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Antibiotic resistance has become a serious threat to public health, thus novel antibiotics are urgently needed to combat drug-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA). The 1,4-dicarbonylthiosemicarbazide is an interesting chemotype that could exhibit antibacterial activity. However, the currently available compounds are not as potent as clinical antibiotics. Herein, we adopted the computer-aided drug design strategy, substructure search, to retrieve antibacterial 1,4-dicarbonylthiosemicarbazide derivatives, and identified compound B5 (Specs ID: AG-690/15432331) from the Specs chemical library that exhibited moderate activity (minimum inhibitory concentration (MIC): 6.25 μg/mL) against Staphylococcus aureus ATCC 29213. Based on that compound, we further designed and synthesized 45 derivatives, and evaluated their antibacterial activity. Eight derivatives were more potent than or equivalent to vancomycin (MIC: 1.56 μg/mL). We compared the three most potent ones for their cytotoxicity to HepG2 and HUVEC cells and selected compound 1b as our lead compound for comprehensive biological evaluation. As a result, compound 1b exhibited a bacteriostatic mode, and was active against a panel of Gram-positive bacteria strains, metabolically stable, and effective to protect the mice from MRSA infection. More importantly, we applied 2D similarity calculation and reverse docking to predict potential targets of compound 1b. Through experimental validation and molecular dynamics simulation, we were able to confirm that compound 1b inhibited Staphylococcus aureus DNA gyrase (IC 50 : 1.81 μM) and DNA supercoiling, potentially by binding to the ATPase domain, where ASP81, GLU58 and GLN91 formed key hydrogen bonds. Taken together, we have discovered a new class of DNA gyrase inhibitors represented by compound 1b for the treatment of MRSA infection, through the design, synthesis, and biological evaluation of novel 1,4-dicarbonylthiosemicarbazides., 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. The Institute of Materia Medica, Chinese Academy of Medical Sciences has filed and been granted a patent that covers compound 1b (Patent Number: ZL201810091202. X)., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Introduction: Urolithiasis is characterized by a high morbidity and recurrence rate, primarily attributed to metabolic disorders. The identification of more metabolic biomarkers would provide valuable insights into the etiology of stone formation and the assessment of disease risk. The present study aimed to seek potential organic acid (OA) biomarkers from morning urine samples and explore new methods based on machine learning (ML) for metabolic risk prediction of urolithiasis., Methods: Morning urine samples were collected from 117 healthy controls and 156 urolithiasis patients. Gas chromatography-mass spectrometry (GC-MS) was used to obtain metabolic profiles. Principal component analysis (PCA) and ML were carried out to screen robust markers and establish a prediction evaluation model., Results: There were 25 differential metabolites identified, such as palmitic acid, L-pyroglutamic acid, glyoxylate, and ketoglutarate, mainly involving arginine and proline metabolism, fatty acid degradation, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylic acid metabolism. The urinary organic acid markers significantly improved the performance of the ML model. The sensitivity and specificity were up to 87.50% and 84.38%, respectively. The area under the receiver operating characteristic curve (AUC) was significantly improved (AUC = 0.9248)., Conclusion: The results suggest that OA profiles in morning urine can improve the accuracy of predicting urolithiasis risk, and possibly help to understand the involvement of metabolic perturbations in metabolic pathways of stone formation and to provide new insights., (The Author(s). Published by S. Karger AG, Basel.)

Psoriasis is a recurrent autoimmune disease characterized by seasonal and latitudinal variations. Double-stranded DNA (dsDNA) is a crucial component of nucleic acids and nucleosomes that provoke innate immune responses. Given the potential influence of climate on immunity and the development of autoimmune diseases, a comprehensive quantitative analysis of dsDNA levels in the population is warranted. In this case-control study conducted from 2016 to 2020, 10,110 psoriasis patients and matched controls from 12 regions in China were included. This study examined variations in serum dsDNA levels based on season and latitude. The results revealed significant associations between geographical location, climatic conditions, and season with serum dsDNA concentration. Individuals residing in Northern China exhibited significantly higher serum dsDNA levels compared to those in the South (1.00 vs. 0.96 ng/ml), and those in medium latitude regions had higher levels than their counterparts in areas with extreme latitudes (0.98 vs. 0.96 ng/ml). Furthermore, individuals in regions with low to medium ultraviolet exposure demonstrated higher serum dsDNA concentrations than those in areas with high ultraviolet levels (1.03 vs. 0.93 ng/ml), and individuals in winter showed higher levels than those in summer (1.03 vs. 0.92 ng/ml). Factors such as sex, UV index, humidity, and sunshine duration were inversely related to serum dsDNA levels, while age and daylight hours showed a positive association. These findings suggest that meteorological and climatic factors play a role in influencing serum dsDNA levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Rotator cuff tears (RCTs) are among the most common musculoskeletal disorders that affect quality of life. This study aimed to investigate the efficacy of ginsenoside Rb1 in RCTs and the mechanisms involved., Methods: First, a fibrotic model of FAPs was induced, and FAPs were cultured in media supplemented with different concentrations of ginsenoside Rb1. Next, a rat model of RCTs was constructed and treated with ginsenoside Rb1. Molecular docking was subsequently utilized to detect the binding of ginsenoside Rb1 and SFRP1. Finally, SFRP1 was knocked down and overexpressed in vivo and in vitro to investigate the mechanism of ginsenoside Rb1 and SFRP1 in RCTs., Results: Compared with the Normal group, FAP viability was decreased, but Collagen II, FN and α-SMA levels were increased in the Control group. After treatment with different concentrations of ginsenoside Rb1, FAP viability increased, but Collagen II, FN and α-SMA levels decreased. Among them, 60 µM ginsenoside Rb1 had the best effect. In vivo experiments revealed that ginsenoside Rb1 improved RCTs in rats. Molecular docking revealed the binding of ginsenoside Rb1 to SFRP1. Additionally, SFRP1 levels were lower in the Control group than in the Normal group. After treatment with ginsenoside Rb1, SFRP1 levels increased. In vivo, overexpressing SFRP1 along with ginsenoside Rb1 treatment further alleviated tendon tissue fibroblast infiltration and fat accumulation and further reduced the expression of Collagen II, FN, and α-SMA. In vitro, overexpressing SFRP1 along with ginsenoside Rb1 treatment further decreased the expression of CaMKII, PLC, PKC, Wnt, and β-catenin, further decreased the Ca 2+ fluorescence intensity and mitochondrial length, increased the red/green intensity, and decreased the MitoSOX fluorescence intensity. Additionally, overexpressing SFRP1 along with ginsenoside Rb1 treatment further increased cell proliferation, decreased apoptosis, reduced the protein expression of Collagen II, FN, and α-SMA in muscle tissue, and further reduced the levels of TNF-α, IL-1β, and IL-6 in the cell supernatant., Conclusions: Ginsenoside Rb1 inhibited the activation of the Wnt signaling pathway by promoting SFRP1 expression, thereby inhibiting mitochondrial function and Ca 2+ absorption to treat fat infiltration and muscle fibrosis caused by RCTs., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Animal Welfare Committee of Central South University (No. 2019sydw0198). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Previous studies have found that fibroblast growth factor receptor 4 (FGFR4) plays a crucial role in tumor development and metastasis. However, the potential role and underlying mechanisms of FGFR4 in the progression of TNBC remain unclear., Methods: Statistical analysis of FGFR4 expression data in public databases was used to reveal its role in TNBC. qRT-PCR was used to detect FGFR4 expression levels. The impact of FGFR4 level changes on TNBC cell proliferation was assessed using CCK-8 and colony formation assays, while Transwell invasion assays and JC-1 staining were employed to analyze the effects of FGFR4 level changes on the invasiveness and survival capability of TNBC cells. Differentially expressed genes were subjected to Gene Ontology, KEGG, and GSEA enrichment analyses to identify associated signaling pathways. Additionally, Oil Red O staining, fatty acid metabolite detection, and Western blot analysis were used to investigate the impact of FGFR4 and its inhibitor fisogatinib, as well as the AKT activator SC79, on the metabolic reprogramming of fatty acids in TNBC cells., Results: FGFR4 was found to be upregulated in breast cancer and correlated with poorer patient outcomes. Inhibition of FGFR4 resulted in reduced cell growth and invasion in TNBC cells. It also led to increased lipid accumulation, upregulated lipid biosynthesis-related genes, and downregulated lipolysis-related genes. Mechanistically, FGFR4 inhibition suppressed the activation of the AKT/RYR2 signaling pathway. Reactivating the AKT pathway reversed the suppressive effects of FGFR4 inhibition on TNBC progression., Conclusion: Dysregulated FGFR4 activates the AKT/RYR2 axis, leading to tumor proliferation, invasion, and altered lipid metabolism in TNBC. FGFR4 inhibition could potentially serve as a novel therapeutic strategy for TNBC treatment., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The specialized metabolism of St. John's wort, Hypericum perforatum L., is a key focus in medicinal plant research due to its hallmark bioactive compounds hyperforin and hypericin. Known for its traditional medicinal uses dating back to ancient times, St. John's wort is currently used for mild depression therapy. Recent research works have shed light on the biosynthesis of various metabolites in this plant, such as flavonoids, xanthones, hyperforin, and hypericin. The elucidation of these pathways, along with the discovery of novel enzymes like hyperforin synthase, support the pharmaceutical research by enabling scalable production of bioactive compounds for the development of new drugs. Elucidation of the hyperforin biosynthesis based on single-cell RNA-seq is an approach that will be expanded and accelerate the gene discovery and full pathway reconstitution of plant specialized metabolites., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships that may be considered as potential competing interests: Evangelos Tatsis reports financial support was provided by National Natural Science Foundation of China. Evangelos Tatsis reports financial support was provided by Chinese Academy of Sciences. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: To compare the safety and efficiency of ultrasound-guided percutaneous radiofrequency ablation (RFA) and surgical resection (SR) for thyroid papillary carcinoma (PTC) in the danger triangle area., Methods: The clinical data of 298 patients who underwent either percutaneous RFA or SR for PTC in the thyroid danger triangle at our hospital between January 2018 and April 2020 were retrospectively analyzed. Propensity score matching is employed to regulate for confounding factors. All patients undergoing ablation were treated using a strategy that combined sufficient paratracheal fluid isolation with a low-power, short electrode. Disease progression was analyzed in patients with T1N0M0 PTC (T1a and T1b) employed in Kaplan‒Meier curves. Treatment parameters and the rates of local recurrence, distant metastasis, and complications are recorded and compared., Results: Of 182 eligible patients who were included, 91 were in the RFA (age 44.84 ± 13.19; 71 females; 77 T1a) and 91 were in the SR (age 47.36 ± 11.05; 68 females; 69 T1a). The average treatment time, length of hospital stays, blood loss volume, and scar length are substantially less in the RFA than in the SR. Major complications as well as postoperative permanent recurrent laryngeal nerve injury and postoperative transient parathyroid dysfunction occurred only in the SR, with a substantial distinction between the two groups (p < 0.05). There is no substantial distinction in the disease progression between RFA and SR treatment of T1N0M0 PTC., Conclusion: RFA is as effective as surgery for PTC in the danger triangle area in the short term, with faster recovery and fewer complications., Clinical Relevance Statement: Radiofrequency ablation has a clinical efficacy comparable to surgery in the treatment of papillary thyroid carcinoma in the danger triangle area in the short term with the advantages of faster recovery and fewer complications when compared with surgery., Key Points: Use of radiofrequency ablation (RFA) in the thyroid danger triangle is still controversial. RFA and surgery groups showed no difference in disease progressions, and no major complications occurred with RFA. Radiofrequency ablation offers a new option for papillary thyroid carcinoma patients in the danger triangle., Competing Interests: Compliance with ethical standards Guarantor The scientific guarantor of this publication is Songsong Wu. Conflict of interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry No complex statistical methods were necessary for this paper. Informed consent Written informed consent was obtained from all subjects (patients) in this study. Ethical approval Institutional Review Board approval was obtained by Fujian Provincial Hospital. Study subjects or cohorts overlap Some study subjects or cohorts have not been previously reported. Methodology RetrospectiveObservationalOne center study, (© 2024. The Author(s), under exclusive licence to European Society of Radiology.)

Macromolecules can gain special properties by adopting knotted conformations, but engineering knotted macromolecules is a challenging task. Here, we unexpectedly find that knots can be efficiently generated in active polymer systems. When one end of an actively reptative polymer is anchored, it undergoes continual self-knotting as a result of intermittent giant conformation fluctuations and the outward reptative motion. Once a knot is formed, it migrates to the anchoring point due to a nonequilibrium ratchet effect. Moreover, when the active polymer is grafted on a passive polymer, it can function as a self-propelling soft needle to either transfer its own knots or directly braid knots on the passive polymer. We further show that these active needles can create intermolecular bridging knots between two passive polymers. Our finding highlights the nonequilibrium effects in modifying the dynamic pathways of polymer systems, which have potential applications in macromolecular topology engineering.

The pervasive use of the plasticizer di(2-ethylhexyl) phthalate (DEHP) poses potential risks to global aquatic ecosystems. This study systematically evaluated the adverse effects of chronic exposure to environmentally relevant concentrations of DEHP on gill tissues of crucian carp, utilizing histological examination, metabolomic, and transcriptomic analysis. The results demonstrated that DEHP induced significant histopathological alterations in gill tissues, with significant enrichment observed in multiple pathways associated with amino acid, hormone, lipid, and xenobiotic metabolism. Metabonomics-transcriptomics analyses indicated that DEHP-induced significantly over-activation of cytochrome P450 1B1-like (p < 0.001) and cytochrome P450 3A30-like (p < 0.05) via the nuclear xenobiotic receptors pathway was a key factor contributing to the disruption of tryptophan metabolism and steroid hormone biosynthesis, as well as inducing circadian rhythm disruption. Moreover, circadian rhythm disruption further exacerbated the imbalance of cytochrome P450 (CYP450) enzyme system as well as linoleic acid, arachidonic acid, sphingolipid, and glycerophospholipid metabolism. Overall, the feedback regulation between the CYP450 enzyme system and circadian rhythms emerged as the primary mechanism underlying DEHP-induced metabolic and transcriptional disruptions, ultimately resulting in gill toxicity. This study not only enriched the toxic effects on aquatic organisms of chronic exposure to DEHP, but provided potential biomarkers for the environmental risk assessment of DEHP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With the tremendous success of the PARP inhibitor olaparib in clinical practice, synthetic lethality has become an important field for the discovery and development of anticancer drugs. More and more synthetic lethality targets have been discovered with the rapid development of biotechnology in recent years. Currently, many drug candidates that were designed and developed on the basis of the concept of synthetic lethality have entered clinical trials. Taking representative synthetic lethal targets Poly ADP-ribose polymerase 1 (PARP1), Werner syndrome helicase (WRN) and protein arginine methyltransferase 5 (PRMT5) as examples, this article briefly discusses the application and research progress of synthetic lethality in the development of anticancer drugs., 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 Gong, Liu, Tang, Wu and Yang.)

The development of a rapid and convenient strategy to regulate the surface microenvironment of inert carbon supports, along with the physicochemical properties of their supported metal nanoparticles, is essential for enhancing catalytic performance. In this study, we describe a straightforward and efficient solid-state microwave method that utilizes a household microwave oven to achieve the co-doping of oxygen and nitrogen in unfunctionalized carbon black (ONCB) using urea as a nitrogen source. The microwave solid-state treatment of commercial carbon black (CB) with urea not only introduces a significant number of heteroatomic functional groups but also substantially increases the pore size and pore volume of the matrix. These enhancements facilitate the uniform growth and dispersion of ultrafine Ru nanoparticles on the surface of ONCB. Consequently, the Ru/ONCB catalyst provides abundant catalytic active sites and mass transfer channels, thereby improving catalytic performance for hydrogen evolution from ammonia borane hydrolysis (ABH). The turnover frequency of Ru/ONCB for ABH reaches 4529 ± 238 min -1 (determined based on Ru dispersion), surpassing a range of analogues and many previously reported carbon-supported Ru catalysts. This study presents a simple and rapid strategy to regulate the surface microenvironment of unfunctionalized carbon support, thereby enhancing the catalytic performance of its supported metal nanoparticles for catalytic hydrogen generation., 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 Inc. All rights reserved.)

Objective: Metastasis of non-small cell lung cancer (NSCLC) is a leading cause of high mortality. In recent years, the role of M2 macrophages in promoting tumor metastasis within the tumor microenvironment has garnered increasing attention. This study aims to investigate the role and potential mechanisms of the ITGB4/GNB5 axis in regulating M2 macrophage reprogramming and influencing NSCLC metastasis., Methods: This study first used single-cell sequencing technology to reveal the diverse subpopulation structure of NSCLC tumor tissues. Data analysis then identified the correlation between M2 macrophages and the malignant phenotype of NSCLC. Flow cytometry and immunohistochemistry were used to detect changes in M2 macrophages in NSCLC tissues. The impact of the ITGB4/GNB5 axis on M2 macrophage function was assessed through RNA sequencing and proteomic analysis. Finally, in vitro cell experiments and in vivo mouse models were used to validate the function and regulatory mechanisms of this axis., Results: Our study found diverse cellular subpopulations in NSCLC tumor tissues, with M2 macrophages closely associated with the malignant phenotype of NSCLC. We identified ITGB4 as a characteristic gene of NSCLC and predicted GNB5 as an interacting gene through database analysis. Activation of the ITGB4/GNB5 axis was shown to enhance M2 macrophage polarization, promoting their accumulation in the tumor microenvironment. This change further facilitated NSCLC invasion and metastasis by modulating related cytokines and signaling pathways. Animal experiments demonstrated that inhibition of the ITGB4/GNB5 axis significantly reduced tumor growth and metastasis., Conclusion: The ITGB4/GNB5 axis reshapes the TME by promoting M2 macrophage polarization and functional enhancement, thereby facilitating tumor invasion and metastasis in NSCLC. This research provides new insights into the molecular mechanisms of NSCLC and offers potential molecular targets for future targeted therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid arthritis (RA) is an enduring autoimmune inflammatory condition distinguished by continual joint inflammation, hyperplasia of the synovium, erosion of bone, and deterioration of cartilage.Fibroblast-like synoviocytes (FLSs) exhibiting "tumor-like" traits are central to this mechanism.ADP-ribosylation factor-like 4c (ARL4C) functions as a Ras-like small GTP-binding protein, significantly impacting tumor migration, invasion, and proliferation.However, it remains uncertain if ARL4C participates in the stimulation of RA FLSs exhibiting "tumor-like" features, thereby fostering the advancement of RA. In our investigation, we unveiled, for the inaugural instance, via the amalgamated scrutiny of single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk-seq) datasets, that activated fibroblast-like synoviocytes (FLSs) showcase high expression of ARL4C, and the ARL4C protein expression in FLSs derived from RA patients significantly surpasses that observed in individuals with osteoarthritis (OA) and traumatic injury (trauma).Silencing of the ARL4C gene markedly impeded the proliferation of RA FLSs by hindered the transition of cells from the G0/G1 phase to the S phase, and intensified cell apoptosis and diminished the migratory and invasive capabilities. Co-culture of ARL4C gene-silenced RA FLSs with monocytes/macrophages significantly inhibited the polarization of monocytes/macrophages toward M1 and the repolarization of M2 to M1.Furthermore, intra-articular injection of shARL4C significantly alleviated synovial inflammation and cartilage erosion in collagen-induced arthritis (CIA) rats. In conclusion, our discoveries propose that ARL4C assumes a central role in the synovial inflammation, cartilage degradation, and bone erosion associated with RA by triggering the PI3K/AKT and MAPK signaling pathways within RA FLSs.ARL4C holds promise as a prospective target for the development of pharmaceutical agents targeting FLSs, with the aim of addressing RA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In response to the escalating threat of microbial resistance, a series of novel pleuromutilin derivatives, conjugated with phenyl-sulfide and boron-containing moieties, were designed and synthesized. Most derivatives, especially 14b and 16b, demonstrated significant efficacy against Gram-positive bacteria, including multidrug-resistant strains, as well as pleuromutilin-resistant strains. Compound 16b showed high stability in the liver microsomes of rats and humans, along with acceptable tolerance in vitro and in vivo. Additionally, compound 16b exhibited promising efficacy in MRSA-infected mouse models. Our data highlight the potential of conjugated pleuromutilin derivatives as valuable agents against drug-resistant bacteria., 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. Published by Elsevier Masson SAS.)

Acute lung injury (ALI) is a serious pulmonary inflammatory disease resulting from excessive reactive oxygen species (ROS) which could cause the damage of the alveolar epithelial cells and capillary endothelial cells. Peroxynitrite, as one of short-lived reactive oxygen species, is closely related to the process of ALI. Thus, it is important to monitor the fluctuation of peroxynitrite in living system for understanding the process of ALI. Herein, the novel mitochondria-targeted fluorescent probe BHMT was designed to respond to peroxynitrite and pH with distinct fluorescence properties respectively. The absorption spectrum of the probe BHMT exhibited a notable red shift as the pH value declined from 8.8 to 2.6. Upon reaction with peroxynitrite, BHMT had a significant increase of fluorescence intensity (63-fold) with maintaining a detection limit of only 43.7 nM. Furthermore, BHMT could detect the levels of endogenous peroxynitrite and image the intracellular pH in ratiometric channels utilizing cell imaging. In addition, BHMT was successfully applied to revealing the relationship between the peroxynitrite and the extent of ALI. Thus, these results indicated the probe BHMT could be a potential tool for diagnosing the early stage of ALI and revealed the peroxynitrite was likely to be a crucial therapeutic target in ALI 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 © 2024 Elsevier B.V. All rights reserved.)

Background: Anti-angiogenic inhibitors and immune checkpoint blockade combination therapy offers a novel approach to circumvent the challenges associated with limited responsiveness to checkpoint inhibitors in bladder cancer. However, the effective strategies for inhibiting angiogenesis in bladder cancer need further elucidation. Objective: This work aims to identify key targets for the effective inhibition of angiogenesis in bladder cancer and to explore the potential benefits of combining anti-angiogenic therapies with immune checkpoint blockade strategies in the treatment of this disease. Methods: Cell-cell interaction analysis was performed using bladder cancer single-cell transcriptome datasets downloaded from the Gene Expression Omnibus (GEO) database to determine the regulatory network driving angiogenesis in bladder cancer. The bladder cancer cell line MBT2 was orthotopically transplanted into mice to investigate the impact of pro-angiogenic molecules on angiogenesis and tumor growth, and to evaluate the synergistic therapeutic potential of a combination therapy targeting angiogenesis and Programmed Cell Death Protein 1 (PD-1). Proliferation and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs) were used to explore the regulatory functions of pro-angiogenic molecules in angiogenesis. Results: Placental growth factor (PGF) is a pro-angiogenic factor in bladder cancer, in addition to vascular endothelial growth factor A (VEGFA). Suppression of PGF reduced the tumor size and angiogenesis in bladder cancer. The expression level of vascular endothelial growth factor receptor 1 (VEGFR1) is higher than that of vascular endothelial growth factor receptor2 (VEGFR2) in the endothelial cells of bladder cancer. The pro-angiogenic activity of PGF is dependent on the expression level of VEGFR1 in endothelial cells. The combined inhibition of PGF and VEGFA exerts a synergistic effect on suppressing tumor growth and angiogenesis. The concurrent inhibition of PGF and VEGFA stands out as the only intervention capable of significantly enhancing the infiltration of CD8 + cytotoxic T cells within the bladder cancer microenvironment. In the bladder cancer mouse model, the introduction of an anti- programmed cell death protein 1 (PD-1) therapeutic regimen combined with the targeted inhibition of PGF and VEGFA, led to a significantly elevated survival rate compared to the outcome observed with anti-PD-1 monotherapy. Conclusion: PGF is a pro-angiogenic molecule in bladder cancer that requires significant expression levels of VEGFR1 in endothelial cells. Notably, the concurrent inhibition of PGF and VEGFA amplifies the therapeutic impact of anti-PD-1 treatment in bladder cancer. These findings provide further insights into the role of PGF in angiogenesis regulation and have conceptual implications for combining anti-angiogenic therapy with immune therapy in bladder cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Plasma protein binding (PPB) is closely related to pharmacokinetics, pharmacodynamics and drug toxicity. Existing models for predicting PPB often suffer from low prediction accuracy and poor interpretability, especially for high PPB compounds, and are most often not experimentally validated. Here, we carried out a strict data curation protocol, and applied consensus modeling to obtain a model with a coefficient of determination of 0.90 and 0.91 on the training set and the test set, respectively. This model (available on the OCHEM platform https://ochem.eu/article/29) was further retrospectively validated for a set of 63 poly-fluorinated molecules and prospectively validated for a set of 25 highly diverse compounds, and its performance for both these sets was superior to that of the other previously reported models. Furthermore, we identified the physicochemical and structural characteristics of high and low PPB molecules for further structural optimization. Finally, we provide practical and detailed recommendations for structural optimization to decrease PPB binding of lead compounds., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To observe the effect of electroacupuncture (EA) on hypoxia-inducible factor (HIF)/vascular endothelial growth factor (VEGF)/Notch signaling pathway and related factors in rats with cerebral ischemia (CI), so as to explore its regulatory mechanism underlying improvement of CI by promoting cerebral microangiogenesis., Methods: Fifteen male SD rats were randomly selected as the sham surgery (sham) group, while other 85 rats were used to prepare CI model according to the modified Zea-Longa method. The successful CI model rats ( n =60) were randomly allocated to model, EA, EA+inhibitor, and inhibitor groups, with 15 rats in each group. EA stimulation (1 Hz/20 Hz, 1-2 mA) was applied to "Baihui"(GV20) and right "Zusanli"(ST36) for 30 min, once a day for 7 days. Rats of the 2 inhibitor groups received intraperitoneal injection of YC-1 (HIF-1α inhibitor, 2.5 mg/kg), once a day for 7 days. The modified neurological severity scale (mNSS, including the motor ［muscular state, abnormal movement］, sensory ［visual, tactile and proprioceptive］, balance and reflex functions, 0-18 points) was used to assess the rats' neurological deficit state. The percentage of cerebral infarct volume was measured after 2, 3, 5-triphenyl tetrazolium chloride (TTC) staining, and pathological changes of the ischemic penumbra cortex were observed after H.E. staining. The immunoactivity of CD34 was determined using immunohistochemistry, followed by calculating the microvascular density (MVD) in the ischemic penumbra cortex, and the expression levels of HIF-1α, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), Notch1, and Delta like 4 ligand (DLL4) mRNAs and proteins in the ischemic penumbra of brain tissue were detected using real-time PCR and Western blot, respectively., Results: In contrast to the sham group, the mNSS score, percentage of cerebral infarct volume, MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 proteins and mRNAs were all significantly increased in the model group ( P <0.01). In comparison with the model group, the mNSS score and percentage of cerebral infarct volume were significantly decreased in the EA group ( P <0.01), and increased in the inhibitor group ( P <0.01), and the MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 proteins and mRNAs were further strikingly increased in the EA group ( P <0.01), but obviously decreased in the inhibitor group ( P <0.05, P <0.01). Comparison between EA and EA+inhibitor groups showed that the effects of EA were basically eliminated in lowering mNSS score and percentage of cerebral infarct volume ( P <0.01), and in up-regulating MVD, and expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 mRNAs and proteins ( P <0.01). The levels of mNSS score and percentage of cerebral infarct volume were markedly higher ( P <0.01) in the inhibitor group than those in the EA+inhibitor group, while the MVD, expression levels of HIF-1α, VEGF, VEGFR2, Notch1 and DLL4 mRNAs and proteins were significantly lower in the inhibitor group than in the EA+inhibitor group ( P <0.01), suggesting an elimination of EA after administration of HIF-1α inhibitor. H.E. staining showed loosened structure and disordered arrangement of neurons, swollen and vacuolized cells with ruptured nuclei, swollen and deformed microvessels in the ischemic penumbra of the brain tissue in the model group, which was improved in the EA group, including reduction of cellular swelling degree and vacuol-like changes, relatively intact of nuclei, and increase of new capillaries., Conclusions: EA of GV20 and ST36 can improve neurological deficit and reduce cerebral infarct volume in CI rats, which may be associated with its functions in promoting angiogenesis in ischemic penumbra area and in up-regulating the activities of HIF/VEGF/Notch signaling pathway and related factors.

Although the mobility of arsenic (As) and cadmium (Cd) in soils during the flooding-drainage process has been intensively studied, predicting their dissolution among various soils still remains a challenge. After comprehensively monitoring multiple parameters related to As and Cd dissolution in 8 soils for a 60-day anaerobic incubation, the redundancy analysis (RDA) and structural equation model (SEM) were employed to identify the key factors and influencing pathways controlling the dynamic release of As and Cd. Results showed that pH alone explained 90.5 % Cd dissolution, while the dissolved-Fe(II) and 5 M-HCl extractable Fe(II) jointly only explained 50.6 % As dissolution. After data normalization, the ratio of Fe(II) to 5 M-HCl extracted total Fe (i.e. Fe tot II /Fe tot ) significantly improved the correlation to R 2  = 0.824 (p < 0.001) with a fixed slope of 0.393 among the 8 soils. Our results highlight the crucial role played by the reduction degree of total iron contents in determining both the reduction and dissolution of As during flooding. In contrast, dissolved-Fe(II) was too vulnerable to soil properties to be a stable indicator of As dissolution. Therefore, we propose to replace the dissolved-Fe(II) with this novel ratio as the key index to quantitatively assess the kinetic change of As solubility potential across various soils under flooding conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Developing a straightforward and general strategy to regulate the surface microenvironment of a carbon matrix enriched with N/B motifs for efficient atomic utilization and electronic state of metal sites in bifunctional hydrogen production via ammonia-borane hydrolysis (ABH) and water electrolysis is a persistent challenge. Herein, we present a simple, green, and universal approach to fabricate B/N co-doped porous carbons using ammonia-borane (AB) as a triple functional agent, eliminating the need for hazardous and explosive functional agents and complicated procedures. The pyrolysis of AB induces the regulation of the surface microenvironment of the carbon matrix, leading to the formation of abundant surface functional groups, defects, and pore structures. This regulation enhances the efficiency of atom utilization and the electronic state of the active component, resulting in improved bifunctional hydrogen evolution. Among the catalysts, B/N co-doped vulcan carbon (Ru/BNC) with 2.1 wt% Ru loading demonstrates the highest performance in catalytic hydrogen production from ABH, achieving an ultrahigh turnover frequency of 1854 min -1 (depending on the dispersion of Ru). Furthermore, this catalyst shows remarkable electrochemical activity for hydrogen evolution in alkaline water electrolysis with a low overpotential of 31 mV at 10 mA cm -2 . The present study provides a simple, green, and universal method to regulate the surface microenvironment of various carbons with B/N modulators, thereby adjusting the atomic utilization and electronic state of active metals for enhanced bifunctional hydrogen evolution., 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 Inc. All rights reserved.)

Background: Treatment of rotator cuff diseases often involves various arthroscopic procedures but their combined effectiveness remains contentious, especially in complex cases., Methods: We focused on patients with degenerative shoulder cuff diseases requiring arthroscopic rotator cuff repair. Searches covered multiple databases (Medline, Embase, Web of Science, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Cochrane Clinical Answers) up to April 1, 2024. Bias risk was assessed using RevMan (v 5.4), and a network meta-analysis was conducted with netmeta (v 2.8)., Result: From 16 studies, 1232 patients (average age, 56.2 years; balanced sex ratio) were included. Arthroscopic rotator cuff repair ranked highest in functional score networks, surpassing other interventions. Physiotherapy was superior for pain relief compared to arthroscopic procedures combined with platelet-rich plasma (mean, 2.5; 95% confidence interval, 4.48-0.52). Arthroscopic rotator cuff repair and subacromial decompression were significantly superior to arthroscopic rotator cuff repair and subacromial decompression combined with platelet-rich plasma (MD, 1.80; 95% CI, 3.39-0.21)., Discussion: Moderate bias risks were noted in both networks due to blinding issues and methodological quality reporting. Arthroscopic rotator cuff repair is favored for improving shoulder function, while other procedures or intra-articular treatments offer no significant benefits. Regarding pain management, physiotherapy is preferred; however, more evidence is needed to support this recommendation and caution is advised., Other: Systematic review registration PROSPERO CRD42023450150., (© 2024. The Author(s).)

Motivation: Target discovery is a crucial step in drug development, as it directly affects the success rate of clinical trials. Knowledge graphs (KGs) offer unique advantages in processing complex biological data and inferring new relationships. Existing biomedical KGs primarily focus on tasks such as drug repositioning and drug-target interactions, leaving a gap in the construction of KGs tailored for target discovery., Results: We established a comprehensive biomedical KG focusing on target discovery, termed TarKG, by integrating seven existing biomedical KGs, nine public databases, and traditional Chinese medicine knowledge databases. TarKG consists of 1 143 313 entities and 32 806 467 relations across 15 entity categories and 171 relation types, all centered around 3 core entity types: Disease, Gene, and Compound. TarKG provides specialized knowledges for the core entities including chemical structures, protein sequences, or text descriptions. By using different KG embedding algorithms, we assessed the knowledge completion capabilities of TarKG, particularly for disease-target link prediction. In case studies, we further examined TarKG's ability to predict potential protein targets for Alzheimer's disease (AD) and to identify diseases potentially associated with the metallo-deubiquitinase CSN5, using literature analysis for validation. Furthermore, we provided a user-friendly web server (https://tarkg.ddtmlab.org) that enables users to perform knowledge retrieval and relation inference using TarKG., Availability and Implementation: TarKG is accessible at https://tarkg.ddtmlab.org., (© The Author(s) 2024. Published by Oxford University Press.)

The clinical outcomes of osteosarcoma are relatively dismal. As immunotherapy has revolutionized treatment for solid tumors, exploring novel immunotherapy-related therapeutic targets for osteosarcoma is important. In this study, we aimed to establish the connection between RNA modification and immunotherapy in osteosarcoma to identify novel therapeutic targets. An RNA modification-related signature was first developed using weight gene correlation network analysis and a machine-learning algorithm, random forest. The signature's prognostic value, drug prediction, and immune characteristics were analyzed. EIF4G2 from the signature was next identified as a critical immunotherapy determinant. EIF4G2 could also promote tumor proliferation, migration, and M2 macrophage migration by single-cell sequencing analysis and in vitro validation. Our signature and EIF4G2 are expected to provide valuable insights into the clinical management of osteosarcoma., (© 2024 Wiley Periodicals LLC.)

In the realm of thrombosis treatment, bioengineered outer membrane vesicles (OMVs) offer a novel and promising approach, as they have rich content of bacterial-derived components. This study centers on OMVs derived from Escherichia coli BL21 cells, innovatively engineered to encapsulate the staphylokinase-hirudin fusion protein (SFH). SFH synergizes the properties of staphylokinase (SAK) and hirudin (HV) to enhance thrombolytic efficiency while reducing the risks associated with re-embolization and bleeding. Building on this foundation, this study introduces two cutting-edge microrobotic platforms: SFH-OMV@H for venous thromboembolism (VTE) treatment, and SFH-OMV@MΦ, designed specifically for cerebral venous sinus thrombosis (CVST) therapy. These platforms have demonstrated significant efficacy in dissolving thrombi, with SFH-OMV@H showcasing precise vascular navigation and SFH-OMV@MΦ effectively targeting cerebral thrombi. The study shows that the integration of these bioengineered OMVs and microrobotic systems marks a significant advancement in thrombosis treatment, underlining their potential to revolutionize personalized medical approaches to complex health conditions., (© 2024 Wiley‐VCH GmbH.)

Electrocatalytic nitrate reduction reaction presents a promising avenue for environmentally friendly ammonia (NH 3 ) synthesis and wastewater treatment. An essential aspect to consider is the meticulous design of electrocatalysts. This study explores the utilization of a Ni-Co alloy nanosheet-decorated three-dimensional titanium dioxide (3D-TiO 2 ) nanobelts electrodeposited on titanium meshes (Ni x Co y @TiO 2 /TM) for efficient electrocatalytic NH 3 production. The optimized Ni 1 Co 3 @TiO 2 /TM electrode achieves a significant NH 3 yield of 676.3 ± 27.1 umol h -1 cm -2 with an impressive Faradaic efficiency (FE) of 95.1 % ± 2.1 % in a 0.1 M KOH solution containing 0.1 M NO 3 - at -0.4 V versus the reversible hydrogen electrode. Additionally, the electrode demonstrates exceptional electrochemical activity for NH 3 synthesis in simulated wastewater, delivering an outstanding NH 3 yield of 751.6 ± 44.3 umol h -1 cm -2 with a FE of 96.8 % ± 0.4 % at the same potential of -0.4 V. Moreover, the electrode exhibits minimal variation in current density, NH 3 yields and FEs throughout the 24-h stability test and the 20-cycle test, demonstrating its excellent stability and durability. This study offers a straightforward electrodeposited approach for the development of 3D-nanostructured alloys as catalysts for NH 3 electrosynthesis from nitrates at room temperature., 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 Inc. All rights reserved.)

3D bioprinting, a significant advancement in biofabrication, is renowned for its precision in creating tissue constructs. Collagen, despite being a gold standard biomaterial, faces challenges in bioink formulations due to its unique physicochemical properties. This study introduces a novel, neutral-soluble, photocrosslinkable collagen maleate (ColME) that is ideal for 3D bioprinting. ColME was synthesized by chemically modifying bovine type I collagen with maleic anhydride, achieving a high substitution ratio that shifted the isoelectric point to enhance solubility in physiological pH environments. This modification was confirmed to preserve the collagen's triple-helix structure substantially. Bioprinting parameters for ColME were optimized, focusing on adjustments to the bioink concentration, extrusion pressure, nozzle speed, and temperature. Results demonstrated that lower temperatures and smaller nozzle sizes substantially improved the print quality of grid structures. Additionally, the application of intermittent photo-crosslinking facilitated the development of structurally robust 3D multilayered constructs, enabling the stable fabrication of complex tissues. Cell viability assays showed that encapsulated cells within the ColME matrix maintained high viability after printing. When compared to methacrylated gelatin, ColME exhibited superior mechanical strength, resistance to enzymatic digestion, and overall printability, positioning it as an outstanding bioink for the creation of durable, bioactive 3D tissues.

Objective: Yao syndrome (YAOS) is formerly called nucleotide-binding oligomerization domain containing 2 ( NOD2) -associated autoinflammatory disease.We report a large cohort of YAOS., Methods: We conducted a retrospective analysis of a cohort of adult patients with systemic autoinflammatory diseases (SAIDs). All patients underwent testing for a periodic fever syndrome gene panel., Results: A total of 194 patients carried NOD2 variants, 152 patients were diagnosed with YAOS, and 42 had mixed autoinflammatory diseases with combined variants in NOD2 and other SAID-associated genes. Demographic, clinical and molecular data were summaried. In sub-group analysis of the 194 patients, individual patients were often identified to carry two or more variants that usually included IVS8 + 158/R702W, IVS8 + 158/L1007fs, IVS8 + 158/V955I, IVS8 + 158/other, or NOD2/ variants in other SAID genes. Ninety-nine patients carried single variants. Taken together, these variants contribute to the disease in combination or individually., Conclusion: This largest cohort has provided comprehensive clinical and genotyping data in YAOS. Variants in the NOD2 gene can give rise to a spectrum from inflammatory bowel disease to autoinflammatory disease.This report further raises awareness of the underdiagnosed disease in the medical community., 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. The author declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Nomani, Wu, Saif, Hwang, Metzger, Navetta-Modrov, Gorevic, Aksentijevich and Yao.)

The design and preparation of anode materials with structural stability, fast ion transmission, and low open-circuit voltage are critical to the development of magnesium ion batteries (MIBs). The feasibility of the unique phase Haeckelite MoS 2 (Hae-MoS 2 ) monolayer with Haeckelite structure as a potential anode material for MIBs was investigated using density functional theory (DFT) calculations. The Hae-MoS 2 monolayer exhibits excellent structural stability and semimetallic characteristics with a Dirac cone located at the Gamma point of band structure. Mg ion is easily adsorbed on the Hae-MoS 2 monolayer surface with an adsorption energy of -2.06 eV and can diffuse rapidly with a low diffusion energy barrier (0.3 eV), indicating excellent charge and discharge rates. Most importantly, the Hae-MoS 2 monolayer exhibits a suitable open-circuit voltage, which falls within the desired voltage range and ensures the safety of battery performance. These exceptional properties indicate that the Hae-MoS 2 monolayer can be proposed as a candidate for anode material for MIBs.

The development of a photosensitizer (PS) that induces pyroptosis could be a star for photodynamic therapy (PDT), particularly with type-I PSs that produce reactive oxygen species (ROS) in a hypoxic tumor microenvironment. Since pyroptosis is a recently characterized cell death pathway, it holds promise for advancing PDT in oncology, with PSs playing a critical role. Herein, we develop a PS named Th-M with aggregation-induced emission (AIE) characteristics for type-I PDT against tongue squamous cell carcinoma (TSCC). Th-M stands out for its exceptional mitochondrial-targeting ability, which triggers mitochondrial dysfunction and leads to Caspase-3 and Gasdermin E (GSDME) cleavage under white light irradiation, inducing pyroptosis in TSCC cells. Our studies verify the effectiveness of Th-M in destroying cancer cells in vitro and suppressing tumor growth in vivo while also demonstrating a favorable biosafety profile. This work pioneers the application of Th-M as a mitochondria-targeted, type-I PS that leverages the mechanism of pyroptosis, offering a potent approach for the treatment of TSSC with promising implications for future PDT of cancers.

Hyperforin is the compound responsible for the effectiveness of St. John's wort (Hypericum perforatum) as an antidepressant, but its complete biosynthetic pathway remains unknown. Gene discovery based on co-expression analysis of bulk RNA-sequencing data or genome mining failed to discover the missing steps in hyperforin biosynthesis. In this study, we sequenced the 1.54-Gb tetraploid H. perforatum genome assembled into 32 chromosomes with the scaffold N50 value of 42.44 Mb. By single-cell RNA sequencing, we identified a type of cell, "Hyper cells", wherein hyperforin biosynthesis de novo takes place in both the leaves and flowers. Through pathway reconstitution in yeast and tobacco, we identified and characterized four transmembrane prenyltransferases (HpPT1-4) that are localized at the plastid envelope and complete the hyperforin biosynthetic pathway. The hyperforin polycyclic scaffold is created by a reaction cascade involving an irregular isoprenoid coupling and a tandem cyclization. Our findings reveal how and where hyperforin is biosynthesized, enabling synthetic-biology reconstitution of the complete pathway. Thus, this study not only deepens our comprehension of specialized metabolism at the cellular level but also provides strategic guidance for elucidation of the biosynthetic pathways of other specializied metabolites in plants., (Copyright © 2024 The Author. Published by Elsevier Inc. All rights reserved.)

Pulmonary actinomycosis is a rare pulmonary infectious disease that is often challenging to diagnose early and has a high misdiagnosis rate. In some cases, it can be particularly difficult to distinguish pulmonary actinomycosis from lung cancer. We herein report a rare case of pulmonary actinomycosis in which the preoperative examinations strongly suggested lung cancer, leading to the patient undergoing right upper lung resection and bronchoplasty. The patient had a good postoperative recovery; however, the postoperative pathology report indicated pulmonary actinomycosis. In this report, we summarize the key aspects of the diagnosis and treatment of pulmonary actinomycosis to aid clinicians in reducing the likelihood of misdiagnosis., Competing Interests: Declaration of conflicting interestsNone of the authors has any conflict of interest to disclose.

Cartilage tissue engineering holds great promise for efficient cartilage regeneration. However, early inflammatory reactions to seed cells and/or scaffolds impede this process. Consequently, managing inflammation is of paramount importance. Moreover, due to the body's restricted chondrogenic capacity, inducing cartilage regeneration becomes imperative. Thus, a controlled platform is essential to establish an anti-inflammatory microenvironment before initiating the cartilage regeneration process. In this study, we utilized fifth-generation polyamidoamine dendrimers (G5) as a vehicle for drugs to create composite nanoparticles known as G5-Dic/Sr. These nanoparticles were generated by surface modification with diclofenac (Dic), known for its potent anti-inflammatory effects, and encapsulating strontium (Sr), which effectively induces chondrogenesis, within the core. Our findings indicated that the G5-Dic/Sr nanoparticle exhibited selective Dic release during the initial 9 days and gradual Sr release from days 3 to 15. Subsequently, these nanoparticles were incorporated into a gelatin methacryloyl (GelMA) hydrogel, resulting in GelMA@G5-Dic/Sr. In vitro assessments demonstrated GelMA@G5-Dic/Sr's biocompatibility with bone marrow stem cells (BMSCs). The enclosed nanoparticles effectively mitigated inflammation in lipopolysaccharide-induced RAW264.7 macrophages and significantly augmented chondrogenesis in BMSCs cocultures. Implanting BMSCs-loaded GelMA@G5-Dic/Sr hydrogels in immunocompetent rabbits for 2 and 6 weeks revealed diminished inflammation and enhanced cartilage formation compared to GelMA, GelMA@G5, GelMA@G5-Dic, and GelMA@G5/Sr hydrogels. Collectively, this study introduces an innovative strategy to advance cartilage regeneration by temporally modulating inflammation and chondrogenesis in immunocompetent animals. Through the development of a platform addressing the temporal modulation of inflammation and the limited chondrogenic capacity, we offer valuable insights to the field of cartilage tissue engineering.

Thin endometrium (TE) is closely associated with infertility in reproductive medicine. Estrogen therapy gains unsatisfactory outcomes. In this study, an artificial mucus based on dopamine (L-DOPA)-modified hyaluronic acid combining phytoestrogen cajaninstilbene acid and rat urinary exosomes (CUEHD) is constructed for TE treatment using a rat TE model. In the rat TE model, the dominant elastic behavior and adhesive properties of CUEHD guarantee adequate retention, rendering superior synergistic treatment efficacy and favorable biosafety characteristics. CUEHD treatment significantly increases endometrial thickness and promotes receptivity and fertility. Mechanistically, estrogen homeostasis, inflammation inhibition, and endometrial regeneration are achieved through the crosstalk between ER-NLRP3-IL1β and Wnt-β catenin-TGFβ-smad signaling pathways. Moreover, the therapeutic potential of exosomes from human urine and adipose tissue-derived stem cells (ADSCs) and rat ADSCs are also demonstrated, indicating extensive use of the artificial mucus system. Thus, this study illustrates a platform combining phytoestrogen and exosomes with promising implications for TE treatment., (© 2024 Wiley‐VCH GmbH.)

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor that initiates a STING-dependent innate immune response, binds tightly to chromatin, where its catalytic activity is inhibited; however, mechanisms underlying cGAS recruitment to chromatin and functions of chromatin-bound cGAS (ccGAS) remain unclear. Here we show that mTORC2-mediated phosphorylation of human cGAS serine 37 promotes its chromatin localization in colorectal cancer cells, regulating cell growth and drug resistance independently of STING. We discovered that ccGAS recruits the SWI/SNF complex at specific chromatin regions, modifying expression of genes linked to glutaminolysis and DNA replication. Although ccGAS depletion inhibited cell growth, it induced chemoresistance to fluorouracil treatment in vitro and in vivo. Moreover, blocking kidney-type glutaminase, a downstream ccGAS target, overcame chemoresistance caused by ccGAS loss. Thus, ccGAS coordinates colorectal cancer plasticity and acquired chemoresistance through epigenetic patterning. Targeting both mTORC2-ccGAS and glutaminase provides a promising strategy to eliminate quiescent resistant cancer cells., (© 2024. The Author(s).)

In the quest to tackle stress urinary incontinence (SUI), the synthesis of cutting-edge biomaterials and regenerative materials has emerged as a promising frontier. Briefly, animal models like vaginal distension and bilateral ovariectomy serve as crucial platforms for unraveling the intricacies of SUI, facilitating the evaluation of innovative treatments. The spotlight, however, shines on the development and application of novel biomaterials-ranging from urethral bulking agents to nano-gel composites-which aim to bolster urethral support and foster tissue regeneration. Furthermore, the exploration of stem cell therapies, particularly those derived from adipose tissues and urine, heralds a new era of regenerative medicine, offering potential for significant improvements in urinary function. This review encapsulates the progress in biomaterials and regenerative strategies, highlighting their pivotal role in advancing the treatment of SUI, thereby opening new avenues for effective and minimally invasive solutions., 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 Tan, Li, Li, Kong, Li and Wu.)

Background: TCbHP (taxane + carboplatin + trastuzumab + pertuzumab) is the preferred neoadjuvant therapy regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no consensus exists regarding whether specific populations may be exempt from carboplatin, allowing for de-escalation to the THP (taxane + trastuzumab + pertuzumab) regimen. Additionally, the optimal number of cycles for neoadjuvant THP remains unclear. We compared the efficacy and safety of neoadjuvant TCbHP and THP regimens, providing clinicians with a nuanced perspective to guide their treatment regimen selection., Methods: This multicenter real-world study included patients with HER2-positive breast cancer undergoing neoadjuvant TCbHP or THP between March 2019 and February 2023. Efficacy was assessed through the pathological complete response (pCR) rate, while safety was evaluated through monitoring adverse events., Results: Among 220 patients, 103 received 6 cycles of TCbHP (TCbHP×6), 83 received 6 cycles of THP (THP×6), and 34 received 4 cycles of THP (THP×4). The TCbHP×6 cohort exhibited a 66% pCR rate compared with 53% in the THP×6 cohort (P = 0.072). Subgroup analysis revealed that in patients aged ≤ 50 years, those with hormone receptor (HR)-negative status, and those with clinical stage T2, the pCR rate of the TCbHP×6 regimen was significantly higher than the THP×6 regimen (P < 0.05). The TCbHP×6 cohort reported higher frequencies of any-grade adverse events (99% versus 86.7%) and grade 3-4 events (49.5% versus 12%) than the THP×6 cohort. Propensity score matching identified 27 patient pairs between the THP×6 and THP×4 cohorts, indicating a significantly higher pCR rate for the THP×6 regimen than the THP×4 regimen (63% versus 29.6%, P = 0.029)., Conclusions: The TCbHP×6 regimen is favored for individuals aged ≤ 50 years and those aged > 50, ≤60 years with HR-negative status or clinical stage T2-4. For patients in compromised general condition or lacking the specified indications, the THP×6 regimen emerges as a lower-toxicity alternative with satisfactory efficacy. To ensure treatment efficacy, a minimum of 6 cycles of neoadjuvant THP is required., (© 2024. The Author(s).)

Electricity-driven nitrate (NO 3 - ) to ammonia (NH 3 ) conversion presents a unique opportunity to simultaneously eliminate nitrate from sewage while capturing ammonia. However, the Faradaic efficiency and ammonia yield in this eight-electron process remain unsatisfactory, underscoring the critical need for more effective electrocatalysts. In this study, a RuCo alloy nanosheets electrodeposited on pinewood-derived three-dimensional porous carbon (RuCo@TDC) is introduced as a highly-efficient electrocatalyst for the nitrate reduction reaction. The RuCo@TDC catalyst exhibits superior electrocatalytic performance, achieving the highest NH 3 yield of 2.02 ± 0.11 mmol h -1 cm -2 at -0.6 V versus the reversible hydrogen electrode (vs. RHE) and the highest Faradaic efficiency of 95.7 ± 0.8 % at -0.2 V vs. RHE in an electrolyte mixture of 0.1 M KOH and 0.1 M KNO 3 . Furthermore, the Zn-NO 3 - battery using RuCo@TDC as the cathode provides a maximum power density of 2.46 mW cm -2 and a satisfactory NH 3 yield of 1110 μg h -1 cm -2 ., 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 Inc. All rights reserved.)

Breast cancer is reported to be one of the most lethal cancers in women, and its multi-target detection can help improve the accuracy of diagnosis. In this work, a cluster regularly interspaced short palindromic repeats (CRISPR)-Cas13a/Cas12a-based system was established for the simultaneous fluorescence detection of breast cancer biomarkers circROBO1 and BRCA1. CRISPR-Cas13a and CRISPR-Cas12a were directly activated by their respective targets, resulting in the cleavage of short RNA and DNA reporters, respectively, thus the signals of 6-carboxyfluorescein (FAM) and 6-carboxy-xrhodamine (ROX) were restored. As the fluorescence intensities of FAM and ROX were dependent on the concentrations of circROBO1 and BRCA1, respectively, synchronous fluorescence scanning could achieve one-step detection of circROBO1 and BRCA1 with detection limits of 0.013 pM and 0.26 pM, respectively. The system was highly sensitive and specific, holding high diagnostic potential for the detection of clinical samples. Furthermore, the competing endogenous RNA mechanism between circROBO1 and BRCA1 was also explored, providing a reliable basis for the intrinsic regulatory mechanism of breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The small molecule epiberberine (EPI) is a natural alkaloid with versatile bioactivities against several diseases including cancer and bacterial infection. EPI can induce the formation of a unique binding pocket at the 5' side of a human telomeric G-quadruplex (HTG) sequence with four telomeric repeats (Q4), resulting in a nanomolar binding affinity ( K D approximately 26 nM) with significant fluorescence enhancement upon binding. It is important to understand (1) how EPI binding affects HTG structural stability and (2) how enhanced EPI binding may be achieved through the engineering of the DNA binding pocket. In this work, the EPI-binding-induced HTG structure stabilization effect was probed by a peptide nucleic acid (PNA) invasion assay in combination with a series of biophysical techniques. We show that the PNA invasion-based method may be useful for the characterization of compounds binding to DNA (and RNA) structures under physiological conditions without the need to vary the solution temperature or buffer components, which are typically needed for structural stability characterization. Importantly, the combination of theoretical modeling and experimental quantification allows us to successfully engineer Q4 derivative Q4-ds-A by a simple extension of a duplex structure to Q4 at the 5' end. Q4-ds-A is an excellent EPI binder with a K D of 8 nM, with the binding enhancement achieved through the preformation of a binding pocket and a reduced dissociation rate. The tight binding of Q4 and Q4-ds-A with EPI allows us to develop a novel magnetic bead-based affinity purification system to effectively extract EPI from Rhizoma coptidis (Huang Lian) extracts.

Although precise regulation of the crystalline structures of metal oxides is an effective method to improve their antibacterial activities, the corresponding mechanisms involved in this process are still unclear. In this study, three kinds of cuprous oxide (Cu 2 O) samples with different structures of cubes, octahedra, and rhombic dodecahedra (c-Cu 2 O, o-Cu 2 O, and r-Cu 2 O) have been successfully synthesized and their antibacterial activities are compared. The antibacterial activities follow the order of r-Cu 2 O > o-Cu 2 O > c-Cu 2 O, revealing the significant dependence of the antibacterial activities on the crystalline structures of Cu 2 O. Quenching experiments, as well as the NBT and DPD experiments indicate that ≡Cu II ─OO • superoxo and ≡Cu II ─OOH peroxo, instead of •OH, O 2 •- , and H 2 O 2 , are the primary oxidizing species in the oxidative damage to E. coli . Raman analysis further confirms the presence of both ≡Cu II ─OO • superoxo and ≡Cu II ─OOH peroxo on the surface of r-Cu 2 O. On the other hand, the NCP experiment reveals that Cu + , instead of Cu 2+ , also contributes to the antibacterial process. This study provides new insight into the antibacterial mechanisms of Cu 2 O.

Owing to their limited accuracy and narrow applicability, current antimicrobial peptide (AMP) prediction models face obstacles in industrial application. To address these limitations, we developed and improved an AMP prediction model using Comparing and Optimizing Multiple DEep Learning (COMDEL) algorithms, coupled with high-throughput AMP screening method, finally reaching an accuracy of 94.8% in test and 88% in experiment verification, surpassing other state-of-the-art models. In conjunction with COMDEL, we employed the phage-assisted evolution method to screen Sortase in vivo and developed a cell-free AMP synthesis system in vitro , ultimately increasing AMPs yields to a range of 0.5-2.1 g/L within hours. Moreover, by multi-omics analysis using COMDEL, we identified Lactobacillus plantarum as the most promising candidate for AMP generation among 35 edible probiotics. Following this, we developed a microdroplet sorting approach and successfully screened three L. plantarum mutants, each showing a twofold increase in antimicrobial ability, underscoring their substantial industrial application values., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Sugar substitutes are popular due to their akin taste and low calories. However, excessive use of aspartame and erythritol can have varying effects. While D-allulose is presently deemed a secure alternative to sugar, its excessive consumption is not devoid of cellular stress implications. In this study, the evolution of Escherichia coli Nissle 1917 (EcN) is directed to utilize allulose as sole carbon source through a combination of adaptive laboratory evolution (ALE) and fluorescence-activated droplet sorting (FADS) techniques. Employing whole genome sequencing (WGS) and clustered regularly interspaced short palindromic repeats interference (CRISPRi) in conjunction with compensatory expression displayed those genetic mutations in sugar and amino acid metabolic pathways, including glnP, glpF, gmpA, nagE, pgmB, ybaN, etc., increased allulose assimilation. Enzyme-substrate dynamics simulations and deep learning predict enhanced substrate specificity and catalytic efficiency in nagE A247E and pgmB G12R mutants. The findings evince that these mutations hold considerable promise in enhancing allulose uptake and facilitating its conversion into glycolysis, thus signifying the emergence of a novel metabolic pathway for allulose utilization. These revelations bear immense potential for the sustainable utilization of D-allulose in promoting health and well-being., (© 2024 Wiley‐VCH GmbH.)

In constructed wetlands (CWs), carbon source availability profoundly affected microbial metabolic activities engaged in both iron cycle and nitrogen metabolism. However, research gaps existed in understanding the biotransformation of nitrogen and iron in response to fluctuations in organic carbon content under day-night alterations. Results demonstrated increased removal efficiency of NO 3 - -N (95.7 %) and NH 4 + -N (75.70 %) under light conditions, attributed to increased total organic carbon (TOC). This enhancement promoted the relative abundance of bacteria involved in nitrogen and iron processes, establishing a more stable microbial network. Elevated TOC content also upregulated genes for iron metabolism and glycolysis, facilitating denitrification. Spearman correlation analysis supported the synergistic mechanisms between FeS 2 -based autotrophic denitrification and TOC-mediated heterotrophic denitrification under light conditions. The significant impact of carbon sources on microbial activities underscores the critical role of organic carbon availability in enhancing nitrogen removal efficiency, providing valuable insights for optimizing FeS 2 -based CWs design and operation strategies., 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.)

Accurate polyp detection is critical for early colorectal cancer diagnosis. Although remarkable progress has been achieved in recent years, the complex colon environment and concealed polyps with unclear boundaries still pose severe challenges in this area. Existing methods either involve computationally expensive context aggregation or lack prior modeling of polyps, resulting in poor performance in challenging cases. In this paper, we propose the Enhanced CenterNet with Contrastive Learning (ECC-PolypDet), a two-stage training & end-to-end inference framework that leverages images and bounding box annotations to train a general model and fine-tune it based on the inference score to obtain a final robust model. Specifically, we conduct Box-assisted Contrastive Learning (BCL) during training to minimize the intra-class difference and maximize the inter-class difference between foreground polyps and backgrounds, enabling our model to capture concealed polyps. Moreover, to enhance the recognition of small polyps, we design the Semantic Flow-guided Feature Pyramid Network (SFFPN) to aggregate multi-scale features and the Heatmap Propagation (HP) module to boost the model's attention on polyp targets. In the fine-tuning stage, we introduce the IoU-guided Sample Re-weighting (ISR) mechanism to prioritize hard samples by adaptively adjusting the loss weight for each sample during fine-tuning. Extensive experiments on six large-scale colonoscopy datasets demonstrate the superiority of our model compared with previous state-of-the-art detectors.

Immune checkpoint inhibitors (ICIs) are effective agents for tumor immunotherapy. However, their clinical effectiveness is unsatisfactory due to off-target effects and a suppressive immune microenvironment. This study developed a nanodrug delivery system for bladder cancer (BCa) using PCL-MPEG and PCL-PEG-CHO to synthesize internal hydrophobic and external hydrophilic micelles (PP) that encapsulated water-insoluble astragaloside IV (PPA). The aldehyde group on the surface of PPA reacted with the amino group of aPD-L1, allowing the decoration of this antibody on the surface of the micelles. The resultingPPA@aPD-L1effectively piggybacked astragaloside IV and aPD-L1 antibody. These findings suggest that PPA@aPD-L1 is relatively stable in circulation and efficiently binds to BCa cells with the aid of aPD-L1. Additionally, this strategy prolongs the drug's retention time in tumors. Compared to PBS, PP, and PPA with PPA + aPD-L1 groups, PPA@aPD-L1significantly prolonged the survival of mice with BCa and reduced tumor volume. Mechanistic studies showed that PPA inhibited the NF-κB and STAT3 signaling pathways in tumor cells. Additionally, PPA@aPD-L1increased IFN-γ and decreased IL-10 expression in bladder tumors, affecting the number and type of intratumorally infiltrating T cells. Our study presents a simple and effective drug delivery system that combines herbal monomers with ICIs. It has demonstrated a potent ability to suppress tumor growth and holds potential for future applications., (© 2024. The Author(s).)

Wireless sensing is a crucial technology for building smart cities, playing a vital role in applications such as human monitoring, route planning, and traffic management. Analyzing the data provided by wireless sensing enables the formulation of more scientific decisions. The wireless sensing of dynamic events is a significant branch of wireless sensing. Sensing the specific times and durations of dynamic events is a challenging problem due to the dynamic event information is concealed within static environments. To effectively sense the relevant information of event occurrence, we propose a wireless sensing method for dynamic events based on RSSI, named RSSI-WSDE. RSSI-WSDE utilizes variable-length sliding windows and statistical methods to process original RSSI time series, amplifying the differences between dynamic events and static environments. Subsequently, z-score normalization is employed to enhance the comparability of the sensing effects for different dynamic events. Furthermore, by setting the adaptive threshold, the occurrence of dynamic event is sensed and the relevant information is marked on the original RSSI time series. In this study, the sensing performance of RSSI-WSDE was tested in indoor corridors and outdoor urban road environments. The wireless sensing of dynamic events, including walking, running, cycling, and driving, was conducted. The experimental results demonstrate that RSSI-WSDE can accurately sense the occurrence of dynamic events, marking the specific time and duration with millisecond-level precision. Moreover, RSSI-WSDE exhibits robust performance in wireless sensing of dynamic events in both indoor and outdoor environments.

Autonomous nanorobots represent an advanced tool for precision therapy to improve therapeutic efficacy. However, current nanorobotic designs primarily rely on inorganic materials with compromised biocompatibility and limited biological functions. Here, we introduce enzyme-powered bacterial outer membrane vesicle (OMV) nanorobots. The immobilized urease on the OMV membrane catalyzes the decomposition of bioavailable urea, generating effective propulsion for nanorobots. This OMV nanorobot preserves the unique features of OMVs, including intrinsic biocompatibility, immunogenicity, versatile surface bioengineering for desired biofunctionalities, capability of cargo loading and protection. We present OMV-based nanorobots designed for effective tumor therapy by leveraging the membrane properties of OMVs. These involve surface bioengineering of robotic body with cell-penetrating peptide for tumor targeting and penetration, which is further enhanced by active propulsion of nanorobots. Additionally, OMV nanorobots can effectively safeguard the loaded gene silencing tool, small interfering RNA (siRNA), from enzymatic degradation. Through systematic in vitro and in vivo studies using a rodent model, we demonstrate that these OMV nanorobots substantially enhanced siRNA delivery and immune stimulation, resulting in the utmost effectiveness in tumor suppression when juxtaposed with static groups, particularly evident in the orthotopic bladder tumor model. This OMV nanorobot opens an inspiring avenue to design advanced medical robots with expanded versatility and adaptability, broadening their operation scope in practical biomedical domains., Competing Interests: Competing interests statement:The authors declare no competing interest.