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Currently there is no standard therapy recommended for second-line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single-agent chemotherapy, and PD-1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum-based chemotherapy at the clinic.The study included patients with thymic carcinoma who failed first-line platinum-based chemotherapy. Kaplan-Meier methods were applied in the study for estimating the progression-free survival (PFS) and overall survival (OS) curves. Pearson chi-square or Fisher's exact chi-square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS.Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second-line therapy. Thirty-six patients (35.9%) received single-agent chemotherapy, and eight patients (8.7%) underwent PD-1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single-agent chemotherapy and PD-1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second-line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3-4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment-related mortality was not found in any of the groups.Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single-agent chemotherapy and PD-1 inhibitors. Multidrug chemotherapy is a choice worth considering for second-line therapy in patients with thymic carcinoma if tolerable.

Background Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. Methods The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan–Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. Results A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. Conclusion A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD.

Background Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. Methods Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. Results Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. Conclusions Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity. Graphical Abstract

BACKGROUND AND AIMS Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. APPROACH AND RESULTS We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. CONCLUSIONS We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.

This study evaluated the effects of the types (MFL and acetate anti-icing filler) and the replacement rate of anti-icing additives on the performance of asphalt mixtures. Additionally, the road performance as well as ice inhibition capacity between environmental (acetate anti-icing filler) and conventional (MFL) anti-icing materials were compared. The equivalent volume displacement method was applied to determine the amount of anti-icing filler in asphalt mixture. In this paper, the high-temperature stability, low-temperature bending properties, water stability, ice inhibition properties and anti-icing persistence of the mixture were investigated in the laboratory. The results show that the ice inhibitor has negative effects on the rutting resistance, crack resistance and moisture sensitivity of the asphalt mixture. Additionally, the adverse effects become more obvious as the replacement rate increases. There was a similar trend in the mixtures with three kinds of ice inhibition filler in general. The tests also proved that the anti-icing fillers can effectively delay and inhibit the occurrence of road icing, weaken the bonding force between pavement surface and the ice layer and make the ice layer easy to be removed. It is found that the comprehensive performance of traditional ice inhibitors is better. Moreover, the high-temperature stability, anti-icing capacity and ice inhibition persistence of environmentally friendly anti-icing additives need to be improved.

To successfully analyze complex samples and detect trace targets, sample pretreatment is essential. Efficient sample pretreatment techniques can remove or reduce interference from the sample matrix. It can also enrich analytes, thereby improving analytical accuracy and sensitivity. In recent years, various sample preparation techniques, including SPE, magnetic dispersion SPE, pipette tip SPE, stir bar extraction, fiber SPME, and in-tube SPME, have received increasing attention in environmental analysis and monitoring. The extraction efficiency mainly depends on the type of adsorbent material. Therefore, the development of efficient adsorbents is a crucial step toward sample preparation. This review summarizes and discusses the research advances in extraction materials over recent years. These extraction materials contain inorganic adsorbents, organic adsorbents, and inorganic-organic hybrid materials such as graphene, graphene oxide, carbon nanotubes, inorganic aerogels, organic aerogels, triazinyl-functionalized materials, triazine-based polymers, molecularly imprinted polymers, covalent organic frameworks, metal-organic frameworks, and their derivatives. These materials have been applied to extract different types of pollutants, including metal ions, polycyclic aromatic hydrocarbons, plasticizers, alkanes, phenols, chlorophenols, chlorobenzenes, polybrominated diphenyl ethers, perfluorosulfonic acids, perfluorocarboxylic acids, estrogens, drug residues, and pesticide residues, from environmental samples (such as water and soil samples). These sample preparation materials possess high surface areas, numerous adsorption sites, and allow extraction via various mechanisms, such as π-π, electrostatic, hydrophobic, and hydrophilic interactions, as well as hydrogen and halogen bond formation. Various sample pretreatment techniques based on these extraction materials have been combined with various detection methods, including chromatography, mass spectrometry, atomic absorption spectroscopy, fluorescence spectroscopy, and ion mobility spectroscopy, and have been extensively used for the determination of environmental pollutants. The existing challenges associated with the development of sample preparation techniques are proposed, and prospects for such extraction materials in environmental analysis and monitoring are discussed. Major trends in the field, including the development of efficient extraction materials with high enrichment ability, good selectivity, excellent thermal stability, and chemical stability, are discussed. Green sample pretreatment materials, environmentally friendly synthesis methods, and green sample pretreatment methods are also explored. Rapid sample pretreatment methods that can be conducted within minutes or seconds are of significant interest. Further, online sample pretreatment and automatic analysis methods have attracted increasing attention. Besides, real-time analysis and in situ detection have been important development directions, and are expected to be widely applicable in environmental analysis, biological detection, and other fields. Modern synthesis technology should be introduced to synthesize specific extraction materials. Controllable preparation methods for extraction materials, such as the in situ growth or in situ preparation of extraction coatings, will acquire importance in coming years. It will also be important to adopt high-performance materials from other fields for sample pretreatment. Organic-inorganic hybrid extraction materials can combine the advantages both organic materials and inorganic materials, and mutually compensate for any disadvantages. Extraction materials doped with nanomaterials are also promising. Although existing sample pretreatment techniques are relatively efficient, it is still imperative to develop novel sample preparation methods.

Background Endostatin and bevacizumab have been approved for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) patients in China; however, the clinical outcomes for each drug combined with platinum-based doublet chemotherapy (PT-DC) have not yet been directly compared. This study sought to assess the clinical outcomes of the 2 drugs combined with PT-DC in the first-line treatment of patients with advanced lung adenocarcinoma. Methods This retrospective cohort study examined the clinical data of patients with metastatic or recurrent lung adenocarcinoma (LUAD) treated with endostatin or bevacizumab combined with PT-DC as the first-line treatment from October 2010 to November 2019. Propensity score matching (PSM) was performed using a 1:1 ratio nearest neighbor algorithm. The effectiveness and safety outcomes for the 2 groups were evaluated. Results A total of 202 patients were enrolled in the study. Of these, the endostatin group comprised 124 patients and the bevacizumab group comprised 78 patients; 67 pairs of patients were identified after PSM. The progression-free survival (PFS) and overall survival (OS) of patients treated with PT-DC + endostatin and PT-DC + bevacizumab were compared [(PFS: before PSM 4.8 vs. 6.5 months, P=0.741; after PSM 6.5 vs. 6.1 months, P=0.402), (OS: before PSM 21.1 vs. 39.3 months, P=0.912; after PSM 23.6 vs. 39.3 months, P=0.579)]. The objective response rates (ORRs) and disease control rates (DCRs) of the 2 groups were comparable (37.7% vs. 50.7%, P=0.094; 89.6% vs. 92.5%, P=0.545). Adverse events (AEs) ≥ grade 3 were not observed in the PT-DC + endostatin group. Three (3.8%) cases of AEs ≥ grade 3 were observed the PT-DC + bevacizumab group, comprising hypertension (n=1), proteinuria (n=1), hemoptysis (n=1). Conclusions This retrospective analysis showed that in first-line treatments, PT-DC + endostatin and PT-DC + bevacizumab appear to produce similar anti-tumor activities in patients with metastatic or recurrent lung adenocarcinoma. PT-DC + bevacizumab tended to result in worse adverse reactions than PT-DC + endostatin.

Background The combination of PD-1/PD-L1 inhibitor and chemotherapy has been clinically confirmed to be beneficial as the first-line treatment of patients with advanced NSCLC. This study aimed to assess the effect of nivolumab + docetaxel versus nivolumab monotherapy in patients with NSCLC after the failure of platinum doublet chemotherapy. Materials and methods The efficacy and toxicity of nivolumab + docetaxel combination therapy versus nivolumab monotherapy were compared in this retrospective study. Primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and toxicity. Results Between November 2017 and December 2019, 77 patients were included in this study, with 58 patients in the nivolumab group and 19 in the nivolumab + docetaxel group. The median follow-up was 18 months, and the PFS was 8 months for patients receiving nivolumab + docetaxel and 2 months for those receiving nivolumab alone (p = 0.001), respectively. Nivolumab + docetaxel showed superior OS compared with nivolumab, with the median OS unreached versus 7 months (p = 0.011). Among patients without EGFR/ALK variation, compared to nivolumab monotherapy, nivolumab + docetaxel showed better PFS (p = 0.04) and OS (p = 0.05). There was no significant difference in grade 3–4 adverse events (AEs) between the two groups (p = 0.253). Conclusions The combination of nivolumab and docetaxel demonstrated a meaningful improvement in progression-free survival and overall survival compared to nivolumab monotherapy, in patients with NSCLC after the failure of platinum doublet chemotherapy, irrespective of EGFR/ALK variation status.

The liver is a vital organ that controls glucose and lipid metabolism, hormone regulation, and bile secretion. Liver injury can occur from various insults such as viruses, metabolic diseases, and alcohol, which lead to acute and chronic liver diseases. Recent studies have demonstrated the implications of long non-coding RNAs (lncRNAs) in the pathogenesis of liver diseases. These newly discovered lncRNAs have various functions attributing to many cellular biological processes via distinct and diverse mechanisms. LncRNA H19, one of the first lncRNAs being identified, is highly expressed in fetal liver but not in adult normal liver. Its expression, however, is increased in liver diseases with various etiologies. In this review, we focused on the roles of H19 in the pathogenesis of liver diseases. This comprehensive review is aimed to provide useful perspectives and translational applications of H19 as a potential therapeutic target of liver diseases.

Broadband transmitted wavefront measurement is a detection method that uses transmitted wavefronts at a few specific wavelengths though a function of Zernike coefficients and wavelength to predict other transmitted wavefronts at any wavelength within a certain range. This method is used when the designed wavelength of the interferometer and the detection wavelength are different. The function of the Zernike coefficients and wavelength can be expressed by the Conrady formula which can be used to describe a monotonic function curve or a function curve with an inflection point. Two methods, i.e., solving and fitting, can be used to determine the coefficients of the Conrady formula. Owing to the inevitable errors in the actual measurements, the fitting method is preferred to determine the coefficients of the Conrady formula. However, by analyzing the Conrady formula, it was found that the curve obtained by fitting the Conrady formula is a monotonic curve. This method cannot be used to obtain a curve with an inflection point or a slow-changing curve in the long waveband. In this paper, we propose an improved data fitting approach that transforms the Conrady formula into a polynomial formula to fit a given set of data for determining the Conrady formula coefficients. The correctness of the method was verified via simulations. Finally, the feasibility of the proposed method was verified by changing the light source and using the Fizeau interferometer to measure the transmitted wavefront of the doublet lens. To ascertain the feasibility of using visible light to predict the invisible light band, a near-infrared 1064 nm light source was added to the experimental set-up to broaden the range of the transmitted wavefront prediction waveband. Experimental results showed that the conversion polynomial fitting method can be used to obtain monotonic curves and the curve with an inflection point and a slow-changing curve in the long waveband, thereby mitigating the limitation of directly fitting the Conrady formula using a set of data points. Furthermore, using this method, we verified that the visible light can be used to predict the transmitted wavefront at any wavelength in the invisible light band. This observation is highly significant for the practical applications of the broadband transmitted wavefront measurement technique.

Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouringTo analyseA multicentre, single-arm, open-label phase 2 study.All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baselineAmong 66 patients with baseline ctDNA sequencing, 46 (70%) had detectablectDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients withThe trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

Aims Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. Methods We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. Results Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. Conclusion Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.

The sound absorption coefficient was evaluated for the acoustic performance of the pavement in many studies, which is an evaluation index generated by the non-contact interaction between the tyre a...

Oxidative stress is considered a possible mechanism of irritable bowel syndrome (IBS) and depression. This study determined the possible association of serum peroxiredoxin 1 (PRDX1; a key antioxidant enzyme) and brain-derived neurotrophic factor (BDNF) with anxiety and depression symptoms in IBS patients.According to the Rome IV diagnostic criteria, 177 IBS patients from February 2019 to July 2019 were included. Serum levels of PRDX1, BDNF, and TNFα were detected by enzyme-linked immunosorbent assay. Levels of anxiety and depression were assessed with the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS).Compared with normal IBS patients, patients with anxiety and depression symptoms had significantly higher serum PRDX1 (p0.001; p=0.002) and TNFα (p0.001; p = 0.002) and significantly lower BDNF (p 0.001; p = 0.002). Serum PRDX1 (r = 0.659, p 0.001; r = 0.466, p 0.001) and TNFα (r = 0.531, p 0.001; r = 0.449, p 0.001) were positively correlated with SAS and SDS, respectively, whereas BDNF was negatively correlated with SAS (r = 0.594, p 0.001) and SDS (r = 0.534, p 0.001). Multivariable regression analysis revealed that IBS severity, BDNF, and PRDX1 were significant predictors of anxiety. BDNF was also a significant predictor of depression.Elevated PRDX1 and decreased BDNF in serum may be closely related to psychological symptoms in IBS. Results of this study suggested that PRDX1 may be an important target for IBS treatment in fighting against intestinal and psychological symptoms.

Beam splitters have a wide range of applications as a key component in optical systems. Adopting beam splitters with geometric defects in an optical system, e.g., an interferometric measurement system, may cause additional optical path difference and degrade the measurement accuracy. The quality inspection of beam splitters is essential to meet the accuracy requirements for modern optical systems. Most of the current quality inspection methods rely on inefficient and inaccurate manual observation. Therefore, for commonly used cube beam splitters (CBSs), we propose a digital method to quantify the geometric quality based on the white light interferometric principle. A Fourier domain analysis is used to calculate the CBS misalignment error and perpendicularity error. This method is verified by inspecting six different CBS samples. The experimental results show that all samples have varying degrees of misalignment and perpendicularity errors. The maximum perpendicularity error is 0.93°, and three of the six samples have misalignment errors larger than 50 µm. Nanometer level precision of the misalignment measurement can be achieved.

In the actual working condition, the cavitation phenomenon is inevitably accompanied by the collapse of a large number of bubbles, and will affect the performance of hydraulic machinery. Therefore, it is of great significance to study the process of multi-bubble collapse. The double bubble system is the most simplified one in multi-bubble system, and it is also the basis of studying multi-bubble. However, the existing bubble dynamic studies mainly focused on single bubble and its interaction with the wall. This paper studies the interaction between two bubbles with different sizes and the influence of the wall on the process of bubble collapse by the VOF method. We have already investigated the interaction between two bubbles with different sizes without a wall (in free water) in our previous study. In this paper, we find that if there is a wall nearby, these two bubbles move close to each other when collapsing, and both move close to the wall at the same time. Through the study of bubble collapse time in the single bubble and the double bubble system, we find that the existence of the wall will delay the collapse time of bubble. However, the existence of the wall can also increase the intensity of collapse and rebound process of the bubble. Through the study of the center displacement of the bubble, we find that the double bubble system can increase the displacement of both bubbles. The method used in this paper can be easily extended to the study of multi-bubble, which provides a feasible method for the simulation of multi-bubble collapse near the wall.

MicroRNA-7 (miR-7) is a small non-coding RNA, which plays critical roles in regulating gene expression of multiple key cellular processes. MiR-7 exhibits a tissue-specific pattern of expression, with abundant levels found in the brain, spleen, and pancreas. Although it is expressed at lower levels in other tissues, including the liver, miR-7 is involved in both the development of organs and biological functions of cells. In this review, we focus on the mechanisms by which miR-7 controls cell growth, proliferation, invasion, metastasis, metabolism, and inflammation. We also summarize the specific roles of miR-7 in liver diseases. MiR-7 is considered as a tumor suppressor miRNA in hepatocellular carcinoma and is involved in the pathogenesis of hepatic steatosis and hepatitis. Future studies to further define miR-7 functions and its mechanism in association with other types of liver diseases should be explored. An improved understanding from these studies will provide us a useful perspective leading to mechanism-based intervention by targeting miR-7 for the treatment of liver diseases.

Lysobacter enzymogenes is a non-flagellated, soil proteobacterium that secretes a diffusible antibiotic known as heat-stable antifungal factor (HSAF) to kill nearby fungi for food. The genome of the model strain OH11 encodes a homologous Wsp system, which is generally deployed by flagellated bacteria to achieve flagella-dependent outputs via a c-di-GMP-FleQ complex, in which c-di-GMP is a ubiquitous dinucleotide second messenger and FleQ is a transcription factor (TF). Here, we show that the Wsp system in the non-flagellated OH11 participates in a unique c-di-GMP-dependent signalling pathway and forms a WspR-CdgL binary complex to alter HSAF production, in which WspR and CdgL act as a c-di-GMP diguanylate cyclase (DGC) and a non-TF binding protein respectively. We found that the phosphorylation of WspR activates its DGC activity and enhances c-di-GMP production while inhibiting HSAF biosynthesis. The phosphorylation of WspR also plays a key role in weakening WspR-CdgL binding and HSAF generation. Interestingly, c-di-GMP binding to CdgL did not seem to induce the disassociation of the WspR-CdgL complex. These observations, along with our earlier findings, lead us to propose a model in which L. enzymogenes re-programs the Wsp system via c-di-GMP signalling to regulate HSAF biosynthesis for the benefit of ecological adaptation.

Objectives To evaluate the effects of UGT1A1*6 and UGT1A1*28 polymorphisms on the safety and efficacy of metronomic irinotecan-based chemotherapy (IBC) in Chinese patients with pulmonary neuroendocrine tumours (PNTs). Methods Sixty-eight PNT patients who received metronomic IBC were observed. The quantitative fluorescent polymerase chain reaction was used to detect UGT1A1*6 and UGT1A1*28 polymorphisms. The follow-up data were collected to investigate the relationship between different genotypes and adverse drug reactions. The clinical outcomes of metronomic IBC were also evaluated. Key findings In the genotype–toxicity association analysis, patients with homozygous UGT1A1*6 had the highest incidence of grade 3-4 diarrhoea (P = 0.010). Compared to other groups, patients with the haplotype of UGT1A1*28 showed a trend towards an increased incidence of grade 4 neutropaenia (P = 0.047). A higher incidence of grade 3–4 leucopaenia was found in groups with UGT1A1*1/*28 (P = 0.023) and UGT1A1*28/*28 (P = 0.022). Grade 1 total bilirubin elevation was associated with the homozygous UGT1A1*6 mutation (P = 0.027) or any UGT1A1*6 variants (P = 0.047). However, neither UGTA1A*28 nor UGT1A1*6 showed any significant association with tumour response or clinical outcomes. Conclusions The impact of UGT1A1 polymorphisms varies in different irinotecan-based chemotherapies. UGT1A1*6 and UGTA1A*28 were useful for the prediction of irinotecan-related severe toxicity in Chinese PNT patients treated with metronomic IBC.

The ability to measure traffic-speed tire-pavement noise in the laboratory is useful for predicting the tire-pavement noise performance of a design mix without conducting expensive and time-consumi...

This investigation was carried out to study the effects of the type and amount of supplementary cementitious materials on mechanical properties and surface durability of Portland cement concrete (P...

The rotor of Permanent Magnet Synchronous Motors (PMSM) is an electromechanical coupled dynamics system. The asymmetrical magnetic field-induced mechanical vibration has important effect on the operation performance of the high speed and high power density PMSM. In this paper, an electromechanical coupled lateral/torsional dynamic model caused by electromagnetic excitation is derived based on a Lagrange–Maxwell approach. The stability of the equilibrium was analyzed using a linearized matrix of the system equation. A stability criteria of coupled torsional-lateral motions was provided, and the influences of the electromagnetic and mechanical parameters on mechanical vibration stability were investigated. Finally, the vibration damping of the electromechanical coupling parameters vibration was explored. These results we represent get us better to understand the nonlinear response of the eccentric PMSM rotor system and are beneficial to control and diagnose the eccentric.

Asphalt mixture is a multi-phase material composed of coarse aggregate, asphalt mortar and air voids. It is of interest to study how the distribution of internal phases of asphalt mixture would aff...