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Kir5.1 encoded by Kcnj16 is an inwardly-rectifying K + channel-subunit and it possibly interacts with Kir4.2-subunit encoded by Kcnj15 for assembling a Kir4.2/Kir5.1 heterotetramer in the basolateral membrane of mouse proximal-tubule. We now used patch-clamp-technique to examine basolateral K + -channels of mouse proximal tubule and immunoblotting/immunofluorescence-staining-microscope (IF) to examine Kir4.2 expression in wild-type and Kir5.1-knockout mice. IF staining shows that Kir4.2 was exclusively expressed in the proximal tubule while Kir5.1 was expressed in the proximal tubule and distal nephrons including distal-convoluted-tubule. Immunoblotting showed that the expression of Kir4.2-monomer was lower in Kir5.1-knockout mice than the wild-type mice. In contrast, Kir4.1-monomer expression was increased in Kir5.1-knockout mice. IF images further demonstrated that the basolateral membrane staining of Kir4.2 was significantly decreased in Kir5.1-knockout mice. This is in sharp contrast to Kir4.1, which also interacts with Kir5.1 in the distal nephron, and IF images show that Kir4.1 membrane expression was still visible and unchanged in Kir5.1-knockout mice. The single channel recording detected a 50-pS inwardly-rectifying K + channel, presumably a Kir4.2/Kir5.1 heterotetramer, in the basolateral membrane of proximal-tubule of Kir5.1-wild-type mice. However, this 50-pS K + channel was completely absent in the basolateral membrane of the proximal tubule of Kir5.1-knockout mice. Moreover, the membrane potential of proximal tubule was less negative in Kir5.1-knockout mice than wild-type mice. We conclude that Kir5.1 is essential for assembling basolateral 50-pS K + channel in proximal-tubule and that deletion of Kir5.1 decreased Kir4.2 expression in the proximal tubule thereby decreasing the basolateral K + conductance and the membrane potentials.

Since 2019, the novel coronavirus (SARS-CoV-2) has caused significant morbidity and millions of deaths worldwide. The Coronavirus Disease 2019 (COVID-19), caused by SARS-CoV-2 and its variants, has further highlighted the urgent need for the development of effective therapeutic agents. Currently, the highly conserved and broad-spectrum nature of main proteases (M pro ) renders them of great importance in the field of inhibitor study. In this study, we categorize inhibitors targeting M pro into three major groups: mimetic, nonmimetic, and natural inhibitors. We then present the research progress of these inhibitors in detail, including their mechanism of action, antiviral activity, pharmacokinetic properties, animal experiments, and clinical studies. This review aims to provide valuable insights and potential avenues for the development of more effective antiviral drugs against SARS-CoV-2., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Calcineurin, protein phosphatase 2B (PP2B) or protein phosphatase 3 (PP3), is a calcium-dependent serine/threonine protein phosphatase. Calcineurin is widely expressed in the kidney and regulates renal Na + and K + transport. In the thick ascending limb, calcineurin plays a role in inhibiting NKCC2 function by promoting the dephosphorylation of the cotransporter and an intracellular sorting receptor, called sorting-related-receptor-with-A-type repeats (SORLA), is involved in modulating the effect of calcineurin on NKCC2. Calcineurin also participates in regulating thiazide-sensitive NaCl-cotransporter (NCC) in the distal convoluted tubule. The mechanisms by which calcineurin regulates NCC include directly dephosphorylation of NCC, regulating Kelch-like-3/CUL3 E3 ubiquitin-ligase complex, which is responsible for WNK (with-no-lysin-kinases) ubiquitination, and inhibiting Kir4.1/Kir5.1, which determines NCC expression/activity. Finally, calcineurin is also involved in regulating ROMK (Kir1.1) channels in the cortical collecting duct and Cyp11 2 expression in adrenal zona glomerulosa. In summary, calcineurin is involved in the regulation of NKCC2, NCC, and inwardly rectifying K + channels in the kidney, and it also plays a role in modulating aldosterone synthesis in adrenal gland, which regulates epithelial-Na + -channel expression/activity. Thus, application of calcineurin inhibitors (CNIs) is expected to abrupt calcineurin-mediated regulation of transepithelial Na + and K + transport in the kidney. Consequently, CNIs cause hypertension, compromise renal K + excretion, and induce hyperkalemia., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Angiotensin-II (Ang-II) perfusion stimulates Kir4.1/Kir5.1 in the distal-convoluted-tubule (DCT) and thiazide-sensitive Na-Cl-cotransporter (NCC). However, the role of Kir4.1/Kir5.1 in mediating the effect of Ang-II on NCC is not understood., Methods: We used immunoblotting and patch-clamp-experiments to examine whether Ang-II-induced stimulation of NCC is achieved by activation of Kir4.1/Kir5.1 of the DCT using kidney-renal-tubule-specific AT1aR-knockout (Ks-AT1aR-KO), Ks-Kir4.1-knockout and the corresponding wild-type mice., Results: Ang-II perfusion for 1, 3 and 7 days progressively increased phosphor-NCC (pNCC) and total-NCC (tNCC) expression and the effect of Ang-II-perfusion on pNCC and tNCC was abolished in Ks-AT1aR-KO. Ang-II perfusion for 1-day robustly stimulates Kir4.1/Kir5.1 in the late DCT (DCT2) and to a lesser degree in the early DCT (DCT1), an effect was absent in Ks-AT1aR-KO mice. However, Ang-II perfusion for 7-days did not further stimulate Kir4.1/Kir5.1 in the DCT2 and only modestly increased Kir4.1/Kir5.1-mediated K + currents in DCT1. Deletion of Kir4.1 not only significantly decreased the expression of pNCC and tNCC but also abolished the effect of 1-day Ang-II perfusion on the expression of phospho-with-no-lysine-kinase-4 (pWNK4), phosphor-ste-20-proline-alanine-rich-kinase (pSPAK), pNCC and tNCC. However, 7-days Ang-II perfusion was still able to significantly stimulate the expression of pSPAK, pWNK4, pNCC and tNCC, and increased thiazide-induced natriuresis in kidney-tubule-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice without obvious changes in K + channel activity in the DCT., Conclusions: Short-term Ang-II induced stimulation of pWNK4, pSPAK and pNCC depends on Kir4.1/Kir5.1 activity. However, long-term Ang-II is able to directly stimulate pWNK4, pSPAK and pNCC by a Kir4.1/Kir5.1 independent mechanism.

Background: Elymus atratus (Nevski) Hand.-Mazz. is perennial hexaploid wheatgrass. It was assigned to the genus Elymus L. sensu stricto based on morphological characters. Its genome constitution has not been disentangled yet., Objective: To identify the genome constitution and origin of E. atratus., Methods: In this study, genomic in situ hybridization and fluorescence in situ hybridization, and phylogenetic analysis based on the Acc1, DMC1 and matK sequences were performed., Results: Genomic in situ hybridization and fluorescence in situ hybridization results reveal that E. atratus 2n = 6x = 42 is composed of 14 St genome chromosomes, 14 H genome chromosomes, and 14 Y genome chromosomes including two H-Y type translocation chromosomes, suggesting that the genome formula of E. atratus is StStYYHH. The phylogenetic analysis based on Acc1 and DMC1 sequences not only shows that the Y genome originated in a separate diploid, but also suggests that Pseudoroegneria (St), Hordeum (H), and a diploid species with Y genome were the potential donors of E. atratus. Data from chloroplast DNA showed that the maternal donor of E. atratus contains the St genome., Conclusion: Elymus atratus is an allohexaploid species with StYH genome, which may have originated through the hybridization between an allotetraploid Roegneria (StY) species as the maternal donor and a diploid Hordeum (H) species as the paternal donor., (© 2024. The Author(s) under exclusive licence to The Genetics Society of Korea.)

Background: To analyse the association among the simultaneous effects of dietary intake, daily life behavioural factors, and frailty outcomes in older Chinese women, we predicted the probability of maintaining physical robustness under a combination of different variables., Methods: The Fried frailty criterion was used to determine the three groups of "frailty", "pre-frailty", and "robust", and a national epidemiological survey was performed. The three-classification decision tree model was fitted, and the comprehensive performance of the model was evaluated to predict the probability of occurrence of different outcomes., Results: Among the 1,044 participants, 15.9% were frailty and 50.29% were pre-frailty; the overall prevalence first increased and then decreased with age, reaching a peak at 70-74 years of age. Through univariate analysis, filtering, and embedded screening, eight significant variables were identified: staple food, spices, exercise (frequency, intensity, and time), work frequency, self-feeling, and family emotions. In the three-classification decision tree, the values of each evaluation index of Model 3 were relatively average; the accuracy, recall, specificity, precision, and F1 score range were between 75% and 84%, and the AUC was also greater than 0.800, indicating excellent performance and the best interpretability of the results. Model 3 takes exercise time as the root node and contains 6 variables and 10 types, suggesting the impact of the comprehensive effect of these variables on robust and non-robust populations (the predicted probability range is 6.67-93.33%)., Conclusion: The combined effect of these factors (no exercise or less than 0.5 h of exercise per day, occasional exercise, exercise at low intensity, feeling more tired at work, and eating too many staple foods (> 450 g per day) are more detrimental to maintaining robustness., (© 2024. The Author(s).)

The depolarization-activated current of intercalated cells in the distal nephron was detected for the first time, and the type of ion channel mediating the current was identified based on electrophysiological and pharmacological properties. The whole-cell current of distal nephron in kidney of C57BL/6J mice was recorded by Axon MultiClamp 700B patch-clamp system, and the effects of several K + channel inhibitors on the depolarization-activated current in intercalated cells were observed. In addition, the immunofluorescence technique was used to investigate the localization of the channel in intercalated cells. The results showed that when K + concentration of the bath solution was equal to intracellular fluid (140 mmol/L K + ), the depolarization-activated current could be recorded in intercalated cells, but this current was not observed in the principal cells. The depolarization-activated current detected in the intercalated cells could be blocked by Kv4.1 inhibitors. The immunofluorescence experiment showed that the fluorescence of Kv4.1 protein was only present in intercalated cells and not observed in principal cells. Kv4.1 protein immunofluorescence was observed in the luminal and basolateral membrane of intercalated cells, but the fluorescence intensity of luminal membrane was higher than that of basolateral membrane. We conclude that the depolarization-activated current detected in intercalated cells is mediated by Kv4.1 and this channel is mainly expressed in the luminal membrane of intercalated cells.

In order to evaluate the feasibility of using Burkholderia sp. Y4 as a cadmium （Cd）-reducing bacterial agent in contaminated wheat fields， the changes in the rhizosphere soil microbial community and Cd available state， as well as the content and transport characteristics of Cd in the wheat root， basal node， internode， and grain under the treatment of strain Y4 were tested using microbial high-throughput sequencing， step-by-step extraction， subcellular distribution， and occurrence analyses. The results showed that root application of strain Y4 significantly reduced the root and grain Cd content of wheat by 7.7% and 30.3%， respectively， compared with that in the control treatment. The Cd content and Cd transfer factor results in wheat vegetative organs showed that strain Y4 reduced the Cd transfer factor from basal node to internode by 79.3%， and Cd content in the wheat internode stem also decreased by 50.9%. The study of Cd occurrence morphology showed that strain Y4 treatment increased the proportion of residual Cd in roots and basal ganglia， decreased the contents of inorganic and water-soluble Cd in roots， and increased the content of residual Cd in basal ganglia. Further examination of the subcellular distribution of Cd showed that the Cd content in root cell walls and basal ganglia cell fluid increased by 21.3% and 98.2%， respectively， indicating that the Cd fixation ability of root cell walls and basal ganglia cell fluid was improved by the strain Y4 treatment. In the rhizosphere soil， it was found that the microbial community structure was changed by strain Y4 application. Under the Y4 treatment， the relative abundance of Burkholderia increased from 9.6% to 11.5%， whereas that of Acidobacteriota decreased. Additionally， the relative abundance of Gemmatimonadales ， Pseudomonadales ， and Chitinophagales were also increased by strain Y4 treatment. At the same time， the application of strain Y4 increased the pH value of rhizosphere soil by 8.3%. The contents of exchangeable Cd， carbonate-bound Cd， and iron-manganese oxide-bound Cd in the soil decreased by 44.4%， 21.7%， and 15.9%， respectively， whereas the proportion of residual Cd reached 53.6%. Root application of strain Y4 increased the contents of nitrate nitrogen and ammonium nitrogen in the soil by 22.0% and 21.4%， respectively， and the contents of alkaline nitrogen also increased to a certain extent. In conclusion， the root application of strain Y4 not only improved soil nitrogen availability but also inhibited Cd transport and accumulation from contaminated soil to wheat grains in a "two-stage" manner by reducing Cd availability in rhizosphere soil and improving Cd interception and fixation capacity of wheat roots and basal nodes. Therefore， Burkholderia Y4 has application potential as a Cd-reducing and growth-promoting agent in wheat.

The pathogenesis of oral squamous cell carcinoma (OSCC) remains unclear. Therefore, clarifying its pathogenesis and molecular-level development mechanism has become the focus of OSCC research. N-acetyltransferase 10 (NAT10) is a crucial enzyme involved in mRNA acetylation, regulating target gene expression and biological functions of various diseases through mediating N4-acetylcytidine (ac4C) acetylation. However, its role in OSCC progression is not well understood. In this study, we showed that NAT10 was significantly upregulated in OSCC tissues compared to normal oral tissues. Moreover, lentivirus-mediated NAT10 knockdown markedly suppressed cell proliferation, migration, and invasion in two OSCC cell lines (SCC-9 and SCC-15). Interestingly, MMP1 was found to be significantly upregulated in OSCC tissues and was a potential target of NAT10. N-acetyltransferase 10 knockdown significantly reduced both the total and ac4C acetylated levels of MMP1 mRNA and decreased its mRNA stability. Xenograft experiments further confirmed the inhibitory effect of NAT10 knockdown on the tumorigenesis and metastasis ability of OSCC cells and decreased MMP1 expression in vivo. Additionally, NAT10 knockdown impaired the proliferation, migration, and invasion abilities in OSCC cell lines in an MMP1-dependent manner. Our results suggest that NAT10 acts as an oncogene in OSCC, and targeting ac4C acetylation could be a promising therapeutic strategy for OSCC treatment., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background/purpose: With the development of computer-assisted surgery, digital guide plate was widely used in vascularized bone flap grafts for mandibular reconstruction. The purpose of this study was to design and manufacture a digital guide plate with drill-hole sharing for mandibular reconstruction and assess for surgical accuracy., Materials and Methods: 17 patients that required mandibular reconstruction using fibula free flap or iliac crest free flap were included in the study. The computed tomography (CT) data of the patient's mandible and pelvis or fibula were acquired preoperatively. A surgical simulation was then performed using computer-aided surgical simulation (CASS) technology based on above date, which allowed the design of two cutting guide and a repositioning guide for mandibular reconstruction. After surgery, the accuracy of reconstruction was evaluated by superimposing the postoperative image onto the preoperative image of mandible, recording the linear and angular deviation of landmarks, measuring the differences between the planned and actual outcomes., Results: The osteotomy and repositioning of fibula or iliac crest segments were successfully performed as planned using surgical guides. The digital guide plate with drill-hole sharing showed excellent accuracy, When the iliac crest or the fibula free flap were used for mandibular reconstruction, the largest mean differences between the preoperative and postoperative were 1.11 mm and 2.8° or 1.3 mm and 3.87°., Conclusion: The digital guide plate with drill-hole sharing designed preoperatively provides a reliable method of for the mandibular reconstruction. This can assist surgeons in accurately performing osteotomy and repositioning fibula or iliac crest segments during the mandibular reconstruction., Competing Interests: The authors have no conflicts of interest relevant to this article., (© 2023 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

We report a base-promoted cyclization with indene-dienes as two carbon building blocks toward diverse spirocyclic indene scaffolds including hexacyclic spiroindenes bearing benzo pyran motifs and pentacyclic spiroindenes containing oxindole units in high yields with excellent diastereoselectivities.

Objective: Astrocytes constitute approximately 30% of cells in gliomas and play important roles in synapse construction and survival. Recently, JAK/STAT pathway activation associated with a new type of astrocyte was reported. However, the implications of these tumor-associated reactive astrocytes (TARAs) in glioma are not known., Methods: We comprehensively assessed TARAs in gliomas, both in single cells and at the bulk tumor level, by analyzing five independent datasets. First, we analyzed two single-cell RNA sequencing datasets of 35,563 cells from 23 patients to estimate the infiltration level of TARAs in gliomas. Second, we collected clinical information and genomic and transcriptomic data of 1,379 diffuse astrocytoma and glioblastoma samples from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas datasets to evaluate the genomic, transcriptomic and clinical characteristics of TARA infiltration. Third, we downloaded expression profiles of recurrent glioblastoma samples from patients receiving PD-1 inhibitors to analyze the predictive value of TARAs for immune checkpoint inhibition., Results: Single-cell RNA sequencing data showed TARAs were abundant in the glioma micro-environment (15.7% in the CGGA dataset and 9.1% in the Gene Expression Omnibus GSE141383 dataset, respectively). Bulk tumor sequencing data showed that the extent of TARA infiltration was highly associated with major clinical and molecular features of astrocytic gliomas. Patients with more TARA infiltration were more likely to have MUC16 , FLG , and PICK3A mutations, chromosome 9p21.3, 10q23.3, and 13q14.2 deletions and 7p11.2 amplification. Gene Ontology analysis revealed that the high level of astrocyte infiltration was characterized by immune and oncogenic pathways, such as the inflammatory response, positive regulation of the JAK-STAT cascade, positive regulation of NIK/NF-kappa B signaling and the tumor necrosis factor biosynthetic process. Patients with greater TARA infiltration showed inferior prognosis. Meanwhile, the extent of reactive astrocyte infiltration exhibited a predictive value for recurrent glioblastoma patients undergoing anti-PD-1 immune therapy., Conclusion: TARA infiltration might promote glioma tumor progression and can be used as a diagnostic, predictive and prognostic marker in gliomas. Prevention of TARA infiltration might be a new therapeutic strategy for glioma., 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 Zhang, Wang, Liu, Wang and Jia.)

The regioselective [3 + 2] cycloaddition reaction of 2-benzylidene-1-indenones with functional olefins was established with DABCO as a base under mild conditions. Using this approach, a series of diversely substituted indanone-fused cyclopentane polycycles with highly crowded multiple substituents were synthesized in high yields.

Dexmedetomidine might reduce delirium after cardiac surgery. We allocated 326 participants to an infusion of dexmedetomidine at a rate of 0.6 μg kg -1 for 10 min and then at 0.4 μg.kg -1 .h -1 until the end of surgery; 326 control participants received comparable volumes of saline. We detected delirium in 98/652 (15%) participants during the first seven postoperative days: 47/326 after dexmedetomidine vs. 51/326 after placebo, p = 0.62, adjusted relative risk (95%CI) 0.86 (0.56-1.33), p = 0.51. Postoperative renal impairment (Kidney Disease Improving Global Outcomes stages 1, 2 and 3) was detected in 46, 9 and 2 participants after dexmedetomidine and 25, 7 and 4 control participants, p = 0.040. Intra-operative dexmedetomidine infusion did not reduce the incidence of delirium after cardiac valve surgery but might impair renal function., (© 2023 Association of Anaesthetists.)

Background: Rheumatoid arthritis (RA) joint inflammation severely affects joint function and quality of life in patients and leads to joint deformities and limb disability. The non-steroidal anti-inflammatory drugs used in the treatment of RA do not fully control the progression of joint inflammation and bone destruction and have notable adverse reactions. Traditional Chinese medicine formula JuanBiQiangGu Granules (JBQG) are commonly used for the treatment of RA inflammation and delay of bone destruction, but has not been evaluated through high-quality clinical studies. There is a pressing need for well-designed, randomized, parallel, controlled clinical studies to evaluate the exact effect of JBQG on RA joint inflammation and improvement of patient quality of life. Methods: This is a randomized, parallel, controlled clinical study in which 144 patients with rheumatoid arthritis who met the inclusion criteria were randomly assigned to 2 groups in a 1:1 ratio. The JBQG group received methotrexate 7.5 mg qw and JBQG granules 8 mg tid, while the MTX group received methotrexate 7.5 mg qw. The endpoint was 12 weeks after treatment. Relevant indices at baseline, 4 weeks, 8 weeks, and 12 weeks after treatment were observed and recorded, and DAS28-ESR, HAQ-DI, and Sharp scores were recorded for each patient. Blood samples were collected to test for CRP, ESR, TNF-α, IL-1β, IL-6, IL-17, and INF-γ, and adverse reactions and liver and kidney function (AST, ALT, Cr, BUN) were recorded for safety assessment. After 12 weeks of treatment, the effect of JBQG granules on disease activity, improvement in bone damage, and patient quality of life scores and safety in RA patients were evaluated. Results: A total of 144 subjects completed treatment (71 in the JBQG group and 73 in the MTX group) and were included in the analysis. At baseline, there were no significant differences between the groups in terms of the observed indicators ( p > 0.05). After treatment, 76.06% of patients in the JBQG group had DAS28-ESR levels below or equal to Low, including 45.07% in Remission and 5.63% in High, compared to 53.1% in the MTX group below or equal to Low, 12.33% in Remission, and 17.81% in High. CRP was significantly reduced (8.54 ± 5.87 vs. 11.86 ± 7.92, p < 0.05, p = 0.005), ESR was significantly reduced (15.1 ± 6.11 vs. 21.96 ± 9.19, p < 0.0001), TNF-α was significantly reduced (1.44 ± 0.83 vs. 1.85 ± 1.07, p < 0.05, p = 0.011), IL-17 was significantly reduced (0.53 ± 0.33 vs. 0.71 ± 0.38, p < 0.05, p = 0.004), and INF-γ was significantly reduced (3.2 ± 1.51 vs. 3.89 ± 1.77, p < 0.05, p = 0.014). The median (IQR) OPG in the JBQG group was 2.54 (2.21-3.01), significantly higher than in the MTX group 2.06 (1.81-2.32), p < 0.0001), and the median (IQR) β -CTX in the JBQG group was 0.4 (0.32-0.43), significantly lower than in the MTX group 0.55 (0.47-0.67), p < 0.0001). The median (IQR) VSA scores were 2 (1-3), a decrease from 3 (2-4) in the MTX group ( p < 0.0001). The median (IQR) Sharp scores were 1 (1-2), a decrease from 2 (1-2) in the MTX group, but the difference was not statistically significant ( p > 0.05, p = 0.28). The median (IQR) HAQ-DI scores were 11 (8-16), significantly lower than in the MTX group 26 (16-30) ( p < 0.0001). The median (IQR) AST in the JBQG group was 16 (12-20), with a significant difference compared to the MTX group 19 (13-25) ( p < 0.01, p = 0.004); the median (IQR) ALT in the JBQG group was 14 (10-18), with a significant difference compared to the MTX group 16 (11-22.5) ( p < 0.05, p = 0.015). There were no statistically significant differences in Cr or BUN ( p > 0.05). Conclusion: JuanBiQiangGu Granules can be used to treat patients with rheumatoid arthritis, alleviate joint inflammation, reduce the incidence of adverse reactions to methotrexate, and has good safety. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/index.html; identifier: ChiCTR2100046373., 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 Ran, Xu, Han, Wang, A, Cao, Meng, Zhang, Xin, Qiu, Xiang, Pei, Gao, Shen, Zhong, Xu, Bian, Xie, Shi, Sun and Xiao.)

Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing-like response of ECM-receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease., (© 2023 Li et al.)

Electron-proton energy relaxation rates are assessed using molecular dynamics (MD) simulations in weakly-coupled hydrogen plasmas. To this end, we use various approaches to extract the energy relaxation rate from MD-simulated temperatures, and we find that existing extracting approaches may yield results with a sizable discrepancy larger than the variance between analytical models, which is further verified by well-known case studies. Present results show that two of the extracting approaches can produce identical results, which is attributed to a proper treatment of relaxation evolution. To discriminate the use of various methods, an empirical criterion with respect to initial plasma temperatures is proposed, which can self-consistently explain the cases considered. In addition, for a transient electron-proton plasma, we show that it is possible to extrapolate the Coulomb logarithm from that derived by initial plasma parameters in a single MD calculation, which is reasonably consistent with previous MD data. Our results are helpful to obtain accurate MD-based energy relaxation rates.

The methodology for the synthesis of fluorene-based atropisomers was developed via the strategy of aromatic ring formation. By this strategy, an efficient benzannulation of indene-based diene with benzoylacetonitrile divergently promoted by DABCO and a chiral organocatalyst was established, and various atropisomeric fluorene-based skeletons were generated in good yields, which not only provide a new strategy for the construction of atropisomeric biaryls but also offer a new member to the atropisomeric family.

At present, many experimental fast reactors have adopted alloy nuclear fuels, for example, U-Zr alloy fuels. During the neutron irradiation process, vacancies and hydrogen (H) impurity atoms can both exist in U-Zr alloy fuels. Here, first-principles density functional theory (DFT) is employed to study the behaviors of vacancies and H atoms in disordered-γ(U,Zr) as well as their impacts on the electronic structure and mechanical properties. The formation energy of vacancies and hydrogen solution energy are calculated. The effect of vacancies on the migration barrier of hydrogen atoms is revealed. The effect of vacancies and hydrogen atom on densities of states and elastic constants are also presented. The results illustrate that U vacancy is easier to be formed than Zr vacancy. The H interstitial prefers the tetrahedral site. Besides, U vacancy shows H-trap ability and can raise the H migration barrier. Almost all the defects lead to decreases in electrical conductivity and bulk modulus. It is also found that the main effect of defects is on the U-5 f orbitals. This work provides a theoretical understanding of the effect of defects on the electronic and mechanical properties of U-Zr alloys, which is an essential step toward tailoring their performance.

Ferroptosis is a kind of iron-dependent regulatory necrosis characterized by the fatal accumulation of iron-dependent lipid peroxides in the plasma membrane and the final oxidative damage of the cell membrane. Morphologically, ferroptosis features high membrane density, decreased or disappeared cristae, rupture of the mitochondrial outer membrane, plasma membrane integrity loss, cytoplasmic swelling, and organelle swelling. Under physiological conditions, ferroptosis occurs through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway, triggered by a series of small molecules inside and outside the cell. At present, it is assumed that ferroptosis is mainly related to abnormal toxicity of iron, lipid peroxidation, and mitochondrial dysfunction. With more detailed studies, ferroptosis plays potential pathogenic roles in multisystem diseases as a pathological response, and targeted regulation of ferroptosis in treating ferroptosis-related diseases has broad prospects. In conclusion, it is of great clinical significance to further clarify the specific mechanism of ferroptosis and explore new strategies for ferroptosis regulation. The present review emphatically summarizes the latest mechanism of ferroptosis, focusing on the regulation mechanism and clinical application of ferroptosis inducers and inhibitors. We are devoted to providing new ideas for the further study of ferroptosis and the diagnosis and treatment of ferroptosis-related multisystem diseases., Competing Interests: Declaration of competing interest The authors declared no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background and Objective: Continuous assessment of disease activity remains a huge challenge during the follow-ups of patients with Crohn's disease (CD). In this paper, we aimed to evaluate the performance of contrast-enhanced ultrasound (CEUS) by comparing with computed tomography enterography (CTE) in the assessment of disease activity in CD., Materials and Methods: Fifty-two patients diagnosed with CD were included in this study, using the CEUS and CTE as imaging methods for comparison. The selected parameters included the location and thickness of the thickest part of the intestinal wall, mesenteric fat proliferation, mesenteric vessels change, enhancement pattern and the presence of complications. Patients were clinically assessed using the Crohn's disease activity index (CDAI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Simple endoscopic score for Crohn's disease (SES-CD) was regarded as the reference standard., Results: The location of the thickest part of the intestinal wall (κ = 0.653), bowel wall thickness (ICC = 0.795), mesenteric vessels change (κ = 0.692) and complications (κ = 0.796) displayed substantial agreement (0.61-0.80) between CEUS and CTE, while the detection of mesenteric fat proliferation (κ = 0.395) and enhancement pattern (κ = 0.288) showed fair consistency (0.21-0.40) for comparison. In CEUS, bowel wall thickness, mesenteric fat proliferation, enhancement pattern and mesenteric vessels change were statistically significant in assessing CD activity, while bowel wall thickness, mesenteric fat proliferation and mesenteric vessels change in CTE. Bowel wall thickness showed the best diagnostic performance in the assessment of CD activity at CEUS and CTE., Conclusion: CEUS provides a radiation-free and effective way to assess the CD activity in comparison with CTE, which also avoids frequent colonoscopy examinations, improves tolerance of patients, and reduces the cost of medical care, thereby serving as a useful tool for CD follow-up., (© 2022. Italian Society of Medical Radiology.)

To explore the efficacy and value of personalized surgical schemes in the repair of maxillary sinus perforation and maxillary sinus fistula based on the size of the maxillary sinus perforation and maxillary sinus fistula. A total of 28 patients with maxillary sinus perforation and maxillary sinus fistula who were admitted to the Department of Oral and Maxillofacial Surgery, Stomatology Hospital of Kunming Medical University from July 2017 to May 2020 were included to conduct a prospective case clinical study. After the inflammation in the maxillary sinus was controlled, a proper surgical repair method was selected according to the size of the perforation and fistula based on the double-layer closure technique. The diameter of the perforation and fistula was measured with the assistance of cone-beam CT. After that, the platelet rich fibrin (PRF) repair was performed on the perforation and fistula with 3 mm≤diameter<7 mm in size in 14 patients. The PRF repair and buccal flap repair were performed on the perforation and fistula with 7 mm ≤diameter<15 mm in size in 7 patients. The adjacent buccal pad repair, palatine flap repair, and buccal flap repair were performed on the perforation and fistula with 15 mm≤ diameter<25 mm in size in 4 patients. The nasolabial axial flap repair and nasolabial free flap repair were performed on the perforation and fistula with a diameter ≥25 mm in size in 3 patients. The medical follow-up was conducted in all patients in the 1st, 2nd, and 4th week after surgery, with an overall success rate reaching 96.4% (27/28) after the initial intervention. The relapse of disease occurred in one patient (4.6%) with diabetes and a smoking history in the 2nd week after surgery. Identifying a proper surgical repair method according to the size of the oral and maxillary sinus perforation and maxillary sinus fistula based on the double-layer closure technique can improve the one-time cure rate in these patients under the premise that the inflammation in the maxillary sinus can be controlled.

We focus on a fundamental task of detecting meaningful line structures, a.k.a., semantic line, in natural scenes. Many previous methods regard this problem as a special case of object detection and adjust existing object detectors for semantic line detection. However, these methods neglect the inherent characteristics of lines, leading to sub-optimal performance. Lines enjoy much simpler geometric property than complex objects and thus can be compactly parameterized by a few arguments. To better exploit the property of lines, in this paper, we incorporate the classical Hough transform technique into deeply learned representations and propose a one-shot end-to-end learning framework for line detection. By parameterizing lines with slopes and biases, we perform Hough transform to translate deep representations into the parametric domain, in which we perform line detection. Specifically, we aggregate features along candidate lines on the feature map plane and then assign the aggregated features to corresponding locations in the parametric domain. Consequently, the problem of detecting semantic lines in the spatial domain is transformed into spotting individual points in the parametric domain, making the post-processing steps, i.e., non-maximal suppression, more efficient. Furthermore, our method makes it easy to extract contextual line features that are critical for accurate line detection. In addition to the proposed method, we design an evaluation metric to assess the quality of line detection and construct a large scale dataset for the line detection task. Experimental results on our proposed dataset and another public dataset demonstrate the advantages of our method over previous state-of-the-art alternatives. The dataset and source code is available at https://mmcheng.net/dhtline/.

In this paper, a core-shell structure nickel disulfide and ZIF-67 composite electrode material (NiS 2 /ZIF-67) was synthesized by a two-step method. Firstly, spherical NiS 2 was synthesized by a hydrothermal method, dispersed in methanol, then reacted and coated by adding cobalt ions and 2-methylimidazole to obtain the NiS 2 /ZIF-67 core-shell composite. The NiS 2 /ZIF-67 composite shows a high specific capacitance (1297.9 F g -1 at 1 A g -1 ) and excellent cycling durability (retaining 110.0% after 4000 cycles at 5 A g -1 ). Furthermore, the corresponding hybrid supercapacitor (NiS 2 /ZIF-67//AC HSC) has an energy density of 9.5 W h kg -1 at 411.1 W kg -1 (6 M KOH) and remarkable cycling stability (maintaining 133.3% after 5000 cycles). Its excellent electrochemical performance may be due to the core-shell structure and the synergistic effect between the transition metal sulfide and metal-organic framework. These results indicate that the NiS 2 /ZIF-67 composite as an electrode material with a core-shell structure has potential application in high-efficiency supercapacitors., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Background: The expression profiles and molecular mechanisms of CXC chemokine receptors (CXCRs) in Lung adenocarcinoma (LUAD) have been extensively explored. However, the comprehensive prognostic values of CXCR members in LUAD have not yet been clearly identified., Methods: Multiple available datasets, including Oncomine datasets, the cancer genome atlas (TCGA), HPA platform, GeneMANIA platform, DAVID platform and the tumor immune estimation resource (TIMER) were used to detect the expression of CXCRs in LUAD, as well as elucidate the significance and value of novel CXCRs-associated genes and signaling pathways in LUAD., Results: The mRNA and/or protein expression of CXCR1, CXCR2, CXCR3, CXCR4, CXCR5 and CXCR6 displayed predominantly decreased in LUAD tissues as compared to normal tissues. On the contrary, compared with the normal tissues, the expression of CXCR7 was significantly increased in LUAD tissues. Subsequently, we constructed a network including CXCR family members and their 20 related genes, and the related GO functions assay showed that CXCRs connected with these genes participated in the process of LUAD through several signal pathways including Chemokine signaling pathway, Cytokine-cytokine receptor interaction and Neuroactive ligand-receptor interaction. TCGA and Timer platform revealed that the mRNA expression of CXCR family members was significantly related to individual cancer stages, cancer subtypes, patient's gender and the immune infiltration level. Finally, survival analysis showed that low mRNA expression levels of CXCR2 (HR = 0.661, and Log-rank P = 1.90e-02), CXCR3 (HR = 0.674, and Log-rank P = 1.00e-02), CXCR4 (HR = 0.65, and Log-rank P = 5.01e-03), CXCR5 (HR = 0.608, and Log-rank P = 4.80e-03) and CXCR6 (HR = 0.622, and Log-rank P = 1.85e-03) were significantly associated with shorter overall survival (OS), whereas high CXCR7 mRNA expression (HR = 1.604, and Log-rank P = 4.27e-03) was extremely related with shorter OS in patients., Conclusion: Our findings from public databases provided a unique insight into expression characteristics and prognostic values of CXCR members in LUAD, which would be benefit for the understanding of pathogenesis, diagnosis, prognosis prediction and targeted treatment in LUAD., (© 2022. The Author(s).)

In order to investigate the effects of Burkholderia sp. Y4 on rice seedlings under cadmium (Cd) stress, seed germination and vermiculite culture experiments were conducted using low Cd-accumulation xiangzaoxian 24 (X24) and high Cd-accumulation Tyou 705 (T705) varieties. The effects of Burkholderia sp. Y4 on rice growth, oxidative damage caused by Cd, and Cd accumulation were studied. Additionally, the Cd 2+ flux rates in the elongation zone of rice roots under Burkholderia sp. Y4 application were detected using non-invasive micro-test technology. Burkholderia sp. Y4 alleviated the inhibition effect of Cd on rice seed germination by 13.8%. After inoculation with Burkholderia sp. Y4 for 7 d, the length of rice roots and buds increased by 83.3% and 12.2%, and their dry weight increased by 56.8% and 12.5%, respectively; those in the 10 d Y4 inoculation group increased by 28.6% and 20.0% in length and by 113.2% and 46.0% in dry weight, respectively. Burkholderia sp. Y4 inoculation also alleviated rice oxidative stress damage caused by Cd. The application of strain Y4 significantly reduced the content of the oxidative damage product malondialdehyde (MDA) in the shoots and roots of rice seedlings by 21.5% and 16.9%, respectively. Under Burkholderia sp. Y4 inoculation, the significant changes in antioxidant enzyme SOD and CAT activities caused by Cd stress disappeared in rice roots; those in shoots also decreased from 176.9% and 74.8% to 53.3% and 21.5%, respectively. Conversely, Burkholderia sp. Y4 inhibited Cd uptake by rice seedlings with different genotypes, including the low Cd-accumulation variety X24 and high Cd-accumulation variety T705. The root application of strain Y4 significantly reduced Cd accumulation in the shoots and roots of rice seedlings by 79.2% and 62.7% in T705 and by 57.3% and 24.1% in X24, respectively. The Cd 2+ flux rate of high Cd-accumulation variety T705 was significantly higher than that of low Cd-accumulation variety X24. Under Burkholderia sp. Y4 inoculation, the yellow membrane was formed on the root surface of rice seedlings, and the Cd 2+ flux rate in the elongation zone of T705 and X24 roots decreased by 36.0% and 35.0% in 3-day-old seedlings, as well as by 44.6% and 24.9% in 10-day-old seedlings, respectively. In conclusion, Burkholderia sp. Y4 inoculation inhibited the toxic effects of Cd on rice seedling growth through alleviating oxidative stress and damage caused by Cd. Furthermore, the root application of Burkholderia sp. Y4 effectively decreased the Cd 2+ flux rate in the elongation zone of roots to inhibit the Cd uptake and accumulation in roots and shoots of rice seedlings. This study provides theoretical basis and data support for the application of Burkholderia sp. Y4 as a Cd-reducing and growth-promoting agent for rice in contaminated farmland.

Background: Elymus breviaristatus and Elymus sinosubmuticus are perennial herbs, not only morphologically similar but also sympatric distribution. The genome composition of E. sinosubmuticus has not been reported, and the relationship between E. sinosubmuticus and E. breviaristatus is still controversial. We performed artificial hybridization, genomic in situ hybridization, and phylogenetic analyses to clarify whether the two taxa were the same species., Results: The high frequency bivalent (with an average of 20.62 bivalents per cell) at metaphase I of pollen mother cells of the artificial hybrids of E. breviaristatus (StYH) × E. sinosubmuticus was observed. It illustrated that E. sinosubmuticus was closely related to E. breviaristatus. Based on genomic in situ hybridization results, we confirmed that E. sinosubmuticus was an allohexaploid, and the genomic constitution was StYH. Phylogenetic analysis results also supported that this species contained St, Y, and H genomes. In their F 1 hybrids, pollen activity was 53.90%, and the seed setting rate was 22.46%. Those indicated that the relationship between E. sinosubmuticus and E. breviaristatus is intersubspecific rather than interspecific, and it is reasonable to treated E. sinosubmuticus as the subspecies of E. breviaristatus., Conclusions: In all, the genomic constitutions of E. sinosubmuticus and E. breviaristatus were StYH, and they are species in the genus Campeiostachys. Because E. breviaristatus was treated as Campeistachys breviaristata, Elymus sinosubmuticus should be renamed Campeiostachys breviaristata (Keng) Y. H. Zhou, H. Q. Zhang et C. R. Yang subsp. sinosubmuticus (S. L. Chen) Y. H. Zhou, H. Q. Zhang et L. Tan., (© 2022. The Author(s).)

Hematopoietic stem and progenitor cells (HSPCs) possess the remarkable ability to regenerate the whole blood system in response to ablated stress demands. Delineating the mechanisms that maintain HSPCs during regenerative stresses is increasingly important. Here, it is shown that Hemgn is significantly induced by hematopoietic stresses including irradiation and bone marrow transplantation (BMT). Hemgn deficiency does not disturb steady-state hematopoiesis in young mice. Hemgn -/- HSPCs display defective engraftment activity during BMT with reduced homing and survival and increased apoptosis. Transcriptome profiling analysis reveals that upregulated genes in transplanted Hemgn -/- HSPCs are enriched for gene sets related to interferon gamma (IFN-γ) signaling. Hemgn -/- HSPCs show enhanced responses to IFN-γ treatment and increased aging over time. Blocking IFN-γ signaling in irradiated recipients either pharmacologically or genetically rescues Hemgn -/- HSPCs engraftment defect. Mechanistical studies reveal that Hemgn deficiency sustain nuclear Stat1 tyrosine phosphorylation via suppressing T-cell protein tyrosine phosphatase TC45 activity. Spermidine, a selective activator of TC45, rescues exacerbated phenotype of HSPCs in IFN-γ-treated Hemgn -/- mice. Collectively, these results identify that Hemgn is a critical regulator for successful engraftment and reconstitution of HSPCs in mice through negatively regulating IFN-γ signaling. Targeted Hemgn may be used to improve conditioning regimens and engraftment during HSPCs transplantation., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Biodiversity loss, exotic plant invasion and climatic change are three important global changes that can affect litter decomposition. These effects may be interactive and these global changes thus need to be considered simultaneously. Here, we assembled herbaceous plant communities with five species richness levels (1, 2, 4, 8 or 16) and subjected them to a drought treatment (no, moderate or intensive drought) that was factorially combined with an invasion treatment (presence or absence of the non-native Symphyotrichum subulatum). We collected litter of these plant communities and let it decompose for 9 months in the plant communities from which it originated. Drought decreased litter decomposition, while invasion by S. subulatum had little impact. Increasing species richness decreased litter decomposition except under intensive drought. A structural equation model showed that drought and species richness affected litter decomposition indirectly through changes in litter nitrogen concentration rather than by altering quantity and diversity of soil meso-fauna or soil physico-chemical properties. The slowed litter decomposition under high species diversity originated from a sampling effect, specifically from low litter nitrogen concentrations in the two dominant species. We conclude that effects on litter decomposition rates that are mediated by changing concentrations of the limiting nutrient in litter need to be considered when predicting effects of global changes such as plant diversity loss., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We study the mechanism of the impact of random media on the stochastic radiation transport based on a one-dimensional (1D) planar model. To this end, we use a random sampling of mixtures combined with a deterministic solution of the time-dependent radiation transport equation coupled to a material temperature equation. Compared to purely absorbing cases [C.-Z. Gao et al., Phys. Rev. E 102, 022111 (2020)10.1103/PhysRevE.102.022111], we find that material temperatures can significantly suppress the impact of mixing distribution and size, which is understood from the analysis of energy transport channels. By developing a steady-state stochastic transport model, it is found that the mechanism of transmission of radiation is distance dependent, which is closely related to the mean free path of photons l&#95;{p}. Furthermore, we suggest that it is the relationship between l&#95;{p} and L (the width of random medium) that determines the impact of random media on the stochastic radiation transport, which is further corroborated by additional simulations. Most importantly, combining the proposed simple relationship and 1D simulations, we resolve the existing disputable issue of the impact of random media in previous multidimensional works, showing that multidimensional results are essentially consistent and the observed weak or remarkable impact of random media is mainly due to the distinctly different relationship between l&#95;{p} and L. Our results may have practical implications in relevant experiments of stochastic radiative transfer.

Natural hybridization has been frequently observed in Triticeae; however, few studies have investigated the origin of natural intergeneric Triticeae hybrids. In the present study, we discovered three putative hybrid Triticeae plants in the Western Sichuan Plateau of China. Morphologically, the putative hybrids were intermediate between Kengyilia melanthera (2n = 6x = 42; StStYYPP) and Campeiostachys dahurica var. tangutorum (2n = 6x = 42; StStYYHH) with greater plant height and tiller number. Cytological analyses demonstrated that the hybrids were hexaploid with 42 chromosomes (2n = 6x = 42). At metaphase I, 12.10-12.58 bivalents and 13.81-14.18 univalents per cell were observed in the hybrid plants. Genomic in situ hybridization demonstrated that the hybrids had StStYYHP genomes. Phylogenetic analysis of Acc1 sequences indicated that the hybrids were closely related to K. melanthera and C. dahurica var. tangutorum. Our morphological, cytological, and molecular analyses indicate that these hexaploid natural hybrid plants may be hybrids of K. melanthera and C. dahurica var. tangutorum., (© 2023 S. Karger AG, Basel.)

Drug problem is a major social and public security problem in the world. Drug abuse poses a great threat to economic development, social stability and public health. In recent years, synthetic drugs represented by methamphetamine have surpassed traditional drugs such as morphine, heroin, ketamine and become one of the most abused drugs in the world. In order to solve the problem of drug abuse, it is of great theoretical value and practical significance to carry out all-round and multi-level scientific research on drug-related issues. Based on the current situation of drug abuse, this article reviews research progresses on the epidemiology of methamphetamine abuse, the monitoring technology, the basic researches on toxicity damage, the withdrawal drug screening, the related clinical comorbidity and the testing technologies, comprehensively presenting the development trend of methamphetamine abuse related issues.

The proliferation of pulmonary artery smooth muscle cells (PASMCs) is an important cause of pulmonary vascular remodelling in hypoxia-induced pulmonary hypertension (HPH). However, its underlying mechanism has not been well elucidated. Connexin 43 (Cx43) plays crucial roles in vascular smooth muscle cell proliferation in various cardiovascular diseases. Here, the male Sprague-Dawley (SD) rats were exposed to hypoxia (10% O 2 ) for 21 days to induce rat HPH model. PASMCs were treated with CoCl 2 (200 µM) for 24 h to establish the HPH cell model. It was found that hypoxia up-regulated the expression of Cx43 and phosphorylation of Cx43 at Ser 368 in rat pulmonary arteries and PASMCs, and stimulated the proliferation and migration of PASMCs. HIF-1α inhibitor echinomycin attenuated the CoCl 2 -induced Cx43 expression and phosphorylation of Cx43 at Ser 368 in PASMCs. The interaction between HIF-1α and Cx43 promotor was also identified using chromatin immunoprecipitation assay. Moreover, Cx43 specific blocker ( 37,43 Gap27) or knockdown of Cx43 efficiently alleviated the proliferation and migration of PASMCs under chemically induced hypoxia. Therefore, the results above suggest that HIF-1α, as an upstream regulator, promotes the expression of Cx43, and the HIF-1α/Cx43 axis regulates the proliferation and migration of PASMCs in HPH., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

To reveal the speciation and pollution status of heavy metal(loid) s (HMs) in the dewatered sewage sludge(SS) of municipal wastewater treatment plants(MWTPs) in China, SS samples were collected from 40 MWTPs located in different regions of China. The total concentrations and geochemical fractions of As, Cd, Cr, Cu, Ni, Pb, and Zn in the SS samples were analyzed. The ecological risks induced by HMs in the SS were assessed based on the toxicity characteristic leaching procedure(TCLP), risk assessment code(RAC), and potential ecological risk index(RI). The median values of HMs in SS followed the order Zn > Cu > Cr > Pb > Ni > As > Cd. The general attainment rates of HMs in SS were satisfactory(>90%). As showed a generally even distribution among all the fractions; Cd and Zn mainly existed in the reducible fraction; Cr mainly occurred in the residual fraction, followed by oxidizable and reducible fractions; Cu mainly occurred in the oxidizable fraction; Ni occurred mainly as exchangeable forms; and Pb mainly occurred in the reducible and residual fractions, with its exchangeable form being the lowest fraction. According to the RAC method, the environmental risks induced by HMs in the SS followed the order Ni > As > Zn > Cd > Cu > Cr > Pb. The ecological risk of Ni was high; Zn, As, and Cd had a medium level of risk; Cr and Cu had a low level of risk; and the risk of Pb was negligible. According to the RI method, Cd and Cu showed the highest potential ecological risk, indicating that these are the primary HM pollutants in the SS. However, if the agricultural application of SS is carried out in accordance with the national standards, the overall level of risk from soil HM pollution is considered relatively low.

The study aims to identify relations of denitrifying bacterial and fungal communities to nitrogen removals in vertical flow wetland microcosms (VFWMs) using four macrophyte species (Iris pseudacorus, Canna glauca, Scirpus validus and Cyperus alternifolius) and three species richness levels (unplanted, monocultured and 4-species mixture) as fixed factors. Results showed that among four macrophyte species, only Canna glauca planting significantly decreased nitrate removal by 87.7% in the VFWMs. The 4-species mixture improved TN and nitrate removals by 84.0% and 91.3%, but decreased ammonium removal by 94.5%. Heatmap and nonmetric multidimensional scaling analyses identified a significant difference in denitrifying bacterial community structure across macrophyte richness levels, but did not identify the difference in denitrifying fungal communities. The redundancy analysis revealed that denitrifying bacterial community individually explained 99.4% and 93.0% variance of nitrogen removals among four macrophyte species and across macrophyte richness levels, while the fungal community only explained 30.7% and 21.8% variance of nitrogen removals. Overall, the macrophyte richness and bacterial denitrifiers are the critical factors of nitrogen removals in the VFWMs, thus providing useful data to design a vertical flow constructed wetland at a full scale., (Copyright © 2021. Published by Elsevier Ltd.)

The combination of endophytes and hyperaccumulator plants can significantly improve the efficiency of heavy metal phytoremediation in contaminated soil. A plant endophyte named Herbaspirillum R-13 was isolated from rice roots in a cadmium (Cd) contaminated paddy field. This strain exhibited a strong tolerance to Cd 2+ and could grow on a solid medium with a Cd 2+ concentration of 300 mg·kg -1 . The R-13 strain was able to produce siderophores and Indole acetic acid (IAA), through color reactions. In addition, Pikovskaya's and Ashby's solid medium tests showed that the R-13 strain had a lower capacity for dissolving phosphorus but a higher capacity for fixing nitrogen. In the pot experiment, high-throughput sequencing technology was used to track the colonization of the R-13 strain in Solanum nigrum L. roots. Three days after inoculation, the relative abundance of Herbaspirillum in the root of Solanum nigrum L. had increased by 201.88% compared to the blank control (CK) and after two inoculations, the relative abundance of Herbaspirillum in the root of Solanum nigrum L. had increased by 1182.44% compared to CK. The relative abundance of Herbaspirillum in the root of Solanum nigrum L. began to decrease significantly from 5 days after inoculation. Inoculation with 20 mL·pot -1 of R-13 fermentation broth resulted in no significant effects on the Cd content of roots, stems, leaves, or fruits of S. nigrum L. With 40 mL·pot -1 of fermentation broth, the Cd content of vegetative organs and fruits was significantly increased. When it reached 200 mL·pot -1 , the Cd content of vegetative organs was the highest, with Cd concentrations in the roots, stems, leaves, and fruits increasing by 84.42%, 43.67%, 64.06%, and 20.29%, respectively. In conclusion, root inoculation with endophytic Herbaspirillum R-13 can significantly increase the relative content of Herbaspirillum in the root system and enhance Cd absorption of S. nigrum L. Therefore, this strain has excellent prospects for application in the phytoremediation of soil contaminated with Cd.

With the enhancement of environmental protection awareness, research on the bioremediation of petroleum hydrocarbon environmental pollution has intensified. Bioremediation has received more attention due to its high efficiency, environmentally friendly by-products, and low cost compared with the commonly used physical and chemical restoration methods. In recent years, bacterium engineered by systems biology strategies have achieved biodegrading of many types of petroleum pollutants. Those successful cases show that systems biology has great potential in strengthening petroleum pollutant degradation bacterium and accelerating bioremediation. Systems biology represented by metabolic engineering, enzyme engineering, omics technology, etc., developed rapidly in the twentieth century. Optimizing the metabolic network of petroleum hydrocarbon degrading bacterium could achieve more concise and precise bioremediation by metabolic engineering strategies; biocatalysts with more stable and excellent catalytic activity could accelerate the process of biodegradation by enzyme engineering; omics technology not only could provide more optional components for constructions of engineered bacterium, but also could obtain the structure and composition of the microbial community in polluted environments. Comprehensive microbial community information lays a certain theoretical foundation for the construction of artificial mixed microbial communities for bioremediation of petroleum pollution. This article reviews the application of systems biology in the enforce of petroleum hydrocarbon degradation bacteria and the construction of a hybrid-microbial degradation system. Then the challenges encountered in the process and the application prospects of bioremediation are discussed. Finally, we provide certain guidance for the bioremediation of petroleum hydrocarbon-polluted environment., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To evaluate the feasibility of applying L-cysteine (L-Cys) as a foliar conditioner for Cd reduction in rice, a field experiment was conducted to investigate the concentration of Cd and mineral elements in rice after the foliar application of L-Cys. The variation in Cd distribution and morphology in key rice organs was examined to study the Cd reduction mechanisms of spraying L-Cys on rice. The results showed that foliar application of L-Cys at the rice-flowering stage significantly decreased Cd concentration in grains, in a concentration dependent manner, without inhibiting the accumulation of mineral elements Ca, Mg, K, Mn, and Zn. With a 10 mmol ·L -1 L-Cys application, Cd concentration in rice grains decreased by 59.2%, to below 0.2 mg ·kg -1 , which is the maximum safety limit in China. Foliar application of L-Cys also inhibited Cd accumulation in rice vegetative organs, including rachises, first nodes, neck-panicles, flag leaves, second internodes, second nodes, second leaves, stalks, and roots (58.3%, 56.0%, 62.7%, 67.0%, 59.3%, 61.5%, 60.2%, 54.9%, and 50.3%, respectively). After transfer factor calculation, first nodes were found to be the key organ for Cd blocking in rice. The application of L-Cys increased Cd transfer from flag leaves and second internodes to first nodes (105.4% and 45.8%, respectively), but decreased Cd transfer from first nodes up to neck-panicles (27.5%). In rice first nodes, the concentrations of Cd in the inorganic, water soluble, and residue states were all lower following L-Cys application, and the proportion of residual Cd increased to 94.4%. Therefore, foliar application of L-Cys significantly inhibited Cd transport and accumulation in rice grains, by decreasing the Cd concentrations of various vegetative organs and improving Cd interception in the first nodes. This is a promising way to produce rice with lower Cd concentrations and normal mineral element concentrations in Cd-contaminated paddy fields.

An efficient cascade reaction of 1-indanylidenemalononitrile with 3-benzylidenebenzofuran-2(3 H )-one divergently promoted by DABCO or chiral organocatalyst was developed under mild reaction conditions, and various spiro-dihydrofluorene-benzofuranones were produced in gratifying results, respectively. It is worth noting that both the spiro and axially chiral products can be obtained by tuning the reaction conditions. The mechanism of the transformation was also studied by quantum chemical calculations.

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. Accumulating researches have highlighted the ability of exosome-encapsulated microRNAs (miRNAs or miRs) as potential circulating biomarkers for lung cancer. The current study aimed to evaluate the significance of mesenchymal stem cells (MSCs)-derived exosomal miR-204 in the invasion, migration, and epithelial-mesenchymal transition (EMT) of NSCLC cells. Initially, the expression of miR-204 in human NSCLC tissues and cells was determined by RT-qPCR, which demonstrated that miR-204 was downregulated in NSCLC tissues and cells. Next, Krüppel-like factor 7 (KLF7) was predicted and validated to be a target of miR-204 using dual-luciferase reporter gene assay. NSCLC A549 cells were treated with MSCs-derived exosomes, after which the migration and invasion of A549 cells were detected and expression of EMT-related proteins (E-cadherin, N-cadherin, and Vimentin), KLF7, p-AKT/AKT, and HIF-1α were measured. The results of gain- and loss-of-function assays revealed that miR-204 overexpression in MSCs-derived exosomes inhibited KLF7 expression and the AKT/HIF-1α pathway activity, resulting in impaired cell migration, invasion, as well as EMT. In conclusion, the key findings of the current study demonstrate that exosomal miR-204 from MSCs possesses anticarcinogenic properties against NSCLC via the KLF7/AKT/HIF-1α axis.

Cd has toxic effects on rice seed germination and plant growth, which may eventually lead to decreased yield and excessive Cd content in rice grains. The potential mechanism of S -allyl-L-cysteine (SAC), a natural sulfur compound derived from garlic extract, in alleviating Cd 2+ stress in young roots and buds of rice seedlings was studied by a seed germination experiment. "Zhong zao 35", one of the main rice varieties in Southern China, was selected as the test material. Firstly, the alleviating effect of SAC on Cd 2+ stress in rice seedling roots and buds was studied. Following this, the physiological mechanism of Cd 2+ stress alleviation by SAC was examined based on the expression of the Cd transporter coding gene using real-time fluorescent quantitative PCR. The results showed that when the Cd 2+ stress concentration reached 50 μmol·L -1 , the young roots and buds of rice seedlings were significantly inhibited, and when the SAC concentration reached 200 μmol·L -1 , Cd 2+ stress was significantly alleviated. Compared to a Cd 2+ stress treatment group, the total root length, surface area, and volume of young roots was increased by 173.5%, 65.52%, and 37.04%, respectively; CAT and SOD activity in young roots and buds was increased by 212.42% and 110.76%, and 31.41% and 47.31%, respectively; MDA and GSH content was decreased by 43.09% and 34.12%, and 33.97% and 35.74%, respectively; and Cd content was decreased by 35.91% and 28.86%, respectively. The results of quantitative real-time PCR showed that the relative expression levels of OsNramp5 and OsHMA2 were significantly reduced by 33.38% and 34.99% compared with the Cd 2+ stress group, respectively. However, the relative expression level of OsHMA3 was significantly increased by 33.96%. From the above experimental results, the main mechanism by which SAC reduces Cd 2+ stress in the young roots and buds of rice is via the regulation of Cd transporter-encoding genes, reducing Cd 2+ transport to young roots and buds, and increasing transport to vacuoles.

Background: The majority of clinical trials of first-line systemic treatments for hepatocellular carcinoma (HCC) used placebo or sorafenib as comparators, and there are limited data providing a cross comparison of treatments in this setting, especially for newly-approved immune checkpoint inhibitor and vascular endothelial growth factor inhibitor combination treatments., Aim: To systematically review and compare response rates, survival outcomes, and safety of first-line systemic therapies for advanced hepatocellular carcinoma., Methods: We searched PubMed, Science Direct, the Cochrane Database, Excerpta Medica Database, and abstracts from the American Society of Clinical Oncology 2020 annual congress. Eligible studies were randomized controlled trials of systemic therapy enrolling adults with advanced/unresectable HCC. Risk of bias was assessed with the Cochrane risk of bias tool for randomized controlled trials. A network meta-analysis was used to synthesize data and perform direct and indirect comparisons between treatments. P value, a frequentist analog to the surface under the cumulative ranking curve, was used to rank treatments., Results: In total, 1398 articles were screened and 27 included. Treatments compared were atezolizumab plus bevacizumab, brivanib, donafenib, dovitinib, FOLFOX4, lenvatinib, linifanib, nintedanib, nivolumab, sorafenib, sunitinib, vandetanib, 11 sorafenib combination therapies, and three other combination therapies. For overall response rate, lenvatinib ranked 1/19, followed by atezolizumab plus bevacizumab and nivolumab. For progression-free survival (PFS), atezolizumab + bevacizumab was ranked 1/15, followed by lenvatinib. With the exception of atezolizumab + bevacizumab [hazard ratios (HR) PFS = 0.90; 95% confidence interval (CI): 0.64-1.25], the estimated HRs for PFS for all included treatments vs lenvatinib were > 1; however, the associated 95%CI passed through unity for bevacizumab plus erlotinib, linifanib, and FOLFOX4. For overall survival, atezolizumab plus bevacizumab was ranked 1/25, followed by vandetanib 100 mg/d and donafinib, with lenvatinib ranked 6/25. Atezolizumab + bevacizumab was associated with a lower risk of death vs lenvatinib (HR os = 0.63; 95%CI: 0.44-0.89), while the HR for overall survival for most other treatments vs lenvatinib had associated 95%CIs that passed through unity. Vandetanib 300 mg/d and 100 mg/d were ranked 1/13 and 2/13, respectively, for the lowest incidence of treatment terminations due to adverse events, followed by sorafenib (5/13), lenvatinib (10/13), and atezolizumab + bevacizumab (13/13)., Conclusion: There is not one single first-line treatment for advanced HCC associated with superior outcomes across all outcome measurements. Therefore, first-line systemic treatment should be selected based on individualized treatment goals., Competing Interests: Conflict-of-interest statement: The authors have no declarations of interest to declare., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Chronic kidney disease (CKD) is a major cause of morbidity and mortality worldwide, imposing a great burden on the healthcare system. Regrettably, effective CKD therapeutic strategies are yet available due to their elusive pathogenic mechanisms. CKD is featured by progressive inflammation and fibrosis associated with immune cell dysfunction, leading to the formation of an inflammatory microenvironment, which ultimately exacerbating renal fibrosis. Transforming growth factor β1 (TGF-β1) is an indispensable immunoregulator promoting CKD progression by controlling the activation, proliferation, and apoptosis of immunocytes via both canonical and non-canonical pathways. More importantly, recent studies have uncovered a new mechanism of TGF-β1 for de novo generation of myofibroblast via macrophage-myofibroblast transition (MMT). This review will update the versatile roles of TGF-β signaling in the dynamics of renal immunity, a better understanding may facilitate the discovery of novel therapeutic strategies against CKD., 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 © 2021 Tang, Chan, Zhang, García Córdoba, Zhang, To, Leung, Lan and Tang.)

Label smoothing is an effective regularization tool for deep neural networks (DNNs), which generates soft labels by applying a weighted average between the uniform distribution and the hard label. It is often used to reduce the overfitting problem of training DNNs and further improve classification performance. In this paper, we aim to investigate how to generate more reliable soft labels. We present an Online Label Smoothing (OLS) strategy, which generates soft labels based on the statistics of the model prediction for the target category. The proposed OLS constructs a more reasonable probability distribution between the target categories and non-target categories to supervise DNNs. Experiments demonstrate that based on the same classification models, the proposed approach can effectively improve the classification performance on CIFAR-100, ImageNet, and fine-grained datasets. Additionally, the proposed method can significantly improve the robustness of DNN models to noisy labels compared to current label smoothing approaches. The source code is available at our project page: https://mmcheng.net/ols/.