Search

Cardiac ischaemia/reperfusion (I/R) impairs mitochondrial function, resulting in excessive oxidative stress and cardiomyocyte ferroptosis and death. Nuclear factor E2-related factor 2 (Nrf2) is a key regulator of redox homeostasis and has cardioprotective effects against various stresses. Here, we tested whether CBR-470-1, a noncovalent Nrf2 activator, can protect against cardiomyocyte death caused by I/R stress. Compared with vehicle treatment, the administration of CBR-470-1 (2 mg/kg) to mice significantly increased Nrf2 protein levels and ameliorated the infarct size, the I/R-induced decrease in cardiac contractile performance, and the I/R-induced increases in cell apoptosis, ROS levels, and inflammation. Consistently, the beneficial effects of CBR-470-1 on cardiomyocytes were verified in a hypoxia/reoxygenation (H/R) model in vitro, but this cardioprotection was dramatically attenuated by the GPX4 inhibitor RSL3. Mechanistically, CBR-470-1 upregulated Nrf2 expression, which increased the expression levels of antioxidant enzymes (NQO1, SOD1, Prdx1, and Gclc) and antiferroptotic proteins (SLC7A11 and GPX4) and downregulated the protein expression of p53 and Nlrp3, leading to the inhibition of ROS production and inflammation and subsequent cardiomyocyte death (apoptosis, ferroptosis and pyroptosis). In summary, CBR-470-1 prevented I/R-mediated cardiac injury possibly through inhibiting cardiomyocyte apoptosis, ferroptosis and pyroptosis via Nrf2-mediated inhibition of p53 and Nlrp3 and activation of the SLC7A11/GPX4 pathway. Our data also highlight that CBR-470-1 may serve as a valuable agent for treating ischaemic heart disease., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gallbladder cancer (GBC) is highly aggressive and has poor prognosis, with most patients only diagnosed at an advanced stage. Furthermore, treatment options are limited, and their effect is unsatisfactory. Bromodomain-containing protein (BRD) is an epigenetic regulator that plays a carcinogenic role in several tumors, including squamous cell lung cancer, acute myeloid leukemia, synovial sarcoma, and malignant rhabdomyosarcoma. However, the expression, biological function, and molecular mechanisms of action of BRD9 in GBC are still unknown. Kaplan-Meier analysis, qRT-PCR, and analysis of clinical features were used to assess the clinical significance of BRD9 in GBC. Cell Counting Kit-8 and colony formation assays were performed to determine the effects of BRD9 on cell growth. The functional role of BRD9 in GBC was explored using qRT-PCR, western blotting, siRNA, and CHIP-qPCR. mRNA sequencing was performed to explore the underlying mechanisms of BRD9, and a nude mouse model of GBC was established to explore the anti-tumor effects of the BRD9 inhibitor I-BRD9 in vivo. BRD9 expression was elevated in GBC tissues compared with adjacent non-tumor tissues, and high BRD9 expression was associated with poor prognosis in patients with GBC. BRD9 knockdown by siRNA significantly decreased cell growth. Targeting BRD9 with I-BRD9 inhibited the proliferation of GBC cells without significant toxic effects. Additionally, I-BRD9 treatment suppressed CST1 expression in GBC cell lines, thereby inhibiting the PI3K-AKT pathway. The transcription factor FOXP1 was found to interact with BRD9 to regulate CST1 expression. Collectively, these results suggest that BRD9 may be a promising biomarker and therapeutic target for GBC., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate Animal experiments involving nude mice met the requirements and were approved by Xinhua Hospital of Shanghai Jiao Tong University School of Medicine (Animal experiment approval number: XHEC–NSFC–2021-093, approval date: February 24, 2021). The study was approved by the Ethics Committee of Xinhua Hospital, Shanghai Jiaotong University School of Medicine. Informed consent was obtained from the patients for this study. Consent for publication All authors have seen and approved the manuscript and consent publication., (© 2024. The Author(s).)

Background: Depression and anxiety disorders are prevalent psychiatric conditions, and currently utilized chemical drugs typically come with significant adverse effects. China boasts a wealth of medicinal and food herbs known for their safe and effective properties., Purpose: This study aimed to develop novel formulations with improved antidepressant and anxiolytic effects derived from medicinal and food herbs., Study Design: Screening combinations with antidepressant and anxiolytic effects using techniques such as network pharmacology and validating their effects in vitro and in vivo experiments., Methods: Utilizing network pharmacology and molecular docking, we identified the top ten medicinal herbs with anxiolytic and antidepressant potential. Herbs with cytoprotective effects and non-toxic characteristics were further screened to formulate the herbal blends. Subsequently, we established a PC12 cell injury model and a chronic unpredictable mild stress (CUMS) model in mice to assess the effects of our formulations., Results: Ten medicinal herbs were initially screened, and six of them were deemed suitable for formulating the blend, namely Gancao, Dazao, Gouqizi, Sangye, Huangqi, and Jinyinhua (GDGSHJ). The GDGSHJ formulation reduced Lactate Dehydrogenase (LDH) leakage, decreased apoptosis, and demonstrated a favorable antidepressant and antianxiety effect in the CUMS mouse model. Besides, GDGSHJ led to the upregulation of serum 5-Hydroxytryptamine (5-HT) content and brain tissue 5-HT, Gamma-aminobutyric acid (GABA), and Dopamine (DA) levels. It also downregulated the expression of SLC6A4 and SLC6A3 genes in the mouse hippocampus while upregulating HTR1A, DRD1, DRD2, and GABRA1 genes., Conclusion: Our formulation exhibited robust antidepressant and antianxiety effects without inducing substantial toxicity. This efficacy appears to be mediated by the expression of relevant genes within the hippocampus of mice. The formulation achieved this effect by balancing 5-HT levels in the serum and DA, GABA, and 5-HT levels within brain tissue., Competing Interests: Declaration of competing interest The authors have no financial interest or other potential conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Globally, streptococcal disease caused by Streptococcus agalactiae is known for its high mortality rate, which severely limits the development of the tilapia breeding industry. As a third-generation vaccine, DNA vaccines have shown great application prospects in the prevention and control of aquatic diseases, but their low immunogenicity limits their development. The combination of DNA vaccines and molecular adjuvants proved to be an effective method for inducing protective immunity. This study constructed recombinant plasmids encoding tilapia HSP70 and IL-1β genes (pcHSP70 and pcIL-1β) to verify their effectiveness as molecular adjuvants for S. agalactiae DNA vaccine (pcSIP) in the immunized tilapia model. The results revealed that serum-specific IgM production, enzyme activities, and immune-related gene expression in tilapia immunized with pcSIP plus pcHSP70 or pcIL-1β were significantly higher than those in tilapia immunized with pcSIP alone. It is worth noting that combination with molecular adjuvants improved the immune protection of DNA vaccines, with a relative percentage survival (RPS) of 51.72% (pcSIP plus pcHSP70) and 44.83% (pcSIP plus pcIL-1β), respectively, compared with that of pcSIP alone (24.14%). Thus, our study indicated that HSP70 and IL-1β in tilapia are promising molecular adjuvants of the DNA vaccine in controlling S. agalactiae infection., (© 2024 John Wiley & Sons Ltd.)

Cardiomyocytes are terminal differentiated cells and have limited ability to proliferate or regenerate. Condition like myocardial infarction causes massive death of cardiomyocytes and is the leading cause of death. Previous studies have demonstrated that cardiac fibroblasts can be induced to transdifferentiate into cardiomyocytes in vitro and in vivo by forced expression of cardiac transcription factors and microRNAs. Our previous study have demonstrated that full chemical cocktails could also induce fibroblast to cardiomyocyte transdifferentiation both in vitro and in vivo. With the development of tissue clearing techniques, it is possible to visualize the reprogramming at the whole-organ level. In this study, we investigated the effect of the chemical cocktail CRFVPTM in inducing in situ fibroblast to cardiomyocyte transdifferentiation with two strains of genetic tracing mice, and the reprogramming was observed at whole-heart level with CUBIC tissue clearing technique and 3D imaging. In addition, single-cell RNA sequencing (scRNA-seq) confirmed the generation of cardiomyocytes from cardiac fibroblasts which carries the tracing marker. Our study confirms the use of small molecule cocktails in inducing in situ fibroblast to cardiomyocyte reprogramming at the whole-heart level and proof-of-conceptly providing a new source of naturally incorporated cardiomyocytes to help heart regeneration., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Psoriasis is an inflammatory skin disease that relapses frequently. Keratinocyte apoptosis dysregulation plays a crucial role in the pathological mechanisms of psoriasis. PANoptosis is a process with intermolecular interaction among pyroptosis, apoptosis, and necroptosis. The mechanism of PANoptosis in the occurrence and development of psoriasis is still unclear. Here we present a novel approach by identifying PANoptosis-related signatures (PANoptosis-sig) from skin tissue of psoriasis patients and healthy controls on transcriptional and protein levels. Five PANoptosis-sig (TYMP, S100A8, S100A9, NAMPT, LCN2) were identified. Enrichment analysis showed they were mainly enriched in response to leukocyte aggregation, leukocyte migration, chronic inflammatory response and IL-17 signaling pathway. Single cell transcriptome analysis showed TYMP and NAMPT were expressed in almost all cell populations, while LCN2, S100A8 and S100A9 were significantly highly expressed in keratinocyte. We then constructed predictive and diagnostic models with the PANoptosis-sig and evaluated their performance. Finally, unsupervised consensus clustering analysis was conducted to ascertain psoriasis molecular subtypes by the PANoptosis-sig. The psoriasis cohort was divided into two distinct subtypes. Immune landscape showed that the stromal score of cluster 1 was significantly higher than cluster 2, while the immune and estimate scores of cluster 2 were expressively higher than cluster 1. Cluster 1 exhibited high expression of Plasma cells, Tregs and Mast cells resting, while cluster 2 showed high expression of T cells, Macrophages M1, Dendritic cells activated, and Neutrophils in immune infiltration analysis. And cluster 2 was more sensitive to immune checkpoints. In conclusion, our findings revealed potential biomarkers and therapeutic targets for the prevention, diagnosis, and treatment of psoriasis, enhancing our understanding of the molecular mechanisms underlying PANoptosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu 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.)

The employment of ultra-low permittivity materials in the configuration of antennas has been demonstrated to augment the antenna bandwidth and diminish signal delay effectively. This study presents three ultra-low permittivity metaphosphate microwave dielectric ceramics (MWDCs). The ALaP 4 O 12 (A = Li, Na, K) metaphosphate ceramics, which all belong to the monoclinic crystal system, exhibit extremely low permittivity (ε r ≈ 5) and excellent quality factor ( Q · f > 10,000 GHz) at a low sintering temperature ( T < 950 °C). Terahertz time-domain spectroscopy indicates that the ε r of ALaP 4 O 12 at terahertz frequencies is comparable to that observed in the microwave band and its value remains stable over an extensive frequency range. Furthermore, the relationship between the crystal structure and the dielectric properties of ALaP 4 O 12 has been analyzed through the lens of chemical bond theory. The highest Q · f value observed for LiLaP 4 O 12 can be attributed to the high chemical bond strength and stability of its crystal structure. The lowest ionic polarizability per unit volume is exhibited by NaLaP 4 O 12 , which results in the lowest pore-corrected permittivity. The thermal expansion of the chemical bonds within KLaP 4 O 12 is considerable, resulting in the highest coefficient of thermal expansion. Finally, the performance of a LiLaP 4 O 12 -based dielectric resonator antenna (DRA) excited by slot-coupled microstrip lines was designed and optimized by using different ceramic radius-to-height (RH) ratios. It was found that when the RH ratio of DRA reached 1.85, both the fundamental mode (HEM 11δ ) and the higher-order mode (HEM 12δ ) of DRA were simultaneously excited. The two modes overlap significantly, resulting in an ultra-wideband (UWB) of 46.8% (bandwidth = 7.93 GHz). Concurrently, the maximum radiation efficiency and gain of the DRA, obtained from the simulation, are 97.9% and 7.92 dBi, respectively. The findings of this study may inform the investigation of ultra-low permittivity phosphorus-based MWDCs and UWB DRAs.

Bacterial aromatic polyketides are compounds with multiple aromatic rings synthesized by bacterial type II polyketide synthases (PKSs), some of which have been developed into clinical drugs. Compounds containing aromatic polyketides synthesized by hybrid type I and type II PKSs are extremely rare. Here, we report the discovery of a gene cluster encoding both modular type I and type II PKSs as well as KAS III through extensive bioinformatics analysis, leading to the characterization of the hybrid polyketide, spirocycline A. The structure of spirocycline A is rare among all aromatic polyketides, featuring a unique starter unit and four spirocycles and forming a dimer. Biosynthetic studies indicate that the starter unit of this molecule is synthesized by type I PKS in collaboration with two trans -acting ketoreductase (KR) and enoylreductase (ER). It is then transferred by KAS III to the type II PKS system, which synthesizes the tricyclic aromatic polyketide backbone. The subsequent formation of the spirocycle and dimerization are carried out by four redox enzymes encoded in the gene cluster. Overall, the discovery of spirocycline A provides a new approach for identifying novel aromatic polyketides and offers potential enzymatic tools for the bioengineering of these hybrid polyketides.

Objective: The uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPARγ agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes. To explore this, we employed human adipocytes differentiated from progenitor cells and examined their acute response to Rsg, to the adenylate-cyclase activator forskolin (Fsk), or to both simultaneously., Methods: Adipocytes generated from primary human progenitor cells were differentiated without exposure to PPARγ agonists, and treated for 3, 6 or 78 h to Fsk, to Rsg, or to both simultaneously. Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 mediated knockout, oxygen consumption and western blotting were used to assess cellular responses., Results: UCP1 mRNA expression was induced within 3 h of exposure to either Rsg or Fsk, indicating that Rsg's effect is independent on additional adipocyte differentiation. Although Rsg and Fsk induced distinct overall transcriptional responses, both induced genes associated with calcium metabolism, lipid droplet assembly, and mitochondrial remodeling, denoting core features of human adipocyte beiging. Unexpectedly, we found that Fsk-induced UCP1 expression was reduced by approximately 80% following CRISPR-Cas9-mediated knockout of PNPLA2, the gene encoding the triglyceride lipase ATGL. As anticipated, ATGL knockout suppressed lipolysis; however, the associated suppression of UCP1 induction indicates that maximal cAMP-mediated UCP1 induction requires products of ATGL-catalyzed lipolysis. Supporting this, we observed that the reduction in Fsk-stimulated UCP1 induction caused by ATGL knockout was reversed by Rsg, implying that the role of lipolysis in this process is to generate natural PPARγ agonists., Conclusions: UCP1 transcription is known to be stimulated by transcription factors activated downstream of cAMP-dependent protein kinases. Here we demonstrate that UCP1 transcription can also be acutely induced through PPARγ-activation. Moreover, both pathways are activated in human adipocytes in response to cAMP, synergistically inducing UCP1 expression. The stimulation of PPARγ in response to cAMP may result from the production of natural PPARγ activating ligands through ATGL-mediated lipolysis., 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 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Azo molecules, being extensively studied as photoswitches, have demonstrated versatile photoswitching performance and applications in solution-phase systems. However, the dense molecular packing and insufficient conformational freedom in the solid/crystalline state typically pose a challenge to their E ⇆ Z isomerization. This study presents a breakthrough in solid-state azo chemistry, where the investigated azobispyrazole molecules are capable of achieving high E → Z photoconversion, ranging from 85% to nearly quantitative (96%), and quantitative Z → E photoswitching in their crystalline states. To the best of our knowledge, azobispyrazoles are the first photoswitchable azo crystals that achieve high-yield bidirectional conversions, particularly the challenging thermodynamically stable-to-metastable E → Z transformation. Crystallographic and computational analyses provide in-depth insights into the photoswitching mechanism and propose that locally distributed free spaces and weak intermolecular interactions within the crystal structures are key factors contributing to the crystalline-state conversion. This work opens up new avenues for the development of promising photoswitchable azo crystals and also underscores the potential application of azobispyrazole crystals as light-responsive materials.

Background: Brain structure injury was presented in acute lymphoblastic leukemia (ALL) after treatment; however, its alterations in new-onset stage are still unclear. We aim to explore white matter (WM) and grey matter (GM) alterations using surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) in new-onset pediatric ALL., Methods: Thirty-five ALL and 33 typically developing (TD) children were prospectively recruited and underwent three-dimensional T1-weighted and diffusion tensor (DTI) imaging. DTI metrics, cortical GM features, and deep GM nuclei volume were compared between groups differences., Results: In ALL, the only increased FA in the body of corpus callosum (P FWE-corrected  = 0.023) and left superior corona radiata (P FWE-corrected  = 0.045) were presented. Relative to TDs, pediatric ALL presented a significant decrease in cortical surface area (CSA), thickness (CT), and volume in orbital gyri, supramarginal gyrus, middle temporal gyrus, and superior temporal gyrus (all CWP = 0.01). Additionally, increased CT and CSA were found in lingual gyrus and left sulcus intermedius primus, respectively (all CWP = 0.01). Smaller volumes in pediatric ALL were observed in bilateral thalamus, caudate, hippocampus, and right putamen (P FDR-corrected  < 0.05)., Conclusion: Widespread brain structural abnormalities were found in new-onset pediatric ALL, which suggest disease itself can cause brain structural injury., Impact: This study revealed the altered white matter integrity and gray matter morphology characteristics in childhood acute lymphoblastic leukemia on new-onset stage. It is suggested that there may be structural impairment before chemotherapy. MRI is a sensitive way for early detection on brain structural damage in childhood acute lymphoblastic leukemia., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and declare that J-LT is a BMJ clinical research editor.

Excessive fluoride ion (F - ) in the environment can affect health and even endanger life when ingested by the human body. However, most fluoride probes have the disadvantages of low sensitivity and long detection time. Herein, fluorescent probe 3a is successfully synthesized by linking two acetylenyltrimethylsilyl groups at both ends of the fluorinated benzothiadiazole core. After the addition of F - to 3a, the emission at 436 nm is significantly quenched and slightly blue-shifted. It is confirmed by electrospray ionization high-resolution mass spectrometry (ESI-HRMS) and density functional theory calculations (DFT) that these changes are due to the F - triggered Si-C bond cleavage and the subsequent inactivation of intramolecular charge transfer (ICT). The detection limit and response time of probe 3a for F - are 10 -8 mol/L and 25 s, respectively. Importantly, fluorescent material 3a can be processed into portable test tools for the visual detection of fluoride ion., 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.)

Objective: To review and compare the efficacy of different delivery modes of decision aids (DAs), including computer-based, print-based, multimedia-based, video-based, and website-based on decision-making outcomes for prostate cancer screening compared to usual care (UC) and among the delivery modes., Methods: PubMed, the Excerpta Medica dataBASE (EMBASE), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Google Advanced Search, and Turning Research Into Practice (TRIP) Database were systematically searched from inception to August 2023. The primary outcomes were knowledge level, knowledge scores, participation in shared decision-making (SDM), decisional conflict, and preference for SDM participation. Secondary outcomes were the proportion of subjects who underwent screening (actual screening utilisation) and the proportion of subjects who intended to be screened (intention to undergo screening). Network and pairwise meta-analyses were performed using random-effects models., Results: Seven systematic reviews were included. Network meta-analysis found that multimedia (relative risk [RR] 1.51, 95% confidence interval [CI] 1.02-2.24), print (RR 1.82, 95% CI 1.23-2.69), and website-based (RR 1.99, 95% CI 1.32-3.01) DAs significantly increased participation in SDM compared to the computer-based DA. There was a significant reduction in the actual screening utilisation in the computer DA arm compared to the other delivery modes. No significant differences between all delivery modes were noted on knowledge levels, knowledge scores, decisional conflict, preference for SDM participation, and intention to undergo screening. The highest mean surface under the cumulative ranking curve for all primary outcomes showed that website-based was the most effective delivery mode, followed by print-based DA. The pairwise meta-analysis showed a significant increase in participants' knowledge level, knowledge scores, a reduced intention to undergo screening and actual screening utilisation compared to UC., Conclusions: The findings suggest that different types of DAs have varying levels of effectiveness in increasing knowledge level, knowledge scores, participation in SDM, and influencing screening behaviours. While website-based DA appeared the most effective, employing the print-based DA could be a practical solution in settings with limited resources., (© 2024 The Author(s). BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

In this work, two novel probes 4a and 4b were synthesized through Suzuki-Miyaura coupling reaction, whose structures were further confirmed by 1 H NMR, 13 C NMR, high-resolution mass spectrometry (HRMS) and X-ray single crystal diffraction. The optical properties of the obtained molecules were investigated accordingly. Owing to different bridging fluorophores, there are certain differences in optical performance and detection ability between the two synthesized compounds. Especially, due to the subtle difference in orbitals energy and electron distribution displayed by the DFT calculations, 4a possesses the characteristics of dual-state emission (DSE) molecule, while 4b is an aggregation-induced emission (AIE) molecule. Interestingly, these two molecules can be developed into multifunctional detection probes, successfully applied for the fluorescence recognition of iron ions and common nitroaromatic compounds (NACs). At the same time, the probe molecules can also be applied to the detection of NACs in aqueous environment. What's more, they can also be loaded on test strips and thin-films for fluorescence identification of NACs, thus being expected to be developed into portable detection tools for NACs., 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.)

The traditional Chinese medicine (TCM) formulation Shengqiyichang Decoction (SQYCD) has been reported to stimulate host immunity, and it has been administered for the treatment of colorectal cancer (CRC). Here, we applied network and bioinformatics analyses to elucidate the mechanisms by which SQYCD ameliorates CRC and validated its modes of action via in vivo and in vitro experiments. We identified 46 active compounds in SQYCD and selected 237 proteins as potential therapeutic targets in CRC, most notably p38 mitogen-activated protein kinase (p38⍺). Bioinformatics analyses demonstrated differential expression in CRC tissues and prognostic value of the genes encoding TNFα, MAPK14, CASP-3, MAPK1, AKT1, PRKACA, VEGF, IL-6, EGFR and ESR1. We then plotted receiver operating curves (ROC) and time-ROC for the differentially expressed genes (DEGs) ESR1 and AKT1 to predict the progress of CRC. We speculated that the AKT/p38α-MAPK signaling pathway is associated with the clinical prognosis of CRC. In a mouse model, we found that SQYCD inhibits CRC tumor growth by increasing CD4 + and CD8 + T cell abundance and decreasing the ratio of T-regulatory cells (Tregs) in the tumor microenvironment. In cultured mouse CRC cells, SQYCD selectively upregulated levels of the CRC-associated protein lymphocyte antigen 6 family member G6D, while the AKT activator SC-79 reversed this effect. The discoveries made herein suggest that SQYCD exerts a therapeutic effect in CRC by inhibiting Treg recruitment via inhibition of the AKT/p38α/LY6G6D signaling axis., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 The Author(s).)

Introduction: Macranthoidin B (MB) is a primary active component of Flos Lonicerae. In Chinese veterinary clinics, Flos Lonicerae is frequently used in combination with florfenicol to prevent and treat infections in livestock and poultry. However, potential interactions between Flos Lonicerae and florfenicol remain unclear. To systematically study these interactions, it is crucial to investigate the individual phytochemicals within Flos Lonicerae . Therefore, MB was selected for this study to assess its effect on the pharmacokinetics of florfenicol in vivo and to explore the underlying mechanisms involved., Methods: Male Sprague-Dawley rats were administered MB (60 mg/kg BW) or sterile water orally for 7 consecutive days. On the 8th day, a single oral dose of florfenicol (25 mg/kg BW) was given. Florfenicol pharmacokinetics were analyzed using ultra-high performance liquid chromatography. The hepatic expression levels of cytochrome P450 (CYP1A2, CYP2C11, CYP3A1), UDP-glucuronosyltransferase (UGT1A1), P-glycoprotein (P-gp), and nuclear receptors, including constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor alpha (RXRα), were quantified via reverse transcription-quantitative polymerase chain reaction and Western blotting (WB). Hepatic CYP1A2 and CYP2C11 activities were measured using a cocktail method. Additionally, the subcellular expression and localization of CAR, PXR, and RXRαin hepatocytes was assessed using WB and immunofluorescence staining., Results: MB significantly reduces the AUC (0-∞) and MRT (0-∞) of florfenicol. MB also markedly upregulates the mRNA and protein expression of hepatic CYP1A2 and CYP2C11, along with their catalytic activities. Substantial upregulation of CAR and PXR proteins occurs in the hepatocyte nucleus, along with significant nuclear colocalization of the transcriptionally active CAR/RXRα and PXR/RXRαheterodimers, indicating MB-induced nuclear translocation of both CAR and PXR., Discussion: These findings suggest that MB-induced alterations in florfenicol pharmacokinetics, particularly its accelerated elimination, may be due to increased expression and activities of CYP1A2 and CYP2C11, with CAR and PXR potentially involved in these regulatory effects. Further investigation is yet needed to fully elucidate the clinical implications of these interactions concerning the efficacy of florfenicol in veterinary medicine., 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 Li, Wang, Zhang, Yin, Yang, Li and Liang.)

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

The selective construction of bridged bicyclic scaffolds has garnered increasing attention because of their extensive use as saturated bioisosteres of arene in pharmaceutical industry. However, in sharp contrast to their racemic counterparts, assembling chiral bridged bicyclic structures in an enantioselective and regioselective manner remains challenging. Herein, we describe our protocol for constructing chiral 2-oxa-3-azabicyclo[3.1.1]heptanes (BCHeps) by enantioselective [4π + 2σ] cycloadditions of bicyclo[1.1.0]butanes (BCBs) and nitrones taking advantage of a chiral copper(II) complex as a Lewis acid catalyst. This method features mild conditions, good functional group tolerance, high yield (up to 99%), and excellent enantioselectivity (up to 99% ee). Density functional theory (DFT) calculation elucidates the origin of the reaction's enantioselectivity and the mechanism of BCB activation by Cu(II) complex.

This study aimed to illustrate the biological behavior and changes in cell function during the progression of apical periodontitis in deciduous teeth and to explore the underlying molecular mechanism. Deciduous teeth periodontal ligament stem cells (DePDLSCs) were derived and their identity was confirmed. The viability, inflammation, and osteogenic ability of cells were tested by exposing them to various concentrations of lipopolysaccharide (LPS) (0-100 μg/mL) using the cell counting kit-8 (CCK-8) assay, reverse transcription polymerase chain reaction (real-time PCR), alkaline phosphatase (ALP) staining, and ALP activity assay. In addition, osteogenic-induced cells with and without 10 μg/mL LPS were harvested for high-throughput sequencing. Based on sequencing data, proinflammatory factors and ALP expression were measured after interference with the PI3K-AKT signaling pathway activator, 740Y-P. LPS biphasically affected the proliferation and osteogenesis of DePDLSCs. Low concentrations of LPS showed stimulatory effects, whereas inhibitory effects were observed at high concentrations. Sequencing analysis showed that the PI3K-AKT signaling pathway was significantly downregulated when DePDLSCs were treated with 10 μg/mL LPS. The LPS-induced inflammation and osteogenesis inhibition of DePDLSCs were partially rescued by 740Y-P treatment. In conclusion, LPS affected DePDLSCs proliferation and osteogenesis in a biphasic manner. Moderate activation of PI3K-AKT signaling pathway was beneficial for osteogenic differentiation and anti-inflammatory effect in DePDLSCs. This research may provide etiological probes for apical periodontitis and its treatment.

Melanoma-associated antigen A6 (MAGEA6) is well known to have oncogenic activity, but the underlying mechanisms by which it regulates tumor progression and chemo-resistance, especially in triple-negative breast cancer (TNBC), have been unknown. In the study, the differential expression genes (DEGs) in TNBC tumor tissues and TNBC-resistant tumor tissues were analyzed based on TCGA and GEO datasets. MAGEA6, as the most significantly expressed gene, was analyzed by RT-qPCR, western blotting and immunohistochemistry assay in TNBC cell lines and tumor tissues. The potential mechanisms that influence chemo-resistance were also evaluated. Results displayed that MAGEA6 was highly expressed in TNBC and involved in drug resistance. MAGEA6 silencing enhanced the chemo-sensitivity of TNBC to doxorubicin (DOX) in vitro and in vivo, as determined by decreasing IC 50 value, proliferation and invasion capacity, and triggering apoptosis. Mechanistically, it was shown that MAGEA6 depletion sensitized TNBC to DOX via regulating autophagy. Ubiquitination assay displayed that knockdown of MAGEA6 decreased the AMPKα1 ubiquitination, thereby elevating the levels of AMPKα1 and p-AMPKα in TNBC cells. Importantly, AMPK inhibitor (Compound C) can reduce the LC3II/I level induced by sh-MAGEA6, indicating that sh-MAGEA6 activated AMPK signaling through suppressing AMPKα1 ubiquitination and then facilitated autophagy in TNBC. Furthermore, we also observed that AMPK is required for SLC7A11 to regulate ferroptosis, and supported the crux roles of MAGEA6/AMPK/SLC7A11-mediated ferroptosis on modulating DOX sensitivity in TNBC cells. These findings indicated that targeting MAGEA6 can enhance the chemo-sensitivity in TNBC via activation of autophagy and ferroptosis; its mechanism involves AMPKα1-dependent autophagy and AMPKα1/SLC7A11-induced ferroptosis., (© 2024. The Author(s).)

The synthesis of novel water-soluble polymers with biodegradability is an effective way to mitigate their negative environmental impacts. In this study, semi-aromatic copolyester poly(butylene succinate-co-butylene terephthalate) (PBST) with exceptional biodegradability is used as the resin matrix. Anionic sodium 1-3-isophthalate-5-sulfonate (SIPA) is introduced as a fourth monomer to prepare random poly(butylene succinate-co-butylene terephthalate-co-butylene 5-sodiosulfoisophthalate) (PBSTS) copolyesters by melt copolymerization. The incorporation of ionic groups enhances the hydrophilicity and water absorption of the copolyesters, resulting in water-soluble materials that exhibit ionic and temperature responsivity. Furthermore, the ionized biodegradable copolyesters demonstrate distinct pH-dependent degradation, which is accelerated at pH = 5.5 and 8.5 but inhibited at pH = 7.2. Degradation assessments in simulated body fluids reveal that the PBSTS copolyesters exhibit significant degradation in gastric fluids at pH = 1.5 with minimal degradation in intestinal fluids at pH = 6.8 and in body fluids at pH = 7.0. This unique degradation performance highlights the potential of these materials for addressing the challenges associated with selective drug delivery and localized controlled release in the human body., 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 B.V.)

A novel reaction of cyclic and acyclic secondary amines with in situ-generated allene intermediate species from nitro-substituted donor-acceptor cyclopropanes is reported. In the presence of a simple inorganic base, NaOH, tetrasubstituted enamine derivatives can be obtained in moderate to excellent yields. The reaction is operationally easy, features mild reaction conditions and simple inorganic bases, and is free of transition metals.

Introduction: This study aims to explore the role of cuproptosis-related genes in ACC, utilizing data from TCGA and GEO repositories, and to develop a predictive model for patient stratification., Methods: A cohort of 123 ACC patients with survival data was analyzed. RNA-seq data of 17 CRGs were examined, and univariate Cox regression identified prognostic CRGs. A cuproptosis-related network was constructed to show interactions between CRGs. Consensus clustering classified ACC into three subtypes, with transcriptional and survival differences assessed by PCA and survival analysis. Gene set variation analysis (GSVA) and ssGSEA evaluated functional and immune infiltration characteristics across subtypes. Differentially expressed genes (DEGs) were identified, and gene clusters were established. A risk score (CRG&#95;score) was generated using LASSO and multivariate Cox regression, validated across datasets. Tumor microenvironment, stem cell index, mutation status, drug sensitivity, and hormone synthesis were examined in relation to the CRG&#95;score. Protein expression of key genes was validated, and functional studies on ASF1B and NDRG4 were performed., Results: Three ACC subtypes were identified with distinct survival outcomes. Subtype B showed the worst prognosis, while subtype C had the best. We identified 214 DEGs linked to cell proliferation and classified patients into three gene clusters, confirming their prognostic value. The CRG&#95;score predicted patient outcomes, with high-risk patients demonstrating worse survival and possible resistance to immunotherapy. Drug sensitivity analysis suggested higher responsiveness to doxorubicin and etoposide in high-risk patients., Conclusion: This study suggests the potential prognostic value of CRGs in ACC. The CRG&#95;score model provides a robust tool for risk stratification, with implications for treatment strategies., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Huang et al.)

The sweetness of apple fruit is a key factor in the improvement of apple varieties, with fructose being the sweetest of the soluble sugars, playing a crucial role in determining the overall sweetness of the apple. Therefore, uncovering the key genes controlling fructose accumulation and deciphering the regulatory mechanisms of fructose are vitally important for the improvement of apple varieties. In this study, through BSA-seq and transcriptome analysis of the 'Changfu 2' × 'Golden Delicious' F1 hybrid population, MdNAC5 was identified as a key regulatory gene for fructose content. MdNAC5 was shown to significantly influence fructose accumulation in both apples and tomatoes. Furthermore, we conducted a detailed identification of sugar transporters and metabolic enzymes in apples, discovering that MdNAC5 can enhance fructose accumulation in vacuoles and the conversion of sucrose to fructose by binding to and activating the promoters of the vacuolar sugar transporter MdTST2 and the neutral invertase MdNINV6. Additionally, MdNAC5 regulated the MdEIN3.4-MdSWEET15a module, strengthening the unloading of sucrose in the phloem of the fruit. Our results reveal a new mechanism by which MdNAC5 regulates fructose accumulation in apples and provide theoretical foundations for improving apple sweetness through genetic modification., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Pathological cardiac hypertrophy, a common feature in various cardiovascular diseases, can be more effectively managed through combination therapies using natural compounds. Harmine, a β-carboline alkaloid found in plants, possesses numerous pharmacological functions, including alleviating cardiac hypertrophy. Similarly, Selenomethionine (SE), a primary organic selenium source, has been shown to mitigate cardiac autophagy and alleviate injury. To explores the therapeutic potential of combining Harmine with SE to treat cardiac hypertrophy. The synergistic effects of SE and harmine against cardiac hypertrophy were assessed in vitro with angiotensin II (AngII)-induced hypertrophy and in vivo using a Myh6 R404Q mouse model. Co-administration of SE and harmine significantly reduced hypertrophy-related markers, outperforming monotherapies. Transcriptomic and metabolic profiling revealed substantial alterations in key metabolic and signalling pathways, particularly those involved in energy metabolism. Notably, the combination therapy led to a marked reduction in the activity of key glycolytic enzymes. Importantly, the addition of the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) did not further potentiate these effects, suggesting that the antihypertrophic action is predominantly mediated through glycolytic inhibition. These findings highlight the potential of SE and harmine as a promising combination therapy for the treatment of cardiac hypertrophy., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Rescuing or compensating mitochondrial function represents a promising therapeutic avenue for radiation-induced chronic wounds. Adult stem cell efficacies are primarily dependent on the paracrine secretion of mitochondria-containing extracellular vesicles (EVs). However, effective therapeutic strategies addressing the quantity of mitochondria and mitochondria-delivery system are lacking. Thus, in this study, we aimed to design an effective hydrogel microneedle patch (MNP) loaded with stem cell-derived mitochondria-rich EVs to gradually release and deliver mitochondria into the wound tissues and boost wound healing. We, first, used metformin to enhance mitochondrial biogenesis and thereby increasing the secretion of mitochondria-containing EVs (termed "Met-EVs") in adipose-derived stem cells. To verify the therapeutic effects of Met-EVs, we established an in vitro and an in vivo model of X-ray-induced mitochondrial dysfunction. The Met-EVs ameliorated the mitochondrial dysfunction by rescuing mitochondrial membrane potential, increasing adenosine 5'-triphosphate levels, and decreasing reactive oxygen species production by transferring active mitochondria. To sustain the release of EVs into damaged tissues, we constructed a Met-EVs@Decellularized Adipose Matrix (DAM)/Hyaluronic Acid Methacrylic Acid (HAMA)-MNP. Met-EVs@DAM/HAMA-MNP can load and gradually release Met-EVs and their contained mitochondria into wound tissues to alleviate mitochondrial dysfunction. Moreover, we found Met-EVs@DAM/HAMA-MNP can markedly promote macrophage polarization toward the M2 subtype with anti-inflammatory and regenerative functions, which can, in turn, enhance the healing process in mice with skin wounds combined radiation injuries. Collectively, we successfully fabricated a delivery system for EVs, Met-EVs@DAM/HAMA-MNP, to effectively deliver stem cell-derived mitochondria-rich EVs. The effectiveness of this system has been demonstrated, holding great potential for chronic wound treatments in clinic.

Background: Hyaluronidase remains the mainstay treatment for skin necrosis due to vascular occlusion after hyaluronic acid (HA) dermal fillers. There is wide variability in protocols for the administration of hyaluronidase. Most protocols, however, lack strong evidence regarding hyaluronidase dosages., Methods: We conducted a systematic review and pilot meta-analysis, searching four international databases from inception until December 2023 for clinical studies reporting on two or more patients receiving hyaluronidase for skin necrosis after hyaluronic acid fillers. Random-effects (DerSimonian and Laird) meta-analyses were conducted. The primary outcome was the pooled proportion of complete scar resolution. We rated intra-study risk of bias using the Joanna Briggs Institute checklists and assessed the certainty of evidence using the GRADE approach., Results: We included 15 studies totaling 223 patients. The pooled proportion of complete scar resolution after hyaluronidase administration was 77.8% (95%-CI: 65.5% to 86.6%, p egger = 0.093, low certainty). Patients treated with high doses of hyaluronidase (>500 international units [IUs]) had lower rates of resolution of 69.6% (95%-CI: 41.2% to 88.3%) compared to those treated with low doses (500IU or less) that had 88.1% rate of resolution (95%-CI: 86.0% to 96.2%), though not statistically significant (p= 0.18). The use of adjunct therapies did not have a statistically significant effect on outcomes., Conclusion: A higher proportion of patients receiving low doses (500IU or less) (88.1%) had complete scar resolution compared to patients receiving high doses (69.7%), though not statistically significant (p=0.18). Future studies should provide more granular details on their protocols to benefit the formulation of evidence-based guidelines in future., Level of Evidence I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., Protocol Registration: CRD42024538661., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background: WALANT has gained much popularity in recent years, especially with COVID-19. However, a recent survey of the American Society for Surgery of the Hand membership (i.e. attendings/consultants) showed that only 17% were exposed to WALANT during residency or fellowship training. There is much interest in WALANT from trainees, but interpretation of the type and volume to be administered is highly varied. Methods: The aims of this study were (1) to survey a group of plastic surgery trainees in the UK about their knowledge of WALANT formulas, and (2) to compare trainee logbook records of WALANT procedures (if available) with published data from the UK. Results: All trainees were familiar with the 'standard' WALANT formula (1% lidocaine, 1:100,000 adrenaline ± 8.4% NaHCO 3 ) described by Lalonde. However, because of local formularies, rather than 1:100,000 adrenaline, all used 1:200,000 adrenaline as it comes premixed in the UK. Other formulas used by UK trainees included 0.5% bupivacaine + 1:200,000 adrenaline, and mixing 1% lidocaine + 1:200,000 adrenaline with 1% lidocaine 1:1. In comparing available trainee WALANT records with published UK data, the average volume of WALANT used was 6.6 mls in the current study versus 12.9 mls for similar procedures (wound debridement and skin closure ± local flap, digital nerve repair, fingertip reconstruction, thenar injuries, phalangeal fracture and single digit extensor repair); specifically, for single digit flexor tendon repairs, this was 10 mls versus 16.3 mls. Conclusions: While the British Society for Surgery of the Hand (BSSH) have developed official guidance for the use of WALANT in the UK, it appears there remains much variation in interpretation and hence, application. Comparison of trainee logbook records of common hand surgery procedures suggests that most can be done with much less WALANT administered than previously reported, with safe and reproducible results. Level of Evidence: Level IV (Therapeutic).

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Due to a lack of ancestry-matched, functional, and segregation data, Asians have a higher rate of receiving a variant of uncertain significance (VUS) result following panel testing. Managing VUS results presents challenges, as it often leads to increased anxiety and distress among cancer patients undergoing genetic testing. This exploratory study aims to investigate the experience of Asian cancer patients upon receiving a VUS result. A qualitative, semi-structured interview study was conducted, involving cancer patients who had received a VUS result through the Cancer Genetics Service of the National Cancer Centre Singapore. Twenty participants were interviewed, and their responses were transcribed and analyzed using thematic analysis to identify key themes. Thematic analysis revealed five major themes: (1) VUS results are interpreted as uncertain outcomes; (2) a VUS result provides relief and prompts positive behavioral adjustments; (3) patients employ fatalism and religion as coping mechanisms to navigate uncertainty; (4) genetic counselors, family, and the community offer reassurance and support; (5) patients value updates on variant classifications for future management. While this novel study provides unique insights into the perspectives of Asian patients who receive VUS results, it also highlights patients' effective management of VUS results and uncertainty, which has implications for improving counseling practices in Asia. Emphasis must be placed on accurate interpretation and clear communication of VUS results to dispel the possibility of misconceptions, misdiagnosis, and mismanagement in cancer care., (© 2024 National Society of Genetic Counselors.)

Pattern recognition receptors are an essential part of the immune system, which detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and help shape both innate and adaptive immune responses. When dsDNA is present, cyclic GMP-AMP Synthase (cGAS) produces a second messenger called cyclic GMP-AMP (cGAMP), which then triggers an adaptor protein called STING, and eventually activates the expression of type I interferon (IFN) and pro-inflammatory cytokines in immune cells. The cGAS-STING signaling pathway has been receiving a lot of attention lately as a key immune-surveillance mediator. In this review, we summarize the present circumstances of the cGAS-STING signaling pathway in viral infections and inflammatory diseases, as well as autoimmune diseases. Modulation of the cGAS-STING signaling pathway provides potential strategies for treating viral infections, inflammatory diseases, and autoimmune diseases., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Background & Aims: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear., Methods: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysM cre OXCT1 f/f (OXCT1 conditional knockout in macrophages) mice., Results: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8 + T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8 + T-cell exhaustion and increasing CD8 + T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8 + T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC., Conclusions: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer., Impact and Implications: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Chronic pain has emerged as a significant public health issue, seriously affecting patients' quality of life and psychological well-being, with a lack of effective pharmacological treatments. Numerous studies have indicated that macrophages play a crucial role in inflammatory pain, and targeting neuro-immune interactions for drug development may represent a promising direction for pain management. Chilobrachys jingzhao (C. jingzhao) is used as a folk medicine of the Li nationality with the efficacy of eliminating swelling, detoxicating, and relieving pain, and the related products are widely used in the market. However, the chemical constituents of C. jingzhao have not been reported, and the pharmacodynamic substance and the precise functional mechanism are unrevealed. Here we isolated a cyclic dipeptide, cyclo(L-Pro-L-Trp) (CPT) from C. jingzhao for the first time. CPT remarkably alleviated formalin-induced inflammatory pain and significantly inhibited inflammatory responses. In vivo, CPT attenuated neutrophil infiltration and plantar tissue edema and suppressed the mRNA expression of pro-inflammatory molecules. In vitro, CPT suppressed inflammation triggered by lipopolysaccharide (LPS) in both RAW 264.7 and iBMDM cells, reducing expressions of inducible nitric oxide synthase (iNOS), superoxide, and pro-inflammatory molecules. A mechanistic study revealed that CPT exerted an anti-inflammatory activity by blocking the mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, as well as alleviating the ubiquitination of tumor necrosis factor receptor-associated factor 6 (TRAF6). Our results elucidated the pharmacodynamic material basis of C. jingzhao, and CPT can be a promising lead for alleviating inflammation and inflammatory pain., 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.)

Combined distal interphalangeal joint (DIP) arthrodesis with proximal interphalangeal joint (PIP) arthroplasty or arthrodesis presents unique challenges. Although less common than isolated surgery for the DIP and PIP joints, with an aging population, combined DIP and PIP procedures are an increasingly encountered occurrence. Anatomical and morphological studies have provided length and width measurement standards for the middle and distal phalanges, allowing for planning to assess the compatibility of strategies. Besides reviewing anatomical studies to provide length and width guidelines for hardware placement, we will also discuss optimal hardware combinations for combined surgical intervention in the DIP and PIP joints. Conflict may exist between hardware used for the DIP arthrodesis and implants used for the PIP arthroplasty. As an example, if K-wires are used for DIP arthrodesis, any intervention in the PIP joint will be compatible. However, if headless screws are used for DIP arthrodesis, these should ideally not reach proximal to the midpoint of the middle phalanx. Other techniques, such as single or multiple oblique screws, and tension bands are compatible with PIP arthroplasty. Hence, options for management of the PIP joint are dependent on the technique used for DIP arthrodesis., Competing Interests: Conflicts of Interest No benefits in any form have been received or will be received related directly to this article., (Copyright © 2024 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Background: Insecticide resistance poses a significant challenge in the implementation of vector-borne disease control strategies. We have assessed the resistance levels of Aedes albopictus to deltamethrin and pyriproxyfen (PPF) in Fujian Province (China) and investigated the correlation between these resistance levels and mutations in the voltage-gated sodium channel (VGSC)., Methods: The WHO bioassay protocol was used to evaluate the resistance coefficient of Ae. albopictus to deltamethrin and PPF, comparing a susceptible population from the Foshan (FS) area with wild populations from the Sanming (SM), Quanzhou (QZ), Zhangzhou (ZZ), Putian (PT) and Fuzhou (FZ) areas in Fujian Province. Genomic DNA was analyzed by PCR and sequencing to detect knockdown resistance (kdr) in the VGSC, specifically at the pyrethroid resistance alleles V1016V, I1532I and F1534F. Molecular docking was also performed to analyze the binding interactions of PPF and its metabolite 4'-OH-PPF to cytochrome P450 (CYP) 2C19, 2C9 and 3A4 and Ae. albopictus methoprene-tolerant receptors (AeMet), respectively., Results: The analysis of resistance to deltamethrin and PPF among Ae. albopictus populations from the various regions revealed that except for the sensitive population in FS and the SM population, the remaining four regional populations demonstrated resistance levels ranging from 4.31- to 18.87-fold for deltamethrin and from 2.85- to 3.62-fold for PPF. Specifically, the FZ and PT populations exhibited high resistance to deltamethrin, whereas the ZZ and QZ populations approached moderate resistance levels. Also, the resistance of the FZ, PT and ZZ populations to PPF increased slowly but consistently with the increasing trend of deltamethrin resistance. Genomic analysis identified multiple non-synonymous mutations within the VGSC gene; the F1534S and F1534L mutations showed significant resistance to deltamethrin in Ae. albopictus. Molecular docking results revealed that PPF and its metabolite 4'-OH-PPF bind to the Ae. albopictus AeMet receptor and CYP2C19., Conclusions: The wild Ae. albopictus populations of Fujian Province showed varying degrees of resistance to deltamethrin and PPF and a trend of cross-resistance to deltamethrin and PPF. Increased vigilance is needed for potential higher levels of cross-resistance, especially in the PT and FZ regions., (© 2024. The Author(s).)

Purpose: The characteristic of RENT3B in cancer remains ambiguous. We aimed to study the relationship between RENT3B and immune infiltration in liver hepatocellular carcinoma (LIHC) and lung squamous cell carcinoma (LUSC)., Patients and Methods: We investigated the expression levels of RENT3B using ONCOMINE and TIMER databases, and assessed the interrelationship between RENT3B expression and survival using PrognoScan, GEPIA, and Kaplan-Meier plotter. Additionally, we examined the association between RENT3B and immune cells in the tumor microenvironment (TME), as well as markers of immune cells, using TIMER. Subsequently, we performed prognostic analysis based on the expression level of RENT3B within specific immune cell subgroups. Furthermore, we evaluated the promoter methylation profile of RENT3B between tumor and normal tissues in LIHC and LUSC using the DNMIVD database., Results: RENT3B exhibited increased levels in both in LIHC and LUSC. High RENT3B expression was associated with unfavorable prognosis in LIHC, whereas it indicated a beneficial prognosis in LUSC. In LIHC, the expression of RENT3B positively correlated with immune infiltration levels of B cells, CD4 + T cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. However, in LUSC, the expression of RENT3B showed a negative correlation with immune infiltration levels of B cells, CD8 + T cells, neutrophils, macrophages, and dendritic cells. RENT3B exhibited positive correlations with 42 immune markers in LIHC, while it displayed negative associations with 10 immune markers in LUSC. Despite variations in immune cell enrichment and reduction subgroups, high RENT3B expression consistently indicated poor prognosis in LIHC, whereas it remained favorable in LUSC. Additionally, there were no significant differences observed in RENT3B promoter methylation between tumor and normal tissues in both LIHC and LUSC., Conclusion: RENT3B can affect the overall tumor prognosis and is associated with immune infiltration, especially in LIHC and LUSC. Consequently, RENT3B can become a prognostic biomarker for LIHC and LUSC., (© 2024. The Author(s).)

A highly effective and enantioselective vinylogous Mannich reaction between benzothiazolimines and γ-butenolides catalyzed by a quinine based squaramide has been disclosed. A series of chiral benzothiazole amines containing a γ,γ-disubstituted butanolide scaffold bearing an adjacent chiral stereocenter have been successfully obtained in good to excellent yields (up to 91%) with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (>20 : 1 dr) with broad substrate generality under mild conditions. The new scaffold integrated with both chiral benzothiazolimine and γ-butenolide moieties may provide a possibility for the development of new pharmaceutical entities.

Metabolic disorders of cancer cells create opportunities for metabolic interventions aimed at selectively eliminating cancer cells. Nevertheless, achieving this goal is challenging due to cellular plasticity and metabolic heterogeneity of cancer cells. This study presents a dual-drug-loaded, macrophage membrane-coated polymeric nanovesicle designed to reprogram cancer metabolism with high specificity through integrated extracellular and intracellular interventions. This nanoformulation can target cancer cells and largely reduce their glucose intake, while the fate of intracellular glucose internalized otherwise is redirected at the specially introduced oxidation reaction instead of inherent cancer glycolysis. Meanwhile, it inhibits cellular citrate intake, further reinforcing metabolic intervention. Furthermore, the nanoformulation causes not only H 2 O 2 production, but also NADPH down-regulation, intensifying redox damage to cancer cells. Consequently, this nanoformulation displays highly selective toxicity to cancer cells and minimal harm to normal cells mainly due to metabolic vulnerability of the former. Once administered into tumor-bearing mice, this nanoformulation is found to induce the transformation of pro-tumor tumor associated macrophages into the tumor-suppressive phenotype and completely inhibit tumor growth with favourable biosafety.

Although the frequency of ancient hybridization across the Tree of Life is greater than previously thought, little work has been devoted to uncovering the extent, timeline, and geographic and ecological context of ancient hybridization. Using an expansive new dataset of nuclear and chloroplast DNA sequences, we conducted a multifaceted phylogenomic investigation to identify ancient reticulation in the early evolution of oaks (Quercus). We document extensive nuclear gene tree and cytonuclear discordance among major lineages of Quercus and relatives in Quercoideae. Our analyses recovered clear signatures of gene flow against a backdrop of rampant incomplete lineage sorting, with gene flow most prevalent among major lineages of Quercus and relatives in Quercoideae during their initial radiation, dated to the Early-Middle Eocene. Ancestral reconstructions including fossils suggest ancestors of Castanea + Castanopsis, Lithocarpus, and the Old World oak clade probably co-occurred in North America and Eurasia, while the ancestors of Chrysolepis, Notholithocarpus, and the New World oak clade co-occurred in North America, offering ample opportunity for hybridization in each region. Our study shows that hybridization-perhaps in the form of ancient syngameons like those seen today-has been a common and important process throughout the evolutionary history of oaks and their relatives. Concomitantly, this study provides a methodological framework for detecting ancient hybridization in other groups., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Organic compost application plays an important role in improving the fertility of Mollisol. However, the effects of different organic composts on carbon sequestration varies greatly and its internal mechanism are unclear. We conducted a field experiment to explore the residual proportion of different organic composts and their effects on carbon emissions in dryland Mollisol in Northeast China. There were a total of seven treatments, including chemical fertilizer control (SNF), organic composts from cattle excreta (CRH), sheep excreta (SHP), chicken excreta (CKN), residue after corn starch production (BCS), residue with crop straws (HRS) and mushroom residue (WMC). We monitored annual soil CO 2 flux by static chamber method, as well as the changes of environmental factors and soil dissolved carbon and nitrogen. The regulatory mechanism of organic component characteristics on carbon residual porprotion of organic composts were examined by neural network analysis. The results showed that compared with the SNF treatment, soil dissolved organic carbon (DOC) and extractable organic nitrogen increased by 26.3%-103.5% and 21.4%-150.0%, respectively. The aromaticity of soil DOC was significantly reduced. Heterotrophic respiration flux was mainly affected by soil temperature and DOC content, while its temperature sensitivity was significantly reduced in the CKN treatment. Annual accumulation of heterotrophic respiration increased from 203 g·C·m -2 of the control to 234-334 g·C·m -2 under treatments with organic composts applications, with the CKN and HRS treatments showing the strongest impact. The annual carbon residual proportion of different organic composts in Mollisol was in an order of CRH (91.2%)> WMC (82.9%)> BCS (82.6%)> SHP (78.1%)> CKN (70.2%)> HRS (69.3%). Hemicellulose content and C/N of organic composts were the key factors, which explained 58.8% and 32.9% of the total variations of carbon residual proportion. Organic compost from cattle excreta had higher residual proportion due to lower C/N, hemicellulose content and soluble polyphenol content, and thus did not significantly affect Mollisol heterotrophic respiration. Therefore, the application of organic compost from cattle excreta was more efficient to improve organic carbon in dryland Mollisol.

Objective: High-risk neuroblastoma patients often have poor outcomes despite multi-treatment options. The risk stratification of high-risk MYCN-not-amplified (HR-MYCN-NA) patients remains difficult. This study aims to identify a gene set signature that can help further stratify HR-MYCN-NA patients for a potential personalized therapeutic strategy., Methods: Three microarrays and one single-cell RNA sequence dataset were acquired and analyzed. Firstly, the prognostic-related genes (PRGs) in HR-MYCN-NA tumor cells were identified using TARGET-NB and GSE137804 datasets. Then, the prognostic model was established by LASSO-Cox regression, and verified in external cohort (GSE49710, GSE45547). Moreover, a time-dependent receiver operating characteristic curve (ROC) and area under the ROC (AUC) was used to assess survival prediction. A nomogram was established to predict the 1-, 3- and 5-year overall survival (OS) of HR-MYCN-NA patients., Results: In the training set, a five-PRGs signature, which include GAL, GFRA3, MARCKS, PSMD13, and ZNHIT3 genes, was identified and successfully stratified HR-MYCN-NA patients into ultra-high risk (UHR) and high-risk (HR) subtypes (HR = 4.29, P < 0.001). ROC curve analysis confirmed its predictive power (AUC = 0.74-0.82), suggesting a good predictive efficacy. Consistently, high-risk scores also predicted worse OS (HR = 2, P = 0.033) in the external validation dataset (AUC = 0.67-0.71). Moreover, the overall C-index of the nomogram was 0.75 (P < 0.001), which indicated good agreement between the observed and predicted survival rates. Further integrating the five PRGs signature with clinical factors, these 5 gene signature (HR = 4.45, P < 0.001) and tumor grade (HR = 4.15, P = 0.02) were found to be independent prognostic factors for HR-MYCN-NA patients., Conclusion: The novel five PRGs signature could well predict the survival of HR-MYCN-NA patients, which may provide constructive information for these subsets., (© 2024. The Author(s).)

Herein, we reported a copper(0)-catalyzed reductive coupling of disulfurating reagents and (hetero)aryl/alkyl halides. Copper(0) can be directly inserted into tetrasulfide and then undergoes reductive coupling with (hetero)aryl Iodides to construct disulfide. The method features the unprecedented use of copper(0)-catalyzed disulfurating reagents (tetrasulfides) in cross-coupling chemistry and is convenient with broad substrate scopes, even applicable to different halogenated hydrocarbons. It is worth noting that the methodology is practical with the late-stage modification of bioactive scaffolds of pharmaceuticals. In the meantime, the synthesis of disulfides is successfully achieved on a gram scale, indicating the approach is highly valuable.

PD-L1-positive extracellular vesicles (PD-L1 + EVs) play a pivotal role as predictive biomarkers in cancer immunotherapy. These vesicles, originating from immune cells (I-PD-L1 + EVs) and tumor cells (T-PD-L1 + EVs), hold distinct clinical predictive values, emphasizing the importance of deeply differentiating the PD-L1 + EV subtypes for effective liquid biopsy analyses. However, current methods such as ELISA lack the ability to differentiate their cellular sources. In this study, a novel step-wedge microfluidic chip that combines magnetic microsphere separation with single-layer fluorescence counting is developed. This chip integrates magnetic microspheres modified with anti-PD-L1 antibodies and fluorescent nanoparticles targeting EpCAM (tumor cell marker) or CD45 (immunocyte marker), enabling simultaneous quantification and sensitive analysis of PD-L1 + EV subpopulations in oral squamous cell carcinoma (OSCC) patients' saliva without background interference. Analysis results indicate reduced levels of I-PD-L1 + EVs in OSCC patients compared to those in healthy individuals, with varying levels of heterogeneous PD-L1 + EVs observed among different patient groups. During immunotherapy, responders exhibit decreased levels of total PD-L1 + EVs and T-PD-L1 + EVs, accompanied by reduced levels of I-PD-L1 + EVs. Conversely, nonresponders show increased levels of I-PD-L1 + EVs. Utilizing the step-wedge microfluidic chip allows for simultaneous detection of PD-L1 + EV subtypes, facilitating the precise prediction of oral cancer immunotherapy outcomes.

Competing Interests: Conflict of interest The authors have no conflicts of interest to declare.

Chromosome congression and alignment are essential for cell cycle progression and genomic stability. Kinesin-7 CENP-E, a plus-end-directed kinesin motor, is required for chromosome biorientation, congression and alignment in cell division. However, it remains unclear how chromosomes are aligned and segregated in the absence of CENP-E in mitosis. In this study, we utilize the CRISPR-Cas9 gene editing method and high-throughput screening to establish CENP-E knockout cell lines and reveal that CENP-E deletion results in defects in chromosome congression, alignment and segregation, which further promotes aneuploidy and genomic instability in mitosis. Both CENP-E inhibition and deletion lead to the dispersion of spindle poles, the formation of the multipolar spindle and spindle disorganization, which indicates that CENP-E is necessary for the organization and maintenance of spindle poles. In addition, CENP-E heterozygous deletion in spleen tissues also leads to the accumulation of dividing lymphocytes and cell cycle arrest in vivo. Furthermore, CENP-E deletion also disrupts the localization of key kinetochore proteins and triggers the activation of the spindle assembly checkpoint. In summary, our findings demonstrate that CENP-E promotes kinetochore-microtubule attachment and spindle pole organization to regulate chromosome alignment and spindle assembly checkpoint during cell division., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

Background: Due to the relative rarity of malignant sublingual gland tumors, diagnosing and treating them clinically pose challenges. Hence, there's a need to explore the pathological types, characteristics, treatment methods, and prognosis of primary malignant tumors of the sublingual gland to improve our understanding and management of these rare yet highly malignant conditions., Methods: This study reviewed cases of primary malignant sublingual gland tumors, analyzing their characteristics. The treatment methods included surgical excision, with additional radiotherapy, or brachytherapy for advanced stages or positive surgical margins. The study also summarized different treatment approaches, including lymph node dissection and soft tissue reconstruction using free flaps such as the anterolateral thigh flap and forearm flap., Results: We have gathered 23 cases of sublingual gland malignancies treated at the Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, from January 2013 to May 2024. The most common pathological types were adenoid cystic carcinoma and mucoepidermoid carcinoma, with rare cases of mucosa-associated lymphoid tissue (MALT) lymphoma and nonspecific salivary gland clear cell carcinoma. Early diagnosis and surgical intervention were crucial for a favorable prognosis. Marginal mandibulectomy was necessary for cases involving the mandible. Patients with positive preoperative lymph node detection required cervical lymph node dissection. Extensive tissue defects in the floor of the mouth were effectively reconstructed with free flaps to prevent oral-mandibular fistula., Conclusion: Surgical excision remains the preferred treatment for malignant sublingual gland tumors. Early diagnosis and comprehensive surgical management are essential for improving prognosis. The study's limitations include a small sample size and short follow-up duration, necessitating further research with larger clinical samples to confirm these findings., (© 2024. The Author(s).)