e., the total variation of Josephson phases along a JJPA is $4\ensuremath{\pi}$. In such JJPAs the characteristic length of the Josephson phase distribution (``the size'' of magnetic fluxon) is drastically reduced to be less than a single cell size. Two extreme dynamic patterns will be distinguished: two weakly interacting and two merged magnetic fluxons, i.e., a $4\ensuremath{\pi}$ kink. Taking into account the repulsive interaction between two magnetic fluxons located in the same or adjacent cells, we obtain the energy band spectrum ${E}_{4\ensuremath{\pi}}(p)$ for a quantum $4\ensuremath{\pi}$ kink. The coherent quantum dynamics of $4\ensuremath{\pi}$ kinks demonstrates the quantum beats with the frequency and amplitude strongly deviating from those observed for two independent magnetic fluxons. In the presence of applied dc and ac bias currents of frequency $f$ a weakly incoherent quantum dynamics of a $4\ensuremath{\pi}$ kink results in the Bloch oscillations and the seminal current steps with values ${I}_{4\ensuremath{\pi}}^{(n)}=enf$ which are two times less than those for two independent magnetic fluxons.

Dynamic Modeling of Liquid Crystal-Based Metasurfaces and Its Application to Reducing Reconfigurability Times

This paper describes and validates for the first time the dynamic modelling of Liquid Crystal (LC)-based planar multi-resonant cells, as well as its use as bias signals synthesis tool to improve their reconfigurability time. The dynamic LC director equation is solved in the longitudinal direction through the finite elements method, which provides the z- and time-dependent inhomogeneous permittivity tensor used in an electromagnetic simulator to evaluate the cells behaviour. The proposed model has been experimentally validated using reflective cells for phase control (reflectarray) and measuring the transient phase, both in excitation and relaxation regimes. It is shown how a very reduced number of stratified layers are needed to model the material inhomogeneity, and that even an homogeneous effective tensor can be used in most of the cases, which allows a model simplification suitable for design procedures without losing accuracy. Consequently, a novel bias signal design tool is proposed to significantly reduce the transition times of LC cells, and hence, of electrically large antennas composed of them. These tools, similar to those used in optical displays, are experimentally validated for the first time at mm- and sub-mm wave frequencies in this work, obtaining an improvement of orders of magnitude.

Polarization Modulator Unit Harness Thermal Design for the Mid- and High-Frequency Telescopes of the LiteBIRD Space Mission

Polarization modulator units (PMUs) represent a critical and powerful component in CMB polarization experiments to suppress the 1/f noise component and mitigate systematic uncertainties induced by detector gain drifts and beam asymmetries. The LiteBIRD mission (expected launch in the late 2020 s) will be equipped with 3 PMUs, one for each of the 3 telescopes, and aims at detecting the primordial gravitational waves with a sensitivity of delta r<0.001. Each PMU is based on a continuously rotating transmissive half-wave plate held by a superconducting magnetic bearing in the 5 K environment. To achieve and monitor the rotation a number of subsystems is needed: clamp and release system and motor coils for the rotation; optical encoder, capacitive, Hall and temperature sensors to monitor its dynamic stability. In this contribution, we present a preliminary thermal design of the harness configuration for the PMUs of the mid- and high- frequency telescopes. The design is based on both the stringent system constraint for the total thermal budget available for the PMUs (lesssim 4 mW at 5 K) and on the requirements for different subsystem: coils currents (up to 10 mA), optical fibers for encoder readout, 25 MHz bias signal for temperature and levitation monitors.

Peripheral sensory neuron CB2 cannabinoid receptors are necessary for both CB2-mediated antinociceptive efficacy and sparing of morphine tolerance in a mouse model of anti-retroviral toxic neuropathy

Painful peripheral neuropathy is a common neurological complication associated with human immunodeficiency virus (HIV) infection and anti-retroviral therapy. We characterized the impact of two CB2 cannabinoid agonists (AM1710 and LY2828360 – ligands differing in signaling bias and CNS penetration) on neuropathic nociception induced by the antiretroviral agent Zalcitabine (2',3'-dideoxycytidine; ddC). We also used a conditional knockout approach to identify cell types mediating CB2 agonist-induced antinociceptive efficacy and sparing of morphine tolerance. AM1710 and LY2828360 alleviated ddC-induced neuropathic nociception in mice of both sexes. These benefits were absent in global CB2 knockout mice, which exhibited robust morphine antinociception. Like morphine, AM1710 blunted ddC-induced increases in proinflammatory cytokine (IL-1β, TNF-α) and chemokine (CCL2) mRNA expression levels. We generated advillinCre/+;CB2f/f conditional knockout mice to ascertain the role of CB2 localized to primary sensory neurons in CB2-mediated therapeutic effects. Antinociceptive efficacy of both AM1710 and LY2828360, but not reference analgesics, were absent in advillinCre/+;CB2f/f mice, which exhibited robust ddC-induced neuropathy. In ddC-treated CB2f/f mice, LY2828360 suppressed development of morphine tolerance and reversed established morphine tolerance, albeit with greater efficacy in male compared to female mice. LY2828360 failed to block or reverse morphine tolerance in advillinCre/+;CB2f/f mice. The present studies indicate that CB2 activation may alleviate HIV-associated antiretroviral neuropathy and identify a previously unreported mechanism through which CB2 activation produces antinociceptive efficacy. Our results also provide the first evidence that a CB2 agonist can reverse established morphine tolerance and demonstrate that CB2 localized to peripheral sensory neurons mediates the opioid tolerance sparing efficacy of CB2 agonists.

Biased Activation Mechanism Induced by GPCR Heterodimerization: Observations from μOR/δOR Dimers.

GPCRs regulate multiple intracellular signaling cascades. Biasedly activating one signaling pathway over the others provides additional clinical utility to optimize GPCR-based therapies. GPCR heterodimers possess different functions from their monomeric states, including their selectivity to different transducers. However, the biased signaling mechanism induced by the heterodimerization remains unclear. Motivated by the issue, we select an important GPCR heterodimer (μOR/δOR heterodimer) as a case and use microsecond Gaussian accelerated molecular dynamics simulation coupled with potential of mean force and protein structure network (PSN) to probe mechanisms regarding the heterodimerization-induced constitutive β-arrestin activity and efficacy change of the agonist DAMGO. The results show that only the lowest energy state of the μOR/δOR heterodimer, which adopts a slightly outward shift of TM6 and an ICL2 conformation close to the receptor core, can selectively accommodate β-arrestins. PSN further reveals important roles of H8, ICL1, and ICL2 in regulating the constitutive β-arrestin-biased activity for the apo μOR/δOR heterodimer. In addition, the heterodimerization can allosterically alter the binding mode of DAMGO mainly by means of W7.35. Consequently, DAMGO transmits the structural signal mainly through TM6 and TM7 in the dimer, rather than TM3 similar to the μOR monomer, thus changing the efficacy of DAMGO from a balanced agonist to the β-arrestin-biased one. On the other side, the binding of DAMGO to the heterodimer can stabilize μOR/δOR heterodimers through a stronger interaction of TM1/TM1 and H8/H8, accordingly enhancing the interaction of μOR with δOR and the binding affinity of the dimer to the β-arrestin. The agonist DAMGO does not change main compositions of the regulation network from the dimer interface to the transducer binding pocket of the μOR protomer, but induces an increase in the structural communication of the network, which should contribute to the enhanced β-arrestin coupling. Our observations, for the first time, reveal the molecular mechanism of the biased signaling induced by the heterodimerization for GPCRs, which should be beneficial to more comprehensively understand the GPCR bias signaling.

Parmodulin, an Allosteric Inhibitor of Protease Activated Receptor 1 (PAR1) Protects Sickle Cell Mice from Thromboinflammation and Endothelial Dysfunction

Protease activated receptor 1 (PAR1) couples the coagulation cascade to endothelial inflammation in many diseases, including sickle cell disease (SCD). PAR1 is a GPCR activated by proteolytic cleavage of an extracellular N-terminus, and demonstrates biased signaling. Activation of PAR1 by thrombin stimulates prothrombotic and proinflammatory signaling, whereas activation by activated protein C (APC) stimulates cytoprotective and anti-inflammatory pathways. The ideal PAR-1 targeted therapy would inhibit detrimental signaling while preserving beneficial signaling. 3K3A-APC is a signaling selective variant of APC that activates cytoprotective PAR1 signaling with minimal anticoagulant effects, demonstrated to have a beneficial role in stroke models. Parmodulin 2 (PM2) is a small molecule allosteric inhibitor of PAR1 that simultaneously blocks detrimental signaling and activate beneficial cytoprotective signaling similar to that induced by APC. We previously demonstrated that endogenous APC-PAR1 signaling contributes to thrombin generation and inflammation in a mouse model of SCD, whereas thrombin-PAR signaling enhances these pathways. We hypothesize that inducing cytoprotective PAR1 signaling with either 3K3A-APC and PM2 will reduce thrombo-inflammation in sickle cell mice at steady state. Townes wild type (HbAA) and sickle (HbSS) mice (male and female, 4 months old) were used in the studies. In the first experiment, HbAA and HbSS (n=4-5 per group) mice were treated daily with either saline (SAL) or 3K3A-APC (0.2mg/kg, BW) for 4 days. Samples were collected 1 hour after final dose. As previously demonstrated, plasma levels of thrombin-anti thrombin (TAT) complexes, the proinflammatory cytokine IL-6, high mobility group box 1 (HMGB1), and, soluble vascular cell adhesion molecule (sVCAM), were increased in HbSS mice compared to HbAA controls. Surprisingly 3K3A-APC treatment did reduce any of these parameters in HbSS mice. APC and its variant 3K3A-APC require binding to the endothelial protein C receptor (EPCR) to activate PAR1; it is known that SCD causes increased EPCR shedding. Indeed, we found that both SAL- and 3K3A-APC treated HbSS mice had elevated sEPCR levels compared to HbAA controls. Together, these data indicate that 3K3A-APC does not affect thrombo-inflammation in HbSS mice at steady state most likely due to by reduced ECPR expression on the endothelium. In the second experiment, HbAA and HbSS (male and female, 4 months old) mice (n=8-11 per group) were treated with vehicle (20% DMSO, 20% PEG800, 60% PBS) or PM2 (10 mg/kg, BW) every other day for 1 week. The last dose was administered on the 8th day 1 hour prior to collecting plasma samples. As expected, HbSS mice had elevated plasma TAT levels compared to HbAA mice (11.04 ± 1.4 vs 45.19 ± 6.3, p<0.05) which was significantly attenuated by PM2 treatment in SS mice (16.17 ± 2, p<0.05). Similar results were observed for IL-6 (AA: 2.06 ± 0.7 vs SS: 29.12 ± 9.6 vs SS+PM2: 5.83 ± 2.9; p<0.05); sVCAM (AA: 330.6 ± 31.5 vs SS: 571.4 ± 50.4 vs SS+PM2: 403.3 ± 41.22; p<0.05) and HMGB1 (AA: 11.46 ± 1.1 vs SS: 25.37 ± 1.5 vs SS+PM2: 19.12 ± 1.7; p<0.05). PM2 had no effect on markers of anemia in HbSS mice including RBC, hematocrit, and reticulocyte counts. In the present study ,3K3A-APC did not attenuate thrombin generation and cytokine production in HbSS mice; this might be due to the shedding of EPCR which is important co-receptor for the protective APC-PAR1 signaling. In contrast, PM2-mediated allosteric inhibition of thrombin/PAR1 and simultaneous induction of APC-like cytoprotective signaling attenuated levels of TAT, IL-6, HMGB1, and sVCAM in HbSS mice. Future studies towards evaluating the effect of PM2 on downstream targets of PAR1 signaling in sickle mice will provide more insight into the mechanism of this protective effect.

Protest participation propensity cues and selective recruitment: Dyadic evidence on rational prospecting

Who takes to the streets to protest matters. Protest sends signals to decision-makers and biased participation leads to biased signals. This paper examines one driver of biased participation, namely protest recruiters behaving as rational prospectors by only inviting others who they believe are likely to agree to the participation request. Extant evidence on rational prospecting is indirect as it draws on data collected among recruits. In contrast, this study employs a direct and dyadic data approach whereby potential recruiters for a labor movement demonstration in Belgium are asked, before the protest takes place, about the political viewpoints of specific others (alters) in their network, and then which alters they have invited to participate. After the event, the same respondents are asked for each alter whether they actually participated. We find that the perceived likelihood that an alter would participate in the event exerts a consistent effect on the actual recruitment effort towards that person. Moreover, recruiters’ perception that an individual is recruitable is mostly accurate; those perceived to have a high propensity to participate are more likely to take part, regardless of being recruited. Most importantly, our findings show that in the case of a labor union demonstration, prospectors evaluate alters who are co-workers differently compared to other types of social ties.

Computationally designed GPCR quaternary structures bias signaling pathway activation

Communication across membranes controls critical cellular processes and is achieved by receptors translating extracellular signals into selective cytoplasmic responses. While receptor tertiary structures can be readily characterized, receptor associations into quaternary structures are challenging to study and their implications in signal transduction remain poorly understood. Here, we report a computational approach for predicting receptor self-associations, and designing receptor oligomers with various quaternary structures and signaling properties. Using this approach, we designed chemokine receptor CXCR4 dimers with reprogrammed binding interactions, conformations, and abilities to activate distinct intracellular signaling proteins. In agreement with our predictions, the designed CXCR4s dimerized through distinct conformations and displayed different quaternary structural changes upon activation. Consistent with the active state models, all engineered CXCR4 oligomers activated the G protein Gi, but only specific dimer structures also recruited β-arrestins. Overall, we demonstrate that quaternary structures represent an important unforeseen mechanism of receptor biased signaling and reveal the existence of a bias switch at the dimer interface of several G protein-coupled receptors including CXCR4, mu-Opioid and type-2 Vasopressin receptors that selectively control the activation of G proteins vs β-arrestin-mediated pathways. The approach should prove useful for predicting and designing receptor associations to uncover and reprogram selective cellular signaling functions.