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Background: The transposons of the hAT superfamily are the most widespread transposons ever known. SLEEPER genes encode domesticated transposases from the hAT superfamily, which may have lost their transposable functions during long-term evolution and transformed into host proteins that regulate plant growth and development., Results: This study identified 162 members of the SLEEPER gene family from Brassica napus. These members are widely distributed on 19 chromosomes, mainly in the Cn subgenome, and have promoters with various cis-acting elements related to hormone regulation, abiotic stress, and growth and development regulation. Most of the genes in this family contain similar conserved domains and motifs, and the closer the genes are distributed on evolutionary branches, the more similar their structures are. Transcriptome sequencing performed on tissues at different growth stages from B. napus line 3529 indicated that these genes had different expression patterns, and nearly half of the genes were not detectably expressed in all samples., Conclusions: This study investigated the gene structure, expression patterns, evolutionary features, and gene localization of the SLEEPER family members to confirm the significance of these genes in the growth of B. napus, providing a reference for the study of transposon domestication and outstanding genetic resources for the genetic improvement of B. napus., (© 2024. The Author(s).)

The first asymmetric synthesis of (-)-penostatins B and D and the practical synthesis of (+)-penostatins A and C have been accomplished through a flexible strategy. The features of the synthesis are a BF 3 ·OEt 2 -mediated Diels-Alder reaction of chiral dienophiles and methylcyclopentadienes with high chemo-, regio-, and stereoselectivity, followed by ozonolysis to install the common trisubstituted cyclopentane intermediate, and a hetero-Diels-Alder reaction with easily tunable facial selectivity, followed by sulfonate elimination to construct both enantiomeric tricyclic systems for penostatins A/C and B/D, respectively.

Aberrant FGF2/FGFR signaling is implicated in lung squamous cell carcinoma (LSCC), posing treatment challenges due to the lack of targeted therapeutic options. Designing drugs that block FGF2 signaling presents a promising strategy different from traditional kinase inhibitors. We previously reported a ColVα1-derived fragment, HEPV (127AA), that inhibits FGF2-induced angiogenesis. However, its large size may limit therapeutic application. This study combines rational peptide design, molecular dynamics simulations, knowledge-based prediction, and GUV and FRET assays to identify smaller peptides with FGF2-blocking properties. We synthesized two novel peptides, HBS-P1 (45AA) and HBS-P2 (66AA), that retained the heparin-binding site. Both peptides demonstrated anti-LSCC and antiangiogenesis properties in cell viability and microvessel network induction assays. In two LSCC subcutaneous models, HBS-P1, with its affinity for FGF2 and enhanced penetration ability, demonstrated substantial therapeutic potential without apparent toxicities. Our study provides the first evidence supporting the development of collagen V-derived natural peptides as FGF2-blocking agents for LSCC treatment.

The single-unit monomer insertion (SUMI), derived from living/controlled polymerization, can be directly functionalized at the end or within the chain of polymers prepared by living/controlled polymerization, offering potential applications in the preparation of polymers with complex architectures. Many scenarios demand the simultaneous incorporation of monomers suitable for different polymerization methods into complex polymers. Therefore, it becomes imperative to utilize SUMI technologies with diverse mechanisms, especially those that are compatible with each other. Here, we reported the orthogonal SUMI technique, seamlessly combining radical and cationic SUMI approaches. Through the careful optimization of monomer and chain transfer agent pairs and adjustments to reaction conditions, we can efficiently execute both radical and cationic SUMI processes in one pot without mutual interference. The utilization of orthogonal SUMI pairs facilitates the integration of radical and cationic reversible addition-fragmentation chain transfer (RAFT) polymerization in various configurations. This flexibility enables the synthesis of diblock, triblock, and star polymers that incorporate both cationically and radically polymerizable monomers. Moreover, we have successfully implemented a mixing mechanism of free radicals and cations in RAFT step-growth polymerization, resulting in the creation of a side-chain sequence-controlled polymer brushes., (© 2024 Wiley-VCH GmbH.)

Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words)., (© 2024. The Author(s).)

Purpose: We developed a novel guider-assisted osteotomy (GAO) procedure to improve the safety of open wedge high tibial osteotomy (OWHTO) and aimed to compare its efficacy and complications with the conventional pendulum-saw osteotomy (PSO)., Methods: This is a retrospective cohort study of patients undergoing either GAO or PSO procedure in the OWHTO to treat varus knee osteoarthritis, who had a minimum of 2 years of follow-up. Patients were propensity score matched (PSM) in a 1:1 ratio based on demographic and clinical data with a caliper width of 0.02. The outcomes assessed involved the hospital for special surgery (HSS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and the Intraoperative and postoperative complications., Results: 199 patients were included in each group after PSM. The mean duration of follow-up was 38.3 ± 8.9 months. The GAO group had a shorter operation duration (104.5 ± 35.7 vs. 112.1 ± 36.0 min, p = 0.027) and fewer times of intraoperative fluoroscopy (4.2 ± 1.4 vs. 6.0 ± 1.4, p < 0.001). At the last follow-up, clinical scores for knee achieved significant improvements in both GAO and PSO groups: HSS (67.5 ± 10.5 vs. 90.2 ± 7.0, p < 0.001; 69.4 ± 8.2 vs. 91.7 ± 6.8, p < 0.001) and WOMAC (65.7 ± 11.6 vs. 25.2 ± 10.4, p < 0.001; 63.3 ± 12.2 vs. 23.8 ± 9.5, p < 0.001). However, no significant difference was observed between groups for any measures (p > 0.05). In addition, the intraoperative complications (0.5% vs. 3.5%, p = 0.068) and the postoperative bone delayed union and nonunion (1.0% vs. 4.5%, p = 0.032) were marginally or significantly reduced in the GAO versus PSO group., Conclusion: GAO demonstrates improvements in intraoperative radiation exposure and complications, with comparable short-term efficacy to PSO, and could be considered a viable alternative in clinical practice., (© 2024. The Author(s).)

Targeted delivery and precise release of toxins is a prospective strategy for the treatment of triple-negative breast cancer (TNBC), yet the flexibility to incorporate both properties simultaneously remains tremendously challenging in the X-drug conjugate fields. As critical components in conjugates, linkers could flourish in achieving optimal functionalities. Here, we pioneered a pH-hypersensitive tumor-targeting aptamer AS1411-triptolide conjugate (AS-TP) to achieve smart release of the toxin and targeted therapy against TNBC. The multifunctional acetal ester linker in the AS-TP site-specifically blocked triptolide toxicity, quantitatively sustained aptamer targeting, and ensured the circulating stability. Furthermore, the aptamer modification endowed triptolide with favorable water solubility and bioavailability and facilitated endocytosis of conjugated triptolide by TNBC cells in a nucleolin-dependent manner. The integrated superiorities of AS-TP promoted the preferential intra-tumor triptolide accumulation in xenografted TNBC mice and triggered the in-situ triptolide release in the weakly acidic tumor microenvironment, manifesting striking anti-TNBC efficacy and virtually eliminated toxic effects beyond clinical drugs. This study illustrated the therapeutic potential of AS-TP against TNBC and proposed a promising concept for the development of nucleic acid-based targeted anticancer drugs., (© 2024. The Author(s).)

Background: The association of low-density lipoprotein cholesterol (LDL-C) and lymphocyte counts with the development of deep vein thrombosis (DVT) has been demonstrated in many fields but remains lacking in open wedge high tibial osteotomy (OWHTO). This study aimed to assess the predictive value of LDL-C to lymphocyte count ratio (LLR) in screening for postoperative new-onset DVT., Methods: Clinical data were retrospectively collected from patients who underwent OWHTO between June 2018 and May 2023. The limited restricted cubic spline (RCS) was conducted to evaluate the nonlinear relationship between LLR and the risk of postoperative new-onset DVT. The receiver operating characteristic (ROC) curves were plotted and the predictive value of biomarkers was assessed. After adjusting for intergroup confounders by propensity score matching, the univariate logistic regression was applied to assess the association between LLR and DVT., Results: 1293 eligible patients were included. RCS analysis showed a linear positive correlation between LLR and the risk of DVT (P for overall = 0.008). We identified LLR had an area under the curve of 0.607, accuracy of 74.3%, sensitivity of 38.5%, and specificity of 80.7%, and LLR > 1.75 was independently associated with a 1.45-fold risk of DVT (95% CI: 1.01-2.08, P = 0.045). Furthermore, significant heterogeneities were observed in the subgroups of age, BMI, diabetes mellitus, hypertension, Kellgren-Lawrence grade, the American Society of Anesthesiologists (ASA) score, and intraoperative osteotomy correction size., Conclusion: LLR is a valuable biomarker for predicting postoperative new-onset DVT in patients with OWHTO, and routine screening is expected to yield positive benefits., (© 2024. The Author(s).)

Tetrandrine (TET) is a natural bis-benzylisoquinoline alkaloid isolated from Stephania species with a wide range of biological and pharmacologic activities; it mainly serves as an anti-inflammatory agent or antitumor adjuvant in clinical applications. However, limitations such as prominent hydrophobicity, severe off-target toxicity, and low absorption result in suboptimal therapeutic outcomes preventing its widespread adoption. Nanoparticles have proven to be efficient devices for targeted drug delivery since drug-carrying nanoparticles can be passively transported to the tumor site by the enhanced permeability and retention (EPR) effects, thus securing a niche in cancer therapies. Great progress has been made in nanocarrier construction for TET delivery due to their outstanding advantages such as increased water-solubility, improved biodistribution and blood circulation, reduced off-target irritation, and combinational therapy. Herein, we systematically reviewed the latest advancements in TET-loaded nanoparticles and their respective features with the expectation of providing perspective and guidelines for future research and potential applications of TET., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Myocardial ischemia/reperfusion (MI/R) is a common cardiovascular disease that seriously affects the quality of life and prognosis of patients. In recent years, matrine has attracted widespread attention in the treatment of cardiovascular diseases. This study designed, synthesized, and characterized 20 new matrine derivatives and studied their protective effects on ischemia-reperfusion injury through in vivo and in vitro experiments. Based on cellular assays, most newly synthesized derivatives have a certain protective effect on Hypoxia/Reoxygenation (H/R) induced H9C2 cell damage, with compound 22 having the best activity and effectively reducing cell apoptosis and necrosis. In vitro experimental data shows that compound 22 can significantly reduce the infarct size of rat myocardium and improve cardiac function after MI/R injury. In summary, compound 22 is a new potential cardioprotective agent that can promote angiogenesis and enhance antioxidant activity by activating ADCY5, CREB3l4, and VEGFA, thereby protecting myocardial cell apoptosis and necrosis induced by MI/R., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Asymmetric catalytic processes promoted by N-heterocyclic carbenes (NHCs) hold great potential for the sustainable preparation of chiral molecules. However, catalyzing the reactions by manipulating the reactive intermediates is challenging. We report herein that the known NHC-catalyzed [3 + 2] annulation reaction between ketimine and enal can also be turned into a [2 + 3] annulation reaction for the highly enantioselective direct synthesis of trifluoroethyl 3,2'-spirooxindole γ-lactams (4) through timely catalysis of the intermediates. DFT calculations revealed that this transformation included the key step of the nucleophilic attack of the Breslow intermediate M2 derived from NHC and enal (2) to the unattacked ketimine (1). Our study demonstrates that it is possible to tune the desired selectivities through the dynamic catalysts of the reactive intermediates., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

For di-nitroaromatics hydrogenation, it is a challenge to achieve the multi-step hydrogenation with high activity and selectivity due to the complexity of the process involving two nitro groups. Consequently, many precious metal catalysts suffer from low activity for this multi-step hydrogenation reaction. Herein, we employ a fully exposed Pt clusters catalyst consisting of an average of four Pt atoms on nanodiamond@graphene (Pt n /ND@G), demonstrating excellent catalytic performance for the multi-step hydrogenation of 2,4-dinitrotoluene. The TOF (40647 h -1 ) of Pt n /ND@G is significantly superior to that of single Pt atoms catalyst, Pt nanoparticles catalyst, and even all the known catalysts. Density functional theory calculations and absorption experiments reveal that the synergetic interaction between the multiple active sites of Pt n /ND@G facilitate the co-adsorption/activation of reactants and H 2 , as well as the desorption of intermediates/products, which is the key for the higher catalytic activity than single Pt atoms catalyst and Pt nanoparticles catalyst., (© 2024. The Author(s).)

Background: Ultrasound-guided thermal ablation (TA) has emerged as a robust therapeutic approach for treating solid tumors in multiple organs, including the thyroid. Yet, its efficacy and safety profile in the management of Graves' Disease (GD) remains to be definitively established., Methods: A retrospective study was conducted on 50 GD patients treated with TA between October 2017 and December 2021. Key metrics like thyroid volume, volume reduction rate (VRR), thyroid hormones, and basal metabolic rate (BMR) were evaluated using paired Wilcoxon tests., Results: The intervention of ultrasound-guided TA yielded a statistically significant diminution in total thyroid volume across all postoperative follow-up intervals-1, 3, 6, and 12 months-relative to pre-intervention baselines (p < 0.001). The median VRR observed at these time points were 17.5%, 26.5%, 34.4%, and 39.8%, respectively. Euthyroid status was corroborated in 96% of patients at the one-year follow-up milestone. Transient tachycardia and dysphonia were observed in three patients, while a solitary case of skin numbness was noted. Crucially, no instances of enduring injury to the recurrent laryngeal nerve (RLN) were documented., Conclusions: Our investigation substantiates ultrasound-guided TA as a pragmatic, well-tolerated, and safe therapeutic modality for GD. It effectively improves symptoms of hyperthyroidism, engenders a substantial reduction in thyroid volume, and restores thyroid hormone and BMR to physiological levels. Given its favorable safety profile, enhanced cosmetic outcomes, and minimally invasive nature, ultrasound-guided TA is a compelling alternative to thyroidectomy for GD patients., (© 2024. The Author(s).)

This study examines why and when proactive employees share knowledge. By integrating the Motivation-Opportunity-Ability Framework and Trait Activation Theory, and incorporating Mindsponge Theory, our multi-level model proposed that job autonomy moderates the impact of proactive personality on knowledge sharing (KS) within and between teams. Transformational leadership exhibits a cross-level effect on job autonomy. Utilizing a two-source, three-time-point research design, we collected data from 63 team leaders and 241 team members across six Chinese companies. Multilevel regression analysis revealed that within teams, increased job autonomy coupled with a proactive personality significantly enhanced KS. Between teams, job autonomy had a positive moderating effect. When job autonomy was low, more proactive teams exhibited less KS, whereas this negative effect was mitigated when job autonomy was high. The cross-level effect of transformational leadership on job autonomy was demonstrated. The theoretical and practical implications of these findings are discussed., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored., Methods: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays., Results: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 cancer cells as compared with two other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without reactive oxygen species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin., Conclusion: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted cancer therapy., (© 2024. The Author(s).)

Alveolar, the smallest structural and functional units within the respiratory system, play a crucial role in maintaining lung function. Alveolar damage is a typical pathological hallmark of respiratory diseases. Nevertheless, there is currently no simple, rapid, economical, and unbiased method for quantifying alveolar size for entire lung tissue. Here, firstly, we conducted lung sample slicing based on the size, shape, and distribution of airway branches of different lobes. Next, we performed HE staining on different slices. Then, we provided an unbiased quantification of alveolar size using free software ImageJ. Through this protocol, we demonstrated that C57Bl/6 mice exhibit varying alveolar sizes among different lobes. Collectively, we provided a simple and unbiased method for a more comprehensive quantification of alveolar size in mice, which holds promise for a broader range of respiratory research using mouse models., Competing Interests: Conflict of Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Epigenetic alterations at cis-regulatory elements (CRE) fine-tune transcriptional output. Epigenetic readers interact with CREs and can cooperate with other chromatin regulators to drive oncogene transcription. Here, we found that the YEATS domain-containing histone acetylation reader ENL (eleven-nineteen leukemia) acts as a key regulator of super-enhancers (SE), which are highly active distal CREs, across cancer types. ENL occupied the majority of SEs with substantially higher preference over typical enhancers, and the enrichment of ENL at SEs depended on its ability to bind acetylated histones. Rapid depletion of ENL by auxin-inducible degron tagging severely repressed the transcription of SE-controlled oncogenes, such as MYC, by inducing the decommissioning of their SEs, and restoring ENL protein expression largely reversed these effects. Additionally, ENL was indispensable for the rapid activation of SE-regulated immediate early genes in response to growth factor stimulation. Furthermore, ENL interacted with the histone chaperone FACT complex and was required for the deposition of FACT over CREs, which mediates nucleosome reorganization required for transcription initiation and elongation. Proper control of transcription by ENL and ENL-associated FACT was regulated by the histone reader BRD4. ENL was overexpressed in colorectal cancer and functionally contributed to colorectal cancer growth and metastasis. ENL degradation or inhibition synergized with BET inhibitors that target BRD4 in restraining colorectal cancer progression. These findings establish the essential role of epigenetic reader ENL in governing SE-driven oncogenic transcription and uncover the potential of ENL intervention to increase sensitivity to BET inhibition., Significance: ENL plays a key role in decoding epigenetic marks at highly active oncogenic super-enhancers and can be targeted in combination with BET inhibition as a promising synergistic strategy for optimizing cancer treatment., (©2024 American Association for Cancer Research.)

Three new annonaceous acetogenins, annotemoyin L ( 1 ), annotemoyin Y ( 2 ) and annotemoyin X, ( 3 ) were isolated from the seeds of Annona squamosa Linn. Their structures were ascertained by chemical methods and spectral data. The cytotoxic activities of compounds against three multidrug-resistant cancer cell lines were evaluated, and compound 3 exerted strong cytotoxicity against SMMC 7721/ADR (IC 50 0.163 μM), A549/T (IC 50 0.064 μM) and MCF-7/ADR (IC 50 0.057 μM).

Background: Photosynthesis is a fundamental process that underlies the formation of crop yield, wherein light serves as the driving force and carbon dioxide (CO 2 ) as the raw material. These two factors have a direct influence on the progress and efficiency of photosynthesis in crops. Rapeseed is one of the four major oilseed crops worldwide. Plateau rapeseed has now become a research hotspot. However, the lack of high-yielding rapeseed germplasm resources on the plateau and the highly efficient strategy for screening them severely affect the development of rapeseed industry in plateau., Results: In the rapeseed experimental fields located on the plateau (Lhasa, Tibet), we measured abundant sunlight, characterized by an average daily photosynthetically active radiation (PAR) of 1413 μmol m -2  s -1 . In addition, the atmospheric CO 2 concentrations range from 300 to 400 ppm, which is only two-thirds of that in the plain (Chengdu, Sichuan). We found that under different measurement conditions of light intensity and CO 2 concentration, different rapeseed genotypes showed significant differences in leaf photosynthetic efficiency during the seedling stage. Moreover, the rapeseed materials with high photosynthetic efficiency under low CO 2 concentrations rather than high light intensity, exhibited significant advantages in biomass, yield, and oil content when cultivated on the plateau, indicating that the CO 2 is the key environmental factor which limited rapeseed production in plateau. Based on photosynthetic efficiency screening under low CO 2 concentrations, six rapeseed varieties SC3, SC10, SC25, SC27, SC29 and SC37, shown significantly higher yields in plateau environment compared to local control variety were obtained. In addition, the adaptability of rapeseed to plateau was found to be related to the activities of key Calvin cycle enzymes and the accumulation of photosynthetic products., Conclusions: This study established a screening strategy for plateau high-yielding rapeseed materials, obtained six varieties which were suitable for plateau cultivation, explored the mechanism of rapeseed response to the plateau environment, and thus provides a feasible strategy for plateau-adapted rapeseed breeding., (© 2024. The Author(s).)

During the COVID-19 pandemic, a significant increased number of masks were used and improperly disposed of. For example, the global monthly consumption of approximately 129 billion masks. Masks, composed of fibrous materials, can readily release microplastics, which may threaten various soil ecosystem components such as plants, animals, microbes, and soil properties. However, the specific effects of mask-derived microplastics on these components remain largely unexplored. Here, we investigated the effects of mask-derived microplastics (grouped by different concentrations: 0, 0.25, 0.5, and 1 % w/w) on soil physicochemical properties, microbial communities, growth performance of lettuce (Lactuca sativa L. var. ramosa Hort.) and earthworm (Eisenia fetida) under laboratory conditions for 80 days. Our findings suggest that mask-derived microplastics reduced soil bulk density while increasing the mean weight diameter of soil aggregates and modifying nutrient levels, including organic matter, potassium, nitrogen, and phosphorus. An increase in the abundance of denitrification bacteria (Rhodanobacteraceae) was also observed. Mask-derived microplastics were found to reduce lettuce germination, and a hormesis effect of low-concentration stimulation and high-concentration inhibition was observed on biomass, chlorophyll, and root activity. While the mortality of earthworms was not significantly affected by the mask-derived microplastics, but their growth was inhibited. Collectively, our results indicate that mask-derived microplastics can substantially impact soil properties, plant growth, and earthworm health, with potential implications for soil ecosystem functionality., 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. Published by Elsevier B.V.)

Celastrol is a quinone methyl triterpenoid monomeric ingredient extracted from the root of Tripterygium wilfordii . Celastrol shows potential pharmacological activities in various diseases, which include inflammatory, obesity, cancer, and bacterial diseases. However, the application prospect of celastrol is largely limited by its low bioavailability, poor water solubility, and undesired off-target cytotoxicity. To address these problems, a number of drug delivery methods and technologies have been reported to enhance the efficiency and reduce the toxicity of celastrol. We classified the current drug delivery technologies into two parts. The direct chemical modification includes nucleic acid aptamer-celastrol conjugate, nucleic acid aptamer-dendrimer-celastrol conjugate, and glucolipid-celastrol conjugate. The indirect modification includes dendrimers, polymers, albumins, and vesicular carriers. The current technologies can covalently bond or encapsulate celastrol, which improves its selectivity. Here, we present a review that focalizes the recent advances of drug delivery strategies in enhancing the efficiency and reducing the toxicity of celastrol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Wang, Li, Lu and Wang.)

Tetrandrine (TET) possesses multiple pharmacological activities and could suppress tumor proliferation via PI3K pathway inhibition. However, inferior antitumor activity and potential toxicity limit its clinical application. In the present study, a series of 14-sulfonamide and sulfonate TET derivatives were designed, synthesized, and evaluated for biological activities. Through structural-activity relationship studies, compound 3c with α, β-unsaturated carbonyl group exhibited the most potent activity against all tested tumor cell lines (including Hela, HCT116, HepG2, MCF-7, and SHSY5Y), as well as negligible toxicity against normal cell lines LO2 and HEK293. Additionally, compound 3c effectively inhibited HCT116 and CT26 cell proliferation in vitro with increased cell proportion in the G2/M phase, activated the mitochondrial apoptosis pathway, and induced colon cancer cell apoptosis by suppressing the PI3K/AKT/mTOR pathway. The further molecular docking results confirmed that compound 3c is potentially bound to multiple residues in PI3K with a stronger binding affinity than TET. Ultimately, compound 3c dramatically suppressed tumor growth in the CT26 xenograft tumor model, without noticeable visceral toxicity detected in the high-dose group. In summary, compound 3c might present new insights for designing new PI3K inhibitors and be a potential candidate for colon cancer treatment., 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 Inc. All rights reserved.)

The sympathetic nervous system (SNS) affects many functions of the body. SNS fibers regulate many aspects of liver function, repair, and regeneration. However, in the model of bile duct ligation (BDL) in rats, the kind of impact caused by the regulation of liver SNS on liver fibrosis and liver regeneration is unclear. The main research objective of this experiment is to examine the effect of SNS on liver fibrosis and liver regeneration. Twenty-four male Sprague-Dawley (SD) rats were assigned randomly to four groups. These groups included the sham surgery group (sham), model group (BDL), 6-hydroxydopamine group (BDL+6-OHDA), and spinal cord injury group (BDL+SCI). In the sham group, only exploratory laparotomy was performed without BDL. In the 6-OHDA group, 6-OHDA was used to remove sympathetic nerves after BDL. In the spinal cord injury group, rats underwent simultaneous BDL and spinal cord injury. After 3 weeks of feeding, four groups of rats were euthanized using high-dose anesthesia without pain. Moreover, liver tissue and blood were taken to detect liver fibrosis and regeneration indicators. After intraperitoneal injection of 6-OHDA into BDL rats, liver fibrosis indicators decreased. The administration of the injection effectively alleviated liver fibrosis and inhibited liver regeneration. However, after SCI surgery in BDL rats, liver fibrosis indicators increased. This resulted in exacerbating liver fibrosis and activating liver regeneration. The SNS plays a role in contributing to the liver injury process in the rat BDL model. Therefore, regulating the SNS may become a novel method for liver injury treatment., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand-based and structure-based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC 50 values below 1000 nM. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K-means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds., (© 2023 John Wiley & Sons Ltd.)

Triple-negative breast cancer (TNBC), as the most aggressive subtype of breast cancer, presents a scarcity of miraculous drugs in suppressing its proliferation and metastasis. Bruceine A (BA) is a functional group-rich quassin compound with extensive and distinctive pharmacological activities. Within the present study, we investigated the capabilities of BA in suppressing TNBC proliferation and metastasis as well as its potential mechanisms. The results displayed that BA dramatically repressed the proliferation of MDA-MB-231 and 4T1 cells with corresponding IC 50 values of 78.4 nM and 524.6 nM, respectively. Concurrently, BA arrested cells in G1 phase by downregulating cycle-related proteins Cyclin D1 and CDK4. Furthermore, BA distinctly induced mitochondrial dysfunction as manifested by diminished mitochondrial membrane potential, elevated reactive oxygen species generation, minimized ATP production, and Caspase-dependent activation of the mitochondrial apoptosis pathway. Additionally, BA restrained the invasion and metastasis of TNBC cells by repressing MMP9 and MMP2 expression. Intriguingly, after pretreatment with MEK activator C16-PAF, the inhibitory effect of BA on MEK/ERK pathway was notably diminished, while the proliferation suppression and metastasis repression exerted by BA were all strikingly curtailed. Molecular docking illustrated that BA potently combined with residues on the MEK1 protein with the presence of diverse intermolecular interactions. Ultimately, BA effectively suppressed tumor growth in the 4T1 xenograft tumor model with no detectable visceral toxicity in the high-dose group and, astonishingly, repressed tumor metastasis in the 4T1-luc lung metastasis model. Collectively, our study demonstrates that BA is a promising chemotherapeutic agent for treating TNBC and suppressing lung metastasis., Competing Interests: Declaration of Competing Interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of the manuscript entitled., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Ursolic acid (UA) can be used in the MS treatment with anti-inflammatory and neuroprotective activities. However, UA is insoluble in water, which may affect its medication effectiveness. In our previous study, UAOS-Na, a water-soluble derivative of UA was obtained. In this study, we evaluated the pharmacological effects and explored its underlying mechanism of UAOS-Na on experimental autoimmune encephalomyelitis (EAE)., Methods: Firstly, the pharmacodynamics of UAOS-Na was investigated in EAE and Cuprizone-induced mice. And then the possible mechanisms were investigated by TMT proteomics and verified by in vitro and in vivo experiments., Results: UAOS-Na (30 mg/kg/d) delayed the onset time of EAE from 11.78 days post immunization (dpi) to 14.33 dpi, reduced the incidence from 90.0% to 42.9%. UAOS-Na (60 mg/kg/d) reduced the serum levels of IFN-γ, IL-17A, TNF-α and IL-6, reduced the mononuclear cell infiltration of spinal cord, and inhibited the overexpression of key transcription factors T-bet and ROR-γt of EAE mouse spinal cord. In addition, UAOS-Na attenuated demyelination and astrogliosis in the CNS of EAE and cuprizone-induced mice. Mechanistically, proteomics showed that 96 differential expression proteins (DEPs) were enriched and 94 were upregulated in EAE mice compared with normal group. After UAOS-Na treatment, 16 DEPs were enriched and 15 were downregulated, and these DEPs were markedly enriched in antigen processing and presentation (APP) signaling pathway. Moreover, UAOS-Na downregulated the protein levels of Tapbp and H2-T23 in MHC-I antigen presentation pathway and reduced the proliferation of splenic CD8 T cells, thereby inhibiting the CNS infiltration of CD8 T cells., Conclusion: Our findings demonstrated that UAOS-Na has both myelin protective and anti-inflammatory effects. And it could reduce the inflammation of MS by downregulating the expression of Tapbp and H2-T23 in the MHC-I antigen presentation pathway., Competing Interests: LC and JD were employed by Amway (Shanghai) Innovation and Science Co., Ltd. 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 Wang, Gu, Yang, Chen, Chen, Du, Wu and Li.)

Cystic echinococcosis (CE) is a worldwide neglected zoonotic disease caused by infection with the larval stage of the tapeworm Echinococcus granulosus sensu lato (E. granulosus s.l.), which predominantly resides in the liver accompanied by mild inflammation. Macrophages constitute the main cellular component of the liver and play a central role in controlling the progression of inflammation and liver fibrosis. However, the role of hepatic macrophages in the establishment and growth of hydatid cysts in the liver during E. granulosus sensu stricto (E. granulosus s.s.) infection has not been fully elucidated. Here, we showed that CD68+ macrophages accumulated in pericystic areas of the liver and that the expression of CD163, a marker of anti-inflammatory macrophages, was more evident in active CE patients than in inactive CE patients. Moreover, in a mouse model of E. granulosus s.s. infection, the pool of hepatic macrophages expanded dramatically through the attraction of massive amounts of monocyte-derived macrophages (MoMFs) to the infection site. These infiltrating macrophages preferentially polarized toward an iNOS+ proinflammatory phenotype at the early stage and then toward a CD206+ anti-inflammatory phenotype at the late stage. Notably, the resident Kupffer cells (KCs) predominantly maintained an anti-inflammatory phenotype to favor persistent E. granulosus s.s. infection. In addition, depletion of hepatic macrophages promoted E. granulosus s.s. larval establishment and growth partially by inhibiting CD4+ T-cell recruitment and liver fibrosis. The above findings demonstrated that hepatic macrophages play a vital role in the progression of CE, contributing to a better understanding of the local inflammatory responses surrounding hydatid cysts and possibly facilitating the design of novel therapeutic approaches for CE., 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.)

Purpose: This study aimed to identify independent risk factors for immediate postoperative deep vein thrombosis (DVT) in patients with open wedge high tibial osteotomy (OWHTO) and to develop and validate a predictive nomogram., Methods: Patients who underwent OWHTO for knee osteoarthritis (KOA) from June 2017 to December 2021 were retrospectively analyzed. Baseline data and laboratory test results were collected, and the occurrence of DVT in the immediate postoperative period was regarded as the study outcome event. Multivariable logistic regression identified independent risk factors associated with a higher incidence of immediate postoperative DVT. The predictive nomogram was constructed based on the analysis results. The stability of the model was further assessed in this study using patients from January to September 2022 as an external validation set., Results: 741 patients were enrolled in the study, of which 547 were used in the training cohort and the other 194 for the validation cohort. Multivariate analysis revealed a higher Kellgren-Lawrence (K-L) grade (III vs. I-II OR 3.09, 95% CI 0.93-10.23. IV vs. I-II OR 5.23, 95% CI 1.27-21.48.), platelet to hemoglobin ratio (PHR) > 2.25 (OR 6.10, 95% CI 2.43-15.33), Low levels of albumin (ALB) (OR 0.79, 95% CI 0.70-0.90), LDL-C > 3.40 (OR 3.06, 95% CI 1.22-7.65), D-dimer > 1.26 (OR 2.83, 95% CI 1.16-6.87) and BMI ≥ 28 (OR 2.57, 95% CI 1.02-6.50) were the independent risk factors of immediate postoperative DVT. The concordance index (C-index) and Brier score of the nomogram were 0.832 and 0.036 in the training set, and the corrected values after internal validation were 0.795 and 0.038, respectively. The receiver-operating characteristic (ROC) curve, the calibration curve, the Hosmer-Lemeshow test, and the decision curve analysis (DCA) performed well in both the training and validation cohorts., Conclusion: This study developed a personalized predictive nomogram with six predictors, which allows surgeons to stratify risk and recommended immediate ultrasound scans for patients with any of these factors., Level of Evidence: III., (© 2023. The Author(s) under exclusive licence to European Society of Sports Traumatology, Knee Surgery, Arthroscopy (ESSKA).)

Background: The effects of secondary collateral compensation on outcomes remain unclear in patients with acute basilar artery occlusion (BAO) after endovascular treatment (EVT). This study aimed to evaluate the benefits of the anastomosis between the posterior inferior cerebellar artery (PICA) and the superior cerebellar artery (SCA) in BAO after EVT., Methods: This cohort study was conducted using data from the Endovascular Treatment for Acute Basilar Artery Occlusion Study Registry. Patients with acute BAO and treated with EVT were included. The primary outcome was a modified Rankin Scale score of 0-2 at 90 days. Safety outcomes included symptomatic intracerebral hemorrhage (SICH) and 90-day mortality., Results: Of the 646 patients included in the study, 196 (30.3%) patients had a PICA-SCA anastomosis. The PICA-SCA anastomosis was significantly associated with independent functional outcome at 90 days (67/196 (34.2%) vs 109/450 (24.2%), adjusted OR (aOR) 1.80 (95% CI 1.13 to 2.86), p=0.01) and was significantly associated with a decreased rate of SICH (40/442 (9.0%) vs 5/193 (2.6%), aOR 0.29 (95% CI 0.11 to 0.76), p=0.01). No significant difference was found between PICA-SCA anastomosis and 90-day mortality (219/450 (48.7%) vs 80/196 (40.8%), aOR 0.72 (95% CI 0.48 to 1.08), p=0.11). Subgroup analysis showed that the association between independent functional outcome and PICA-SCA anastomosis was strongest in patients with middle BAO (27/77 (35.1%) vs 22/118 (18.6%), aOR 2.64 (95% CI 1.13 to 6.15), p=0.03)., Conclusions: The PICA-SCA anastomosis is significantly associated with better functional outcomes in patients with acute BAO after EVT, especially in those with middle BAO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Mining activities induce some social problems, such as polluted environments, the destruction of aquatic live, which have long been debated by scholars and practitioners. To mitigate this problem, underpinning dynamic capability view, our study explores whether the digital transformation (DT) affects corporate social responsibility (CSR) by using 1308 Chinese mining A-shared listed firms from 2010 to 2021, and how the potential relationship is moderated by environmental uncertainty (EU) and supply chain concentration (SCC). Applying fixed effects regressions, we find that DT fosters CSR in the mining industry, but CSR performance is weakened when DT processed at higher EU and SCC respectively. Our findings enrich the literature on CSR of mining industry and highlight that DT is an important driver that shapes CSR practice., Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

MicroRNA-21 (miRNA-21) is a kind of RNA that exists in biological fluids such as blood, urine and saliva. It has over expression in liver cancer and has different expression in different stages of cancer. However, due to the characteristics of small base number, short length, low abundance and easy degradation of miRNA-21, the detection of miRNA-21 is a challenging subject. Visualization, sensitive, specific and stable detection of tumor suppressor or oncogene microRNAs (miRNAs) remains challenging and is highly significant for clinical diagnostics. To solve this problem, we have developed a target-triggered hybridization assembly DNA machine for intracellular miRNA imaging based on strand displacement amplification (SDA) and branched hybridization chain reaction (B-HCR). In this approach, the target miRNA could hybridize with the template probe to trigger the SDA, resulting in the formation of nicked fragments (NFs) that hybridized with hairpin probe1 (HP1). The opened HP1 could hybridize with hairpin probe2 (HP2), leading to the self-assembly of hyperbranched DNA nanostructures through B-HCR. As expected, the newly developed method exhibits a detection limit down to 11.3 pM miRNA-21 and achieves high selectivity toward miRNA-21 against other interfering miRNAs. Due to its superior sensitivity and selectivity, our method can be further used to detect miRNA-21 in human serum samples. By taking advantage of intelligent design, the proposed method was also used for image miRNA-21 expression levels in different cell lines. This method shows a broad application in clinical diagnosis., (© 2023. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)

The exploration of non-noble metal catalysts for alkane dehydrogenation and their catalytic mechanisms is the priority in catalysis research. Here, we report a high-density coordinatively unsaturated Zn cation (Zn cus ) catalyst for the direct dehydrogenation (DDH) of ethylbenzene (EB) to styrene (ST). The catalyst demonstrated good catalytic performance (∼40% initial EB conversion rate and >98% ST selectivity) and excellent regeneration ability in the reaction, which is attributed to the high-density (HD) distribution and high-stability structure of Zn cus active sites on the surface of zinc silicate (HD-Zn cus @ZS). Density functional theory (DFT) calculations further illustrated the reaction pathway and intermediates, supporting that the Zn cus sites can efficiently activate the C-H bond of ethyl on ethylbenzene. Developing the high-density Zn cus catalyst and exploring the catalytic mechanism laid a good foundation for designing practical non-noble metal catalysts.

Supramolecular electronics provide an opportunity to introduce molecular assemblies into electronic devices through a combination of noncovalent interactions such as [π···π] and hydrogen-bonding interactions. The fidelity and dynamics of noncovalent interactions hold considerable promise when it comes to building devices with controllable and reproducible switching functions. Here, we demonstrate a strategy for building electronically robust switches by harnessing two different noncovalent interactions between a couple of pyridine derivatives. The single-supermolecule switch is turned ON when compressing the junction enabling [π···π] interactions to dominate the transport, while the switch is turned OFF by stretching the junction to form hydrogen-bonded dimers, leading to a dramatic decrease in conductance. The robustness and reproducibility of these single-supermolecule switches were achieved by modulating the junction with Ångström precision at frequencies of up to 190 Hz while obtaining high ON/OFF ratios of ∼600. The research presented herein opens up an avenue for designing robust bistable mechanoresponsive devices which will find applications in the building of integrated circuits for microelectromechanical systems.

Background: Cardiac fibrosis contributes to myocardial remodeling after myocardial infarction (MI), which may facilitate the progression to end-stage heart failure. Dengzhan Shengmai capsule (DZSMC), a traditional Chinese formula derived from Shen-mai powder, has shown remarkable therapeutic effects against cardiovascular diseases. However, the effect of DZSMC on cardiac fibrosis and its potential mechanism are ill-defined., Purpose: To evaluate the effects of DZSMC on cardiac fibrosis after myocardial infarction (MI) and investigate its underlying mechanism., Method: In vivo, MI rat models were established by permanently ligation of left anterior descending coronary arteries (LAD) and then were intragastrically treated with DZSMC or captopril for 5 weeks. Ex vivo, an everted intestinal sac model was used to study the intestinal absorption components of DZSMC, which were further identified through an ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS) method. In vitro, a myocardium fibrotic model was constructed by stimulating primary cardiac fibroblasts (CFs) with 1 μM Ang II. Subsequently, the absorbent solution of DZSMC from the intestinal sac was performed on the cell models to further elucidate its anti-fibrotic effects and underling mechanism., Results: In vivo results showed that DZSMC significantly improved cardiac function and inhibited pathological myocardial fibrosis in post-MI rats in a dose dependent manner. Histological analysis and western blot results demonstrated that DZSMC treatment significantly reduced the expression of extracellular matrix (ECM)-related proteins, including LTBP2, TGF-βR1, Smad3 and pSmad3, in myocardial tissue of MI rats. Ex vivo results showed that 18 absorbed components were identified, mainly consisting of phenolic acids, flavonoids and lignans, which may be responsible for the anti-fibrotic effects. Further in vitro results validated that DZSMC attenuated myocardial fibrosis by suppressing the expression of LTBP2, TGF-β1 and pSmad3., Conclusion: DZSMC ameliorates cardiac function and alleviates cardiac fibrosis, which may be mediated by inhibition of CFs activation and reduction of excessive ECM deposition via LTBP2 and TGF-β1/Smad3 pathways., Competing Interests: Declaration of Competing Interest The authors have no potential conflict of interest to disclose., (Copyright © 2023. Published by Elsevier GmbH.)

The utilization of carbon resources stored in plastic polymers through chemical recycling and upcycling is a promising approach for mitigating plastic waste. However, most current methods for upcycling suffer from limited selectivity towards a specific valuable product, particularly when attempting full conversion of the plastic. We present a highly selective reaction route for transforming polylactic acid (PLA) into 1,2-propanediol utilizing a Zn-modified Cu catalyst. This reaction exhibits excellent reactivity (0.65 g g cat -1  h -1 ) and selectivity (99.5 %) towards 1,2-propanediol, and most importantly, can be performed in a solvent-free mode. Significantly, the overall solvent-free reaction is an atom-economical reaction with all the atoms in reactants (PLA and H 2 ) fixed into the final product (1,2-propanediol), eliminating the need for a separation process. This method provides an innovative and economically viable solution for upgrading polyesters to produce high-purity products under mild conditions with optimal atom utilization., (© 2023 Wiley-VCH GmbH.)

Infection with the cestode Echinococcus multilocularis (E. multilocularis) causes alveolar echinococcosis (AE), a tumor-like disease predominantly affecting the liver but able to spread to any organ. T cells develop functional defects during chronic E. multilocularis infection, mostly due to upregulation of inhibitory receptors such as T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and programmed death-1 (PD-1). However, the role of lymphocyte activation gene-3 (LAG3), an inhibitory receptor, in AE infection remains to be determined. Here, we discovered that high expression of LAG3 was mainly found in CD4+ T cells and induced regulatory T cells (iTregs) in close liver tissue (CLT) from AE patients. In a mouse model of E. multilocularis infection, LAG3 expression was predominantly found in T helper 2 (Th2) and Treg subsets, which secreted significantly more IL-4 and IL-10, resulting in host immune tolerance and disease progression at a late stage. Furthermore, LAG3 deficiency was found to drive the development of effector memory CD4+ T cells and enhance the type 1 CD4+ T-cell immune response, thus inhibiting metacestode growth in vivo. In addition, CD4+ T cells from LAG3-deficient mice produced more IFN-γ and less IL-4 when stimulated by E. multilocularis protoscoleces (EmP) antigen in vitro. Finally, adoptive transfer experiments showed that LAG3-knockout (KO) CD4+ T cells were more likely to develop into Th1 cells and less likely to develop into Tregs in recipient mice. Our work reveals that high expression of LAG3 accelerates AE disease progression by modulating the immune imbalance of CD4+ T-cell subsets. These findings may provide a novel immunotherapeutic strategy against E. multilocularis infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Li 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.)

Despite numerous reports on phytoremediation of heavy metals contaminated soil, there are few reports on plant retention of heavy metals in the mining area slope. This study was the first of its kind to explore the cadmium (Cd) retention capacity of the blueberry (Vaccinium ashei Reade). Firstly, we investigated the stress response of blueberry to different soil Cd concentrations (1, 5, 10, 15, 20 mg/kg) to assess its potential for phytoremediation by pot experiments. The results showed that the blueberry biomass exposed to 10 and 15 mg/kg Cd was significantly increased compared with the control (1 mg/kg Cd); the blueberry crown increased by 0.40% and 0.34% in 10 and 15 mg/kg Cd-contaminated soil, respectively, compared with control; the blueberry heigh did not even change significantly in each treatment group; the total chlorophyll content, peroxidase and catalase activity of blueberry were enhanced in 5-20 mg/kg Cd treatments. Furthermore, the Cd contents of blueberry in the root, stem and leaf increased significantly as the Cd concentration of soil increased. We found that more Cd accumulated in blueberry root: the bioaccumulation concentration factor was root > stem > leaf for all groups; the residual-Cd (Cd speciation) in soil increased by 3.83%-411.11% in blueberry-planted versus unplanted groups; blueberry improved the Cd-contaminated soil micro-ecological environment including soil organic matter, available K and P, as well as microbial communities. Then, to investigate the effect of blueberry cultivation on Cd migration, we developed a bioretention model and revealed that soil Cd transport along the model slope was significantly weakened by blueberry cultivation, especially at the bottom of the model. In a word, this research suggests a promising method for the phytoremediation of Cd-contaminated soil and the reduction of Cd migration in mining areas., 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. Published by Elsevier Ltd.)

Bruceine A (BA), a quassic ester from bruceine javanica , regulates diverse intracellular signal transduction pathways and manifests a variety of biological activities, however, its pharmacological mechanism in treating colon cancer (CC) is unclear. In this study, we investigated the anticancer effects of BA on CC cells and the underlying mechanisms. The network pharmacology research indicated that Akt1 and Jun and PI3K/Akt pathways are the predominant targets and critical signaling pathways, respectively, for BA treatment of CC. Meanwhile, molecular docking results implied that BA could conjugate to pivotal proteins in the PI3K/Akt pathway. BA remarkably suppressed the proliferation of CC cells HCT116 and CT26 with 48-h IC50 of 26.12 and 229.26 nM, respectively, and the expression of p-PI3K/p-Akt was restrained by BA at the molecular level as verified by Western blot assay. Further mechanistic studies revealed BA impacted cell cycle-related proteins by regulating the expression of P27 (a protein bridging the PI3K/Akt signaling pathway with cycle-related proteins), arresting the cell cycle in the G2 phase, inhibiting the proliferation of HCT116 and CT26, and facilitated the apoptosis in CC cells by activating the mitochondria-associated apoptosis protein Bax and accumulating reactive oxygen species, in addition to BA apparently inhibited the migration of CC cells. Taken together, our results demonstrated that BA might be a promising chemotherapy drug in the treatment of CC., 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, Cao, Zuo, Cheng, Liu, Xia, Ren, Deng, Wang and Lu.)

A stereoselective and column-economic approach to (+)-penostatins A and C has been developed. The multisubstituted A ring and B/C rings in their unique tricyclic framework are constructed through a Diels-Alder reaction/ozonolysis sequence and an exo intramolecular hetero-Diels-Alder reaction with high chemo-, regio-, and stereoselectivity. Using this route, (+)-penostatins A and C can be synthesized in 19 and 20 steps, respectively, with a good overall yield involving only five or six column chromatographic purifications.

Biomarkers are essential in biology, physiology, and pharmacology; thus, their detection is of extensive importance. Fluorescent probes provide effective tools for detecting biomarkers exactly. Excited state intramolecular proton transfer (ESIPT), one of the significant photophysical processes that possesses specific photoisomerization between Keto and Enol forms, can effectively avoid annoying interference from the background with a large Stokes shift. Hence, ESIPT is an excellent choice for biomarker monitoring. Based on the ESIPT process, abundant probes were designed and synthesized using three major design methods. In this review, we conclude probes for 14 kinds of biomarkers based on ESIPT explored in the past five years, summarize these general design methods, and highlight their application for biomarker detection in vitro or in vivo .

Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogene ETS2 was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with the ETS2 promoter and was required for the transcription activation of ETS2. Strikingly, the ETS2-SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level of ETS2 expression. The tumor-specific activation of ETS2-SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in the ETS2-SE and the genetic variant modulated the level of ETS2 expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing of MECOM induced significant downregulation of ETS2 in CRC cells, and the level of MECOM and ETS2 correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenic ETS2 expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription., (© 2023. The Author(s).)

Background and Purpose: As a complex and challenging complication for the patients with diabetes mellitus, diabetic ulcers are difficult to heal and current strategies cannot fulfill the patients' requirements. Pien Tze Huang (PZH) is a standardized medicine approved for various wounds treatments, and this study systematically investigated the effect and mechanism of intragastric administration of PZH (I-PZH) on diabetic wound healing., Methods and Results: The effect of I-PZH on the healing of full-thickness wounds in rats with diabetes mellitus which was induced by high fat diet followed by streptozotocin injection was evaluated, and RNA sequencing (RNA-seq) and targeted central carbon metabolism metabolomics were combined to explore the underlying mechanism. I-PZH promoted wound healing, facilitated extracellular matrix synthesis, and maintained body weight of rats, but did not affect fasting blood glucose levels. Additionally, I-PZH significantly decreased 8-OHdG, cleaved caspase 3 and MMP9 levels, and increased TGF-β1 expression. RNA-seq analysis showed that I-PZH inhibited inflammation and that the vital common targets were TLR2, IL-17A and IL-1β; specifically affected "energy derivation by oxidation of organic compounds" with UQCRC1, NDUFS3 and SDHA as vital specific targets. Further experiments confirmed that I-PZH reduced TLR2, IL-17A and IL-1β, increased UQCRC1, SDHA, NDUFS3, promoted ATP synthesis and restored activity of mitochondrial respiratory chain complexes I and III in diabetic wounds. Metabolomics by HPLC-MS/MS analysis showed that I-PZH reversed multiple energy metabolism-related metabolites such as glucuronic acid, GMP, d-gluconic acid, cis-aconitic acid, ribose 5-phosphate and pantothenate., Conclusion: This study highlights the important role of inflammation and energy generation in diabetic wound healing, reveals wound repair mechanism of PZH and promotes its clinical application in diabetic wound treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier GmbH.)

Background: Acute ischemic stroke due to basilar artery occlusion (BAO) is associated with the highest mortality in patients with large vessel occlusion. This study aimed to identify modifiable risk factors of early mortality in patients with BAO., Methods and Results: This was a cohort study of consecutive patients with BAO admitted to 47 stroke centers in China between January 2014 and May 2019. The primary outcome was all-cause mortality within 7 days after hospitalization. Of 829 patients, 164 died (0-3 days: 115; 4-7 days: 49) within 7 days after hospitalization. Among pre- and periprocedural variables, higher admission National Institutes of Health Stroke Scale (NIHSS, adjusted OR, 1.06, 95% CI: 1.04-1.09; p < 0.001), lower admission posterior circulation-Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS, adjusted OR, 0.88, 95% CI: 0.79-0.98; p = 0.02), lower Basilar Artery on Computed Tomography Angiography score (BATMAN, adjusted OR, 0.84, 95% CI: 0.76-0.93; p = 0.001), and recanalization failure (adjusted OR, 2.99, 95% CI: 2.04-4.38; p < 0.001) were independently associated with a higher risk of early mortality. Herniation (adjusted OR, 2.84, 95% CI: 1.52-5.30; p = 0.001) is an independent postprocedural predictor of early mortality. In patients dying ≤3 days, higher NIHSS (p < 0.001), lower pc-ASPECTS (p = 0.01), lower BATMAN (p = 0.004), recanalization failure (p < 0.001), herniation (p = 0.001), gastrointestinal hemorrhage (p = 0.046), and absence of pneumonia (p < 0.001) were independent predictors of early mortality. Higher NIHSS (p = 0.01), recanalization failure (p < 0.001), and pneumonia (p = 0.03) were independently associated with early mortality between 4 and 7 days., Conclusions: Recanalization failure, herniation, gastrointestinal hemorrhage, and pneumonia are potentially modifiable risk factors for early mortality in basilar artery occlusion., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: This study was designed to investigate clinical efficiency and application indications of hepatic lobe hyperplasia techniques for advanced hepatic alveolar echinococcosis (AE) patients., Methods: A retrospective case series covering 19 advanced hepatic AE patients admitted to the First Affiliated Hospital of Xinjiang Medical University from September 2014 to December 2021 and undergoing hepatic lobe hyperplasia techniques due to insufficient remnant liver volume were analyzed. Changes of liver function, lesions volume, remnant liver volume, total liver volume before and after operation have been observed., Results: Among the patients, 15 underwent portal vein embolization (PVE). There was no statistical difference in total liver volume and lesions volume before and after PVE (P > 0.05). However, the remnant liver volume was significantly increased after PVE (P < 0.05). The median monthly increase rate in future liver remnant volume (FLRV) after PVE stood at 4.49% (IQR 3.55-7.06). Among the four patients undergoing two-stage hepatectomy (TSH), FLRV was larger than that before the first stage surgery, and the median monthly increase rate in FLRV after it stood at 3.34% (IQR 2.17-4.61). Despite no statistical difference in total bilirubin (TBil), albumin (Alb), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) in all patients with PVE, four patients who underwent TSH showed a decrease in ALT, AST and GGT. During the waiting process before the second stage operation, no serious complications occurred in all patients., Conclusions: For patients suffering from advanced hepatic AE with insufficient FLRV, PVE and TSH are safe and feasible in promoting hepatic lobe hyperplasia., (© 2022. The Author(s).)

A new synthetic strategy for C7-carbasugars is developed via an intramolecular Morita-Baylis-Hillman reaction, in which a substituted dial precursor prepared from d-mannose cyclizes smoothly in the presence of DMAP to afford polyhydroxylated cyclohex-1-enecarbaldehyde with good yield. By employment of the cyclization products as key intermediates, the first syntheses of carbasugar ester 1 and epicorepoxydon A, as well as practical syntheses of epoxydines B and C, (-)-MK7607, (-)-streptol, and (-)-gabosine E are achieved.

Excessive accumulation of heavy metal(loid)s in agricultural environment usually originates from anthropogenic activities. Both large diversities of emission sources and complexity of plant accumulation challenge the understanding of the site-specific effects of emission sources on heavy metal(loid)s in wheat grains. Herein, both soil samples and wheat grain samples (n = 80) were collected from the farmland of Jiyuan City, China. Soil and grain burdens of heavy metal(loid)s were determined by inductively coupled plasma mass spectrometry (ICP-MS) and/or X-ray fluorescence spectrometry (XRF). The quotients (Q) were developed to indicate relative impacts of industrial plants and traffic to soil sites. Principal component analysis-absolute principal component scores-multivariate linear regression (PCA-APCS-MLR) analysis was conducted to reveal the source contributions to heavy metal(loid)s in grains, considering Q values, soil, and wheat grain data. Results showed that contributions of main sources and factors drastically varied with soil sites, and usually overlapped to different extents. For grain Cd and grain Pb, natural soil silicate (0.066/0.104 mg/kg) and iron-bearing minerals (- 0.044/ - 0.174 mg/kg) contributed to high extents, while metal smelting activities (0.018/0.019 mg/kg) and agronomic activities (- 0.017/ - 0.019 mg/kg) unexpectedly posed low or moderate contributions. The pH-mediated availability of soil Cd (0.035 mg/kg) and the sand-dust weather (0.028 mg/kg) also made considerable contributions to grain Cd. For grain As, both natural soil iron-bearing (- 0.048 mg/kg) and silicate minerals (- 0.013 mg/kg) made negative contributions. The results benefit to the decision-making of pollution remediation of farmland soils in the regional scales., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Clubroot disease, caused by Plasmodiophora brassicae , is a devastating disease that results in substantial yield loss in Brassicaceae crops worldwide. In this study, we identified a clubroot disease resistance (CR) Brassica napus , "Kc84R," which was obtained by mutation breeding. Genetic analysis revealed that the CR trait of "Kc84R" was controlled by a single dominant locus. We used the bulked segregant analysis sequencing (BSA-seq) approach, combined with genetic mapping based on single nucleotide polymorphism (SNP) markers to identify CR loci from the F 2 population derived from crossing CR "Kc84R" and clubroot susceptible "855S." The CR locus was mapped to a region between markers Bn SNP14198336 and Bn SNP14462201 on the A03 chromosome, and this fragment of 267 kb contained 68 annotated candidate genes. Furthermore, we performed the CR relation screening of candidate genes with the model species Arabidopsis. An ERF family transcriptional activator, Bn ERF034, was identified to be associated with the CR, and the corresponding Arabidopsis homozygous knockout mutants exhibited more pronounced resistance compared with the wild-type Col-0 and the transgenic lines of BnERF034 in response to P. brassicae infection. Additionally, the expression analysis between resistant and susceptible materials indicated that BnERF034 was identified to be the most likely CR candidate for the resistance in Kc84R. To conclude, this study reveals a novel gene responsible for CR. Further analysis of BnERF034 may reveal the molecular mechanisms underlying the CR of plants and provide a theoretical basis for Brassicaceae resistance breeding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Su and Wang.)

Sclerotinia sclerotiorum , a worldwide distributed fungal pathogen, causes serious adverse effects on the yield and seed quality of rapeseed. Polygalacturonase-inhibiting proteins (PGIPs) can protect the cell wall from degradation by pathogen-secreted polygalacturonases (PGs). The present study found several PGIPs from Oryza sativa , especially OsPGIP6 and 3 have much higher inhibitory activities to SsPGs than BnPGIP2 from Brassica napus . Among them, OsPGIP1, 4, 6 can significantly elevate the resistance of transgenic Arabidopsis to S. sclerotiorum . Subsequently, OsPGIP1, 3, 4, 6 were subjected to SSR resistance assay in transgenic rapeseed plants. Among which, OsPGIP6 showed the highest resistance to S. sclerotiorum . At 48 h after detached leaves inoculation, the lesion area of OE-OsPGIP6 rapeseed plants is only 17.93% of the non-transgenic line, and 22.17, 21.32, 52.78, 56.47%, compared to OE-BnPGIP2, OE-OsPGIP1, OE-OsPGIP2, OE-OsPGIP4, respectively. Furthermore, the lesion area of OE-OsPGIP6 reached 10.11% compared to WT at 72 hpi. Also, the lesion length on the stem of OE-OsPGIP6 plants was reduced by 36.83% compared to WT. These results reveal that OsPGIP family, especially OsPGIP6 , has a great potential in rapeseed S. sclerotiorum -resistance breeding., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yin, Wang, Li, Luo, Wei, Wang, Jiang, Lin and Zhao.)