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High-precision global navigation satellite system (GNSS) positioning for automatic driving in urban environments remains an unsolved problem because of the impact of multipath interference and non-line-of-sight reception. Recently, methods based on data-driven deep reinforcement learning (DRL), which are adaptable to nonstationary urban environments, have been used to learn positioning-correction policies without strict assumptions about model parameters. However, the performance of DRL relies heavily on the amount of training data, and high-quality, available GNSS data collected in urban environments are insufficient because of issues such as signal attenuation and large stochastic noise, resulting in poor performance and low training efficiency for DRL. In this paper, we propose a DRL-based positioning correction method with an adaptive reward augmentation method (ARAM) to improve the GNSS positioning accuracy in nonstationary urban environments. To address the problem of insufficient training data in the target domain environment, we leverage sufficient data collected in source domain environments to compensate for insufficient training data, where the source domain environments can be in different locations than the target environment. We then employ ARAM to achieve domain adaptation that adaptively modifies data matching between the source domain and target domain by a simple modification to the reward function, thus improving the performance and training efficiency of DRL. Hence, our novel DRL model can achieve an adaptive dynamic-positioning correction policy for nonstationary urban environments. Moreover, the proposed positioning-correction algorithm can be flexibly combined with different model-based positioning approaches. The proposed method was evaluated using the Google smartphone decimeter challenge data set and the Guangzhou GNSS measurement data set, with results demonstrating that our method can obtain an improvement of approximately 10% in positioning performance over existing model-based methods and 8% over learning-based approaches.

Abstract Objective This study aimed to explore the characteristics of carbapenem-resistant Enterobacterales (CRE) patients in the intensive care unit (ICU) in different regions of Henan Province to provide evidence for the targeted prevention and treatment of CRE. Methods This was a cross-sectional study. CRE screening was conducted in the ICUs of 78 hospitals in Henan Province, China, on March 10, 2021. The patients were divided into provincial capital hospitals and nonprovincial capital hospitals for comparative analysis. Results This study involved 1009 patients in total, of whom 241 were CRE-positive patients, 92 were in the provincial capital hospital and 149 were in the nonprovincial capital hospital. Provincial capital hospitals had a higher rate of CRE positivity, and there was a significant difference in the rate of CRE positivity between the two groups. The body temperature; immunosuppressed state; transfer from the ICU to other hospitals; and use of enemas, arterial catheters, carbapenems, or tigecycline at the provincial capital hospital were greater than those at the nonprovincial capital hospital (P

Abstract Fungal pathogens typically use secreted effector proteins to suppress host immune activators to facilitate invasion. However, there is rarely evidence supporting the idea that fungal secretory proteins contribute to pathogenesis by transactivating host genes that suppress defense. We previously found that pathogen Magnaporthe oryzae induces rice Bsr-d1 to facilitate infection and hypothesized that a fungal effector mediates this induction. Here, we report that MoSPAB1 secreted by M. oryzae directly binds to the Bsr-d1 promoter to induce its expression, facilitating pathogenesis. Amino acids 103-123 of MoSPAB1 are required for its binding to the Bsr-d1 promoter. Both MoSPAB1 and rice MYBS1 compete for binding to the Bsr-d1 promoter to regulate Bsr-d1 expression. Furthermore, MoSPAB1 homologues are highly conserved among fungi. In particular, Colletotrichum fructicola CfSPAB1 and Colletotrichum sublineola CsSPAB1 activate kiwifruit AcBsr-d1 and sorghum SbBsr-d1 respectively, to facilitate pathogenesis. Taken together, our findings reveal a conserved module that may be widely utilized by fungi to enhance pathogenesis.

A Ge-doped dual-core dispersion compensation photonic crystal fiber (DC-DCPCF) is proposed. The small diameters of two layers’ air holes make DC-DCPCF form a dual-core structure, which is conducive to broadband dispersion compensation. Low Ge-doped silica as the only background material reduces the preparation difficulty and cost. It is inversely designed by using artificial neural network (ANN) combined with differential evolution algorithm (DE) to obtain target dispersion compensation. ANN replaces the finite element method to accomplish fast forward prediction of DC-DCPCF properties. DE solves the single solution problem of single or cascade network that makes it flexible and reproducible. The results demonstrate that the designed DC-DCPCF can not only compensate 45 and 25 times its length of Corning single-mode fiber 28 (SMF28) in S+C+L+U bands and E+S+C+L+U bands respectively, but also accurately compensate the residual dispersion with effective dispersion compensation being only +0.005∼+0.842ps/(nm·km) and −0.03∼+1.31ps/(nm·km), respectively. In addition, the kappa values of DCP-PCF are well matched with SMF28 in the broadband wavelength range. It takes only about 10 seconds to complete the inverse design of the target DC-DCPCF. It provides a design method for custom DC-DCPCF and an efficient inverse design solution for photonic automation in fiber optical communication systems.

Abstract Broadband optical frequency comb (OFC) generation based on a single electro-absorption modulator (EAM) is proposed. The EAM is driven by a radio frequency (RF) multi-frequency signal generated by a multiplication coupler composed of an electrical power splitter and an arithmetic circuit. Thus the number of comb-lines of the generated OFC can be increased. A complete theoretical model of OFC generation by an EAM driven by nth power of the RF source is established, and the performance of the OFC is analyzed by using OptiSystem software. The results show that, the number of comb-lines of the OFC is positively correlated with the number of multiplication of the RF source signal. The frequency spacing of the comb-lines is twice the frequency of the RF source signal and is tunable by adjusting the frequency of the RF source signal. Increasing chirp factor and modulation index of EAM could increase the number of comb-lines of the generated OFC. The amplitude of the RF source signal had little impact on the flatness of the OFC and the average OFC power. The scheme developed is not only simple and low-cost, but also can produce a large number of comb-lines. Graphical Abstract

Serum uric acid level above 7 mg/dl is defined as hyperuricemia, which gives rise to the monosodium urate (MSU), causing gout and urolithiasis. Hyperuricemia is an independent risk factor as well as a marker for hypertension, heart failure, atherosclerosis, atrial fibrillation, and chronic kidney disease. MSU crystals, soluble uric acid (UA), or oxidative stress derived from xanthine oxidoreductase (XOR) might be plausible explanations for the association of cardio-renovascular diseases with hyperuricemia. In macrophages, MSU activates the Nod-like receptor family, pyrin domain containing 3(NLRP3) inflammasome, and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Soluble UA accumulates intracellularly through UA transporters (UAT) in vascular and atrial myocytes, causing endothelial dysfunction ad atrial electrical remodeling. XOR generates reactive oxygen species (ROS) that lead to cardiovascular diseases. Since it remains unclear whether asymptomatic hyperuricemia could be a risk factor for cardiovascular and kidney diseases, European and American guidelines do not recommend pharmacological treatment for asymptomatic patients with cardio-renovascular diseases. The Japanese guideline, on the contrary, recommends pharmacological treatment for hyperuricemia with CKD to protect renal function, and it attaches importance of the cardio-renal interaction for the treatment of asymptomatic hyperuricemia patients with hypertension and heart failure.

Abstract Objective To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures. Methods The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago. Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment. T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed. Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked. Results Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types. Evidence of increased Treg competence was observed after each treatment course. CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells. Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk. In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells. Conclusions Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments. Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types. Several immune measures were identified as possible biomarkers of lesion activity. Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS. Trial registration Parent trials for this study are registered with ClinicalTrials.gov : CARE-MS II: NCT00548405 , CARE-MS II extension: NCT00930553 and ISS: NCT01307332 .

This study was conducted to determine the nutritional composition [acid detergent fibre (ADF), neutral detergent fibre (NDF), ether extract (EE) and crude protein (CP)], digestible energy (DE) and metabolizable energy (ME) of rapeseed meals (RSM) differing in glucosinolates (GLS) contents fed to growing pigs. One hundred and thirty-eight crossbred barrows with initial body weight (BW) of 39.0 ± 1.9 kg were allotted to 1 of 23 diets. Results showed that the content of GLS in RSM ranged from 1.72 to 62.94 mol/g DM with a coefficient of variation (CV) of 89%. The concentration of ADF ranged from 22.78 to 35.71% with a mean of 28.79% [DM (CV = 16.22%)]. The concentration of ether extract (EE) ranged from 1.42% to 14.55% with a mean of 7.78% [DM (CV = 45.16%)]. DE and ME values of the 22 RSM ranged from 10.10 to 15.42 MJ/kg DM and 9.09 to 14.94 MJ/kg DM (P

Introduction: Human induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called “iCell cardiomyocytes” under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na+ and Ca2+ currents. Methods: iCell cardiomyocytes were cultured for 8–14 days (38–44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na+ channel current (INa) and L-type Ca2+ channel current (ICaL) were evaluated by the whole-cell patch clamp. Results: iCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of INa, ICaL, and rapidly-activating delayed-rectifier K+ channel current were −62.7 ± 13.7, −8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K+ channel currents were observed, whereas the T-type Ca2+ channel or slowly-activating delayed-rectifier K+ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked INa in a concentration-dependent manner with IC50 of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak INa block with a higher IC50 of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked ICaL with IC50 of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively. Conclusions: In iCell cardiomyocytes, INa was blocked by the class Ia and Ic antiarrhythmic agents and ICaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity. Keywords: iCell cardiomyocytes, class I antiarrhythmic agents, Na+ channel current, L-type Ca2+ channel current

Abstract Local anesthetics (LAs) inhibit endoplasmic reticulum-associated protein degradation, however the mechanisms remain elusive. Here, we show that the clinically used LAs pilsicainide and lidocaine bind directly to the 20S proteasome and inhibit its activity. Molecular dynamic calculation indicated that these LAs were bound to the β5 subunit of the 20S proteasome, and not to the other active subunits, β1 and β2. Consistently, pilsicainide inhibited only chymotrypsin-like activity, whereas it did not inhibit the caspase-like and trypsin-like activities. In addition, we confirmed that the aromatic ring of these LAs was critical for inhibiting the proteasome. These LAs stabilized p53 and suppressed proliferation of p53-positive but not of p53-negative cancer cells.

Background: Pilsicainide, classified as a relatively selective Na+ channel blocker, also has an inhibitory action on the rapidly-activating delayed-rectifier K+ current (IKr) through human ether-a-go-go-related gene (hERG) channels. We studied the effects of chronic exposure to pilsicainide on the expression of wild-type (WT) hERG proteins and WT-hERG channel currents, as well as on the expression of mutant hERG proteins, in a heterologous expression system. Methods: HEK293 cells stably expressing WT or mutant hERG proteins were subjected to Western blotting, immunofluorescence microscopy and patch-clamp experiments. Results: Acute exposure to pilsicainide at 0.03–10 μM influenced neither the expression of WT-hERG proteins nor WT-hERG channel currents. Chronic treatment with 0.03–10 μM pilsicainide for 48 h, however, increased the expression of WT-hERG proteins and channel currents in a concentration-dependent manner. Chronic treatment with 3 μM pilsicainide for 48 h delayed degradation of WT-hERG proteins and increased the channels expressed on the plasma membrane. A cell membrane-impermeant pilsicainide derivative did not influence the expression of WT-hERG, indicating that pilsicainide stabilized the protein inside the cell. Pilsicainide did not influence phosphorylation of Akt (protein kinase B) or expression of heat shock protein families such as HSF-1, hsp70 and hsp90. E4031, a chemical chaperone for hERG, abolished the pilsicainide effect on hERG. Chronic treatment with pilsicainide could also increase the protein expression of trafficking-defective mutant hERG, G601S and R752W. Conclusions: Pilsicainide penetrates the plasma membrane, stabilizes WT-hERG proteins by acting as a chemical chaperone, and enhances WT-hERG channel currents. This mechanism could also be applicable to modulations of certain mutant-hERG proteins.

The study was conducted to develop and validate an equation to predict the metabolizable energy (ME) of double-low rapeseed cakes (DLRSC) for growing pigs based on their chemical compositions. In Experiment 1, 66 growing pigs (initial body weight 36.6 ± 4.1 kg) were allotted randomly to a completely randomized design with 11 diets. The diets included a corn–soybean meal basal diet and 10 test diets containing 19.22% DLRSC supplemented at the expense of corn, soybean meal, and lysine. Neutral detergent fiber (NDF), crude fiber (CF), and gross energy (GE) were the best predictors to determine ME. The best-fit prediction equation of ME (MJ/kg) was ME = 9.33 − 0.09 × NDF − 0.25 × CF + 0.59 × GE (R2 = 0.93). In Experiment 2, a total of 144 growing pigs (initial body weight 29.7 ± 2.7 kg), with six pigs per pen and six pens per treatment, were assigned randomly to four treatments in a completely randomized block design for a 28-day feeding trial. A corn–soybean meal basal diet was prepared, and three additional diets were formulated by adding 7%, 14%, and 21% DLRSC to the basal diet at the expense of soybean meal. All diets were formulated to provide equal standardized ileal digestibility (SID) Lys/ME ratio and SID essential amino acids/SID Lys ratio. Increasing dietary levels of DLRSC had no effect on average daily feed intake, average daily gain, and feed-to-gain ratio. The caloric efficiency of ME (31.83, 32.44, 31.95, and 32.69 MJ/kg, respectively) was not changed by increasing the dietary concentration of DLRSC. Increasing dietary levels of DLRSC linearly reduced (p < 0.05) the concentrations of triiodothyronine and tetraiodothyronine in serum, as well as apparent total tract digestibility of DM, GE, crude protein, acid detergent fiber, and organic matter of the diet. In conclusion, the ME prediction equation obtained in Experiment 1 accurately estimates the ME value of DLRSC fed to growing pigs.

A highly flexible microwave photonic single-passband filter is proposed and experimentally demonstrated. Two different light waves with their polarizations aligned with two principal axes of a polarization modulator are modulated, and two phase-modulated signals with opposite phase modulation indices are generated. Two different lower parts of the lower sidebands are removed by a fiber Bragg grating (FBG) to convert two phase-modulated signals into two intensity-modulated signals. Two high-pass frequency responses with different cut-off frequencies are realized. Since the two converted intensity-modulated signals are out of phase, the overlapped frequency responses are cancelled, and a single-passband filter is realized. The bandwidth and the central frequency can be tuned independently by properly adjusting the two wavelengths simultaneously. Furthermore, both the bandwidth and the central frequency can be simultaneously tuned by adjusting one of the two wavelengths. A theoretical analysis is performed, and an apodized FBG is fabricated and incorporated into the proposed single-passband filter. The simulated results and the experimental results agree very well.

Background: The human ether-a-go-go-related gene (HERG) encodes the α-subunit of rapidly activating delayed-rectifier potassium channels. Mutations in this gene cause long QT syndrome type 2 (LQT2). In most cases, mutations reduce the stability of the channel protein, which can be restored by heat shock (HS). Methods: We identified the novel mutant A78T-HERG in a patient with LQT2. The purpose of the current study was to characterize this mutant protein and test whether HS and heat shock factors (HSFs) could stabilize the mutant protein. A78T-HERG and wild-type HERG (WT-HERG) were expressed in HEK293 cells and analyzed by immunoblotting, immunoprecipitation, immunofluorescence, and whole-cell patch clamping. Results: When expressed in HEK293 cells, WT-HERG gave rise to immature and mature forms of the protein at 135 and 155 kDa, respectively. A78T-HERG gave rise only to the immature form, which was heavily ubiquitinated. The proteasome inhibitor MG132 increased the expression of immature A78T-HERG and increased both the immature and mature forms of WT-HERG. WT-HERG, but not A78T-HERG, was expressed on the plasma membrane. In whole-cell patch clamping experiments, depolarizing pulses evoked E4031-sensitive HERG channel currents in cells transfected with WT-HERG, but not in cells transfected with A78T-HERG. The A78V mutant, but not A78G mutant, remained in the immature form similarly to A78T. Maturation of the A78T-HERG protein was facilitated by HS, expression of HSF-1, or exposure to geranyl geranyl acetone. Conclusions: A78T-HERG was characterized by protein instability and reduced expression on the plasma membrane. The stability of the mutant was partially restored by HSF-1, indicating that HSF-1 is a target for the treatment for LQT2 caused by the A78T mutation in HERG.

Pathogenic species of Leptospira cause leptospirosis, a global zoonotic disease. Our previous work showed that leptospires survive and replicate in human macrophages but are killed in murine macrophages. However, the mechanism responsible for the different intracellular fates of leptospires within the macrophages of different hosts remains unclear.The present study demonstrates that infection with Leptospira interrogans caused significant up-regulation of reactive oxygen species (ROS) and superoxide in J774A.1 cells but did so to a lesser extent in THP-1 cells. The up-regulation of ROS and superoxide was significantly inhibited by the NADPH oxidase inhibitor apocynin. The damaged leptospires and remnants of leptospires within membrane-bound vacuoles were significantly inhibited by apocynin in J774A.1 cells but were less inhibited in THP-1 cells. In addition, apocynin significantly prevented damage to leptospires and the co-localization of L. interrogans with lysosomes in J774A.1 cells but did so to a lesser extent in THP-1 cells. Furthermore, the relative fluorescence intensity levels of intracellular leptospires and the viability of the intracellular leptospires increased in apocynin pretreated J774A.1 and THP-1 cells after 2 h of infection.The present study, based on our previous findings, further demonstrated that ROS contributed substantially to the bactericidal ability of mouse macrophages to kill intracellular leptospires. However, ROS did not contribute as much in human macrophages, which partially explains the different intracellular fates of L. interrogans in human and mouse macrophages.

Elastic net model is widely used in high-dimensional statistics for parameter regression and variable selection, which has been proved that the performance is often better than the lasso. However, it can only deals with data containing Gaussian noise, so it is not suitable for modern complex highdimensional data. Fortunately, an adaptive and robust minimization model, which combines the lp-norm data fidelity and elastic net regularization, has been proposed to deal with different types of noises and inherit the advantages of the elastic net in prediction accuracy. The double non-smoothness in objective function makes it challenging to minimize the model. After investigation, we find that the optimization algorithm is currently limited to the first-order alternating direction method of multipliers (ADMM), which is relatively lower in the recovered solutions' accuracy and relatively slower in the calculation speed. Therefore, we are committed to developing a fast and effective algorithm based on second-order information. Specifically, we propose a preconditioned proximal point algorithm (abbreviated as P-PPA) to solve the considered model by adding a proximal term. In theory, we analyze the consistency between the solution of the surrogate model and the original model. In addition, a key subproblem in P-PPA is solved by superlinear or even quadratically convergent semismooth Newton methods from the dual perspective. Finally, a large number of numerical experiments on high-dimensional simulated and real examples fully verify that our proposed algorithm is superior to ADMM in terms of calculation accuracy and speed. [ABSTRACT FROM AUTHOR]

Over the fast few years, the numerical success of the generalized alternating direction method of multipliers (GADMM) proposed by Eckstein and Bertsekas [Math. Progam. 1992] has inspired intensive attention in analyzing its theoretical convergence properties. This paper is devoted to the linear convergence rate of the semi-proximal GADMM (sPGADMM) for solving linearly constrained convex composite optimization problems. The semi-proximal terms contained in each subproblem possess the abilities of handling with multi-block problems efficiently. We initially present some important inequalities for the sequence generated by the sPGADMM, and then establish the local linear convergence rate under the assumption of calmness. As a by-product, the global convergence property is also discussed. [ABSTRACT FROM AUTHOR]

Abstract The burgeoning interest in decentralized applications (Dapps), spurred by advancements in blockchain technology, underscores the critical role of smart contracts. However, many Dapp users, often without deep knowledge of smart contracts, face financial risks due to hidden vulnerabilities. Traditional methods for detecting these vulnerabilities, including manual inspections and automated static analysis, are plagued by issues such as high rates of false positives and overlooked security flaws. To combat this, the article introduces an innovative approach using the bidirectional encoder representations from transformers (BERT)‐ATT‐BiLSTM model for identifying potential weaknesses in smart contracts. This method leverages the BERT pre‐trained model to discern semantic features from contract opcodes, which are then refined using a Bidirectional Long Short‐Term Memory Network (BiLSTM) and augmented by an attention mechanism that prioritizes critical features. The goal is to improve the model's generalization ability and enhance detection accuracy. Experiments on various publicly available smart contract datasets confirm the model's superior performance, outperforming previous methods in key metrics like accuracy, F1‐score, and recall. This research not only offers a powerful tool to bolster smart contract security, mitigating financial risks for average users, but also serves as a valuable reference for advancements in natural language processing and deep learning.