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Background: Sepsis is a life-threatening severe inflammatory reaction caused by the host's dysregulated response to infection. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to occur in 50 % of patients with septic shock. Currently, the pathophysiological mechanism of SIMD is complex, and there is no targeted treatment. Elabela is another endogenous ligand of Aplnr (APJ). The protective effect of APJ on the heart has been proven. Elabela (Ela) has been shown to have a variety of cardiovascular protective effects. However, there are no studies demonstrating the protective effect of Ela-APJ axis on SIMD., Materials and Methods: In vivo, C57BL/J mice were injected subcutaneously with 1 mg/kg/d Ela for 2 weeks, and in vitro, AC16 cells were treated with 1 μM Ela for 24 h. A 7-0 thread was used to ligate the distal end of the cecum, followed by puncture with a 20-gauge needle. Once a small amount of fluid leaks out, release the cecum back into the abdominal cavity. We measured the survival rates of the mice, performed ultrasound on their hearts, and evaluated the effects of the treatments. The serum and cell supernatant were extracted to detect myocardial injury markers and pyroptosis-related indicators. Western blotting was used to detect autophagy and pyroptosis-related protein. Molecular docking and other experiments were also used to detect changes in related proteins., Results: In vivo, Ela significantly improved the survival rate of septic mice, improved cardiac function, and reduced the production of myocardial injury markers, oxidative stress and pyroptosis. In vitro, Ela unblocked autophagy flow by affecting TFEB transcription. Autophagy reduces inflammation and oxidative stress by selectively degrading inflammatory bodies and ultimately alleviates pyroptosis., Conclusion: We had demonstrated for the first time that in sepsis, Ela promoted the degradation of inflammasomes, reduced oxidative stress, and inhibited the occurrence of pyroptosis by unblocking autophagy flow., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Non-structural protein 2 (nsp2) exists in all coronaviruses (CoVs), while its primary function in viral pathogenicity, is largely unclear. One such enteric CoV, porcine epidemic diarrhea virus (PEDV), causes high mortality in neonatal piglets worldwide. To determine the biological role of nsp2, we generated a PEDV mutant containing a complete nsp2 deletion (rPEDV-Δnsp2) from a highly pathogenic strain by reverse genetics, showing that nsp2 was dispensable for PEDV infection, while its deficiency reduced viral replication in vitro . Intriguingly, rPEDV-Δnsp2 was entirely avirulent in vivo , with significantly increased productions of IFNB (interferon beta) and IFN-stimulated genes (ISGs) in various intestinal tissues of challenged newborn piglets. Notably, nsp2 targets and degrades TBK1 (TANK binding kinase 1), the critical kinase in the innate immune response. Mechanistically, nsp2 induced the macroautophagy/autophagy process and recruited a selective autophagic receptor, NBR1 (NBR1 autophagy cargo receptor). NBR1 subsequently facilitated the K48-linked ubiquitination of TBK1 and delivered it for autophagosome-mediated degradation. Accordingly, the replication of rPEDV-Δnsp2 CoV was restrained by reduced autophagy and excess productions of type I IFNs and ISGs. Our data collectively define enteric CoV nsp2 as a novel virulence determinant, propose a crucial role of nsp2 in diminishing innate antiviral immunity by targeting TBK1 for NBR1-mediated selective autophagy, and pave the way to develop a new type of nsp2-based attenuated PEDV vaccine. The study also provides new insights into the prevention and treatment of other pathogenic CoVs. Abbreviations : 3-MA: 3-methyladenine; Baf A1: bafilomycin A 1 ; CoV: coronavirus; CQ: chloroquine; dpi: days post-inoculation; DMVs: double-membrane vesicles; GABARAP: GABA type A receptor-associated protein; GFP: green fluorescent protein; GIGYF2: GRB10 interacting GYF protein 2; hpi: hours post-infection; IFA: immunofluorescence assay; IFIH1: interferon induced with helicase C domain 1; IFIT2: interferon induced protein with tetratricopeptide repeats 2; IFITM1: interferon induced transmembrane protein 1; IFNB: interferon beta; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; nsp2: non-structural protein 2; OAS1: 2'-5'-oligoadenylate synthetase 1; PEDV: porcine epidemic diarrhea virus; PRRs: pattern recognition receptors; RIGI: RNA sensor RIG-I; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TCID 50 : 50% tissue culture infectious doses; VSV: vesicular stomatitis virus.

There is a noticeable gap in the literature regarding research on halogen-substitution-regulated ferroelectric semiconductors featuring multiple phase transitions. Here, a new category of 1D perovskite ferroelectrics (DFP) 2 SbX 5 (DFP + = 3,3-difluoropyrrolidium, X - = I - , Br - , abbreviated as I-1 and Br-2) with twophase transitions (PTs) is reported. The first low-temperature PT is a mmmFmm2 ferroelectric PT, while the high-temperature PT is a counterintuitive inverse temperature symmetry-breaking PT. By the substitution of iodine with bromine, the Curie temperature (Tc) significantly increases from 348 K of I-1 to 374 K of Br-2. Their ferroelectricity and pyroelectricity are improved (Ps value from 1.3 to 4.0 µC cm -2 , p e value from 0.2 to 0.48 µC cm -2  K -1 for I-1 and Br-2), while their optical bandgaps increased from 2.1 to 2.7 eV. A critical slowing down phenomenon is observed in the dielectric measurement of I-1 while Br-2 exhibits the ferroelastic domain. Structural and computational analyses elucidate that the order-disorder movement of cations and the distortion of the chain perovskite [SbX 5 ] 2- anions skeleton lead to PT. The semiconductor properties are determined by [SbX 5 ] 2- anions. The findings contribute to the development of ferroelectric semiconductors and materials with multiple PTs and provide materials for potential applications in the optoelectronic field., (© 2024 Wiley‐VCH GmbH.)

Background: The protective effectiveness provided by naturally acquired immunity against SARS-CoV-2 reinfection remain controversial., Objective: To systematically evaluate the protective effect of natural immunity against subsequent SARS-CoV-2 infection with different variants., Methods: We searched for related studies published in seven databases before March 5, 2023. Eligible studies included in the analysis reported the risk of subsequent infection for groups with or without a prior SARS-CoV-2 infection. The primary outcome was the overall pooled incidence rate ratio ( IRR ) of SARS-CoV-2 reinfection/infection between the two groups. We also focused on the protective effectiveness of natural immunity against reinfection/infection with different SARS-CoV-2 variants. We used a random-effects model to pool the data, and obtained the bias-adjusted results using the trim-and-fill method. Meta-regression and subgroup analyses were conducted to explore the sources of heterogeneity. Sensitivity analysis was performed by excluding included studies one by one to evaluate the stability of the results., Results: We identified 40 eligible articles including more than 20 million individuals without the history of SARS-CoV-2 vaccination. The bias-adjusted efficacy of naturally acquired antibodies against reinfection was estimated at 65% (pooled IRR  = 0.35, 95% CI = 0.26-0.47), with higher efficacy against symptomatic COVID-19 cases (pooled IRR  = 0.15, 95% CI = 0.08-0.26) than asymptomatic infection (pooled IRR  = 0.40, 95% CI = 0.29-0.54). Meta-regression revealed that SARS-CoV-2 variant was a statistically significant effect modifier, which explaining 46.40% of the variation in IRR s. For different SARS-CoV-2 variant, the pooled IRRs for the Alpha (pooled IRR  = 0.11, 95% CI = 0.06-0.19), Delta (pooled IRR  = 0.19, 95% CI = 0.15-0.24) and Omicron (pooled IRR  = 0.61, 95% CI = 0.42-0.87) variant were higher and higher. In other subgroup analyses, the pooled IRR s of SARS-CoV-2 infection were statistically various in different countries, publication year and the inclusion end time of population, with a significant difference ( p  = 0.02, p  < 0.010 and p  < 0.010), respectively. The risk of subsequent infection in the seropositive population appeared to increase slowly over time. Despite the heterogeneity in included studies, sensitivity analyses showed stable results., Conclusion: Previous SARS-CoV-2 infection provides protection against pre-omicron reinfection, but less against omicron. Ongoing viral mutation requires attention and prevention strategies, such as vaccine catch-up, in conjunction with multiple factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Cai, Yan, Wang, Sun, Wei and Hao.)

To investigate the impact and potential mechanisms of extracts from different parts of Liparis nervosa on neuroinflammation by lipopolysaccharide(LPS)-induced BV-2 microglial cells. The materials of L. nervosa were subjected to crushing, ethanol extraction, and concentration to obtain an alcohol extract. Subsequently, the extract was further extracted to obtain petroleum ether extract, ethyl acetate extract, N-butanol extract, and aqueous phase extract. The ethyl acetate extract was separated into distillate(1)-(6)using D101 macroporous resin column chromatography. The experiment was divided into control group, LPS model group, L. nervosa extract group, and LPS + L. nervosa group. LPS was utilized to induce a neuroinflammatory cell model in BV-2 microglial cells. The Griess test was utilized for detecting the production of nitric oxide(NO) in the cell supernatant. Cell viability was detected by MTT assay. The release of interleukin-6(IL-6) and tumor necrosis factor alpha(TNF-α) in the cell supernatant was quantified using ELISA.RT-qPCR was utilized to assess the m RNA levels of pro-inflammatory cytokines inducible nitric oxide synthase(iNOS), cyclooxygenase-2(COX-2), interleukin( IL)-6, IL-1β, and TNF-α. The protein expression of i NOS, COX-2, nuclear factor kappa-B p65(p65), p-p65, extracellular signal-regulated kinase(ERK), p-ERK, c-jun N-terminal kinase(JNK), p-JNK, p38 mitogen-activated protein kinase(p38), and p-p38 MAPK(p-p38) were also evaluated by Western blot. The chemical composition of active substances in L. nervosa was analyzed using the UHPLC-Q-Exactive Orbitrap technology and literature comparison. Our findings indicate that extracts from different parts of L. nervosa exhibit a significant reduction in the release of NO from LPS-induced BV-2 microglial cells.Specifically, the ethyl acetate extract demonstrates the most notable inhibitory effect without causing cell toxicity. Additionally, the distillate(6) extracted from the ethyl acetate exhibits a reduction in the m RNA and protein levels of i NOS, COX-2, IL-6, IL-1β, and TNF-α in a dose-dependent manner, and it inhibits the protein expression of p-p65, p-ERK, p-p38, and p-JNK in LPS-induced BV-2 microglial cells. A total of 79 compounds in the distillate(6) were identified by mass spectrometry, including 12 confirmed compounds with anti-inflammatory effects. This study confirmed the remarkable efficacy of L. nervosa extract in the treatment of neuroinflammation, which may be achieved through the inhibition of NF-κB and MAPK signaling pathways.

Background: Recurrent pregnancy loss (RPL) is associated with variable causes. Its etiology remains unexplained in about half of the cases, with no effective treatment available. Individuals with RPL have an irregular iron metabolism. In the present study, we identified key genes impacting iron metabolism that could be used for diagnosing and treating RPL., Methods: We obtained gene expression profiles from the Gene Expression Omnibus (GEO) database. The Molecular Signatures Database was used to identify 14 gene sets related to iron metabolism, comprising 520 iron metabolism genes. Differential analysis and a weighted gene co-expression network analysis (WGCNA) of gene expression revealed two iron metabolism-related hub genes. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were used on clinical samples to confirm our results. The receiver operating characteristic (ROC) analysis and immune infiltration analysis were conducted. In addition, we analyzed the distribution of genes and performed CellChat analysis by single-cell RNA sequencing., Results: The expression of two hub genes, namely, CDGSH iron sulfur domain 2 (CISD2)and Cytochrome P450 family 17 subfamily A member 1 (CYP17A1), were reduced in RPL, as verified by both qPCR and immunohistochemistry. The Gene Ontology (GO) analysis revealed the genes predominantly engaged in autophagy and iron metabolism. The area under the curve (AUC) demonstrated better diagnostic performance for RPL using CISD2 and CYP17A1. The single-cell transcriptomic analysis of RPL demonstrated that CISD2 is expressed in the majority of cell subpopulations, whereas CYP17A1 is not. The cell cycle analysis revealed highly active natural killer (NK) cells that displayed the highest communications with other cells, including the strongest interaction with macrophages through the migratory inhibitory factor (MIF) pathway., Conclusions: Our study suggested that CISD2 and CYP17A1 genes are involved in abnormal iron metabolism, thereby contributing to RPL. These genes could be used as potential diagnostic and therapeutic markers for RPL., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue., Methods: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis., Result: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences., Conclusion: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Miao Yan reports financial support was provided by Hunan Medical Association. Miao Yan reports financial support was provided by the Health Commission of Hunan Provincial. Miao Yan reports financial support was provided by International Research Center for Precision Medicine., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Triple-negative breast cancer (TNBC) is a subtype of BC with high rates of mortality. The mechanism of PTPRG-AS1 in ferroptosis of TNBC was investigated. Methods: Chromatin immunoprecipitation and dual-luciferase reporter assays were used to measure intermolecular relationships. MTT and colony formation assays detected cell viability and proliferation. Kits detected Fe 2+ and reactive oxygen species levels. The role of PTPRG-AS1 in tumor growth was analyzed in vivo . Results: PTPRG-AS1 was increased in TNBC tissues and cells. PTPRG-AS1 silencing increased the reduction of glutathione and GPX4, increased Fe 2+ and reactive oxygen species in erastin-treated cells and inhibited proliferation. POU2F2 transcriptionally upregulated PTPRG-AS1 . PTPRG-AS1 targeted miR-376c-3p to upregulate SLC7A11 . PTPRG-AS1 knockdown suppressed tumor growth in vivo . Conclusion: POU2F2 transcriptionally activates PTPRG-AS1 to modulate ferroptosis and proliferation by miR-376c-3p/SLC7A11, promoting TNBC.

Background: Sepsis is a systemic inflammatory syndrome that can lead to multiple organ dysfunction and life-threatening complications. Sepsis-induced myocardial dysfunction (SIMD) has been confirmed to be present in half of patients with septic shock, increasing their mortality rate to 70-90%. The pathogenesis of SIMD is complex, and no specific clinical treatment has yet been developed. Caloric restriction mimetics (CRM), compounds that simulate the biochemical and functional properties of CR, can improve cardiovascular injury by activating autophagy. This study investigated the effect of a new type of CRM which can induce hypoxia, the SGLT nonspecific inhibitor phlorizin on SIMD., Materials and Methods: In vivo, phlorizin was administered at 1 mg/kg/day intragastrically for 28 days. In vitro, AC16 was treated with 120 μM phlorizin for 48 h. Echocardiography was used to assess cardiac function. Myocardial injury markers were detected in serum and cell supernatant. Western blotting was employed to detect changed proteins associated with apoptosis and autophagy. Immunofluorescence, immunohistochemistry, co-immunoprecipitation, molecular docking, and other methods were also used to illustrate cellular changes., Results: In vivo, phlorizin significantly improved the survival rate and cardiac function after sepsis injury, reduced markers of myocardial injury, inhibited myocardial apoptosis and oxidative stress, and promoted autophagy. In vitro, phlorizin alleviated the apoptosis of AC16, as well as inhibited oxidative stress and apoptotic enzyme activity. Phlorizin acts on autophagy at multiple sites through low energy (activation of AMPK) and hypoxia (release of Beclin-1 by Hif-1α/Bnip3 axis), promoting the formation and degradation of autophagosomes., Conclusion: We indicated for the first time that phlorizin could inhibit glucose uptake via GLUT-1 and conforms to the metabolic characteristics of CRM, it can induce the hypoxic transcriptional paradigm. In addition, it inhibits apoptosis and improves SIMD by promoting autophagy generation and unobstructing autophagy flux. Moreover, it affects autophagy by releasing Beclin-1 through the Hif-1α/Bnip3 axis., 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 Elsevier B.V. All rights reserved.)

The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused serious harm to human health and struck a blow to global economic development. Research on SARS-CoV-2 has greatly benefited from the use of reverse genetics systems, which have been established to artificially manipulate the viral genome, generating recombinant and reporter infectious viruses or biosafety level 2 (BSL-2)-adapted non-infectious replicons with desired modifications. These tools have been instrumental in studying the molecular biological characteristics of the virus, investigating antiviral therapeutics, and facilitating the development of attenuated vaccine candidates. Here, we review the construction strategies, development, and applications of reverse genetics systems for SARS-CoV-2, which may be applied to other CoVs as well., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Publishing services by Elsevier B.V. All rights reserved.)

The electrocaloric effect (ECE) is a novel technology that offers high efficiency and environmental friendliness, making it suitable for solid-state refrigeration applications. Among the extensively studied ECE materials, lead scandium tantalate (PST) stands out for its excellent performance. However, its applications are restricted by its narrow working temperature range. To overcome this limitation, we explore the enhancement of the ECE through zirconium ion doping. We synthesized PbSc 0.5-0.5 x Ta 0.5-0.5 x Zr x O 3 samples ( x = 0, 0.025, 0.05, 0.075). The introduction of zirconium ions led to an increase in the Curie temperature from 28.9 °C ( x = 0) to 55.5 °C ( x = 0.075 ) . Additionally, the relaxation factor γ of the ceramics increased from 1.40 ( x = 0) to 1.59 ( x = 0.075). The temperature span ( T span ) exhibited a rising trend with increasing x , reaching 10.9 K at x = 0.075. The maximum temperature change (Δ T max ) was observed at x = 0.025, with a value of 1.94 K. X-ray diffraction (XRD) patterns revealed that zirconium ion doping influenced the B-site ordering degree, thereby regulating the ECE. To further validate the results, we employed direct measurements and thermodynamic calculations. Overall, the regulation of ionic ordering through zirconium doping effectively enhances the ECE performance. These findings contribute to the development of advanced materials for solid-state refrigeration technologies.

Molecular ferroelectric materials have been widely used in capacitors and sensors due to their low cost, light weight, flexibility and good biocompatibility. Organic-inorganic hybrid complexes, on the other hand, have received a great deal of attention in the luminescence field due to their low cost and simple preparation. The combination of ferroelectricity and photoluminescence in organic-inorganic hybrid materials not only leads to tunable optical properties, but also enriches potential applications of multifunctional ferroelectrics in optoelectronic devices. Here, we report a new luminescent ferroelectric material (1,3-dicyclohexylimidazole) 2 MnCl 4 (DHIMC). Thermogravimetric analysis (TGA) was used to measure the mass change of the material at a measurement rate of 20 K min -1 from room temperature to 900 K, and we found that this material has good thermostability, which is up to 383 K. Meanwhile, UV-vis measurements showed that it is also a fluorescent material emitting a strong green fluorescence at the wavelength of 525 nm. The ferroelectricity of the crystal was determined by two different methods: the Sawyer-Tower method and the double-wave method (DWM). Particularly, the single crystal experiences a phase transition from the ferroelectric phase to the paraelectric phase during the heating/cooling process at 318 K/313 K and the space group changes from P 1̄ (centrosymmetric) to P 1 (non-centrosymmetric). This work will enrich multifunctional luminescent ferroelectric materials and their application in display and sensing.

Objective: To investigate the association between physical exercise and non-alcoholic fatty liver disease (NAFLD) in people infected with HBV. Methods: The information about the 3 813 participants infected with HBV, including the prevalence of NAFLD, prevalence of physical exercise and other covariates, were collected from the National Science and Technology Major Project of China during 2016-2020. The logistic regression model was used to evaluate the association between physical exercise and NAFLD in HBV infected patients, and subgroup analysis was performed to identify the effect modifiers. Results: A total of 2 259 HBV infected participants were included in the final analysis and 454 (20.10%) had NAFLD. After adjusting for covariates, we found that moderate physical exercise was a protective factor for NAFLD ( OR =0.66, 95% CI : 0.46-0.94). Subgroup analysis suggested that the protective effect of moderate physical exercise on NAFLD might be stronger in women ( OR =0.61, 95% CI : 0.36-1.01), those <45 years old ( OR =0.24, 95% CI : 0.06-0.80), those who had low education level ( OR =0.16, 95% CI : 0.04-0.49), those who had low annual income ( OR =0.39, 95% CI : 0.16-0.89 for <30 000 yuan RMB; OR =0.64, 95% CI : 0.40-1.00 for 30 000-80 000 yuan RMB), those who had hypertension ( OR =0.45, 95% CI : 0.21-0.88), those with BMI ≥24.0 kg/m 2 ( OR =0.66, 95% CI : 0.43-1.01), those who had more daily fruit or vegetable intake ( OR =0.61, 95% CI : 0.38-0.97), those who had more daily meat intake ( OR =0.49, 95% CI : 0.23-0.97), and those who had no smoking history ( OR =0.66, 95% CI : 0.45-0.95) or passive smoking exposure ( OR =0.61, 95% CI : 0.37-0.97). Conclusions: Among HBV infected patients, moderate physical exercise was negatively associated with the prevalence of NAFLD. Women, young people, those who had low education level, those who had low annual income, those with hypertension, those with high BMI, those who had more daily fruit or vegetable and meat intakes, and those who had no smoking history or passive smoking exposure might be more sensitive to the protective effect.

Monolayer molybdenum disulfide (MoS 2 ) nanoenzymes exhibit a piezoelectric polarization, which generates reactive oxygen species to inactivate tumors under ultrasonic strain. However, its therapeutic efficiency is far away from satisfactory, due to stackable MoS 2 , quenching of piezo-generated charges, and monotherapy. Herein, chitosan-exfoliated monolayer MoS 2 (Ch-MS) is composited with atomic-thin MXene, Ti 3 C 2 (TC), to self-assemble a multimodal nanoplatform, Ti 3 C 2 -Chitosan-MoS 2 (TC@Ch-MS), for tumor inactivation. TC@Ch-MS not only inherits piezoelectricity from monolayer MoS 2 , but also maintains remarkable stability. Intrinsic metallic MXene combines with MoS 2 to construct an interfacial Schottky heterojunction, facilitating the separation of electron-hole pairs and endowing TC@Ch-MS increase-sensitivity magnetic resonance imaging responding. Schottky interface also leads to peroxidase mimetics with excellent catalytic performance toward H 2 O 2 in the tumor microenvironment under mechanical vibration. TC@Ch-MS possesses the superior photothermal conversion efficiency than pristine TC under near-infrared ray illumination, attributed to its enhanced interlaminar conductivity. Meanwhile, TC@Ch-MS realizes optimized efficiency on tumor apoptosis with immunotherapy. Therefore, TC@Ch-MS achieves an integrated diagnosis and multimodal treatment nanoplatform, whereas the toxicity to normal tissue cells is negligible. This work may shed fresh light on optimizing the piezoelectric materials in biological applications, and also give prominence to the significance of intrinsic metallicity in MXene., (© 2022 Wiley-VCH GmbH.)

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

Purpose: The appropriate management of spinal tuberculosis (TB) is challenging for clinicians and the key to treat spinal TB. Surgery and long course anti-TB chemotherapy may not be necessary to all situations. This study aimed to characterize the clinical features and factors affecting treatment outcomes., Patients and Methods: A retrospective study of patients with spinal TB over a 5-year period at a teaching hospital in central China was conducted. Features of patients with spinal TB who received different treatment modalities and factors associated with patient outcomes at the end of chemotherapy were analyzed., Results: Forty-five patients (21 men and 24 women) with spinal TB were available for analysis. The mean age was 55.39 ± 14.94 years. The most common vertebral area involved was the lumbar (42.2%). The mean number of vertebrae involved was 2.20 ± 0.59. 27 patients (60.0%) received surgical treatment, of which 21 (77.8%) received radical surgical treatment. Thirty-five patients (77.8%) had achieved a favorable status. Statistically, there was no significant correlation between favorable status and surgery, but among 27 surgical patients with spinal tuberculosis, patients receiving radical surgery tended to achieve good prognosis ( P = 0.010; odds ratio = 0.053; 95% confidence interval 0.006-0.493). Moreover, there was no significant difference between long course and short course of anti-TB chemotherapy in prognosis in different treatment modalities., Conclusion: Although the patients with spinal TB who needed surgical treatment often got a better prognosis when they had radical surgery, surgery was not actually a factor for the favorable outcomes of patients with spinal TB. In different treatment modalities, there was no additional benefit in longer anti-TB chemotherapy periods., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Tang et al.)

Efficient bioconversion of methanol, which can be generated from greenhouse gases, into valuable resources contributes to achieving climate goals and developing a sustainable economy. The methylotrophic yeast Ogataea methanolica is considered to be a suitable host for efficient methanol bioconversion because it has outstanding characteristics for the better adaptive potential to a high methanol environment (i.e., greater than 5%). This capacity represents a huge potential to construct an innovative carbon-neutral production system that converts methanol into value-added chemicals under the control of strong methanol-induced promoters. In this review, we discuss what is known about the regulation of methanol metabolism and adaptation mechanisms for 5% methanol conditions in O. methanolica in detail. We also discuss about the potential to breed "super methylotrophic yeast," which has potent growth characteristics under high methanol conditions., (© 2022 John Wiley & Sons Ltd.)

Background: Acute myocardial infarction (AMI) is a critical cardiovascular disease (CVD). Laminin (LN) is involved in the process of myocardial fibrosis and ventricular remodeling observed in AMI; however, there are currently no studies on the correlation between LN and AMI prognosis., Purpose: To explore the predictive value of serum LN levels for major adverse cardiovascular events (MACE) in patients, 6 months after an acute myocardial infarction., Methods: A total of 202 AMI patients who were hospitalized in the Department of Cardiology of the Second Affiliated Hospital of Nantong University between December 2019 and December 2020 were included. The observation endpoint was the occurrence of MACE. Univariate and multivariate logistic analyses were used to evaluate the relationships between the variables and endpoint. The predictive value of LN for MACE in AMI patients was assessed using receiver operating characteristic (ROC) analysis., Results: A total of 47 patients developed MACE. Univariate logistic analysis showed that smoking, emergency percutaneous coronary intervention (EPCI), age, cardiac troponin I (c-TNI) levels, N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels, and LN levels were associated with the occurrence of MACE ( p < 0.05). Multivariate logistic analysis showed that LN was an independent predictor of MACE (odds ratio [OR] = 1.021, 95%CI: 1.014-1.032, p < 0.001). According to the ROC curve, LN can be used as an effective predictor of MACE (AUC = 0.856, 95%CI: 0.794-0.918, p < 0.001). According to the cutoff value, LN>58.80 ng/ml (sensitivity = 83.00%, specificity = 76.80%) or LN>74.15 ng/ml (sensitivity = 76.6%, specificity = 83.2%) indicate a poor prognosis for AMI. Different cut-off values are selected according to the need for higher sensitivity or specificity in clinical applications., Conclusions: LN may be a predictor of MACE following AMI in patients and could be utilized as a novel substitute marker for the prevention and treatment of AMI., (Copyright © 2022 Xu, Xie, Wang, Chen, Cai, Tian and Zhang.)

Aim: Systemic inflammation plays an important role in the occurrence and development of acute heart failure. The modified Glasgow Prognostic Score (mGPS) and "lymphocyte C-reactive protein score" (LCS) are used to assess the inflammation levels in cancer patients. The purpose of this study was to assess the prognostic value of these two inflammation-related scoring systems in patients with acute heart failure., Methods: Two hundred and fifty patients with acute heart failure were enrolled in this study. The mGPS and LCS scores were recorded after admission. All patients were divided into 2 groups: the death group and the survival group according to the 3-month follow-up results. The predictive values of mGPS and LCS were assessed using receiver-operating characteristic (ROC) analyses. Univariate and multivariate logistic analyses were used to evaluate the relationships between variables and endpoint., Results: The levels of mGPS and LCS in the death group were significantly higher than those in the survival group (P < 0.05). The areas under the ROC curve of the mGPS and LCS for predicting death were 0.695 (95%CI: 0.567~0.823) and 0.736 (95%CI: 0.616~0.856), respectively. Multivariate analysis demonstrated that both LCS, LVEF and serum direct bilirubin were independent predictors of all-cause death, excluding mGPS., Conclusions: Compared with mGPS, LCS is independently associated with short-term outcomes in patients with acute heart failure. LCS was a clinically promising and feasible prognostic scoring system for patients with acute heart failure., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Xie, Lyu, Zhou, Cai, Qi and Zhang.)

Objective: To investigate the effect of intra-articular berberine injection on the structural remodeling of subchondral bone plate and osteoprotegerin/receptor activator of nuclear factor kappa-B ligand(OPG/RANKL) system expression in rabbits with osteoarthritis(OA)., Methods: Forty 12-month-old male rabbits with an average of(2.73±0.18) kg of body weight, underwent left anterior cruciate ligament transection(ACLT), and were divided into berberine group and placebo groups after operation, 20 rabbits in each group. The berberine group received intra-articular injection of 100 μmol/L berberine 0.3 ml every week for 6 weeks. In placebo group, the same dose of 0.9% sodium chloride injection was injected into the left knee joint cavity every week for 6 weeks. Another 20 12-month-old male rabbits, weighing (2.68±0.18) kg, underwent sham operation on the left knee joint without intra-articular injection intervention (sham operation group). On the last day of the sixth week after operation, three groups of animals were sacrificed to obtain knee joint specimens. The femoral medial condyle samples were obtained for histological evaluation of cartilage and subchondral bone, Mankin scoring system was used to evaluate articular cartilage structure. Image-Pro Plus(IPP) software was used to evaluate subchondral bone plate bone volume(BV), bone volume/total volume(BV/TV), trabecular circumference(TC), mean trabecular thickness (Tb.Th). Real-time quantitative reverse transcription polymerization Enzyme chain reaction(reverse transcription-polymerase chain reaction, RT-PCR) was used to detect the mRNA expression levels of OPG and RANKL in subchondral bone tissue at 6 weeks after operation., Results: The cartilage structure evaluation showed that the surface of cartilage tissue in the sham operation group was smooth and flat, and the safranin coloration was full in the full thickness of the cartilage;the cartilage tissue in the berberine group showed uneven surface layer, and the staining of safranin O was mildly decreased;the surface layer fibrosis was seen in placebo group, Safranin O faded significantly. The Mankin score in the berberine group was lower than that in placebo group( P <0.01), but higher than that in sham operation group( P <0.01). The structural evaluation of subchondral bone plate showed that the trabecular bone in sham-operated group was densely arranged;after berberine intervention, the trabeculae were closely arranged;the subchondral bone trabeculae in placebo group were relatively sparse, and the distance between trabeculae was wider. Subchondral bone plate IPP software evaluation showed that BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group( P <0.01), BV, BV/TV, TC, Tb.Th in berberine group were higher than those in placebo group( P <0.01), while lower than the sham operation group ( P <0.01). PCR test results showed that the expression of OPG mRNA in the berberine group was significantly higher than that in placebo group( P <0.01), and OPG mRNA in the berberine group was lower than that in sham operation group ( P <0.01). There was no significant difference in mRNA expression of RANKL among three groups( P >0.05);the ratio of OPG/RANKL in berberine group was higher than that in placebo group( P <0.01), but lower than that in sham operation group( P <0.01)., Conclusion: Intra-articular injection of berberine can effectively inhibit the resorption of subchondral bone in the early stage of OA and delay the development of the disease. The specific mechanism may be that berberine maintains the balance of OPG/RANKL system by up-regulating the expression of OPG gene in subchondral bone.

Background: Cardiac troponins are highly sensitive and specific biomarkers for cardiac injury. Previous studies evaluating the effect of positive airway pressure (PAP) on cardiac troponins in patients with sleep-disordered breathing (SDB) have yielded conflicting results. The meta-analysis was performed to examine the effect of PAP on cardiac troponins in SDB patients., Methods: PubMed, Web of Science, and EMBASE before September 2021 on original English language studies were searched. The data on cardiac troponins in both baseline and post-PAP treatment were extracted from all studies. The data on the change of cardiac troponins in both PAP and control group were extracted from randomized controlled trials. Standardized mean difference (SMD) was used to synthesize quantitative results., Results: A total of 11 studies were included. PAP treatment was not associated with a significant change in cardiac troponin T between the baseline and post-PAP treatment (SMD = -0.163, 95% confidence interval [CI] = -0.652 to 0.326, z = 0.65, p = .514). The pooled estimate of SMD of cardiac troponin I between the pre- and post-PAP treatment was 0.287, and the 95% CI was -0.586 to 1.160 (z = 0.64, p = .519). The pooled SMD of change of cardiac troponin T between the PAP group and control group was -0.473 (95% CI = -1.198 to 0.252, z = 1.28, p = .201)., Conclusions: This meta-analysis revealed that PAP treatment was not associated with any change of cardiac troponin in SDB patients., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals LLC.)

SrTiO 3 is a model of the perovskite-like compounds for structural transition which inducing the intriguing physical properties around the critical phase transition temperature T AFD (antiferrodistortive, abbrev. as AFD). Here we report that the electrical transport behavior is a new way to quantify Nb concentration for Nb-doped SrTiO 3 . The lattice parameter (c), phase transition temperature (T AFD ), and the carrier concentration (n) of SrTiO 3 may be manipulated by niobium doping. T AFD increases with increasing the niobium content in a rate of about 30 K per (wt%, i.e. niobium element's weight verses total weight) niobium and n in a rate of about 2.5 [Formula: see text] 10 20 /cm 3 per (wt%) niobium., (© 2022. The Author(s).)

Solid-state crystals with two distinct dielectric states can be a physical practice in binary-based technologies. A large dielectric switch effect up to 10 3 caused by an order-disorder structural phase transition is found in cyclopropylamine perchlorate (CPA-ClO 4 ) crystals at temperatures around 230 K ( T c ) and 220 K ( T ' c ). Large dielectric switch effects here can be compared to that of the famous ceramic oxide dielectrics. As far as we know, this is the highest dielectric switch effect in simple organic salt crystals and organic-metal compounds so far. If the phase transition temperature can be adjusted by molecular manipulation, one of the most promising candidates for technological applications may emerge in the future.

Organic-inorganic hybrid ferroelectrics (OIHFs) have fueled enormous interest benefiting from their less environmental pollution, performance-tailored functionality, low product costs as well as tunability of structures. However, the lack of material synthesis approaches and diverse targeted molecular design is a stumbling block for designing novel OIHFs rationally. Here, we report a unique organic-inorganic hybrid ferroelectric (3,3-difluoropyrrolidine) 2 CdCl 4 1 and another novel nonferroelectric crystal (3,3-difluoropyrrolidine) 2 Cd 2 Cl 6 2 by changing various crystallization solvents. Significantly, 1 presents a ferroelectric phase transition behavior at ∼367 K, and the distinct symmetry breaking, i.e., mmmFm , sets up a biaxial ferroelectric with four equivalent directions of polarization, which has a P r ∼ 0.77 μC/cm 2 . Systematic studies prove that ferroelectricity can be ascribed to the synergistic effects of the distortion of the inorganic anion skeleton and the ordering of organic cations. This work reveals the potential of constructing novel ferroelectrics based on the solvent selective effect and pyrrolidinium as organic cations.

Background: Atrophic gastritis is a precancerous lesion of the stomach. It has been reported that pepsinogen (PG) can reflect the morphology and function of the gastric mucosa, and it is therefore used as a marker for the early diagnosis of atrophic gastritis., Aim: To evaluate the diagnostic value of serum PG for degree of gastric mucosal atrophy in asymptomatic Chinese upon physical examination., Methods: Medical data were collected from subjects who underwent transnasal gastroscopy between October 2016 and October 2018. For each study subject, serum PG levels and presence of Helicobacter pylori ( H. pylori ) infection were investigated. Pathology was evaluated using the Operative Link for Gastritis Assessment (OLGA) classification and Operative Link on Gastric Intestinal Metaplasia Assessment (OLGIM) systems. All statistical analyses were carried out using SPSS statistical software., Results: A total of 2256 subjects were enrolled and 1922 cases were finally included in the study. Based on the OLGA grading system, the levels of PGI were slightly decreased, while those of PGII were slightly increased. The PGI/PGII ratio (PGR) was reduced with increasing atrophy. The association between PG and OLGA grading was higher compared with that between PG and the OLGIM grading system. Compared with the OLGA-0 group, a statistically significant difference was observed in the mean age of OLGA-I, III, and IV groups ( P < 0.05). In the H. pylori -positive subjects, the PGR levels were notably lower in the OLGA-I, II, and III groups compared with the OLGA-0 group ( P < 0.05). H. pylori -positive subjects exhibited significantly higher PGI and PGII serum levels and a significantly lower PGR compared with H. pylori -negative patients in different OLGA groups ( P < 0.05)., Conclusion: Serum PG levels may represent a non-invasive screening marker for gastric mucosal atrophy in asymptomatic subjects., Competing Interests: Conflict-of-interest statement: The authors declare that they have no related financial relationships to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

In this study, we analysed the intracellular fatty acid profiles of Komagataella phaffii during methylotrophic growth. K. phaffii grown on methanol had significantly lower total fatty acid contents in the cells compared with glucose-grown cells. C18 and C16 fatty acids were the predominant fatty acids in K. phaffii, although the contents of odd-chain fatty acids such as C17 fatty acids were also relatively high. Moreover, the intracellular fatty acid composition of K. phaffii changed in response to not only carbon sources but also methanol concentrations: C17 fatty acids and C18:2 content increased significantly as methanol concentration increased, whereas C18:1 and C18:3 contents were significantly lower in methanol-grown cells. The intracellular content of unidentified compounds (C n H 2n O 4 ), on the other hand, was significantly greater in cells grown on methanol. As the intracellular contents of these C n H 2n O 4 compounds were significantly higher in a gene-disrupted strain for glutathione peroxidase (gpx1Δ) than in the wild-type strain, we presume that the C n H 2n O 4 compounds are fatty acid peroxides. These results indicate that K. phaffii can coordinate intracellular fatty acid composition during methylotrophic growth in order to adapt to high-methanol conditions and that certain fatty acid species such as C17:0, C17:1, C17:2 and C18:2 may be related to the physiological functions by which K. phaffii adapts to high-methanol conditions., (© 2021 John Wiley & Sons, Ltd.)

Objective: The growth of oviduct mucosa in the uterine cavity was observed by co-culture of oviduct mucosa cells and endometrial cells in different proportions to study the possibility and function of the growth of oviduct mucosa in the uterine cavity., Methods: The extracted cells were identified by immunofluorescence with cytokeratins 19 (CK19) and vimentin. A Cell Counting Kit-8 (CCK8) experiment, cell decidualization induction, and HE staining were performed after the co-culture of two kinds of cells in different proportions., Results: 1) The cells could grow normally when the two cells were co-cultured indirectly. 2) A CCK8 test of oviduct mucosa cells showed that the growth rate of each group was similar after the indirect co-culture of two kinds of cells in different proportions, which was in line with the growth law of normal cells. 3) Immunofluorescence identification of the cells showed that most of the two kinds of cells in the second passage were CK19 positive and were epithelial cells, while most of the cells in the fifth passage expressed positive vimentin antibody and were stroma cells. 4) After cell decidualization induction, the cell morphology of each group showed deciduation-like changes. 5) After decidualization, the cell morphology of each group was similar after HE staining., Conclusion: Oviduct mucosa cells can grow normally in the uterine environment. In the uterine environment with different degrees of endometrial loss, the growth rate of oviduct mucosa cells is not inhibited. Its morphology does not change, and it can undergo decidualization in vitro., Competing Interests: The authors declare that they have no competing interests., (© 2021 Wu et al.)

2D MXene, Ti 3 C 2 (TC), has displayed enormous potential in applications in photothermal therapy (PTT), attributing to its biocompatibility and outstanding photothermal conversion capability. However, some tumor ablations are difficult to be realized completely by monotherapy due to the essential defects of monotherapy and intricate tumor microenvironment (TME). In this work, the appropriate doped Fe 2+ ions are anchored into the layers of 2D ultrathin TC nanosheets (TC NSs) to synthesize a novel multifunctional nanoshell of Fe(II)-Ti 3 C 2 (FTC) through interlayer electrostatic adsorption. FTC possesses superior photothermal conversion efficiency (PTCE) than TC NSs, attributing to the enhanced conductivity promoted by interlaminar ferrous ion-channels. Moreover, Fenton reaction based on ferrous ions endows FTC the abilities of reactive oxide species (ROS) releasing and glutathione (GSH) suppression triggered by near-infrared (NIR) laser, featuring splendid biocompatibility and curative effect in hypoxic TME. Meanwhile, magnetic resonance imaging (MRI) responding in FTC reveals the potential as an integrated diagnosis and treatment nanoplatform. FTC could provide new insights into the development of multimoded synergistic nanoplatform for biological applications, especially breaking the shackles of MXenes merely used as a photo-thermal agent (PTA), adopting it to bioimaging sensor and drug loading., (© 2021 Wiley-VCH GmbH.)

Joint replacement surgery is one of the orthopedic surgeries with high successful rates; however, wear debris generated from prostheses can ultimately lead to periprosthetic osteolysis and failure of the implant. The implant-derived particulate debris such as ultrahigh molecular weight polyethylene (UHMWPE) can initiate the local immune response and recruit monocytic cells to phagocytose particles for generating reactive oxygen species (ROS). ROS induces osteoclastogenesis and macrophages to secrete cytokines which ultimately promote the development of osteolysis. In this work, we develop the few-layered Nb 2 C (FNC) as an antioxidant which possesses the feature of decreasing the production of cytokines and inhibiting osteoclastogenesis by its ROS adsorption. Moreover, local injection of FNC attenuates the UHMWPE-induced osteolysis in a mouse calvarial model. In sum, our results suggest that FNC can be used for treating osteolytic bone disease caused by excessive osteoclastogenesis., (© 2021 The Authors.)

Since methylotrophic yeasts such as Ogataea methanolica can use methanol as a sole carbon feedstock, they could be applied to produce valuable products from methanol, a next-generation energy source synthesized from natural gases, using genetic engineering tools. In this study, metabolite profiling of O. methanolica was conducted under glucose (Glc) and low and high methanol (L- and H-MeOH) conditions to show the adaptation mechanism to a H-MeOH environment. The yeast strain responded not only to the presence of methanol but also to its concentration based on the growth condition. Under H-MeOH conditions, O. methanolica downregulated the methanol utilization, glycolytic pathway and alcohol oxidase (AOD) isozymes and dihydroxyacetone synthase (DAS) expression compared with L-MeOH-grown cells. However, levels of energy carriers, such as ATP, were maintained to support cell survival. In H-MeOH-grown cells, reactive oxygen species (ROS) levels were significantly elevated. Along with increasing ROS levels, ROS scavenging system expression was significantly increased in H-MeOH-grown cells. Thus, we concluded that formaldehyde and H 2 O 2 , which are products of methanol oxidation by AOD isozymes in the peroxisome, are overproduced in H-MeOH-grown cells, and excessive ROS derived from these cells is generated in the cytosol, resulting in upregulation of the antioxidant system and downregulation of the methanol-utilizing pathway to suppress overproduction of toxic intermediates., (© 2021 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.)

At present, prognostic biomarkers of acute coronary syndrome (ACS) are fewer. The aim of this study was to explore the predictive value of soluble osteoclast-associated receptor (sOSCAR) level for the major adverse cardiovascular events (MACE) occurring within 30 days after ACS. From January to August 2020, a total of 108 patients with ACS who were admitted to our hospital, were enrolled in this study. Of the 108 patients, 79 were men and 29 women. Patient-related data, including age, sex, body mass index, history of type 2 diabetes, history of hyperlipidemia and serum sOSCAR level, were collected. All patients were followed up for 30 days. Based on MACE occurrence, the 108 patients were divided into MACE group (n = 17) and non-MACE group (n = 91). The baseline data were compared between the two groups, MACE-independent risk factors were identified by multivariate regression analysis, and the predictive value of sOSCAR for MACE occurring within 30 days after CAS was analyzed using receiver operating characteristic (ROC) curve. At the same time, according to the type of ACS, the 108 patients with ACS were divided into unstable angina (UA) group (n = 29), non ST-segment elevation myocardial infarction (USTEMI) group (n = 45) and ST-segment elevation myocardial infarction (STEMI) group (n = 34), and then the sOSCAR level and MACE incidence were observed in each group. The serum sOSCAR level was significantly lower in the MACE group [130(100,183)] than in the non-MACE group [301(220,370)] (P = 0.000). The area under ROC curve of sOSCAR level for MACE occurring within 30 days after CAS was 0.860 with 95%CI 0.782-0.919, P < 0.001. Multivariate regression analysis indicated that the sOSCAR level was an independent risk factor for the MACE occurring within 30 days after CAS (OR 0.26, 95%CI 0.087-0.777, P = 0.04). The MACE incidence (0%) was the lowest but the sOSCAR level was the highest in the UA group, while in the STEMI group, the MACE incidence (23.53%) was the higest but the sOSCAR level was the lowest among the UA, STEMI and NSTEMI groups. Serum sOSCAR level may be used as a predictor of MACE occurring within the short-term after ACS. The higher the sOSCAR level, the lower the MACE incidence.

Background: Numerous researchers have shown that there is a close correlation between red cell distribution width (RDW) and cardiovascular disease such as heart failure, coronary heart disease, and atrial fibrillation. This study was designated to investigate the correlation between RDW and the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol (HAS-BLED) score., Methods: The HAS-BLED scores of 251 hospitalized patients with non-valvular atrial fibrillation were calculated and the receiver operating characteristics were used to evaluate the predictive value of RDW on high HAS-BLED score (≥3 scores). Multiple logistic regression analysis was used to analyze the independent predictor of high HAS-BLED scores., Results: Correlation analysis between RDW and HAS-BLED scores showed the RDW was positively correlated with HAS-BLED score, with r=0.393 (P<0.0001). The RDW of the high HAS-BLED score group was higher than that of the no-high HAS-BLED score group. The area under the receiver operating characteristic curve of RDW was 0.796 (0.740-0.844, P<0.0001) to predict a high HAS-BLED score, and multiple logistic regression analysis showed that a high RDW value could be used as an independent predictor of high HAS-BLED., Conclusions: RDW value is associated with HAS-BLED value, and can be used as the independent predictive factor of high HAS-BLED scores., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-21-567). The authors have no conflicts of interest to declare., (2021 Journal of Thoracic Disease. All rights reserved.)

Animal osteoarthritis (OA) models have been developed to understand OA progression and evaluate new OA therapies. However, individual variations in joint lesions remain a critical problem in most current OA models. We established a novel rabbit model by creating a longitudinal tear in the medial meniscus body that was reproducible and similar to posttraumatic biomechanical disturbances in human OA. New Zealand rabbits underwent surgery and were assessed for 9 weeks. The rabbits were randomized into the sham control, medial meniscal tear (MMT), and anterior cruciate ligament transection (ACLT) groups. The animals were sacrificed at 4, 6, and 9 weeks posttreatment. The knee joints were harvested for histological and gene expression assessments. Both the MMT and ACLT procedures led to time-dependent degenerative changes in the femoral condyle cartilage. At each time point, the MMT group cartilage showed more severe degenerative changes than did the ACLT group cartilage. Consistently, inflammatory cytokine and catabolic gene expression were significantly higher, and anabolic gene expression was significantly lower in the MMT group than in the ACLT group. MMT treatment caused more severe structural damage to the cartilage and higher catabolic gene expression levels than the ACLT model at each time point. The MMT model may be highly beneficial in investigating posttraumatic OA (PTOA) development, especially PTOA from a meniscal injury. The MMT model replicated key features of human PTOA, including meniscal lesions, inflammatory responses, and the progression to osteoarthritic cartilage degeneration, thereby providing an exciting new avenue for translating promising treatments to clinical practice., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

Type 2 diabetes (T2D) is characterized by islet β-cell dysfunction and impaired suppression of glucagon secretion of α-cells in response to oral hyperglycaemia. Bile acid (BA) metabolism plays a dominant role in maintaining glucose homeostasis. So we evaluated the association of fasting serum total bile acids (S-TBAs) with insulin sensitivity, islet β-cell function and glucagon levels in T2D. Total 2,952 T2D patients with fasting S-TBAs in the normal range were recruited and received oral glucose tolerance tests for determination of fasting and postchallenge glucose, C-peptide and glucagon. Fasting and systemic insulin sensitivity were assessed by homeostasis model assessment (HOMA) and Matsuda index using C-peptide, i.e., IS HOMA-cp and ISI M-cp , respectively. Islet β-cell function was assessed by the insulin-secretion-sensitivity-index-2 using C-peptide (ISSI2 cp ). The area under the glucagon curve (AUC gla ) was used to assess postchallenge glucagon. The results showed IS HOMA-cp , ISI M-cp and ISSI2 cp decreased, while AUC gla notably increased, across ascending quartiles of S-TBAs but not fasting glucagon. Moreover, S-TBAs were inversely correlated with IS HOMA-cp , ISI M-cp and ISSI2 cp (r = -0.21, -0.15 and -0.25, respectively, p < 0.001) and positively correlated with AUC gla (r = 0.32, p < 0.001) but not with fasting glucagon (r = 0.033, p = 0.070). Furthermore, after adjusting for other clinical covariates by multiple linear regression analyses, the S-TBAs were independently associated with IS HOMA-cp (β = -0.04, t = -2.82, p = 0.005), ISI M-cp (β = -0.11, t = -7.05, p < 0.001), ISSI2 cp (β = -0.15, t = -10.26, p < 0.001) and AUC gla (β = 0.29, t = 19.08, p < 0.001). Increased fasting S-TBAs are associated with blunted fasting and systemic insulin sensitivity, impaired islet β-cell function and increased glucagon levels in response to glucose challenge in T2D.

The detoxification effects of licorice are believed to be related to its pharmacokinetic (PK) interference. This paper aimed to evaluate the effects of licorice water extracts (LWE) on the pharmacokinetics of brucine. Rats were administered brucine and/or LWE. The pharmacokinetic behavior of brucine and bioactive components of licorice were quantified by HPLC-MS/MS. P-glycoprotein (P-gp) inhibitor verapamil, real time PCR, vesicular transport assay and everted gut sacs were employed to investigate its possible mechanism. We found LWE reduced the Cmax and AUC of oral brucine in a dose-dependent way. In contrast, the AUC values of intraperitoneal brucine showed no significant difference between LWE treated and untreated rats, which indicating the intestinal absorption of brucine was influenced by LWE. We found that high dose of LWE activated the transport activity of P-gp in vesicular transport assay, while the mRNA level of P-gp in the intestinal was not affected by licorice. Moreover, high dose of LWE decreased the intestinal absorption of brucine in the everted gut sacs model, which could over turned by verapamil. These results suggested that a single high dose of LWE could impair the intestine absorption of brucine, and its potential mechanism may be mediated by P-gp in intestine.

Musculoskeletal disorders related to ageing are one of the most common causes of mortality and morbidity among elderly individuals worldwide. The typical constitutive components of the musculoskeletal system, including bone, muscle, and joints, gradually undergo a process of tissue loss and degeneration as a result of life-long mechanical and biological stress, ultimately leading to the onset of a series of age-related musculoskeletal diseases, including osteoporosis (OP), sarcopenia, and osteoarthritis (OA). Dehydroepiandrosterone (DHEA), a precursor of androgen secreted mainly by the adrenal gland, has attracted much attention as a marker for senescence due to its unique age-related changes. This pre-hormone has been publicly regarded as an "antidote for ageing" because of its favourable effect against a wide range of age-related diseases, such as Alzheimer disease, cardiovascular diseases, immunosenescence and skin senescence, though its effect on age-related musculoskeletal diseases has been explored to a lesser extent. In the present review, we summarized the action of DHEA against OP, sarcopenia and OA. Extensive detailed descriptions of the pathogenesis of each of these musculoskeletal disorders are beyond the scope of this review; instead, we aim to highlight the association of changes in DHEA with the processes of OP, sarcopenia and OA. A special focus will also be placed on the overlapping pathogeneses among these three diseases, and the molecular mechanisms underlying the action of DHEA against these diseases are discussed or postulated., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The emerging two-dimensional (2D) materials such as graphene have opened the door to industrial applications. Here, we consider the oxide perovskite monolayer of SrTiO 3 (STO), LaAlO 3 (LAO) and their heterostructures as the 2D transitional metal system. Results show that a band-gap transition from indirect to direct occurs when the separated monolayer STO (indirect band gap of 3.210 eV), and LAO (indirect band gap of 4.024 eV), form the heterostructures (direct band gap of 2.976 eV). The obtained bandgap for the stable bilayers may effectively be modulated by biaxial strains from  -12% to 8%. With 12% compressive biaxial strain, the band gap reduces to be 0.23 eV. The optical properties for the stable bilayers are also tuned by the biaxial strain. When the strain increases from compressive strain to tensile strain, the strongest peak of the imaginary part of dielectric function red shifts to lower energy. In comparing with the monolayer STO and LAO, the elastic property enhances obviously for the stable heterostructure, suggesting the heterostructure can be more stable freestanding or may be applied in device fabrications.

Objective: This study summarizes and compares clinical and laboratory characteristics of 34 patients admitted to the intensive care unit (ICU) for complications from coronavirus disease 2019 (COVID-19) at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China from Jan. 22 to Mar. 5, 2020., Methods: A total of 34 patients were divided into two groups, including those who required noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) with additional extracorporeal membrane oxygenation (ECMO) in 11 patients. Clinical features of COVID-19 patients were described and the parameters of clinical characteristics between the two groups were compared., Results: The rates of the acute cardiac and kidney complications were higher in IMV cases than those in NIV cases. Most patients had lymphocytopenia on admission, with lymphocyte levels dropping progressively on the following days, and the more severe lymphopenia developed in the IMV group. In both groups, T lymphocyte counts were below typical lower limit norms compared to B lymphocytes. On admission, both groups had higher than expected amounts of plasma interleukin-6 (IL-6), which over time declined more in NIV patients. The prothrombin time was increased and the levels of platelet, hemoglobin, blood urea nitrogen (BUN), D-dimer, lactate dehydrogenase (LDH), and IL-6 were higher in IMV cases compared with NIV cases during hospitalization., Conclusions: Data showed that the rates of complications, dynamics of lymphocytopenia, and changes in levels of platelet, hemoglobin, BUN, D-dimer, LDH and IL-6, and prothrombin time in these ICU patients were significantly different between IMV and NIV cases.

Purpose: Serum complement C3 has been shown to contribute to the incidence of type 2 diabetes (T2D), but how serum complement C3 affects islet β-cell function throughout the course of T2D is unclear. This study explored whether serum complement C3 is independently associated with changes in islet β-cell function over time in patients with T2D., Methods: Serum complement C3 was measured, and endogenous β-cell function was evaluated by area under the C-peptide curve (AUC cp ) during an oral glucose tolerance test (OGTT) in 411 patients with T2D at baseline from 2011 to 2015. Next, 347 of those patients with available data were pooled for a final follow-up analysis from 2014 to 2018. Changes in islet β-cell function at follow-up were evaluated by AUC cp percentage changes (ΔAUC cp %). In addition, other possible clinical risks for diabetes were also examined., Results: The 347 patients included in the analysis had a diabetes duration of 4.84 ± 3.63 years at baseline. Baseline serum complement C3 (baseline C3) levels were positively correlated with baseline natural logarithm of AUC cp (lnAUC cp ) (n = 347, r = 0.288, p < 0.001), and baseline C3 was independently associated with baseline lnAUC cp (β = 0.17, t = 3.52, p < 0.001) after adjustment for baseline glycemic status and other clinical confounders by multivariate liner regression analysis. Compared with the baseline values, complement C3 changes (ΔC3) and ΔAUC cp % was -0.15 ± 0.28 mg/ml and -17.2 ± 18.4%, respectively, at a follow-up visit 4.57 ± 0.78 years later. Moreover, ΔC3 was positively correlated with ΔAUC cp % (n = 347, r = 0.302, p < 0.001). Furthermore, each 0.1 mg/ml increase in ΔC3 was associated with a higher ΔAUC cp % (1.41% [95% CI, 0.82-2.00%]) after adjusting for changes in glycemic status and other clinical confounders at follow-up., Conclusions: In addition to serum complement C3 being independently associated with islet β-cell function at baseline, its changes were also independently associated with changes in islet β-cell function over time in patients with T2D.

Purpose: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML)., Methods: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping., Results: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p<0.001). Patients with MMR and CMR achieve higher trough concentrations than those without MMR and CMR, respectively (1486.40±703.38 vs 1121.17±527.14 ng mL-1, p=0.007; 1528.00±709.98 vs 1112.67±518.35 ng mL-1, p=0.003, respectively). Carriers of A allele in SLCO1A2 -361G>A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively., Conclusion: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML.

This study aimed to simultaneously determine mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in the plasma and to evaluate the impact of different food patterns on the relative bioavailability and pharmacokinetics of a single oral dose of 5-ASA in healthy subjects. In this single-dose, open-label, 3-period, 3-treatment crossover study, the subjects received a single, oral dose of 500-mg enteric-coated mesalazine tablet together with either a low-fat or a high-fat breakfast or under fasting condition (reference). The pharmacokinetic parameters were determined by noncompartmental methods and analyzed with a linear mixed-effect model. The geometric least squares mean ratio for the area under the plasma concentration-time curve from zero to infinity of N-Ac-5-ASA was 1.05 (90% confidence interval [CI], 0.70-1.58) for high-fat/fasted condition and 1.06 (90%CI, 0.82-1.36) for low-fat/fasted condition. The least squares mean ratio of 5-ASA was 0.86 (90%CI, 0.65-1.14) for high-fat/fasted condition and 0.78 (90%CI, 0.60-1.02) for low-fat/fasted condition. All P values were >.05. The mean maximum plasma concentration and the time to reach the maximum plasma concentration of N-Ac-5-ASA were 2084 ng/mL, 8 hours; 2639 ng/mL, 11 hours, and 2409 ng/mL, 9 hours for fasted, high-fat, and low-fat, respectively. The values of 5-ASA were 1950 ng/mL, 7 hours; 2869 ng/mL, 9 hours; and 2837 ng/mL, 8 hours for fasted, high-fat, and low-fat condition. 5-ASA was well tolerated under all 3 conditions. Food delayed the absorption of 5-ASA, especially a high-fat meal. Therefore, enteric-coated mesalazine tablets should be taken before meals to avoid causing patients slow response and any effect of food on its efficacy., (© 2019, The American College of Clinical Pharmacology.)

Licorice, one of the most widely used medicinal herbs in East Asia, has effects such as anti-inflammation, antioxidant, and detoxifying. This study aimed to evaluate the protective effect of licorice on brucine-induced nephrotoxicity. Sprague Dawley rats were administered with brucine intraperitoneally for 7 consecutive days with or without treatment with licorice. The content of blood urea nitrogen and creatinine in serum, the activities of superoxide dismutase and content of glutathione, malonaldehyde in kidney tissue were detected. Hematoxylin-eosin staining was employed to observe the histopathological changes of kidney. The expression and phosphorylation levels of protein were evaluated by Western blotting and immunohistochemical analysis. The results illustrated that treatment with licorice extracts (LE) significantly protected against the brucine-induced nephrotoxicity by reducing the content of blood urea nitrogen and serum creatinine, attenuating pathologic damage. The unbalance of oxidative stress was repaired by LE via increasing the level of glutathione, promoting the activities of superoxide dismutase and decreasing the content of malonaldehyde. In addition, LE overturned the influence of brucine on apoptosis-related protein and signal transducer and activator of transcription-3 (STAT3) activation. Taken together, these data demonstrate that licorice may attenuate brucine-induced nephrotoxicity via inactivation of oxidative stress and mitochondrial-mediated apoptosis pathway. More importantly, the renoprotective effects may be mediated, at least partly, by preventing the activation of STAT3 protein.

We obtained one new molecular ferroelectric material tris(2-hydroxyethyl) ammonium bromide ( TAB ) that crystallizes in aqueous solution at room temperature with a space group of R 3 m which belongs to ten polar space groups. There is a paraelectric-to-ferroelectric phase transition at 424 K (from hexagonal R 3̅ m to hexagonal R 3 m phase). Such a high transition temperature is close to that of diisopropylamine bromide (426 K) and higher than that of many other molecular ferroelectrics, such as triethylmethylammonium tetrabromoferrate(III) (360 K); some of the organic-inorganic perovskite ferroelectrics, such as (cyclohexylammonium) 2 PbBr 4 (363 K); and some inorganic ferroelectrics, including BaTiO 3 (393 K). The saturated polarization and the coercive field of TAB measured from the ferroelectric hysteresis loop are about 0.54 μC·cm -2 and 0.62 kV/cm, respectively. Given its superior performance, including high phase transition temperature, room-temperature ferroelectricity, small coercive electric field, and adjustable ladder-shaped dielectric constant, TAB will have many potential applications.

Osteoarthritis (OA) is the most common form of degenerative arthropathy, and the primary symptom is chronic joint pain. Dehydroepiandrosterone (DHEA) exerts a chondroprotective effect against OA and has been reported to have potent structure-modifying effects on osteoarthritic cartilage, thereby attenuating disease progression. However, the ability of DHEA to modulate OA-related pain has not yet been verified. Recent evidence suggests that there may be a link between the pharmacological effects of DHEA and pain generation. For example, DHEA synthesized in the adrenal gland interferes directly with nerve growth factor (NGF) receptors, a major biochemical contributor to peripheral hypersensitivity. Similarly, endogenous DHEA produced in the spinal cord exerts a regulatory effect on nociception in neuropathic rats. In this short review, we discuss recent studies concerning crucial signalling cascades and molecular mechanisms involved in pain generation as well as the potential link between DHEA activity and nociception. Particular attention is given to the putative molecular mechanisms underlying the favourable efficacy of DHEA against pain generation. Elucidating the molecular mechanisms of DHEA against osteoarthritic pain may pave the way for the discovery and development of novel anti-OA drugs, as effective drugs for OA treatment are not currently available., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Hybrid organic-inorganic halide perovskites (HOIPs) MAPbBr 3 and their ramifications have emerged because of the photovoltaic, optical, and other fascinating performances of HOIPs in recent years. However, many intrinsic properties, such as crystal structure and ferroelectricity, are still controversial. In this work, the ferroelectricity of the orthorhombic and tetragonal MAPbBr 3 single crystal was confirmed through the dielectric behavior versus bias electric field ε( E), the temperature-dependent pyroelectric current with positive/negative poling, and the positive-up-negative-down (PUND) measurements. The electric field dependence of dielectric constant curves shows a butterfly type shape in the orthorhombic and tetragonal phase. The pyroelectric current shows two maxima at 155 and 245 K, corresponding to ferroelectric-ferroelectric and ferroelectric-paraelectric phase transitions, respectively. In particular, the direction of the pyroelectric current can be reversed by a positive or negative poling electric field, which is the assertive evidence of ferroelectricity. The PUND measurements act as the most convincing proof of the ferroelectricity of the MAPbBr 3 single crystal. This work reports new evidence of the ferroelectric properties of the MAPbBr 3 single crystal, which provides the intrinsic property when considering their high power conversion efficiencies.

Objective: Renal cancer represents about 3% of all human cancers. Clear cell renal cell carcinoma (ccRCC) is the main type of renal cancer. MicroRNAs (miRNAs) have been reported to play crucial roles in the carcinogenesis of human cancers. This study was aimed to investigate the expression of miR-1294 and the mechanisms underlying miR-1294-mediated ccRCC progression., Materials and Methods: The miR-1294 expression levels in ccRCC cell lines were analyzed by quantified real time-PCR (qRT-PCR). The effect of the miR-1294 expression on the overall survival of ccRCC patients was analyzed by the Kaplan-Meier Plotter. Cell proliferation, colony growth, and cell invasion were examined by cell counting kit-8 assay, colony formation assay, and transwell invasion assay, respectively. The luciferase activity reporter assay and Western blot assay were conducted to validate the connection between miR-1294 and homeobox A6 (HOXA6)., Results: MiR-1294 was downregulated in ccRCC cell lines and correlated with the poor overall survival of ccRCC patients. The overexpression of miR-1294 inhibits ccRCC cell proliferation, colony growth, and cell invasion. HOXA6 was validated as a target of miR-1294 and negatively regulated by miR-1294. The overexpression of HOXA6 attenuated the miR-1294-mediated effects on ccRCC cellular functions., Conclusions: Our results indicated that miR-1294 functions as a tumor suppressor in ccRCC. MiR-1294 suppressed cell proliferation, colony formation, and invasion in ccRCC partially via targeting HOXA6.

Purpose: To compare efficacy and safety of postponing administration of aprepitant and routine triple-antiemetic treatment for chemotherapy-induced nausea and vomiting in patients who received docetaxel and cisplatin multi-day chemotherapy treatment, and to evaluate the effect of aprepitant on docetaxel pharmacokinetics in the Chinese population., Methods: A total of 24 cancer patients (including 5 females and 19 males, 22-74 years old) received two cycles of high-emetic DP (docetaxel 75 mg/m 2  on day 1 + cisplatin 25 mg/m 2 on days 1-3) regimen. A randomized, two-period and cross-over study was applied for prevention of chemotherapy-induced nausea and vomiting. The patients in group A took aprepitant 125 mg on day 1 and 80 mg on days 2-3 (administered aprepitant 1 h before chemotherapy). In group B, the patients took aprepitant 125 mg on day 2, 80 mg on days 3-4, which was delayed 1 day than group A. Efficacy and safety in overall phase were evaluated within 5 days after initiation of chemotherapy. Simultaneously, the differences in the pharmacokinetic parameters of docetaxel between two different antiemetic treatments are compared., Results: The CR rate of delayed-phase nausea was compared between the routine triple-antiemetic treatment (group A) and the aprepitant delayed 1-day administration treatment (group B), and the difference was statistically significant (16.7% vs 45.8% P < 0.05), despite there were similar for two groups in the CR rate of acute-phase nausea and vomiting, and delayed-phase vomiting. In two groups, the area under the docetaxel curve (AUC 0-t values) (mean ± SD) of docetaxel was 1134.21 ± 732.55 (ng h/mL) and 1080.94 ± 585.09 (ng h/mL), and the geometric means were 944.82 and 902.10 (ng h/mL), respectively. There was no significant difference in AUC values between the two antiemetic treatments (P > 0.05), as well as C max , CL z , T 1/2z , MRT and T max ., Conclusions: Delayed administration of aprepitant provided superior delayed-phase nausea protection for patients who received cisplatin-based chemotherapy in comparison with the routine triple-antiemetic treatment. In addition, in the routine triple-antiemetic treatment, aprepitant did not significantly affect the main pharmacokinetic parameters of docetaxel.

Aim: This study aimed to establish a population pharmacokinetic (PPK) model in Chinese patients with chronic myeloid leukemia, and to quantify the effects of pharmacogenetics on pharmacokinetic parameters of imatinib., Methods: A total of 229 plasma concentrations from 170 patients were analyzed. Nonlinear mixed effect model was used to establish the PPK model., Results: A one-compartment model with first-order absorption and first-order elimination adequately describes imatinib pharmacokinetics. Actual bodyweight shows slight effect on the estimated apparent clearance (CL/F) of imatinib in this study population. The final PPK model is: K a (1/h) = 0.329; CL/F (l/h) = 9.25 × (actual bodyweight/70) 0.228 ; V/F(l) = 222., Conclusion: Actual bodyweight has a slight effect on CL/F. Demographics, physiopathology and pharmacogenetics covariates have no significant effects on imatinib pharmacokinetics.