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In this study, 80 carbapenem-resistant Klebsiella pneumoniae (CR-KP) and 160 carbapenem-susceptible Klebsiella pneumoniae (CS-KP) strains detected in the clinic were selected and their matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) peaks were collected. K-means clustering was performed on the MS peak data to obtain the best "feature peaks", and four different machine learning models were built to compare the area under the ROC curve, specificity, sensitivity, test set score, and ten-fold cross-validation score of the models. By adjusting the model parameters, the test efficacy of the model is increased on the basis of reducing model overfitting. The area under the ROC curve of the Random Forest, Support Vector Machine, Logistic Regression, and Xgboost models used in this study are 0.99, 0.97, 0.96, and 0.97, respectively; the model scores on the test set are 0.94, 0.91, 0.90, and 0.93, respectively; and the results of the ten-fold cross-validation are 0.84, 0.81, 0.81, and 0.85, respectively. Based on the machine learning algorithms and MALDI-TOF MS assay data can realize rapid detection of CR-KP, shorten the in-laboratory reporting time, and provide fast and reliable identification results of CR-KP and CS-KP., Competing Interests: Declaration of competing interest The authors of this manuscript, Xiaobo Xu, declare that they have no conflicts of interest regarding this research. This study was conducted without any financial support or involvement from any commercial entities. Xiaobo Xu have no affiliations with organizations that might have a financial interest in the content of this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial-mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy., (© 2024 International Federation for Cell Biology.)

Over the past few decades, there have been advancements in the development of high-performance tissue adhesives as alternatives to traditional sutures and staples for rapid and effective wound closure post-surgery. While tissue adhesives offer advantages such as ease of use, short application time, and minimal tissue damage, they also face challenges related to biocompatibility, biodegradability, and adhesive strength. In this study, L-lysine diisocyanate (LDI) and trimethylolpropane (TMP) were utilized as the primary raw materials to produce a prepolymer terminated with NCO, resulting in the development of a new biocompatible polyurethane tissue adhesive (TMP-LDI). Additionally, SiO 2 nanoparticles were incorporated into the prepolymer, significantly enhancing the adhesive strength of the TMP-LDI tissue adhesive through the "nanobridging effect," achieving a strength of 170.4 kPa. Furthermore, the SiO 2 /TMP-LDI tissue adhesive exhibited satisfactory temperature change during curing and degradation performance. In vitro and in vivo studies demonstrated that SiO 2 /TMP-LDI exhibited good biocompatibility, efficient hemostasis, antimicrobial properties, and the ability to promote wound healing. This research presents a novel approach for the development of tissue adhesives with superior adhesive performance., (© 2024 Wiley Periodicals LLC.)

Radical coupling of thiols is an attractive route for the synthesis of disulfides, but this approach should be promoted by strong oxidants and/or metal salts in combination with additives, which limits its substrate scope and application. In this work, the N -anomeric amide was first found to be able to realize the conversion of thiols to sulfur radicals with high efficiency in the absence of an oxidant or any additives for the synthesis of symmetrical disulfides. The protocol features mild reaction conditions, good functional group tolerance, and moderate to excellent yields., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Growing evidence demonstrates that the synergistic interaction of far-red light with shorter wavelength lights could evidently improve the photosynthesis efficiency of multiple species. However, whether/how far-red light affects sink organs and consequently modulates the source‒sink relationships are largely unknown., Results: Here, equal intensities of white and far-red lights were added to natural light for grape plantlets to investigate the effects of far-red light supplementation on grapevine growth and carbon assimilate allocation, as well as to reveal the underlying mechanisms, through physiological and transcriptomic analysis. The results showed that additional far-red light increased stem length and carbohydrate contents in multiple organs and decreased leaf area, specific leaf weight and dry weight of leaves in comparison with their counterparts grown under white light. Compared to white light, the maximum net photosynthetic rate of the leaves was increased by 31.72% by far-red light supplementation, indicating that far-red light indeed elevated the photosynthesis efficiency of grapes. Transcriptome analysis revealed that leaves were most responsive to far-red light, followed by sink organs, including stems and roots. Genes related to light signaling and carbon metabolites were tightly correlated with variations in the aforementioned physiological traits. In particular, VvLHCB1 is involved in light harvesting and restoring the balance of photosystem I and photosystem II excitation, and VvCOP1 and VvPIF3, which regulate light signal transduction, were upregulated under far-red conditions. In addition, the transcript abundances of the sugar transporter-encoding genes VvSWEET1 and VvSWEET3 and the carbon metabolite-encoding genes VvG6PD, VvSUS7 and VvPGAM varied in line with the change in sugar content., Conclusions: This study showed that far-red light synergistically functioning with white light has a beneficial effect on grape photosystem activity and is able to differentially affect the growth of sink organs, providing evidence for the possible addition of far-red light to the wavelength range of photosynthetically active radiation (PAR)., (© 2024. The Author(s).)

The treatment of non-small cell lung cancer (NSCLC) patients harboring a proto-oncogene tyrosine-protein kinase c-ros oncogene 1 (ROS1) fusion gene has greatly benefited from the use of crizotinib. However, drug resistance inevitably occurs after 1 year of treatment. Clinical studies have shown that patients with an L2026M mutation in the ROS1 kinase domain account for about 6% of the total number of crizotinib-resistant cases, which is an important group that cannot be ignored. To explore the mechanism involved, we constructed the HLA class II histocompatibility antigen gamma chain (CD74)-ROS1 L2026M mutant gene by fusion polymerase chain reaction (PCR) and transfected it into H460 and A549 cells. We found that the invasion and metastasis abilities of drug-resistant cells were increased. The results of monodansylcadaverine (MDC) staining, Acridine orange (AO) staining, and western blot indicated that the autophagy level of CD74-ROS1 L2026M mutant NSCLC cells was increased compared with the CD74-ROS1 group, and the inhibition of autophagy could reverse the increased invasion and metastasis abilities caused by the L2026M mutation. In addition, the L2026M mutation led to excessive activation of the MEK/ERK pathway, and MEK inhibitors could reduce the autophagy level, invasion, and metastasis abilities of cells; additionally, this process could be blocked by rapamycin, an activator of autophagy. Furthermore, crizotinib treatment activated expression of Src homology region 2 domain-containing phosphatase-2 (SHP2; also known as PTPN11) to upregulate the MEK/ERK pathway, and the combination of MEK inhibitors and crizotinib increased apoptosis compared with crizotinib alone. In conclusion, our results indicate that the MEK/ERK pathway mediates the induction of invasion, metastasis, and crizotinib resistance through autophagy caused by CD74-ROS1 L2026M mutation in NSCLC cells, and targeting MEK could reverse these processes., (© 2023 Federation of European Biochemical Societies.)

A palladium-catalyzed (3 + 2) annulation of 2-methylbenzoic acid with maleimide using Ac-Leu-OH as a powerful ligand has been reported. Through a site-selective γ-C(sp 3 )-H olefination reaction and a sequential decarboxylative cross-coupling reaction, a five-membered cyclic ring was obtained as the final product. This novel reaction features great site selectivity and reactivity to generate various cyclic products in moderate to good yields.

Medical dressings, as a cover for wounds, can replace damaged skin in the wound healing process to play a temporary barrier role, avoid or control wound infection, and provide a favorable environment for wound healing. Therefore, there is an urgent need for medical antimicrobial dressings for the treatment of chronic wounds. Although traditional polyurethane foam has been widely used in medical dressings, conventional polyurethane foams are primarily prepared using nonbiocompatible isocyanate-based compounds, which are potentially hazardous for both operators and applications in the medical field. Here, we propose nonisocyanate polyurethane foams naturally derived from lignin by enzymatic lignin alkylation, cyclic carbonation modification, and polymerization with diamine and the addition of a blowing agent. Silver nanoparticle solution was added during foaming to confer antimicrobial properties. This lignin-based nonisocyanate polyurethane/silver composite foam (named NIPU foam-silver) using a green synthesis method has good mechanical properties, which can be used to manufacture polyurethane/silver foams, and thermal and antimicrobial properties. Notably, NIPU foam-Ag showed more than 95% bactericidal efficacy against both Escherichia coli and Staphylococcus aureus within 4 h. Evaluation of in vitro wounds in mice showed that this antimicrobial composite foam rapidly promotes wound healing and repairs damaged tissue. This suggests that this biobased biodegradable antimicrobial foam has significant scope for clinical applications in wound management.

Benzalkonium chloride (BC) is widely used for disinfection in the food industry. However, Listeria monocytogenes strains with resistance to BC have been reported recently. In L. monocytogenes , the Agr communication system consists of a membrane-bound peptidase AgrB, a precursor peptide AgrD, a histidine kinase (HK) AgrC, and a response regulator (RR) AgrA. Our previous study showed that the agr genes are significantly upregulated by BC adaptation. This study aimed to investigate the role of the Agr system in BC resistance in L. monocytogenes . Our results showed that the Agr system was involved in BC resistance. However, a direct interaction between BC and AgrC was not observed, nor between BC and AgrA. These results indicated that BC could induce the Agr system via an indirect action. Both AgrBD and AgrC were required for growth under BC stress. Nevertheless, when exposed to BC, the gene deletion mutant ∆ agrA strain exhibited better growth performance than its parental strain. The RR Lmo1172 played a role in BC resistance in the ∆ agrA strain, suggesting that Lmo1172 may be an alternative to AgrA in the phosphotransfer pathway. Phosphorylation of Lmo1172 by AgrC was observed in vitro. The cognate HK Lmo1173 of Lmo1172 was not involved in BC stress, regardless of whether it was as the wild-type or the ∆ agrA mutant strain. Our evidence suggests that the HK AgrC cross-phosphorylates its noncognate RR Lmo1172 to cope with BC stress when the cognate RR AgrA is absent. In vivo, further studies will be required to detect phosphotransfer of AgrC/AgrA and AgrC/Lmo1172.

The construction of an effective antibacterial micro-environment to prevent infection and biofilm formation is critically important for the design of wound dressings. Herein, a novel hydrogel wound dressing was fabricated by embedding Au nanoparticles-decorated halloysite nanotubes (Au@HNTs) into the lignin-based hydrogel matrix containing polyvinyl alcohol and chitosan. The resulting composite hydrogel, noted as LPC-Au@HNTs, exhibited an excellent photothermal antibacterial activity owing to the embedded Au@HNTs in which Au nanoparticles were generously filled into the lumen of Halloysite nanotubes. The typical sample containing 4 wt% of Au@HNTs in the composite hydrogel (LPC-Au@HNTs4) had good mechanical and photothermal properties. The surface temperature of as-prepared hydrogel increased to 57.59 °C after 5 min upon NIR light irradiation (808 nm) at 1.0 W/cm 2 . The photothermal effect endowed the hydrogel dressing with excellent antibacterial activity, with significantly enhanced inhibition rates of Escherichia coli (99.00 %) and Staphylococcus aureus (98.88 %). Experiments in a mouse full-thickness skin defect wound model also showed that the hydrogel dressing had a facilitative effect on the repair of traumatic surfaces. This study provides a broadly appliable wound dressing for treating bacteria-infected wounds, greatly contributing to the design of photothermal antibacterial biomedical materials for wound healing., 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.)

Purpose: Prior studies revealed several beneficial aspects of being authentic, such as higher subjective well-being, more harmonious interpersonal relationships, and better workplace performance. However, how authenticity relates to unethical cheating behaviors in the academic context remains to be seen. Based on the literature review, the present study hypothesized that authenticity may be negatively linked to academic cheating through the mediating path of mastery approach goals., Methods: In Study 1, 250 college students self-reported their demographics and academic performance, and completed the scales of authenticity, academic cheating, mastery approach goals, and social desirability. In Study 2, 111 college students completed the same measures as in Study 1 at two different time points (5 months in between)., Results: In Study 1, the results indicated that authenticity was positively associated with mastery approach goals, and both were negatively associated with academic cheating. After controlling for the confounding effect of gender, age, academic performance, and social desirability, mastery approach goals were identified as a mediator in the authenticity-academic cheating relationship. In Study 2, the correlation result confirmed the association patterns found in Study 1. Moreover, cross-lagged analysis supported the directionality proposed in the mediation model., Conclusion: The findings identified the mediating role of mastery approach goals in the link between authenticity and academic cheating, supporting the motivated cognition perspective of personality, the motivational model of academic cheating, and the self-determination theory. Implications, limitations, and directions for future research were provided., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Xu et al.)

Green development is the necessary path and fundamental way for urban development. Exploring the influence mechanism and spatial effect of green development on the urban human settlement resilience is conducive to promoting high-quality and sustainable urban development. We used the entropy method, super-efficient SBM model, spatial econometric model and threshold model to analyze the spatial spillover effect of green development efficiency on urban human settlement resilience and its nonlinear impact in the Yangtze River Delta(YRD) urban agglomeration. The results indicated that During the study period, the level of green development efficiency and urban settlement resilience was on the rise, and the spatial differences between different regions was significant. The green development efficiency of each city in the YRD urban agglomeration has a significant contribution to urban human settlement resilience in the region, but has a negative spatial effect on the level of urban human settlement resilience in the neighboring region. At different population density levels, the effect of green development efficiency on urban human settlement resilience shows a significant "V" non-linear characteristic. Furthermore, the influence of green development efficiency on urban human settlement resilience increases in a stepwise manner under different industrial structure distribution. The results of this study can help provide a reference basis for the creation of high-level, high-quality green and livable resilient cities in the YRD urban agglomeration under the concept of green development, and provide relevant experience for the construction of livable cities in other regions of China., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In this work, high-performance, light-stimulation healable, and closed-loop recyclable covalent adaptable networks are successfully synthesized from natural lignin-based polyurethane (LPU) Zn 2+ coordination structures (LPUxZy). Using an optimized LPU (LPU-20 with a tensile strength of 28.4 ± 3.5 MPa) as the matrix for Zn 2+ coordination, LPUs with covalent adaptable coordination networks are obtained that have different amounts of Zn. When the feed amount of ZnCl 2 is 9 wt%, the strength of LPU-20Z9 reaches 37.3 ± 3.1 MPa with a toughness of 175.4 ± 4.6 MJ m -3 , which is 1.7 times of that of LPU-20. In addition, Zn 2+ has a crucial catalytic effect on "dissociation mechanism" in the exchange reaction of LPU. Moreover, the Zn 2+ -based coordination bonds significantly enhance the photothermal conversion capability of lignin. The maximum surface temperature of LPU-20Z9 reaches 118 °C under the near-infrared illumination of 0.8 W m -2 . This allows the LPU-20Z9 to self-heal within 10 min. Due to the catalytic effect of Zn 2+ , LPU-20Z9 can be degraded and recovered in ethanol completely. Through the investigation of the mechanisms for exchange reaction and the design of the closed-loop recycling method, this work is expected to provide insight into the development of novel LPUs with high-performance, light-stimulated heal ability, and closed-loop recyclability; which can be applied toward the expanded development of intelligent elastomers., (© 2023 Wiley-VCH GmbH.)

Pyrazoles as an important class of heterocyclic compounds, are widely found in pharmaceuticals and bioactive natural products. Herein we report a [3 + 2] cycloaddition reaction for the synthesis of a series of pyrazoles, with the yield up to 77%. This approach exhibits many notable features, such as convenient operating conditions, excellent functional group compatibility and readily accessible raw materials, providing an alternative route for the construction of pyrazole derivatives.

Introduction: The distinction between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) holds clinical significance in staging, therapeutic intervention, and prognosis assessment for multiple lung cancer. Lineage tracing by clinicopathologic features alone remains a clinical challenge; thus, we aimed to develop a multi-omics analysis method delineating spatiotemporal heterogeneity based on tumor genomic profiling., Methods: Between 2012 and 2022, 11 specimens were collected from two patients diagnosed with multiple lung cancer (LU1 and LU2) with synchronous/metachronous tumors. A novel multi-omics analysis method based on whole-exome sequencing, transcriptome sequencing (RNA-Seq), and tumor neoantigen prediction was developed to define the lineage. Traditional clinicopathologic reviews and an imaging-based algorithm were performed to verify the results., Results: Seven tissue biopsies were collected from LU1. The multi-omics analysis method demonstrated that three synchronous tumors observed in 2018 (LU1B/C/D) had strong molecular heterogeneity, various RNA expression and immune microenvironment characteristics, and unique neoantigens. These results suggested that LU1B, LU1C, and LU1D were MPLC, consistent with traditional lineage tracing approaches. The high mutational landscape similarity score (75.1%), similar RNA expression features, and considerable shared neoantigens (n = 241) revealed the IPM relationship between LU1F and LU1G which were two samples detected simultaneously in 2021. Although the multi-omics analysis method aligned with the imaging-based algorithm, pathology and clinicopathologic approaches suggested MPLC owing to different histological types of LU1F/G. Moreover, controversial lineage or misclassification of LU2's synchronous/metachronous samples (LU2B/D and LU2C/E) traced by traditional approaches might be corrected by the multi-omics analysis method. Spatiotemporal heterogeneity profiled by the multi-omics analysis method suggested that LU2D possibly had the same lineage as LU2B (similarity score, 12.9%; shared neoantigens, n = 71); gefitinib treatment and EGFR , TP53 , and RB1 mutations suggested the possibility that LU2E might result from histology transformation of LU2C despite the lack of LU2C biopsy and its histology. By contrast, histological interpretation was indeterminate for LU2D, and LU2E was defined as a primary or progression lesion of LU2C by histological, clinicopathologic, or imaging-based approaches., Conclusion: This novel multi-omics analysis method improves the accuracy of lineage tracing by tracking the spatiotemporal heterogeneity of serial samples. Further validation is required for its clinical application in accurate diagnosis, disease management, and improving prognosis., Competing Interests: XZ, JP, HB, and QO are employees of Nanjing Geneseeq Technology Inc., China. The remaining 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 © 2023 Song, Zhou, Zhao, Zhang, Xu, Zhang, Pang, Bao, Ji, Zhan, Wang, Ou and Hu.)

C-H borylation is one of the powerful C-H bond functionalization reactions. In this context, a metal-free C-H borylation of benzophenones using hydrazone as the traceless directing group has been reported. The dibromoboron intermediates can be obtained in excellent yields, and the corresponding arylboronic esters are generated in moderate to excellent yields. Furthermore, the borylated compounds can be transformed in a one-pot method, avoiding the loss of overall yield caused by the separation of the arylboronic esters.

The quality of planting materials is the foundation for productivity, longevity, and berry quality of perennial grapevines with a long lifespan. Manipulating the nursery light spectrum may speed up the production of healthy and high-quality planting vines but the underlying mechanisms remain elusive. Herein, the effects of different monochromatic lights (green, blue, and red) on grapevine growth, leaf photosynthesis, whole-plant carbon allocation, and transcriptome reprograming were investigated with white light as control. Results showed that blue and red lights were favorable for plantlet growth in comparison with white light. Blue light repressed excessive growth, significantly increased the maximum net photosynthetic rate (Pn) of leaves by 39.58% and leaf specific weight by 38.29%. Red light increased the dry weight of the stem by 53.60%, the starch content of the leaf by 53.63%, and the sucrose content of the stem by 230%. Green light reduced all photosynthetic indexes of the grape plantlet. Photosynthetic photon flux density (PPFD)/Ci-Pn curves indicated that blue light affected photosynthetic rate depending on the light intensity and CO 2 concentration. RNA-seq analysis of different organs (leaf, stem, and root) revealed a systematic transcriptome remodeling and VvCOP1 (CONSTITUTIVELY PHOTOMORPHOGENIC 1), VvHY5 (ELONGATED HYPOCOTYL5), VvHYH (HY5 HOMOLOG ) , VvELIP (early light-induced protein) and VvPIF3 (PHYTOCHROME INTERACTING FACTOR 3) may play important roles in this shoot-to-root signaling. Furthermore, the correlation network between differential expression genes and physiological traits indicated that VvpsbS (photosystem II subunit S), Vvpsb28 (photosystem II subunit 28), VvHYH , VvSUS4 (sucrose synthase 4), and VvALDA (fructose-bisphosphate aldolase) were pertinent candidate genes in responses to different light qualities. Our results provide a foundation for optimizing the light recipe of grape plantlets and strengthen the understanding of light signaling and carbon metabolism under different monochromatic lights., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

A tandem diolefination reaction of benzaldehyde has been developed via Pd-catalyzed β-C(sp 2 )-H olefination of the benzene ring and tandem C(sp 2 )-H olefination of acrylate. 2-((Aminooxy)methyl)benzonitrile was involved with the benzaldehyde substrate as a remote directing group to realize the C-H bond activation. The control experiments proved that the presence of a remote cyano group is essential for this novel diolefination reaction.

Mastitis is an inflammatory disease caused by microbial infection. Chlorogenic acid (CGA), one of the major phenolic acids in Taraxacum officinale, has natural antioxidant and anti-inflammatory properties in various cell types; however, the effects of CGA on Lipoteichoic acid (LTA)-induced bovine mammary epithelial cells (BMECs) have not been investigated. In this study, the CGA content in T. officinale was determined by High-performance liquid chromatography (HPLC). BMECs were infected with LTA to induce the mastitis model. Different concentrations of CGA were administered after establishing the LTA infection. The results showed that the T. officinale contained CGA 1.36 mg/g. CGA significantly reduced the pro-inflammatory gene and protein expression of TNF-α, IL-6, and IL-1β. In addition, CGA downregulated the NO, TLR2, and NF-κB signaling pathways in LTA-infected bovine mammary epithelial cells. Our results indicate that CGA reduced the expression of TNF-α, IL-6, IL-1β, and TLR2 by inhibiting the phosphorylation of proteins in the NF-κB signaling pathways in a dose-dependent manner. This finding suggests that CGA may be a potential agent for the treatment of mastitis in dairy cows., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Xu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical benefit in cancer immunotherapy and are rapidly transforming the practice of advanced lung cancer. However, resistance routinely develops in patients treated with ICIs. We conducted this retrospective study to provide an overview on clinical characteristics of ICI resistance, optimal treatment beyond disease progression after prior exposure to immunotherapy, as well as potential prognostic factors of such resistance., Methods: 190 patients diagnosed with unresectable lung cancer who received at least one administration of an anti-programmed cell death 1 (PD-1)/anti-programmed cell death-ligand 1(PD-L1) at any treatment line at Zhongshan Hospital Fudan University between Sep 2017 and December 2019 were enrolled in our study. Overall survival (OS) and progression-free survival (PFS) were analyzed. Levels of plasma cytokines were evaluated for the prognostic value of ICI resistance., Results: We found that EGFR/ALK/ROS1 mutation and receiving ICI treatment as second-line therapy were risk factors associated with ICI resistance. Patients with bone metastasis at baseline had a significantly shorter PFS1 time when receiving initial ICI treatment. Whether or not patients with oligo-progression received local treatment seemed to have no significant effect on PFS2 time. Systemic therapies including chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. TNF, IL-6 and IL-8 were significantly elevated when ICI resistance. Lower plasma TNF level and higher plasma IL-8 level seemed to be significantly associated with ICI resistance. A nomogram was established to prognosis the clinical outcome of patients treated with ICIs., Conclusion: Patients with EGFR/ALK/ROS1 mutation, or those receiving ICI treatment as second-line therapy had higher risk of ICI resistance. Patients with bone metastasis had poor prognosis during immunotherapy. For those patients with oligo-progression after ICI resistance, combination with local treatment did not lead to a significantly longer PFS2 time. Chemotherapy and anti-angiogenic therapy rather than continued immunotherapy beyond ICI resistance had significant effect on PFS2 time. Levels of plasma cytokines including TNF, IL-6 and IL-8 were associated with ICI resistance., 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 © 2023 Zhou, Lu, Zhu, Ding, Zhang, Xu, Gao, Zhou, Song and Hu.)

Targeted therapy is an essential treatment for non-small cell lung cancer (NSCLC) that is always associated with the drug resistance. c-ros oncogene 1 (ROS1) gene point mutation is one of the leading factors causing drug resistance. However, the point mutation cell models of crizotinib are challenging to obtain, causing few reports on the drug resistance mechanism and the treatment strategy. We constructed CD74-ROS1 D2033N and CD74-ROS1 S1986F point mutant plasmids by fusion PCR technology and transfected them into A549 cells. Western blot and MTT assay proved that the drug-resistant cell lines were successfully transfected. The transwell assay confirmed that the mutant cells' motor abilities were significantly increased compared with the wild-type group. In addition, focal adhesion kinase (FAK) was significantly increased in mutant cells. Moreover, crizotinib resistance occurred in the mutant cells through the activation of FAK / phosphatidylinositol 3-kinase (PI3K) / protein kinase B (AKT) pathway. Next, crizotinib was combined with defactinib, a FAK inhibitor, to further explore its therapeutic effect. The results showed that the combination could significantly inhibit the proliferation, invasion and migration of mutant cells. In conclusion, we proved that CD74-ROS1 D2033N and CD74-ROS1 S1986F point mutant NSCLC cells were resistant to crizotinib through the activation of FAK/PI3K/AKT signaling pathway, and inhibiting FAK/PI3K/AKT signaling pathway activation by defactinib could overcome drug resistance in mutant cells., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

This study aims to investigate the effects of 1,25-dihydroxyvitamin D3 (1,25(OH) 2 VitD 3 ) on osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and the activity of hPDLSC sheets and the differences in the tissue regeneration activity of hPDLSC sheets on tooth root fragment treated by different methods. Healthy caries-free premolars were collected. The hPDLSCs were obtained by enzymatic digestion. Surface markers of stem cells were analyzed by flow cytometry and the multidirectional differentiation ability of hPDLSCs was detected. During the osteogenic differentiation of hPDLSCs, 1,25(OH) 2 VitD 3 was added and the effect of 1,25(OH) 2 VitD 3 on osteogenic differentiation of hPDLSCs was assessed using Western blotting, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay, cell staining, and immunofluorescence. After hPDLSC sheets were prepared, histology and immunofluorescence analysis of the effect of 1,25(OH) 2 VitD 3 on sheet activity were performed. In addition, root fragments were prepared and treated with scaling, 24% EDTA (ethylenediamide tetraacetic acid), and Er,Cr:YSGG lasers, respectively, and the tissue regeneration activity of hPDLSC sheets on different root fragments were observed. 1,25(OH) 2 VitD 3 promoted the high gene and protein expressions of osteogenic markers ALP (alkaline phosphatase), Runx2, and OPN (osteopontin antibody) in hPDLSCs, along with enhanced ALP activity and staining, alizarin red staining, and immunofluorescence staining, indicating that the osteogenic differentiation ability of hPDLSCs was improved. Extracellular matrix secretion was increased in hPDLSC sheets, along with the positive expressions of the protein markers fibronectin and collagen I, suggesting that 1,25(OH) 2 VitD 3 could enhance these effects. In addition, the root fragments treated by Er,Cr:YSGG laser were more suitable for the attachment and regeneration of hPDLSC sheets, demonstrating that 1,25(OH) 2 VitD 3 could improve the tissue regeneration performance of these sheets. 1,25(OH) 2 VitD 3 can promote osteogenic differentiation of hPDLSCs and thus plays an active role in hPDLSC sheet formation and tissue regeneration. In addition, the Er,Cr:YSGG laser can be used as the recommended treatment method for the root surface regenerated by hPDLSCs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The Dark Triad has been found to be associated with malevolent creativity (MC) in terms of trait level, and its underlying mechanism remains unclear. Based on the cognitive-affective processing system theory and the existing studies, the current study aimed to explore the internal mechanism between the Dark Triad and MC behavioral tendencies/performance. The results revealed that the Dark Triad is positively related to MC behavioral tendencies through trait aggression and general creativity behavioral tendencies. Regarding MC performance, the Dark Triad is positively related to the originality of malevolent ideas through MC behavioral tendencies, but this effect is only significant at low-to-medium levels of moral identity. In line with moral identity theory, a higher moral identity may prevent individuals from acting immorally due to their desire to maintain their moral image, which may further suppress malevolent idea generation. Therefore, cultivating moral identity may be an effective approach to weaken the Dark Triad-MC performance association.

Histone deacetylase (HDAC)-targeted probes and prodrugs are crucial for cancer theranostics. We developed a self-immolative design that enables in vivo activatable near-infrared fluorescence (NIRF) and photoacoustic (PA) imaging and prodrug release in response to HDAC. This design comprises a phenyl ester linker with tunable reactivity, facilitating efficient release of caged fluorophores/drugs upon deacetylation. We engineered a new fluorophore using a spirocyclic xanthene scaffold with ring-open property, affording NIRF/PA detection with high contrast. We showed that a nitro-substituted self-immolative linker allows sensitive NIRF/PA in vivo imaging of HDAC with minimal interference. A highly efficient prodrug system was further developed for targeted therapy in HDAC-overexpressed triple negative breast tumors in mice. Our study provides a valuable paradigm for HDAC-targeted NIRF/PA imaging and prodrug release in vivo, highlighting its potential for bioimaging and drug development., (© 2022 Wiley-VCH GmbH.)

A metal-free visible-light-driven cascade cyclization reaction to synthesize 3-methyl-3-acetophenone-2-oxindoles and 3-methyl-3-(methylsulfonyl)benzene-2-oxindoles in yields up to 96% and 99%, via benzoyl and phenylsulfinyl radicals with acrylamide derivatives is reported, respectively. Extensive studies, including gram-scale, radical capture and isotope experiments, were performed to indicate that the reaction may involve a radical process.

A novel route has been described for C-H borylation and hydroxylation of benzenethiols directed by adamantane-1-carbonyl using BBr 3 . The protocol generates corresponding arylboronic esters and phenols in moderate to excellent yields under metal-free conditions. In addition, the borylated product can be transformed and the directing group can be removed in good yields, which will facilitate the synthesis of structurally diverse benzenethiols.

Scorpion peptides have good therapeutic effect on chronic ulcer of diabetic foot, but the related pharmacological mechanism has remained unclear. The different proteins and bacteria present in ulcer exudates from chronic diabetic foot patients, treated with scorpion antimicrobial peptide at different stages, were analyzed using isobaric tags for quantification-labeled proteomics and bacteriological methods. According to the mass spectrometry data, a total of 1865 proteins were identified qualitatively, and the number of the different proteins was 130 (mid/early), 401 (late/early), and 310 (mid, late/early). In addition, functional annotation, cluster analysis of effects and the analysis of signal pathway, transcription regulation, and protein-protein interaction network were carried out. The results showed that the biochemical changes of wound microenvironment during the treatment involved activated biological functions such as protein synthesis, cell proliferation, differentiation, migration, movement, and survival. Inhibited biological functions such as cell death, inflammatory response, immune diseases, and bacterial growth were also involved. Bacteriological analysis showed that Burkholderia cepacia was the main bacteria in the early and middle stage of ulcer exudate and Staphylococcus epidermidis in the late stage. This study provides basic data for further elucidation of the molecular mechanism of diabetic foot., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Zhixiang Tan et al.)

Palladium-catalyzed sequential C(sp 3 )-H and C(sp 2 )-H bond diolefination reaction of o -toluidine has been realized for the first time using acetyl-protected aminoethyl phenyl thioether ligands. This novel reaction allows for preparation of the conjugated diene structure via an immediate second olefination on the basis of the first C(sp 3 )-H olefination in one pot. Various triflyl-protected anilines and acrylates were used as coupling partners elegantly. Furthermore, the unpurified diolefination products can be easily converted to tetrahydroquinoline derivatives.

Growing evidence highlights that glycolysis and tumor-derived lactate could skew tumor-associated macrophages (TAMs) toward an immunosuppressive phenotype. However, the updated research has not been systematically summarized yet. TAMs are educated by the tumor microenvironment (TME) and exert immunosuppressive functions and tumorigenic effects via multiple biological processes. It is well known that lactate generated by aerobic glycolysis is significantly accumulated in TME and promotes tumor progression in solid tumors. Moreover, some recent research demonstrated that glycolysis is activated in TAMs to support M2-like polarization, which is absolutely in contrast with the metabolic profile of M2 macrophages in inflammation. Notably, lactate produced by high levels of glycolysis is not only a metabolic by-product but also an oncometabolite. TAMs could access the biological information delivered by lactate and further enhance protumor functions such as immunosuppression and angiogenesis. Here, we outline the connection between glycolysis and TAM phenotype to elucidate the metabolic characteristics of TAMs. Further, insights into the specific molecular mechanisms of lactate-induced TAM polarization and potential therapeutic targets are summarized. We sought to discuss the reciprocal interaction between tumor cells and TAMs mediated by lactate, which will lay a foundation for the research aiming to elucidate the complex functions of TAMs., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A practical method for the deoxygenation of α-hydroxyl carbonyl compounds under mild reaction conditions is reported here. The use of cheap and easy-to-handle Na 2 S·9H 2 O as the reductant in the presence of PPh 3 and N -chlorosuccinimide (NCS) enables the selective dehydroxylation of α-hydroxyl carbonyl compounds, including ketones, esters, amides, imides and nitrile groups. The synthetic utility is demonstrated by the late-stage deoxygenation of bioactive molecule and complex natural products.

Knowing the molecular mechanism of male sterility in alfalfa is important to utilize the heterosis more effectively. However, the molecular mechanisms of male sterility in alfalfa are still unclear. In this study, the bulked segregant analysis (BSA) and bulked segregant RNA-seq (BSR) were performed with F2 separation progeny to study the molecular mechanism of male sterility in alfalfa. The BSA-seq analysis was located in a candidate region on chromosome 5 containing 626 candidate genes which were associated with male sterility in alfalfa, while the BSR-seq analysis filtered seven candidate DEGs related to male sterility, and these candidate genes including EF-Tu , β-GAL , CESA , PHGDH , and JMT . The conjunctive analyses of BSR and BSA methods revealed that the genes of Msβ-GAL and MsJMT are the common detected candidate genes involved in male sterility in alfalfa. Our research provides a theory basis for further study of the molecular mechanism of male sterility in alfalfa and significant information for the genetic breeding of Medicago sativa .

A novel route has been reported for C-H hydroxylation of benzyl compounds directed by a 3,4,5-tribromopyrazole auxiliary via boronation/oxidation using BBr 3 and NaBO 3 ·4H 2 O. The strategy exhibits outstanding site selectivity and affords the corresponding phenols in moderate to excellent yields under metal-free conditions. Besides, this protocol can be achieved in one pot, which is highly promising as a practical method for use in a multistep organic synthetic process.

Listeria monocytogenes is a major foodborne pathogen that can cause listeriosis in humans and animals. Andrographolide is known as a natural antibiotic and exhibits good antibacterial activity. We aimed to investigate the effect of andrographolide on two quorum-sensing (QS) systems, LuxS/AI-2 and Agr/AIP of L. monocytogenes , as well as QS-controlled phenotypes in this study. Our results showed that neither luxS expression nor AI-2 production was affected by andrographolide. Nevertheless, andrographolide significantly reduced the expression levels of the agr genes and the activity of the agr promoter P 2 . Results from the crystal violet staining method, confocal laser scanning microscopy (CLSM), and field emission scanning electron microscopy (FE-SEM) demonstrated that andrographolide remarkably inhibited the biofilm-forming ability of L. monocytogenes 10403S. The preformed biofilms were eradicated when exposed to andrographolide, and reduced surviving cells were also observed in treated biofilms. L. monocytogenes treated with andrographolide exhibited decreased ability to secrete LLO and adhere to and invade Caco-2 cells. Therefore, andrographolide is a potential QS inhibitor by targeting the Agr QS system to reduce biofilm formation and virulence of L. monocytogenes .

Atrial fibrillation (AF) is a common arrhythmia affecting 8-10% of the population older than 80 years old. The importance of early diagnosis of atrial fibrillation has been broadly recognized since arrhythmias significantly increase the risk of stroke, heart failure and tachycardia-induced cardiomyopathy with reduced cardiac function. However, the prevalence of atrial fibrillation is often underestimated due to the high frequency of clinically silent atrial fibrillation as well as paroxysmal atrial fibrillation, both of which are hard to catch by routine physical examination or 12-lead electrocardiogram (ECG). The development of wearable devices has provided a reliable way for healthcare providers to uncover undiagnosed atrial fibrillation in the population, especially those most at risk. Furthermore, with the advancement of artificial intelligence and machine learning, the technology is now able to utilize the database in assisting detection of arrhythmias from the data collected by the devices. In this review study, we compare the different wearable devices available on the market and review the current advancement in artificial intelligence in diagnosing atrial fibrillation. We believe that with the aid of the progressive development of technologies, the diagnosis of atrial fibrillation shall be made more effectively and accurately in the near future.

Objective: We aimed to evaluate the clinical characteristics and long-term prognosis of brain arteriovenous malformations (bAVMs) treated with multimodality management of one-staged hybrid operation., Methods: We identified bAVM patients treated with one-staged hybrid operation from a multicenter prospective cohort study (NCT03774017) between January 2016 and June 2020. Patients were divided into unruptured and ruptured groups by the hemorrhagic presentation. Long-term (>12 months) neurological disability, postoperative complications of stroke, and nidus obliteration were evaluated and compared between groups. Prognostic predictors associated with outcomes were analyzed., Results: A total of 130 patients were identified in the study receiving one-staged hybrid operations, including 61 unruptured cases and 69 ruptured cases. Mean age was 29.1 years old, with 78 (60.0%) being male. Patients included in the study were followed up for a mean period of 37.4 (11.07) months. The annual hemorrhagic risk was 4.2% per year. Thirteen postoperative stroke events were detected in 11 patients (8.5%). Long-term disability occurred in 6.9% of cases, and 86.2% of patients experienced an unchanged or improved neurological status at the last follow-up. All patients achieved complete obliteration on follow-up angiographies. Increased AVM volume was associated with a higher risk of postoperative stroke (odds ratio (OR) 1.021, 95% confidence interval (CI) 1.006-1.037, and P = 0.006). Poor neurological status (OR 6.461, 95% CI 1.309-31.889, and P = 0.022) and infratentorial location (OR 5.618, 95% CI 1.158-27.246, and P = 0.032) were independent predictors for long-term disability., Conclusions: One-staged hybrid operation of embolization combined microsurgical resection can be performed as a safe and effective strategy for bAVM treatments. Long-term prognosis of complete obliteration with low rates of morbidity and mortality can be achieved. Unruptured and ruptured bAVMs acquired similar favorable outcomes after the multimodality treatment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yuanfeng Jiang et al.)

Background: Immune checkpoint inhibitors (ICIs) have led to dramatic improvements in survival a subset of patients with non-small cell lung cancer (NSCLC); however, they have been shown to cause life-threatening toxicity such as immune checkpoint inhibitor-related pneumonitis (CIP). Our previous studies have shown that chronic obstructive pulmonary disease (COPD) and circulating cytokines are associated with clinical outcomes in NSCLC patients receiving ICIs. However, the relationship between these factors and the development of CIP is unclear. In this study, we retrospectively assessed NSCLC patients receiving ICIs to identify CIP risk factors., Methods: This retrospective cohort study reviewed medical records of NSCLC patients receiving ICIs targeting programmed cell death 1 (PD-1) or its ligand PD-L1 between March 2017 and December 2020 at Zhongshan Hospital Fudan University. CIP was diagnosed by the treating investigator. Clinical characteristics and baseline plasma cytokines were collected. Logistic regression was used to compare clinical characteristics and circulating cytokine levels between patients with and without CIP to identify CIP risk factors., Results: Of 164 NSCLC patients who received ICIs, CIP developed in 20 cases (12.2%). The presence of COPD [odds ratio (OR), 7.194; 95% confidence interval (CI): 1.130 to 45.798; P=0.037] and PD-L1 expression of ≥50% (OR, 7.184; 95% CI: 1.154 to 44.721; P=0.035) were independently associated with a higher incidence of CIP, whereas a higher baseline level of interleukin-8 (IL-8) was associated with a lower incidence of CIP (OR, 0.758; 95% CI: 0.587 to 0.978; P=0.033). The independent risk factors from final multivariate analysis were incorporated into a nomogram to predict the incidence of CIP. The nomogram model receiver operating characteristic (ROC) curve had a good predictive accuracy of 0.883 (95% CI: 0.806 to 0.959)., Conclusions: Increased risk of CIP independently associated with history of COPD, tumor PD-L1 expression ≥50%, and low baseline IL-8 level. The nomogram may hold promise for CIP risk assessment in the administration of ICIs., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-72/coif). Dr. ZZ has received consulting fees from AstraZeneca. Dr. JWN received Research Funding from Companies Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen and AbbVie; Consulting or Advisory Role from Companies AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology and Turning Point Therapeutics; Honoraria from Companies CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME and MJH Life Sciences CME. The other authors have no conflicts of interest to declare., (2022 Translational Lung Cancer Research. All rights reserved.)

Background: This study aims to evaluate the biomechanical stability of a novel lateral plate (NLP) that can be used in oblique lateral lumbar fusion (OLIF)., Methods: In vitro biomechanical tests were performed on 6 fresh calf lumbar vertebrae specimens. The surgical segment was set at L3-L4. Each specimen was tested in the following order: intact state (INT); OLIF cage only/stand-alone (SA); cage supplemented with lateral screw-rod (LSR); cage supplemented with novel lateral plate (NLP); and cage supplemented with unilateral or bilateral pedicle screw-rod (UPS or BPS). A pure moment of ±7.5 Nm was applied to the specimen to produce 6 different motion directions, including flexion and extension, lateral bending, and axial rotation, and the range of motion (ROM) of L3-L4 in each direction was recorded., Results: In addition to flexion-extension, NLP reduced the ROM of SA (P < 0.05). In flexion-extension, the ROM of NLP was similar to those of SA and LSR (P > 0.05); compared to pedicle screw-rod (PSD), the ROM of NLP was higher (P < 0.05). In lateral bending, the ROM of NLP was close to that of LSR and PSD (P > 0.05). In axial rotation, the ROM of NLP was higher than that of PSD (P < 0.05), and close to that of LSR (P > 0.05)., Conclusions: NLP can enhance surgical segment stability in all directions of motion, similar to LSR, but weaker than UPS and BPS in flexion-extension and rotation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

A novel ligand propan-2-one O -( p -tolylcarbamoyl) oxime ( L7 ) has been developed to promote C(sp 2 )-H olefination of benzoic acids and phenylacetic acids via a palladium catalyst. With the subsequent lactonization of the olefinated products through 1,4-addition, highly monoselective cyclic lactone products of benzofuranones and benzopyrones were obtained in moderate to excellent yields. The DFT calculation demonstrated that the novel ligand propan-2-one O -( p -tolylcarbamoyl) oxime ( L7 ) could improve the C-H activation reaction to give cyclic lactone products elegantly.

A highly efficient Rh(III)-catalyzed cascade C-H activation/annulation of sulfoximines with iodonium ylides under metal-oxidant-free conditions has been reported. The fused cyclohexanone-1,2-benzothiazine scaffold is readily achieved with a one-pot process in this reaction. This protocol exhibits good functional group tolerance and moderate to excellent yields. Additionally, the olefination of the target product illustrates the promising usefulness of this strategy.

N719 dye ( cis -[Ru(4-carboxy-4'-carboxylate-2,2'-bipyridine) 2 (NCS) 2 ]) contains two carboxylic acid/carboxylate groups and two isothiocyanato (NCS) ligands and exhibit different spatial adsorption orientations during adsorption on different substrate surfaces. However, the effect of spatially adsorption orientations on the adsorption process has been rarely reported. This paper presents a detailed study of the adsorption kinetics and thermodynamics of N719 molecules based on a quartz crystal microbalance under variable temperature conditions using TiO 2 or Au substrate surfaces to induce changes in the geometrical orientation molecules. This work also reveals the adsorption properties of carboxylate groups and NCS ligands acting as anchoring groups. Research results have shown that the surface N719 molecular density of the TiO 2 substrate is higher than that of the Au substrate. Adsorption kinetics have shown that the adsorption rate of N719 molecules on the Au substrate surface with NCS ligands as anchor groups is slightly higher than that of carboxylate as the anchor groups on the TiO 2 substrate surface, and in the case of the former adsorption mode, the desorption is more pronounced. Under two different spatial orientation adsorption modes, both exhibit physical adsorption. The thermodynamics of molecular adsorption with different spatial orientations show that all adsorption processes are spontaneous and endothermic. This work is beneficial for understanding the mechanism of adsorption of dye molecules, dye molecule synthesis method, ligand selection, and improvement of device efficiency.

The promotion of information flow reinforces the interactive cooperation and evolutionary process among cities. In the information age, public online search is a typical behavior of Internet society, which is the key to information flow generation and agglomeration. In this study, we attempt to explore the evolutionary characteristics of intercity networks driven by public online social behavior in the information age and construct an information flow network (IFN) from the perspective of public search attention. We also explore the evolution of the IFN in terms of the whole network, node hierarchy, and subgroup aggregation. Meanwhile, we also discuss the impact of the sustainable driving factors on the IFN. Finally, an empirical study was conducted in Guanzhong Plain Urban Agglomeration (GPUA). Our results show that: (1) the information flow in GPUA fluctuating upward in the early study period and gradually decreasing in the later study period. However, the agglomeration degree of information flow in the urban agglomeration continues to increase. (2) The hierarchical structure of urban nodes in GPUA presents a trend of "high in the middle and low on both sides", and the formation of subgroups is closely related to geographic location. (3) The driving factors all impacting the IFN include public ecology, resource investment, information infrastructure, and economic foundation. This study provides theoretical and practical support for exploring the intercity network and promotes the sustainable urban development.

Positive allosteric modulators (PAMs) of human metabotropic glutamate receptor 2 (hmGlu 2 ) are well-known in the treatment of psychiatric disorders for their higher selectivity and lower tolerance risk. A variety of PAMs have been reported over the last decade and two compounds were in Phase II clinical trials for schizophrenia and anxiety. These trials were discontinued on account of the unsatisfactory therapeutic efficacy, but PAMs were explored as novel treatments for addiction and epilepsy. Thus, it is still important to explore novel hmGlu 2 PAMs in the near future. Nowadays, the challenges in optimizing drug potency and improving scaffold diversity for PAMs are the noncomprehensive character analyses of multiple scaffolds; the exploration of the binding modes of PAMs in the allosteric binding site have been proposed to reduce this difficulty. However, there has been no comprehensive research about the binding profiles of PAMs in the hmGlu 2 receptor. To address this issue, this work explores the binding characters of eight PAMs representing five chemical series by multiple computational methods. As a result, the shared binding modes of the eight studied PAMs interacting with 15 residues in the allosteric binding site were defined. In addition, the reduced hydrophobicity with low electronegativity of R 1 , increased hydrophobicity with low negative electron density of R 2 and the electronegativity of the linker were identified as indicators that regulate the affinity of PAMs. This finding agrees well with the physicochemical properties of reported multiple series PAMs. This comprehensive work sheds additional light on the binding mechanism and physicochemical regularity underlining PAMs affinity and could be further utilized as a structural and energetic blueprint for discovering and assessing novel PAMs for hmGlu 2 .

A practical and mild method for the switchable synthesis of sulfoxides or sulfones via selective oxidation of sulfides using cheap N -fluorobenzenesulfonimide (NFSI) as the oxidant has been developed. These highly chemoselective transformations were simply achieved by varying the NFSI loading with H 2 O as the green solvent and oxygen source without any additives. The good functional group tolerance makes the strategy valuable.

It is widely documented that students with lower family socioeconomic status (SES) tend to have higher test anxiety than their peers from higher SES families. However, few studies have empirically examined the underlying mechanism whereby family SES shapes students' test anxiety. To bridge this gap, the present study proposed and tested a serial mediation model in which family SES is associated with students' test anxiety through the indirect effect of parental psychological control, access to learning resources, and academic self-efficacy. The sample comprised 354 Chinese high school students (134 boys; mean age = 16.15 years old). The results were as follows: (1) higher family SES was associated with increased access to learning resources, higher academic self-efficacy, lower parental psychological control, and lower test anxiety. In contrast, test anxiety was associated with decreased access to learning resources, lower academic self-efficacy, and higher parental psychological control; and (2) the mediation model indicated parental psychological control, learning resources, and academic self-efficacy functioned as serial mediators in the relationship between family SES and students' test anxiety (i.e., family SES → psychological control and learning resources → academic self-efficacy → test anxiety). The findings are discussed in the framework of the family stress/investment models and social cognitive theory. Concrete suggestions for how low SES parents can help decrease their children's test anxiety are provided., (© 2021 Scandinavian Psychological Associations and John Wiley & Sons Ltd.)

Escherichia coli can survive improper disinfection processes, which is a potential source of contamination of food products. Benzalkonium chloride (BC) is a common disinfectant widely used in food industry. Bacterial quorum sensing (QS) plays a major role in food spoilage, biofilm formation and food-related pathogenesis. Understanding QS can help to control the growth of undesirable food-related bacteria. The LuxS/AI-2 QS system of E. coli has been confirmed to regulate many important phenotypes including biofilm formation and motility. In the current study, we aimed to investigate the effect of sublethal concentrations of BC on the LuxS/AI-2 system of E. coli isolates from retail meat samples, as well as bacterial biofilm formation and motility. Our results showed that sublethal concentrations of BC promoted AI-2 production in four test E. coli isolates. The results from microplate assay and confocal laser scanning microscopy (CLSM) analysis indicated that sublethal concentrations of BC enhanced biofilm formation of E. coli. When treated with sublethal concentrations of BC, exopolysaccharides (EPS) production during biofilm development increased significantly and swimming motility of tested isolates was also promoted. The expression levels of luxS, biofilm-associated genes and flagellar motility genes were increased by BC at sublethal concentrations. Our findings underline the importance of proper use of the disinfectant BC in food processing environments to control food contamination by E. coli., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Lead (Pb) is a serious heavy metal soil pollutant. It can be absorbed and accumulated by plant roots and impact plant growth. Medicago sativa L. (alfalfa) is a low-input forage and potential bioenergy crop, and improving its yield and quality has always been a focus of the alfalfa breeding industry. Little is known about the mechanism by which alfalfa responds to Pb stress at the molecular level. In this study, three alfalfa genotypes (a lead-resistant type (LR), a lead-sensitive type (LS) and an intermediate type (IN)) with contrasting abilities to resist lead were exposed to different durations of Pb treatment. Next-generation sequencing (NGS)-based RNA-seq technology was employed to characterize the root transcriptomes of three genotypes of alfalfa and identify differentially expressed genes (DEGs) during Pb stress. Genotypes LR and LS displayed different mechanisms of tolerance. In LR, the accumulation of more resistant substances was induced by the upregulation of sucrose synthase, glucan endo-1,3-beta-glucosidase, beta-amylase 3, probable trehalose-phosphate phosphatase J, 6-phosphofructo-2-kinase delta-1-pyrroline-5-carboxylate synthase (P5CS) and δ-ornithine aminotransferase (δ-OAT). In addition, flavin monooxygenase (YUCCA), 4-coumarate:CoA ligase-like protein (4CL), cinnamoyl-CoA reductase-like protein (CCR), ferulate 5-hydroxylase (F5H) and caffeic acid O-methyltransferase (COMT) were upregulated, leading to root development in a short time under Pb stress. Further study of the expression levels of metal transport-related genes, such as NRAMP (metal transporter), MATE (multidrug and toxin extrusion), HIPPs (heavy metal-associated isoprenylated plant proteins), MTP (metal tolerance protein), and ABC transporter, suggested that these genes were differentially expressed after lead treatment in the three alfalfa genotypes. Our research provides useful information for further studies on the molecular mechanism of Pb resistance in Medicago sativa L., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (MTB), has similar clinical, radiological, and histopathological characteristics to sarcoidosis (SA). Accurately distinguishing SA from TB remains a clinical challenge., Methods: A total of 44 TB patients and 47 SA patients who were clinically diagnosed using chest radiography, pathological examination, routine smear microscopy, and microbial culture were enrolled in this study. The MTB genome was captured and sequenced directly from tissue specimens obtained upon operation or biopsy, and the feasibility of next-generation sequencing (NGS) for the MTB genome in the differential diagnosis of TB from SA was evaluated., Results: Using a depth >10× and coverage >15% of the sequencing data, TB patients were identified via the NGS approach directly using operation or biopsy specimens without clinical pretreatment. The sensitivity, specificity, and concordance of the NGS method were 81.8% (36/44), 95.7% (45/47), and 89.0% (81/91), respectively (kappa = 0.78, 95% confidence interval 0.65-0.91; P<0.001)., Conclusions: This study established an improved NGS strategy for rapidly distinguishing patients with TB from those with SA and has potential clinical benefits., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cardiac amyloidosis is caused by the deposition of misfolded protein fibrils into the extracellular space of the heart. The diagnosis of cardiac amyloidosis remains challenging because of the heterogeneous manifestations of the disease. There are many different types of amyloidosis with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis being the most common types of cardiac amyloidosis. Endomyocardial biopsy is considered the gold standard for diagnosing cardiac amyloidosis and differentiating amyloid subtypes, but its use is limited because of the invasive nature of the procedure, with risks for complications and the need for specialized training and centers to perform the procedure. Radionuclide cardiac imaging has recently become the most commonly performed test for the diagnosis of ATTR amyloidosis but is of limited value for the diagnosis of AL amyloidosis. Positron emission tomography has been increasingly used for the diagnosis of cardiac amyloidosis and its applications are expected to expand in the future. Imaging protocols are under refinement to achieve better quantification of the disease burden and prediction of prognosis.

The direct arylation of aliphatic ketones has been developed via Pd-catalyzed β-C(sp 3 )-H bond functionalization with 2-(aminooxy)- N , N -dimethylacetamide as a novel transient directing group (TDG), which showed remarkable directing ability to generate arylated products in moderate to good yields. Furthermore, the reaction can tolerate abundant substrate of ketones and aryl iodides. This study expands the scope of applications for TDGs.

Background: Hydroxychloroquine or chloroquine with or without the concomitant use of azithromycin have been widely used to treat patients with SARS-CoV-2 infection, based on early in vitro studies, despite their potential to prolong the QTc interval of patients., Objective: This is a systematic review and metanalysis designed to assess the effect of hydroxychloroquine with or without the addition of azithromycin on the QTc of hospitalized patients with COVID-19., Materials and Methods: PubMed, Scopus, Cochrane and MedRxiv databases were reviewed. A random effect model meta-analysis was used, and I-square was used to assess the heterogeneity. The prespecified endpoints were ΔQTc, QTc prolongation > 500 ms and ΔQTc > 60 ms., Results: A total of 18 studies and 7179 patients met the inclusion criteria and were included in this systematic review and meta-analysis. The use of hydroxychloroquine with or without the addition of azithromycin was associated with increased QTc when used as part of the management of patients with SARS-CoV-2 infection. The combination therapy with hydroxychloroquine plus azithromycin was also associated with statistically significant increases in QTc. Moreover, the use of hydroxychloroquine alone, azithromycin alone, or the combination of the two was associated with increased numbers of patients that developed QTc prolongation > 500 ms., Conclusion: This systematic review and metanalysis revealed that the use of hydroxychloroquine alone or in conjunction with azithromycin was linked to an increase in the QTc interval of hospitalized patients with SARS-CoV-2 infection that received these agents.