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The protein factor Glomulin (Glmn) is a regulator of the SCF (Skp1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex. Mutations of Glmn lead to glomuvenous malformations. Glmn has been reported to be associated with FK506-binding proteins (FKBP). Here we present in vitro binding analyses of the FKBP-Glmn interaction. Interestingly, the previously described interaction of Glmn and FKBP12 was found to be comparatively weak. Instead, the closely related FKBP12.6 and FKBP51 emerged as novel binding partners. We show different binding affinities of full length and truncated FKBP51 and FKBP52 mutants. Using FKBP51 as a model system, we show that two amino acids lining the FK506-binding site are essential for binding Glmn and that the FKBP51-Glmn interaction is blocked by FKBP ligands. This data suggest FKBP inhibition as a pharmacological approach to regulate Glmn and Glmn-controlled processes.

Terahertz (THz) wireless communication is envisioned as a promising technology, which is capable of providing ultra-high-rate transmission up to Terabit per second. However, some hardware imperfections, which are generally neglected in the existing literature concerning lower data rates and traditional operating frequencies, cannot be overlooked in the THz systems. Hardware imperfections usually consist of phase noise, in-phase/quadrature imbalance, and nonlinearity of power amplifier. Due to the time-variant characteristic of phase noise, frequent pilot insertion is required, leading to decreased spectral efficiency. In this paper, to address this issue, a novel pilot design strategy is proposed based on index modulation (IM), where the positions of pilots are flexibly changed in the data frame, and additional information bits can be conveyed by indices of pilots. Furthermore, a turbo receiving algorithm is developed, which jointly performs the detection of pilot indices and channel estimation in an iterative manner. It is shown that the proposed turbo receiver works well even under the situation where the prior knowledge of channel state information is outdated. Analytical and simulation results validate that the proposed schemes achieve significant enhancement of bit-error rate performance and channel estimation accuracy, whilst attaining higher spectral efficiency in comparison with its classical counterpart. [ABSTRACT FROM AUTHOR]

The media-based modulation (MBM) system, which varies its channel state by controlling the on/off status of the radio frequency (RF) mirrors, and embeds additional information bits into the mirror activation pattern, is capable of achieving significant throughput and desirable bit-error-rate (BER) performance. Hence, it has attracted increasing attention from researchers of wireless communication community. In this paper1, the information secrecy issue for MBM is investigated, and a secure single-input-multiple-output MBM (SIMO-MBM) system is proposed utilizing physical-layer security techniques. By considering the time-division duplexing (TDD) mode with channel reciprocity property, the legitimate channel state information (CSI) is applied to secure the data transmission of SIMO-MBM. More specifically, on one hand, adaptive phase rotation is imposed on the transmitted signals, where the rotation angle is determined by the phase of legitimate CSI; on the other hand, the mapping rule between the mirror activation pattern and binary bits is changed according to the amplitude of legitimate CSI. The BER performance of the eavesdropper is investigated via theoretical derivations, and the system secrecy mutual information is also derived, based on which the optimal design of the adaptive phase rotation strategy is provided. Theoretical and simulative results demonstrate that the proposed secure SIMO-MBM system is capable of enhancing the data confidentiality whilst keeping reliable data transmission. [ABSTRACT FROM AUTHOR]

Terahertz (THz) communication has emerged as a promising technology that efficiently alleviates the scarcity of the frequency resources, and is capable of providing Terabit-per-second (Tbps) data transmission. However, the hardware impairments, which are usually omitted in the low-rate systems, have a detrimental impact on the THz communication link. These hardware imperfections, including in-phase/quadrature (I/Q) imbalance, phase noise and nonlinearities of the power amplifier, can be approximately modelled as complex-Gaussian distortions at both the transmitter and the receiver. In this paper, the channel estimator and signal detector (CE/SD) design of the THz-band spatial modulation (THz-SM) system is investigated, where the counterparts for classical low-rate SM are no longer applicable. More specifically, a dual-stage maximum-likelihood (ML) channel estimator is proposed containing two phases of candidate acquirement and exhaustive search. Then a novel low-complexity mean-least-squares (MLS) channel estimator is developed by considering the hardware impairments in an averaging manner. Besides, the optimal detector for THz-SM is designed by taking hardware impairments into account. Simulation results validate that the proposed CE/SD design is capable of attaining reliable data transmission in THz-SM with hardware imperfections. [ABSTRACT FROM AUTHOR]

In this letter, resource management (RM) for hybrid wireless communication systems between vehicles and infrastructures is investigated, where radio frequency and visible light communications coexist. Specifically, the RM issue is formulated as an optimization problem of the lower bound of energy efficiency over multiple consecutive data transmission slots, which considers the variations of link availability in high-mobility scenarios and requires merely incomplete channel state information. An RM algorithm is proposed to solve this problem and simulations results demonstrate the energy efficiency enhancement of our proposed algorithm. [ABSTRACT FROM AUTHOR]

Angiotensin I-Converting Enzyme (ACE, CD143) Gene plays a crucial role in the pathology of carcinomas in many cancers including colorectal cancer (CRC). However, the methylation of ACE was rarely reported. In this study, our purpose was to investigate the methylation status of ACE and explored its prognostic value in CRC. The expression of ACE was detected by quantitative real-time polymerase chain reaction (qRT-PCR) analysis while the methylation status of ACE was measured via methylation-specific polymerase chain reaction (MSP). The result demonstrated that ACE expression was up-regulated in tumour tissues and HT-29 cells compared with the controls. ACE was also confirmed to be hypomethylated in CRC. Next, we evaluated the influence of ACE hypomethylation on cell growth. It was proved to be a favourable factor for the cell proliferation, cell colony forming, but an inhibitor for the cell apoptosis of CRC cells according to MST assay, colony forming assay and flow cytometry assay. ACE hypomethylation was also considered to be related to the prognosis of CRC through Cox regression analysis. Taken together, the over-expression of ACE was regulated by its hypomethylation and the ACE hypomethylation might be an independent prognostic indicator in CRC. [ABSTRACT FROM AUTHOR]

The primary objective of this study is to compare pedestrian evacuation strategies in the large-scale public space (LPS) using microscopic model. Data were collected by video recording from Tian-yi square for 36 hours in city of Ningbo, China. A pedestrian evacuation simulation model was developed based on the social force model (SFM). The simulation model parameters, such as reaction time, elasticity coefficient, sliding coefficient, et al, were calibrated using the real data extracted from the video. Five evacuation strategies, strategy 1 (S1) to strategy 5 (S5) involving distance, density and capacity factors were simulated and compared by indicators of evacuation time and channel utilization rate, as well as the evacuation efficiency. The simulation model parameters calibration results showed that a) the pedestrians walking speed is 1.0 ~ 1.5m/s; b) the pedestrians walking diameter is 0.3 ~ 0.4m; c) the frequency of pedestrian arrival and departure followed multi-normal distribution. The simulation results showed that, (a) in terms of total evacuation time, the performance of S4 and S5 which considering the capacity and density factors were best in all evacuation scenarios, the performance of S3 which only considering the density factor was the worst, relatively, and S1 and S2 which considering the distance factor were in the middle. (b) the utilization rate of channels under S5 strategy was better than other strategies, which performs best in the balance of evacuation. S3 strategy was the worst, and S1, S2 and S4 were in the middle. (c) in terms of the evacuation efficiency, when the number of evacuees is within 2, 500 peds, the S1 and S2 strategy which considering the distance factor have best evacuation efficiency than other strategies. And when the number of evacuees is above 2, 500 peds, the S4 and S5 strategy which considering the capacity factor are better than others. [ABSTRACT FROM AUTHOR]

Dual-mode index modulation aided orthogonal frequency division multiplexing (DM-OFDM) is recently proposed, where subcarriers are partitioned into OFDM subblocks, divided into two groups within each subblock, and modulated by two differentiable constellation alphabets. In DM-OFDM, additional bits can be transmitted through indices of subcarriers modulated by the same constellation alphabet. In this letter, generalized DM-OFDM (GDM-OFDM) is proposed, where the number of subcarriers modulated by the same constellation mode in each subblock is alterable. By applying such enhancements, the spectral efficiency can be improved at the cost of marginal performance loss. Moreover, since the bit error rate performance of GDM-OFDM degrades at low signal-to-noise ratios, an interleaving technique is employed to address this issue. At the receiver, a maximum-likelihood detector and a reduced-complexity log-likelihood ratio detector are employed for demodulation. Simulation results demonstrate that the proposed GDM-OFDM is capable of enhancing the spectral efficiency compared with DM-OFDM at the cost of negligible performance loss, and the interleaved GDM-OFDM can harvest on performance gain over GDM-OFDM. [ABSTRACT FROM PUBLISHER]

Background: Purinergic P2 receptors, which can be divided into ionotropic P2X receptors and metabotropic P2Y receptors, mediate cellular signal transduction of purine or pyrimidine nucleoside triphosphates and diphosphate. Based on the wide expression of purinergic P2 receptors in tissues and organs, their significance in homeostatic maintenance, metabolism, nociceptive transmission, and other physiological processes is becoming increasingly evident, suggesting that targeting purinergic P2 receptors to regulate biological functions and signal transmission holds significant promise for disease treatment., Aim of Review: This review highlights the detailed mechanisms by which purinergic P2 receptors engage in physiological and pathological progress, as well as providing prospective strategies for discovering clinical drug candidates., Key Scientific Concepts of Review: The purinergic P2 receptors regulate complex signaling and molecular mechanisms in nervous system, digestive system, immune system and as a result, controlling physical health states and disease progression. There has been a significant rise in research and development focused on purinergic P2 receptors, contributing to an increased number of drug candidates in clinical trials. A few influential pioneers have laid the foundation for advancements in the evaluation, development, and of novel purinergic P2 receptors modulators, including agonists, antagonists, pharmaceutical compositions and combination strategies, despite the different scaffolds of these drug candidates. These advancements hold great potential for improving therapeutic outcomes by specifically targeting purinergic P2 receptors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Production and hosting by Elsevier B.V.)

As a member of purinoceptors, the P2Y 6 receptor (P2Y 6 R) plays a crucial role in modulating immune signals and has been considered as a potential therapeutic target for inflammatory diseases. On the basis of the speculated probable conformation and binding determinants of P2Y 6 R, a hierarchical strategy that combines virtual screening, bioassays, and chemical optimization was presented. A potent P2Y 6 R antagonist (compound 50 ) was identified to possess excellent antagonistic activity (IC 50 = 5.914 nM) and high selectivity. In addition, binding assays and chemical pull-down experiments confirmed that compound 50 was nicely bound to P2Y 6 R. Notably, compound 50 could effectively ameliorate DSS-induced ulcerative colitis in mice through inhibiting the activation of NLRP3 inflammasome in colon tissues. Moreover, treatment with compound 50 reduced LPS-induced pulmonary edema and infiltration of inflammatory cells in mice. These findings suggest that compound 50 could serve as a specific P2Y 6 R antagonist for treating inflammatory diseases and deserve further optimization studies.

It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.

Single-photon avalanche diode (SPAD) is a promising photosensor because of its high sensitivity to optical signals in weak illuminance environment. Recently, it has drawn much attention from researchers in visible light communications (VLC). However, existing literature only deals with the simplified channel model, which only considers the effects of Poisson noise introduced by SPAD, but neglects other noise sources. Specifically, when an analog SPAD detector is applied, there exists Gaussian thermal noise generated by the transimpedance amplifier (TIA) and the digital-to-analog converter (D/A). Therefore, in this paper, we propose an SPAD-based VLC system with pulse-amplitude-modulation (PAM) under Poisson-Gaussian mixed noise model, where Gaussian-distributed thermal noise at the receiver is also investigated. The closed-form conditional likelihood of received signals is derived using the Laplace transform and the saddle-point approximation method, and the corresponding quasi-maximum-likelihood (quasi-ML) detector is proposed. Furthermore, the Poisson-Gaussian-distributed signals are converted to Gaussian variables with the aid of the generalized Anscombe transform (GAT), leading to an equivalent additive white Gaussian noise (AWGN) channel, and a hard-decision-based detector is invoked. Simulation results demonstrate that, the proposed GAT-based detector can reduce the computational complexity with marginal performance loss compared with the proposed quasi-ML detector, and both detectors are capable of accurately demodulating the SPAD-based PAM signals.