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ABSTRACT Numerous host factors, in addition to human angiotensin-converting enzyme 2 (hACE2), have been identified as coreceptors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), demonstrating broad viral tropism and diversified druggable potential. We and others have found that antihistamine drugs, particularly histamine receptor H1 (HRH1) antagonists, potently inhibit SARS-CoV-2 infection. In this study, we provided compelling evidence that HRH1 acts as an alternative receptor for SARS-CoV-2 by directly binding to the viral spike protein. HRH1 also synergistically enhanced hACE2-dependent viral entry by interacting with hACE2. Antihistamine drugs effectively prevent viral infection by competitively binding to HRH1, thereby disrupting the interaction between the spike protein and its receptor. Multiple inhibition assays revealed that antihistamine drugs broadly inhibited the infection of various SARS-CoV-2 mutants with an average IC50 of 2.4 µM. The prophylactic function of these drugs was further confirmed by authentic SARS-CoV-2 infection assays and humanized mouse challenge experiments, demonstrating the therapeutic potential of antihistamine drugs for combating coronavirus disease 19.IMPORTANCEIn addition to human angiotensin-converting enzyme 2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can utilize alternative cofactors to facilitate viral entry. In this study, we discovered that histamine receptor H1 (HRH1) not only functions as an independent receptor for SARS-CoV-2 but also synergistically enhances ACE2-dependent viral entry by directly interacting with ACE2. Further studies have demonstrated that HRH1 facilitates the entry of SARS-CoV-2 by directly binding to the N-terminal domain of the spike protein. Conversely, antihistamine drugs, primarily HRH1 antagonists, can competitively bind to HRH1 and thereby prevent viral entry. These findings revealed that the administration of repurposable antihistamine drugs could be a therapeutic intervention to combat coronavirus disease 19.

Abstract Background The association between the triglyceride-glucose (TyG) index and arterial stiffness in individuals with normoglycaemia remains unclear. We aimed to evaluate the relationship between the TyG index and arterial stiffness in Japanese individuals with normoglycaemia, providing additional evidence for predicting early arterial stiffness. Methods This study included 15,453 adults who participated in the NAGALA Physical Examination Project of the Murakami Memorial Hospital in Gifu, Japan, from 2004 to 2015. Data on clinical demographic characteristics and serum biomarker levels were collected. The TyG index was calculated from the logarithmic transformation of fasting triglycerides multiplied by fasting glucose, and arterial stiffness was measured using the estimated pulse wave velocity calculated based on age and mean blood pressure. The association between the TyG index and arterial stiffness was analysed using a logistic regression model. Results The prevalence of arterial stiffness was 3.2% (500/15,453). After adjusting for all covariates, the TyG index was positively associated with arterial stiffness as a continuous variable (adjusted odds ratio (OR) = 1.86; 95% Confidence Interval = 1.45–2.39; P

Inflammation is a complex host defensive response against various disease-associated pathogens. A baseline extent of inflammation is supposed to be tightly associated with a sequence of immune-modulated processes, resulting in the protection of the host organism against pathogen invasion; however, as a matter of fact is that an uncontrolled inflammatory cascade is the main factor responsible for the host damage, accordingly suggesting a significant and indispensable involvement of negative feedback mechanism in modulation of inflammation. Evidence accumulated so far has supported a repressive effect of the canonical Wnt/β-catenin pathway on microbial-triggered inflammation via diverse mechanisms, although that consequence is dependent on the cellular context, types of stimuli, and cytokine environment. It is of particular interest and importance to comprehend the precise way in which the Wnt/β-catenin pathway is activated, due to its essential anti-inflammatory properties. It is assumed that an inflammatory milieu is necessary for initiating and activating this signaling, implying that Wnt activity is responsible for shielding tissues from overwhelming inflammation, thus sustaining a balanced physiological condition against bacterial infection. This review gathers the recent efforts to elucidate the mechanistic details through how Wnt/β-catenin signaling modulates anti-inflammatory responses in response to bacterial infection and its interactions with other inflammatory signals, which warrants further study for the development of specific interventions for the treatment of inflammatory diseases. Further clinical trials from different disease settings are required.

Abstract The association of adiposity indices with prehypertension remains unclear in the Chinese non‐hypertensive population. This study aimed to compare the association of adiposity indices, including waist circumference (WC), waist‐to‐height ratio, body roundness index (BRI), a body shape index (ABSI), and conicity index (CI), and prehypertension in the Chinese population. We recruited 61 475 participants from a population‐based screening project in Guangdong province, China. Multiple logistic regression analyses were performed to detect the association between the six adiposity indices and prehypertension. Receiver operator characteristic curve (ROC) analysis was used to evaluate the predictive values of adiposity indices to prehypertension. The individuals were divided into two categories by blood pressure (BP) levels: normotension (

ObjectivesObservational studies have demonstrated that household income is associated with morbidity of mental disorders. However, a causal relationship between the two factors remains unclear. Therefore, we investigated the causal relationship between household income status and genetic liability of mental disorders using a bidirectional Mendelian randomization (MR) study.MethodsThis MR study included a large cohort of the European population from publicly available genome-wide association study datasets. A random-effects inverse-variance weighting model was used as the main standard, with MR-Egger regression, weighted median, and maximum likelihood estimations performed concurrently as supplements. Sensitivity analysis, consisting of heterogeneity and horizontal pleiotropy tests, was performed using Cochran’s Q test, MR-Egger intercept, and MR-PRESSO tests to ensure the reliability of the conclusions.ResultsA higher household income tended to be associated with a lower risk of genetic liability for depression (odds ratio [OR]: 0.655, 95% confidence interval [CI] = 0.522–0.822, p

Line contact structures, such as the contact between graphite brick and graphite tenon, widely exist in high-temperature gas-cooled reactors. Due to the stress concentration effect, the line contact area is one of the dangerous positions prone to failure in the nuclear reactor core. In this paper, the failure mechanism of line contact structures composed of IG11 nuclear graphite column and brick were investigated by means of experiment and finite element simulation. It was found that the failure process mainly includes three stages: firstly, the damage accumulation in nuclear graphite material led to the characteristic yielding of the line contact structure, but no macroscopic failure can be observed at this stage; secondly, the stresses near the contact area met Mohr failure criterion, and a crack initiated and propagated laterally in the contact zone, that is, local macroscopic failure occurred at this stage; finally, a second crack initiated in the contact area and developed in to a Y-shape, resulting in the final failure of the structure. This study lays a foundation for the structural design and safety assessment of high-temperature gas-cooled reactors.

Hepatitis B virus (HBV) infection remains a major health problem worldwide, and the current antiviral therapy, including nucleoside analogs, cannot achieve life-long cure, and clarification of antiviral host immunity is necessary for eradication. Here, we found that a clathrin-binding membrane protein epsin3 (EPN3) negatively regulates the expression of HBV RNA. EPN3 expression was induced by transfection of an HBV replicon plasmid, and reduced HBV-RNA level in hepatic cell lines and murine livers hydrodynamically injected with the HBV replicon plasmid. Viral RNA reduction by EPN3 was dependent on transcription, and independent from epsilon structure of viral RNA. Viral RNA reduction by overexpression of p53 or IFN-α treatment, was attenuated by knockdown of EPN3, suggesting its role downstream of IFN-α and p53. Taken together, this study demonstrates the anti-HBV role of EPN3. The mechanism how it decreases HBV transcription is discussed.

As a critical material in very/high-temperature gas-cooled reactors, graphite material directly affects the safety of the reactor core structures. Owing to the complex structures of graphite material in reactors, the material typically undergoes complex stress states. It is, therefore, necessary to study its mechanical properties, failure modes, and strength criteria under complex stress states so as to provide guidance for the core structure design. In this study, compressive failure tests were performed for graphite material under the condition of different confining pressures, and the effects of confining pressure on the triaxial compressive strength and Young's modulus of graphite material were studied. More specifically, graphite material based on the fracture surfaces and fracture angles, the graphite specimens were found to exhibit four types of failure modes, i.e., tension failure, shear-tension failure, tension-shear failure and shear failure, with increasing confining pressure. In addition, the Mohr strength envelope of the graphite material was obtained, and different strength criteria were compared. It showed that the parabolic Mohr-Coulomb criterion is more suitable for the strength evaluation for the graphite material.

Objective: To identify feature immune-related genes (IRGs) in patients with hypertrophic cardiomyopathy (HCM) and verify their ability to diagnose HCM.Methods: The GSE160997 dataset on cardiac tissue from 18 HCM patients and 5 controls was downloaded from the Gene Expression Omnibus database. A false discovery rate 1 were the filters applied to identify the differentially expressed genes (DEGs). The differentially expressed IRGs were the intersection results between the DEGs and an IRG dataset from the IMMPORT database. The protein-protein interaction network of differentially expressed IRGs was constructed, and the top 20 hub genes with the most adjacent nodes in the network were selected. The least absolute shrinkage and selection operator regression algorithm and a random forest algorithm were used to identify the feature IRGs as biomarkers that were then verified against GSE36961.Results: A total of 1079 DEGs were identified in GSE160997. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that immune-related mechanisms play an important role in the pathogenesis of HCM. A total of 121 differentially expressed IRGs were identified, and 5 feature IRGs were selected, 4 of which were confirmed as potential biomarkers of HCM by external verification with excellent discrimination ability. A diagnosis model of HCM based on the four feature IRGs was developed and visualized as a nomogram with a C-index of 0.925 (95% confidence interval 0.869–0.981).Conclusion: Our study identified four feature IRGs as biomarkers for the diagnosis of HCM, offering an innovative perspective of the underlying immune-related pathological molecular mechanisms.

Physical salt attack (PSA) is one of the dominant durability issues of cement-based materials, where salt crystallization pressure is the driving force inducing damage. However, research on the temperature-related deterioration behavior of cement-based materials is limited. In this study, salt-contaminated cement mortars were rewetted at different temperatures. The assessment criteria were based on the visual appearance, weight evolution and size distribution of scaled materials, and the alterations in the microstructure were investigated by microscopy, thermal and mineralogical analyses. The results indicated that more severe damage developed at 5 °C than that at 20 °C due to the greater crystallization pressure caused by the conversion from thenardite (Na2SO4) to mirabilite (Na2SO4·10H2O) at the lower temperature. No damage was observed at 35 °C, since the repeated dissolution and re-crystallization of thenardite were harmless for the specimens. In addition, two distinct damage patterns were observed for PSA performed at 5 °C and 20 °C, namely, granular disintegration and contour scaling.

As one typical heterogeneous material, the heterogeneity of rock micro parameters has an important effect on its macro mechanical behavior. The study of the heterogeneity of micro parameters is more important to reveal the root cause of deformation and failure. However, as a typical heterogeneous material, the current testing and inversion method is not suitable for micro parameters measurement for the rock. Aiming at obtaining the distribution of micro Young’s modulus and micro Poisson’s ratio of the rock, based on the digital image correlation method (DIC) and finite element method (FEM), this paper proposed a parameter field inversion method, namely the DF-PF inversion method. Its inversion accuracy is verified using numerical simulation and laboratory uniaxial compression test. Considering the influences of heterogeneity, stress state and dimension difference, the average inversion error of Young’s modulus field and Poisson’s ratio field are below 10%, and the proportion of elements with an error of less than 15% accounts for more than 86% in the whole specimen model. Compared with the conventional measuring method, the error of macro Young’s modulus and macro Poisson’s ratio calculated by the DF-PF inversion method is less than 2.8% and 9.07%, respectively. Based on the statistical analysis of Young’s modulus field and Poisson’s ratio field, the parameter homogeneity and quantitative function relation between the micro parameter and the principal strain can also be obtained in laboratory tests. The DF-PF inversion method provides a new effective method of testing Young’s modulus field and Poisson’s ratio field of the rocks under complex stress states.

The damage development trend of concrete with cracks in salt-freezing environment is systematically studied. The cracks are also tested in intact concrete for comparison, and crack characterization is introduced. The mass loss, the relative dynamic elastic modulus, and the change of crack width are analyzed. Results show that the crack width increases as the salt-freezing cycle progresses. Following the development trend of the cracks, concrete cracks can be divided into three categories: 0–40, 40–100, and 100–150 μm. The mass loss increases significantly, and the change of relative dynamic elastic modulus decreases in concrete with an initial crack compared with the intact concrete. When the crack width is 80 μm, a maximum mass loss rate of 0.19% and a minimum relative dynamic elastic modulus of 75.81% can be obtained. These test results prove that crack and freeze-thaw coupling can influence each other and accelerate the failure of concrete. Overall, this study can serve as a basis for the durability design and life improvement of concrete structures.

Residual stress within a structural component can significantly affect the mechanical performance and stability of a structure. Therefore, it is crucial to find a way to determine the residual stress distribution to maintain the normal working of structures. Conventional methods for residual stress determination primarily include experimental testing, finite element simulations and inverse identification. However, these methods suffer from disadvantages of high testing costs, long calculation time and low inverse efficiency. To avoid these shortcomings, this study developed a high-performance method based on a deep learning technique. In this method, an artificial neural network was used to replace the finite element calculation in the finite element model updating (FEMU) technique and the residual stress distribution of structural components was inversely obtained based on the measured residual stresses of a finite number of measuring points. Compared with the conventional FEMU technique, the calculation efficiency of the proposed method was considerably improved. Furthermore, the accuracy and efficiency of the method were verified by simulated four-point bending experiments considering an elastic-plastic material.

As a key material in high-temperature gas-cooled reactors (HTGR), nuclear graphite is a type of quasi-brittle material with complex damage mechanisms. However, it is difficult to characterise the damage properties of nuclear graphite under complex stress states using conventional testing approaches or inverse methods. In this study, a hybrid identification method based on 8-node quadrilateral element digital image correlation (Q8-DIC), a double iterative finite element model updating (FEMU) technique, and artificial neural networks (ANNs) is presented to characterise the damage properties of IG11 graphite material under complex stress states. First, this method is verified using simulated tests on a ring under diametrical compression, then applied to actual mechanical testing of graphite material to evaluate its damage properties. Finally, factors affecting the evolution of damage are discussed. The results indicate that the first principal strain has the most significant effect on the damage evolution of the graphite material. Keywords: Nuclear graphite, Damage, Complex stress states, Inverse identification, Artificial neural networks

Durability improvement is always important for steel–concrete structures exposed to chloride salt environment. The present research investigated the influence of a novel nano-precursor inhibiting material (NPI), organic carboxylic acid ammonium salt, on the mechanical and transport properties of concrete. The NPI caused a slight reduction in the strength of concrete at later ages. NPI significantly decreased water absorption and slowed down the speed of water absorption of concrete. In addition, the NPI decreased the charge passed and the chloride migration coefficient, and the results of the natural chloride diffusion showed that the NPI decreased the chloride concentration and the chloride diffusion coefficient. The NPI effectively improved the resistance of chloride penetration into testing concrete. The improvement in the impermeability of concrete was ascribed to the incorporation with the NPI, which resulted in increasing the contact angle of cement pastes. The contact angle went up from 17.8° to 85.8° for 0% and 1.2% NPI, respectively, and cement pastes became less hydrophilic. Some small pore throats were unconnected. Besides, the NPI also optimized the pore size distribution of hardened cement paste.

The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.

Comprehensively elucidating the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) latency is a priority to achieve a functional cure. As current 'shock' agents failed to efficiently reactivate the latent reservoir, it is important to discover new targets for developing more efficient latency-reversing agents (LRAs). Here, we found that TRIM28 potently suppresses HIV-1 expression by utilizing both SUMO E3 ligase activity and epigenetic adaptor function. Through global site-specific SUMO-MS study and serial SUMOylation assays, we identified that P-TEFb catalytic subunit CDK9 is significantly SUMOylated by TRIM28 with SUMO4. The Lys44, Lys56 and Lys68 residues on CDK9 are SUMOylated by TRIM28, which inhibits CDK9 kinase activity or prevents P-TEFb assembly by directly blocking the interaction between CDK9 and Cyclin T1, subsequently inhibits viral transcription and contributes to HIV-1 latency. The manipulation of TRIM28 and its consequent SUMOylation pathway could be the target for developing LRAs.

Digital image correlation (DIC) is a popular photomechanics method for deformation measurement. The conventional subset-based DIC method obtains the displacement vectors at the subset centers, but cannot calculate the deformation on the specimen edges, which may contain very useful information because specimens usually have greater deformation on edges, especially on curved edges due to stress concentration. In this study, the capability of a mesh-based DIC method using 8-node quadrilateral elements (Q8-mesh-DIC) in boundary deformation measurement was investigated and highlighted for specimens with non-uniform deformation. The results were compared with those obtained by some conventional subset-based DIC methods, and the accuracy of the boundary deformation measurement was verified through simulated and real experiments. The Q8-mesh-DIC appears to be more suitable for the boundary deformation measurement of non-uniform deformation fields.

Characterizing global mechanical behavior accurately is important for a detailed understanding of the deformation mechanism of rock material. In this paper, a new characterization model of the global mechanical behavior of rock is proposed, based on the structural characteristics of rock deformation. Uniaxial compression tests were carried out using the digital image correlation method and acoustic emission to obtain the interrelationship between mechanical behavior and deformation evolution. The test results show that the appearance of deformation localization leads to non-linear evolution of global mechanical behavior in a rock specimen. Further, due to the gradual evolution of deformation localization bands, the rock specimen evolves from a complete whole to a rock structure with a “weak interlayer”. Thus, the global mechanical behavior of the rock specimen depends heavily on the structural evolution process, especially when close to failure. A simplified characterization model was established according to the deformation process. The finite element method was used to verify the rationality of the proposed structural model. The verification result showed that under uniaxial compression, the structural model can reproduce the global mechanical behavior evolution process of the rock specimen.

Phosphorus (P) deficiency often occurs in paddy fields due to its high fixation, and low solubility and mobility in soils, especially under water stress. Available soil P and plant P uptake could be improved through the application of zeolite. However, little is known about the impact of zeolite on P uptake in rice under water stress. A two-year lysimetric experiment using a split-split plot design investigated the effects of zeolite (0 or 15 t ha−1) and P (0 or 60 kg ha−1) applications on water use, P uptake, and grain yield in rice under two irrigation management systems (continuous flooding irrigation (CF) and improved alternate wetting and drying irrigation (IAWD)). Both irrigation systems produced equivalent effective panicles and grain yield. Compared with CF, IAWD reduced water use and aboveground P uptake and improved water-use efficiency (WUE) in rice. The applications of zeolite or P alone increased grain yield, WUE, soil available P, and stem, leaf, and panicle P concentration, and aboveground P uptake, but had no significant effect on water use. The enhanced grain yield induced by zeolite was related to the increase in aboveground P uptake. The zeolite application enhanced NH4+−N retention in the topsoil and prevented NO3−−N from leaching into deeper soil layers. Moreover, Zeolite made lower rates of P fertilizer possible in paddy fields, with benefits for remaining P supplies and mitigating pollution due to excessive P. These results suggest that the combined application of zeolite and P under improved AWD regime reduced water use, improved P uptake and grain yield in rice, and alleviated environment risk.

Transforming growth factor (TGF)-β inhibits hepatitis B virus (HBV) replication although the intracellular effectors involved are not determined. Here, we report that reduction of HBV transcripts by TGF-β is dependent on AID expression, which significantly decreases both HBV transcripts and viral DNA, resulting in inhibition of viral replication. Immunoprecipitation reveals that AID physically associates with viral P protein that binds to specific virus RNA sequence called epsilon. AID also binds to an RNA degradation complex (RNA exosome proteins), indicating that AID, RNA exosome, and P protein form an RNP complex. Suppression of HBV transcripts by TGF-β was abrogated by depletion of either AID or RNA exosome components, suggesting that AID and the RNA exosome involve in TGF-β mediated suppression of HBV RNA. Moreover, AID-mediated HBV reduction does not occur when P protein is disrupted or when viral transcription is inhibited. These results suggest that induced expression of AID by TGF-β causes recruitment of the RNA exosome to viral RNP complex and the RNA exosome degrades HBV RNA in a transcription-coupled manner.