Search

Wei Cao,* Shuai Song,* Guojian Fang,* Yingze Li, Yuepeng Wang, Qun-Shan Wang Department of Cardiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qun-Shan Wang; Yuepeng Wang Email wangqunshan@xinhuamed.com.cn; wangyuepeng@xinhuamed.com.cnBackground: Atrial fibrosis serves as a disease initiating mechanism in the development of atrial fibrillation. Angiotensin II (Ang-II), a key mediator for atrial fibrosis, aberrantly activates atrial fibroblasts (AFs) into myofibroblasts, resulting in subsequent excessive synthesis and deposition of extracellular matrix (ECM). Cadherin-11 (CDH11) is essential in the development of non-cardiac fibrotic diseases. In this study, we investigated its role in the pathogenesis and underlying mechanism of atrial fibrillation.Methods: We obtained left atrial tissues from either patients with atrial fibrillation or Ang-II-induced atrial fibrosis mice. We utilized a global CDH11 knockout mouse (CDH11−/-) model to determine the effect of CDH11 on AF cell proliferation, migration, ECM synthesis/deposition. RNA-Seq of isolated AFs from CDH11−/- or normal mice was performed and differential expressed genes were analyzed. The mouse susceptibility to atrial fibrillation was examined by cardiac electrophysiology.Results: We found that cadherin-11 was significantly up-regulated in fibrotic atrial tissue from patients with atrial fibrillation and Ang-II-induced mice. Both normal and CDH11−/- mice did not develop atrial fibrosis at resting state. However, after Ang-II infusion, unlike severe atrial fibrosis occurred in normal mice, CDH11−/- mice displayed a reduced atrial fibrosis. Atrial fibroblasts with CDH11 deletion from CDH11−/- mice showed reduction in Ang-II-induced cell proliferation, migration and ECM synthesis/deposition, indicating the involvement of CDH11 in atrial fibrosis. Consistently, RNA-Seq of CDH11-null AFs uncovered significant decrease in pro-fibrotic gene expression. In addition, we identified reduction of transcripts associated with Smad2/3, ERK1/2 and JNK pathways. Further, CDH11−/- mice showed a significantly attenuated Ang-II-induced susceptibility to atrial fibrillation.Conclusion: Our results indicate that CDH11 potentiates Ang-II-induced activation of AFs. The pathogenesis of atrial fibrosis is through CDH11 mediated stimulation of Smad2/3, ERK1/2 and JNK pathways. Thus, CDH11 might serve as a novel therapeutic target for ameliorating the development of atrial fibrillation.Keywords: atrial fibrillation, atrial fibrosis, atrial fibroblast, cadherin-11, angiotensin-II

Qi-Shan Wang,* Bing-Xin Xu,* Kai-Jian Fan, Yun-Wu Li, Jing Wu, Ting-Yu Wang Departments of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this work.Correspondence: Ting-Yu Wang Email drtywang@163.comPurpose: To overcome negative adverse effects and improve therapeutic index of dexamethasone (Dex) in rheumatoid arthritis (RA), we developed a novel sustained release formulation-intra-articular injectable dexamethasone-loaded thermosensitive hydrogel (DLTH) with chitosan-glycerin-borax as carrier for the remission of inflammation and pain. The focus of this article is to explore both anti-inflammatory and pain-relieving effects of DLTH joint injection in bovine type-II collagen-induced arthritis (CIA) rats.Methods: Wistar rats were randomized into three groups, including the normal group (n=6), the model group (n=6) and the DLTH group (n=10). Joint injection of DLTH (1mg/kg Dex per rat) was injected on day 12 in the DLTH group twice a week for three weeks. Clinical signs of body weight, paw swelling and arthritis scores, histologic analysis, hind paw mechanical withdrawal threshold (MWT), plantar pressure pain threshold (PPT) were taken into consideration. Serum contents of IL-17A, prostaglandin E2 (PGE2), prostacyclin 2 (PGI2) and prostaglandin D2 (PGD2), real-time polymerase chain reaction (PCR) analysis of inflammatory factors and pain-related mediators in synovium and dorsal root ganglia (DRG), Western blotting of NF-κB in synovium were all evaluated.Results: Paw swelling, arthritis scores and joint inflammation destruction were all attenuated in the DLTH-treated group. Results showed that DLTH not only down-regulated serum IL-17A, but also mRNA levels of inflammatory factors and NGF, and key proteins contents of the NF-κB pathway in synovium. Increases of MWT and PPT in DLTH-treated rats elucidated pain-reducing effects of DLTH. Elevated serum PGD2 levels and declines of serum PGE2 and PGI2, and inflammatory and pain-related genes in DRGs in the DLTH group were also recorded.Conclusion: These data elucidated that DLTH joint injection impeded synovial inflammation processes through down-regulating transcription activity of NF-κB pathway, and intra-articular DLTH may aid in the regulation of RA pain through regulating inflammation and pain conduction process.Keywords: anti-inflammatory, dexamethasone-loaded thermosensitive hydrogel; DLTH, pain-relieving, rheumatoid arthritis; RA

Qiang-Song Wang,1,2,* Xiao-Ning Zhu,1,* Heng-Li Jiang,1,* Gui-Fang Wang,3 Yuan-Lu Cui1 1Tianjin State Key Laboratory of Modern Chinese Medicine, Research Center of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 2Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, 3Pharmacy Department, Baokang Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China *These authors contributed equally to this work Abstract: Zuojin Pill (ZJP), a traditional Chinese medicine formula, consists of Coptis chinensis Franch. and Evodia rutaecarpa (Juss.) Benth. in a ratio of 6:1 (w/w) and was first recorded in “Danxi’s experiential therapy” for treating gastrointestinal disorders in the 15th century. However, the poor solubility of alkaloids from ZJP restricted the protective effect in treating gastritis and gastric ulcer. The aim of the study was to investigate the protective mechanism of mucoadhesive microspheres loaded with alkaloids from C. chinensis Franch. and E. rutaecarpa (Juss.) Benth. on ethanol-induced acute gastric mucosal injury in rats. Surface morphology, particle size, drug loading, encapsulation efficiency, in vitro drug release, mucoadhesiveness, and fluorescent imaging of the microspheres in gastrointestinal tract were studied. The results showed that the mucoadhesive microspheres loaded with alkaloids could sustain the release of drugs beyond 12 hours and had gastric mucoadhesive property with 82.63% retention rate in vitro. The fluorescence tracer indicated high retention of mucoadhesive microspheres within 12 hours in vivo. The mucoadhesive microspheres loaded with alkaloids could reduce the gastric injury by decreasing the mucosal lesion index, increasing the percentage of inhibition and increasing the amount of mucus in the gastric mucosa in an ethanol-induced gastric mucosal injury rat model. Moreover, the mucoadhesive microspheres loaded with alkaloids reduce the inflammatory response by decreasing the levels of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), downregulating the mRNA expression of inducible nitric oxide synthase, TNF-α, and IL-1β in gastric mucosa. All the results indicate that mucoadhesive microspheres loaded with alkaloids could not only increase the residence time of alkaloids in rat stomach, but also exert gastroprotective effects through reducing the inflammatory response on ethanol-induced gastric mucosal damage. Thus, these microspheres could be developed as a potential controlled release drug for treatment of gastric ulcer. Keywords: alkaloids, mucoadhesive microspheres, alginate, chitosan, anti-inflammatory, gastric mucosal injury

Qiushi Wang,1 Jianghong Mou,1 Xin Yang,1 Yong He,2 Zengpeng Li,1 Qingya Luo,1 Yanqing Li,1 Li Lin,1 Yu Ma,1 Hualiang Xiao11Department of Pathology, 2Department of Respiration, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of ChinaBackground: The clinical characteristics of epidermal growth factor receptor (EGFR) hotspot mutations, such as deletions in exon 19, substitution of L858R in exon 21, and mutations in exon 20, have been widely reported in nonsmall cell lung cancer. However, the clinical features of other low frequency EGFR mutations in these four exons (especially the relationship with smoking history), eg, substitutions of G719S/A/C in exon 18 and L861Q in exon 21, remain unclear. This study investigated the relationship between G719S/A/C and L861Q mutations (in exon 18 and 21) and smoking history.Methods: Specimens from 194 patients with lung adenocarcinoma were analyzed for EGFR mutations in exons 18–21 by high-resolution melting curve analysis and amplification refractory mutation technology to establish the relationship between G719S/A/C and L861Q mutations and smoking history.Results: Ninety-six of 194 tumors (49.5%) were confirmed to be EGFR mutation-positive. Among these mutations, 71 of 104 (68.3%) were from never smokers, six of 17 (35.3%) were from former smokers, and 19 of 73 (26.0%) were from current smokers (P < 0.001). The mutation rate in heavy smokers (5/23, 21.7%) was significantly lower than in light smokers (20/67, 29.9%) and never smokers (71/104, 68.3%, P < 0.001). Seven low frequency EGFR mutations (four substitutions of G719S, and G719 A, respectively, and three of L861Q in exon 21) were identified. Five of these mutations were derived from smokers (one former light smoker, one current heavy smoker, and three current light smokers). Four of these patients had been treated with tyrosine kinase inhibitors and all had a partial response, with median overall survival (14.5 months) and median progression-free survival (6.8 months), being longer than in patients with similarly staged lung adenocarcinoma without EGFR mutation or treatment with tyrosine kinase inhibitors (6.8 and 3.1 months, respectively, according to data from an as yet unpublished study at our institution).Conclusion: This study provides further evidence that smoking status, include years of smoking and number of cigarettes smoked per day, plays an important role in EGFR mutation in patients with lung adenocarcinoma. Five of seven specimens with G719S/A or L861Q mutations coming from smokers indicates that there may be a relationship between G719S/A or L861Q mutation and smoking history. However, regardless of the influence of smoking, the effectiveness of tyrosine kinase inhibitors was satisfactory in four patients harboring G719S/A and L861Q EGFR mutation.Keywords: EGFR, lung adenocarcinoma, G719S/A, L861Q, smoking history

Ye Zhang,1 Qiang-Song Wang,1 Yuan-Lu Cui,1 Fan-Cui Meng,2 Ke-Ming Lin11Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People's Republic of China; 2Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, People's Republic of ChinaAbstract: Icariin is a bioactive herbal ingredient isolated from Herba epimedii, which has been widely used for the treatment of osteoporosis and male sexual dysfunction in traditional Chinese medicine. The major objective of this work is to investigate the different enhancing effects of β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) on the intestinal absorption of icariin, and to identify the molecular mechanisms of this action. Host–guest-type interactions of icariin with cyclodextrins nanocavities were unambiguously demonstrated by the phase-solubility diagram, ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry, and two dimensional proton nuclear magnetic resonance rotating-frame Overhauser effect spectroscopy. These results were further supported using molecular modeling studies. The rat single-pass intestinal perfusion model showed that the absorption of icariin was affected by P-glycoprotein (Pgp). The icariin/HP-β-CD inclusion complex provided greater enhancement in the intestinal absorption than the icariin/β-CD inclusion complex. Therefore, the enhancing effect was involved in a solubilizing effect and/or Pgp inhibitory effect. Finally, fluorescence anisotropy measurements and Pgp adenosine triphosphatase (ATPase) assay demonstrated that β-CD exhibited no effect on Pgp, while HP-β-CD showed inhibition by restraining the Pgp ATPase activity rather than changing the fluidity of cell membrane.Keywords: icariin, cyclodextrin, inclusion complex, molecular modeling, P-glycoprotein (Pgp), intestinal absorption

The objective of this study was to reveal flame spread characteristics of the insulation material, expanded polystyrene (EPS) with different thicknesses under different environmental conditions (pressure and oxygen concentration). Experiments were carried out in small-scale flame spread experimental benches in the Tibetan plateau and Hefei, respectively, with EPS sample sheets inclined horizontally. Changes in the flame spread speed, average length of the pool fire, average maximum flame height, and maximum flame temperature in the surface flame zone were used to determine the effect of the plateau and plain environments on flame spread characteristics. The results showed that with the increase in sample thickness, the values of these parameters increased both in Lhasa and Hefei. The values of flame spread speed, average length of the pool fire, and average maximum flame height in Hefei were all larger than those in Lhasa, while the maximum flame temperature in the surface flame zone in Hefei was less than that in Lhasa for the EPS of the same thickness. [ABSTRACT FROM PUBLISHER]

Breast cancer subtypes display different metastatic organotropism. Identification of the mechanisms underlying subtype-specific organotropism could help uncover potential approaches to prevent and treat metastasis. In this study, we found that forkhead box F2 (FOXF2) promoted the seeding and proliferative recovery from dormancy of luminal breast cancer (LumBC) and basal-like breast cancer (BLBC) cells in the bone by activating the NF-κB and BMP signaling pathways. FOXF2 promoted LumBC cell seeding but not proliferative recovery in the lung by activating the BMP signaling pathway. Conversely, FOXF2 suppressed the seeding and proliferative recovery of BLBC cells in the lung by repressing the TGFβ signaling pathway. FOXF2 directly upregulated RelA/p65 transcription and expression in LumBC and BLBC cells by binding to the RELA proximal promoter region and RelA/p65 bound to the FOXF2 proximal promoter region to upregulate expression, forming a positive feedback loop. Targeting the NF-κB pathway efficiently prevented the metastasis of FOXF2-overexpressing breast cancer cells to the bone, whereas inhibiting TGFβ signaling blocked the metastasis of BLBC with low FOXF2 expression to the lung. These findings uncover critical mechanisms of breast cancer subtype-specific organotropism and provide insights into precision assessment and treatment strategies. Significance: FOXF2 regulates signaling pathways in a subtype-specific manner to coordinate the fate of disseminated breast cancer cells in distant organs, suggesting that FOXF2 functions could be harnessed to prevent organ-specific metastasis. See related commentary by Bado, p. 639., (©2024 American Association for Cancer Research.)

Background: Bisdemethoxycurcumin (BDMC), the primary active compound found in turmeric, exhibits diverse pharmacological properties. The study aimed to investigate the mechanisms underlying the protective effects of BDMC in traumatic brain injury (TBI)., Methods: A rat TBI model was established using the Feeney's freefall epidural impact method, followed by BDMC treatment. Rat cortical neuron cells were exposed to hydrogen peroxide (H 2 O 2 ) to induce oxidative stress and then treated with BDMC. The cells were also pretreated with autophagy inhibitor 3-MA and heat shock protein 90 alpha family class A member 1 (HSP90AA1) inhibitor 17-AAG. Additionally, the experiments also involved treating H 2 O 2 -exposed cortical neurons with 17-AAG and silencing HSP90AA1 expression. Co-immunoprecipitation was utilized to verify interactions between HSP90AA1 and transcription factor EB (TFEB), TFEB and nuclear factor erythroid 2 related factor 2 (Nrf2), and the localization of these complexes in the cytoplasm and nucleus., Results: BDMC treatment significantly reduced modified neurological severity scores, brain water content, inflammatory infiltration, oxidative stress, and apoptosis in the cerebral cortex of TBI rats. Additionally, BDMC treatment elevated the expression of Beclin 1 and light chain 3 (LC3) II/LC3 I ratio while decreasing p62 expression. It also promoted TFEB nuclear translocation and increased HSP90AA1 levels in both the cytoplasm and nucleus, along with elevated nuclear Nrf2 expressions in TBI models. In vitro experiments showed decreased malondialdehyde levels, elevated glutathione peroxidase and superoxide dismutase levels upon BDMC treatment, along with repressed cortical neurons apoptosis, elevated Beclin 1 and LC3 II/LC3 I expressions, decreased p62 expressions, reduced cytoplasmic TFEB expression, increased nuclear TFEB and Nrf2 expression, and elevated HSP90AA1 expression in the cytoplasm and nucleus. Mechanistically, BDMC mediated autophagy and oxidative stress by activating HSP90AA1/TFEB/Nrf2 axis. Finally, HSP90AA1 was shown to regulate Nrf2 expression by binding to TFEB in the cellular model., Conclusions: BDMC alleviated TBI in rats by regulating autophagy and oxidative stress through HSP90AA1-mediated nuclear translocation of TFEB., 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 © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Cardiac atrophy is one of the critical characteristics of cancer cachexia though its mechanisms had not been fully clarified. In the present study, to study the mechanisms of cardiac atrophy in cancer cachexia and search for possible drug targets, cancer cachexia mice bearing C26 colon tumor cells and cultured H9c2 cardiomyocytes induced with simulated cancer cachexia injuries were used as in vivo and in vitro model, respectively. Results of both spatial metabolomics and LC-MS non-targeted metabolomics analysis of heart tissues suggested the disturbance of glycerophospholipid and fatty acid metabolism in the cancer cachexia hearts. Results of lipidomic analysis confirmed that the fatty acid composition of glycerophospholipids changed and the levels of linoleic acid (LA)-rich cardiolipins (CLs) significantly decreased. GC-MS analysis of fatty acids profile confirmed that the level of LA significantly increased and the ratio value of ω-6/ω-3 polyunsaturated fatty acids (PUFA) also increased in the cancer cachexia hearts. In H9c2 cardiomyocytes induced by simulated cancer cachexia injuries, degradation of CLs were also observed. Furthermore, SS-31, a tetrapeptide targeting CLs, could protect the H9c2 cardiomyocytes under simulated cancer cachexia injury by ameliorating the degradation of CLs, inhibiting apoptosis and attenuating the decrease in cell size. Collectively, these results have provided new insights into the cardiac atrophy in cancer cachexia, in which degradation of glycerophospholipids such as CLs and increase in LA and AA-related oxylipins might be important contributing factors and possible therapy targets., Competing Interests: Declaration of competing interest All authors in this article declare no conflict of interest to this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The microalgal-bacterial consortium (MBC) system is recognized as an advanced approach for nitrogen and phosphorus removal in wastewater treatment. However, the influence of microalgae on bacterial community dynamics and niche differentiation across varying seasonal conditions remains unexplored. In this study, we established a pilot-scale continuous-flow MBC system to disentangle, for the first time, the impact of microalgae on seasonal bacterial community succession by conducting monthly time-series sampling over a full seasonal cycle. Notably, a core microbiome consisting of 528 ASVs displaying significant seasonal rhythms was identified in both activated sludge (AS) and MBC systems. Unlike the random drift-driven assembly observed in the AS system, microalgae can recruit dominant species that respond to environmental fluctuations to form a core microbiome (heterogeneous selection), thereby enhancing community stability. Concurrently, microalgae facilitated niche differentiation within the core microbiome, driving transition from generalist to specialist species, which in turn promoted synergistic interactions that can improve nitrification and denitrification functions. Additionally, microalgae strengthened the correlation between functional species in the core microbiome and seasonal variations in light and temperature, as well as with regulating the efficiency of nitrogen and phosphorus removal by influencing the abundance of these functional species. These findings deepen our understanding of bacterial ecology based on microalgae management and provide a foundation further for the study of community regulation strategy of MBC systems., 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 © 2025. Published by Elsevier Ltd.)

Patients with estrogen receptor-positive (ER+) breast cancer require long-term endocrine therapy. However, endocrine resistance remains a critical issue to be addressed. Herein, we show that ERα repressed FOXF2 transcription in ER+ breast cancer through facilitating H3K27me3 deposition around its genomic locus, therefore endocrine therapy triggered FOXF2 transcription via loss of H3K27me3. FOXF2 transactivation orchestrated endocrine resistance and bone metastasis. Mechanistically, FOXF2 acted as a pioneer factor to globally activate enhancers of genes involved in epithelial-mesenchymal transition/epithelial-osteogenic transition, as well as super-enhancers of NCOA3 (a coactivator of FOXF2) and SP1 (an upstream transactivator of FOXF2) by recruitingSMARCC1 that mediates the reorganization of chromatin architecture. Additionally, FOXF2 expression levels in the tumors of ER+ breast cancer predicted response to endocrine therapeutic drugs and the outcome of patients. Targeting BRD4, an essential transcriptional coactivator of FOXF2, significantly inhibited FOXF2-orchestrated endocrine resistance and bone metastasis. Our findings uncover a crucial mechanism underlying endocrine resistance and provide a promising strategy for managing endocrine-resistant 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 © 2025 Elsevier B.V. All rights reserved.)

Globally, the continuous spread and evolution of SARS-CoV-2, along with its variants, profoundly impact human well-being, health, security, and the growth of socio-economic. In the field of development of drugs against COVID-19, the main protease (M pro ) is a critical target as it plays a core role in the lifecycle of SARS-CoV-2. Bofutrelvir acts as a potent inhibitor of SARS-CoV-2 M pro , demonstrating high efficacy and broad-spectrum antiviral activity. Compared to therapies that require pharmacokinetic boosters, such as ritonavir, the monotherapy approach of Bofutrelvir reduces the risk of potential drug interactions, making it suitable for a wider patient population. However, further studies on the potency and mechanism of inhibition of Bofutrelvir against the M pro of COVID-19 and its variants, together with other coronaviruses, are needed to prepare for the possibility of a possible re-emerging threat from an analogous virus in the future. Here, we reveal the effective inhibition of Bofutrelvir against the M pro of SARS-CoV-2, SARS-CoV, and HCoV-229E through FRET and crystallographic analysis. Furthermore, the inhibitory mechanisms of Bofutrelvir against two SARS-CoV-2 M pro mutants (G15S and K90R) were also elucidated through FRET and crystallographic studies. Through detailed analysis and comparison of these crystal structures, we identified crucial structural determinants of inhibition and elucidated the binding mode of Bofutrelvir to M pro s from different coronaviruses. These findings are hopeful to accelerate the development of safer and more potent inhibitors against the M pro of coronavirus, and to provide important references for the prevention and treatment of similar viruses that may emerge in the future., 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.)

Semen traits play a crucial role in pig reproduction and fertility. However, limited data availability hinder a comprehensive understanding of the genetic mechanisms underlying these traits. In this study, we integrated 597 299 ejaculates and 3 596 sequence data to identify genetic variants and candidate genes related to four semen traits, including sperm progressive motility (MOT), semen volume, sperm concentration (CON), and effective sperm count (SUM). A cross-ancestry meta-genome-wide association study was conducted to detect 163 lead single nucleotide polymorphisms (SNPs) associated with MOT, CON, and SUM. Subsequently, transcriptome-wide association studies and colocalisation analyses were integrated to identify 176 candidate genes, many of which have documented roles in spermatogenesis or male mammal semen traits. Our analysis highlighted the potential involvement of CSM5, PDZD9, and LDAF1 in regulating semen traits through multiple methods. Finally, to validate the function of significant SNPs, we performed genomic feature best linear unbiased prediction in 348 independent pigs using identified trait-related SNP subsets as genomic features. We found that integrating the top 0.1, 1, and 5% significant SNPs as genomic features could enhance genomic prediction accuracy for CON and MOT compared to traditional genomic best linear unbiased prediction. This study contributes to a comprehensive understanding of the genetic mechanisms of boar semen traits and provides insight for developing genomic selection models., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Collagen-induced arthritis (CIA) model was induced in C57BL/6 wild-type (wt) and C57BL/6 miR-204/-211 double-knockout (dKO) mice to investigate the role of miR-204/-211 in suppressing splenic inflammation in rheumatoid arthritis (RA)., Methods: Differences of miR-204/-211 and structure-specific recognition protein 1 (SSRP1) in the spleen of DBA/1J wt and CIA mice were detected via PCR and immunohistochemistry. CIA was induced in both C57BL/6 wt and C57BL/6 miR-204/-211 dKO mice, and the onset of CIA and disease severity were statistically analyzed. Immunohistochemistry staining of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and SSRP1 in spleen or knee joints was performed and analyzed. In CIA miR-204/-211 dKO mice, AAV-shSSRP1 was intra-articularly injected, with both the AAV-shRNA Ctrl and AAV-shRNA Ctrl CIA groups receiving the same dose of AAV-shRNA. Spleen sections were stained with hematoxylin and eosin (H&E)., Results: Compared to wt mouse spleens, aberrant expression of miR-204/-211 and SSRP1 was observed in the spleens of CIA mice. Immunized dKO mice exhibited a higher incidence of CIA onset and a more exacerbated RA disease phenotype, characterized by increased spleen inflammation score and elevated levels of IL-1β, TNF-α, and SSRP1 expression. AAV-shSSRP1 injection in CIA dKO mice significantly reduced spleen inflammation scores, IL-1β and TNF-α expression levels, and down-regulated Ki-67 expression compared to CIA dKO mice., Conclusion: Knockout of miR-204/-211 exacerbated the onset of CIA in C57BL/6 mice, while miR-204/-211 played a protective role against the progression of splenic inflammatory and proliferative progression in RA by targeting SSRP1., 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: The optimal glycosylated hemoglobin (HbA1c) target in type 2 diabetes mellitus (T2DM) patients remains controversial, especially in patients with concomitant coronary heart disease (CHD). This study aimed to investigate the correlation between baseline HbA1c and long-term prognosis in CHD patients with T2DM., Methods: The study enrolled 6,839 CHD patients with T2DM and measured HbA1c at admission in a multicenter prospective observational cohort. Patients were divided into two groups according to baseline HbA1c levels: optimal glycemic control group (HbA1c < 7.0 %, n = 3023) and poor glycemic control group (HbA1c ≥ 7.0 %, n = 3816). The study endpoints were all-cause death and major adverse cardiac and cerebrovascular events (MACCEs)., Results: The median follow-up period was 2.1 years. During this period, 229 (3.3 %) all-cause deaths, 165 (2.4 %) cardiac deaths, and 759 (11.1 %) MACCEs occurred. Unadjusted Kaplan-Meier analysis showed that the incidences of all-cause death, cardiac death, non-fatal MI, unplanned revascularization, and MACCEs were significantly lower in the HbA1c < 7.0 % group than in the HbA1c ≥ 7.0 % group (P < 0.05). Multivariate Cox hazard analysis indicated that the incidences of all-cause death, cardiac death and MACCEs were significantly lower in the HbA1c < 7.0 % group compared to the HbA1c ≥ 7.0 % group [all-cause death: hazard ratio (HR) 1.969, 95 % confidence interval (CI) 1.421-2.729; cardiac death: HR 2.515, 95 % CI 1.647-3.839; MACCEs: HR 1.345, 95 % CI 1.150-1.573; P < 0.001]., Conclusions: Baseline HbA1c level was associated with all-cause death, cardiac death, and MACCEs in CHD patients with T2DM., Competing Interests: The authors declare that the study has no competing interests., (© 2024 Published by Elsevier Ltd.)

Objective: A shared decision-making (SDM) model-based intervention programme was implemented for a population at high risk for diabetes to explore its effectiveness in intervening with blood glucose levels in this population., Methods: One hundred residents were selected according to the principle of voluntary participation and divided into the intervention group (n = 50) and the control group (n = 50) by using multistage cluster sampling. The control group received only brief diabetes knowledge education through a disease brochure issued by the hospital; the intervention group implemented a SDM model based on large classroom and individualised education for 4 months. Univariate analysis and generalised estimating equation fitting model were used to analyse the effect of intervention on blood glucose parameters in the study subjects., Results: Univariate analysis showed that after 4 months of intervention, fasting blood glucose was lower in the intervention group than in the control group (5.57 ± 0.56 vs. 6.07 ± 0.77, F = 45.721, p < 0.001); glycosylated hemoglobin was lower in the intervention group than in the control group (5.91 ± 0.28 vs. 6.02 ± 0.24, F = 25.998, p < 0.001), decreased by 0.26% in the intervention group and increased by 0.01% in the control group. One-way analysis of variance (ANOVA) showed that fasting blood glucose and glycosylated hemoglobin in the intervention group decreased to different extents from baseline. The generalised estimation equation was fitted with the intervention programme, gender, hypertension, smoking, alcohol consumption, physical activity, age, waist circumference, body mass index, baseline fasting blood glucose, and baseline glycosylated hemoglobin as independent variables, and fasting blood glucose and baseline glycosylated hemoglobin as dependent variables. Results showed that compared with the control group, fasting blood glucose and glycosylated hemoglobin levels were significantly different between the two groups (p < 0.001)., Conclusion: Applying an intervention programme based on SDM model to people at high risk of diabetes can improve patients' adherence to self-management and establish a good lifestyle, thus contributing to their good glycemic control., (© 2024 John Wiley & Sons Ltd.)

Background: The circadian variation pattern of sudden cardiac arrest (SCA) occurred in Chinese community including both community healthcare centres and primary hospitals remains unknown. This study analysed the circadian variation of SCA in the Chinese community., Methods: Data between 2018 and 2022 from the remote ECG diagnosis system of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine were analysed to examine the circadian rhythm of SCA, stratified by initial shockable (ventricular tachycardia or ventricular fibrillation) versus non-shockable (asystole or pulseless electrical activity) rhythm., Results: Among 10 210 cases of SCA, major cases (8736, 85.6%) were non-shockable and 1474 (14.4%) cases were shockable. The circadian rhythm of SCA was as follows: peak time was from 08:00 to 11:59 (30.1%), while deep valley was from 00:00 to 03:59 (7.5%). The proportions of events by non-shockable and shockable events were similar and both reached their peak from 08:00 to 11:59, with a percentage of 29.0% and 36.4%, respectively. Multivariable analysis showed that the relative risk of shockable compared with non-shockable arrests was lower between 00:00 and 03:59 (adjusted OR (aOR): 0.72, 95% CI: 0.54 to 0.97, p=0.028) and 04:00 to 07:59 (aOR: 0.60, 95% CI: 0.46 to 0.79, p<0.001), but higher between 08:00 and 11:59 (aOR: 1.34, 95% CI: 1.09 to 1.64, p=0.005)., Conclusions: In Chinese community, there is a distinct circadian rhythm of SCA, regardless of initial rhythms. Our findings may be helpful in decision-making, in that more attention and manpower should be placed on the morning hours of first-aid and resuscitation management in Chinese community., Competing Interests: Competing interests: Y-BW and Z-XC were employed by the company Shanghai Siwei Medical Co. Ltd. The remaining authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: The exclusive breastfeeding condition in China is not optimism now. Maternal breastfeeding self-efficacy stands as a pivotal factor influencing exclusive breastfeeding. Interestingly, studies have suggested that father support breastfeeding self-efficacy is a pivotal mediator in infant breastfeeding. Thus, the current research aimed to investigate the association between father support breastfeeding self-efficacy and exclusive breastfeeding at six weeks postpartum, and the influencing factors of father support breastfeeding self-efficacy., Methods: This research was structured as a multi-centre cross-sectional study, involving 328 fathers, whose partners were six weeks postpartum, and recruited from two public hospitals in Southeast China. Self-designed demographic questionnaires, namely, Father Support Breastfeeding Self-Efficacy Scale-Short Form, Breastfeeding Knowledge Questionnaire, Positive Affect Scale and the 14-item Fatigue Scale, were applied. Descriptive statistics, Chi-square test, logistic regression univariate analysis and multiple linear regression were used to analyse data., Results: Results indicate a significant difference between the infant feeding methods at six weeks postpartum and fathers with different levels of support breastfeeding self-efficacy (p < 0.05). Particularly, father support breastfeeding self-efficacy positively affected exclusive breastfeeding at six weeks postpartum after adjusting all the demographic characteristics of fathers (OR: 2.407; 95% CI: 1.017-4.121). Moreover, results show that the significant influencing factors of father support breastfeeding self-efficacy include breastfeeding knowledge, fatigue, positive affect, successfully experienced helping mothers to breastfeed, spousal relationships and companionship time., Conclusions: High-level father support breastfeeding self-efficacy effectively increased exclusive breastfeeding rate at six weeks postpartum. To enhance the exclusive breastfeeding rate, nurses or midwives can endeavour to design educational programmes or take supportive interventions customised for fathers, such as enhancing their breastfeeding knowledge education, reducing fatigue and mobilising positive emotions, thereby bolstering paternal self-efficacy in breastfeeding., (© 2024. The Author(s).)

Studying the genetic regulation of protein expression (through protein quantitative trait loci (pQTLs)) offers a deeper understanding of regulatory variants uncharacterized by mRNA expression regulation (expression QTLs (eQTLs)) studies. Here we report cis-eQTL and cis-pQTL statistical fine-mapping from 1,405 genotyped samples with blood mRNA and 2,932 plasma samples of protein expression, as part of the Japan COVID-19 Task Force (JCTF). Fine-mapped eQTLs (n = 3,464) were enriched for 932 variants validated with a massively parallel reporter assay. Fine-mapped pQTLs (n = 582) were enriched for missense variations on structured and extracellular domains, although the possibility of epitope-binding artifacts remains. Trans-eQTL and trans-pQTL analysis highlighted associations of class I HLA allele variation with KIR genes. We contrast the multi-tissue origin of plasma protein with blood mRNA, contributing to the limited colocalization level, distinct regulatory mechanisms and trait relevance of eQTLs and pQTLs. We report a negative correlation between ABO mRNA and protein expression because of linkage disequilibrium between distinct nearby eQTLs and pQTLs., (© 2024. The Author(s).)

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Exploring charge transfer channels in the Z-scheme heterojunction is an essential challenge. A strategy to precisely connect g-C 3 N 4 with SrTiO 3 through sharing N atoms was developed to create a chemically bonded Z-scheme heterojunction photocatalyst (STON/CNx). By sharing the N atoms, not only was the activity of the photocatalytic reduction of CO 2 greatly improved, but the selectivity of the product was also changed. The CH 4 product rate over optimal STON/CNx was 102.4 μmol g -1 h -1 , with a 98.9% product selectivity. Both characterization and theoretical calculations indicate that N atoms tightly connect the heterostructures and serve as a channel for electron transport, facilitating the transfer of photogenerated electrons. This research lays a way for creating a sharing atoms' Z-scheme interface, providing the potential for exciting future photocatalytic applications.

Ticks are important vectors of zoonotic pathogens, and represent an increasing threat for human and animal health. Considering the complex natural environments of Ningxia Hui Autonomous Region, China, we expect the diverse tick species in this region. Here, we conduct a field survey on parasitic and host-seeking ticks. A total of 10,419 ticks were collected, which belonged to nine species of four genera. There were significant differences in terms of vegetation index, altitude, and seven climatic factors among the four tick genera - Hyalomma, Dermacentor , Haemaphysalis, and Ixodes , except between Haemaphysalis and Ixodes , where no significant differences were observed in these factors. The ecological niche modelling revealed that the suitable habitats for Hyalomma asiaticum was in the northwest Ningxia, with annual ground surface temperature as the most important factor. The suitable area for Dermacentor nuttalli was in the southwest and eastern regions of Ningxia with elevation as the highest contribution. D. silvarum was best suited to the southern Ningxia also with elevation as the most important factor. The four tick species including Haemaphysalis longicornis , Hae. qinghaiensis , Hae. japonica , and Ixodes persulcatus were best suited to the southernmost Ningxia with annual precipitation as the main factors for Hae. longicornis and elevation for the other three ticks. The results of predicted potential distribution of different tick species provide a scientific basis for the prevention and control of ticks and tick-borne diseases in the region. Furthermore, the subsequent impacts of the Greening Program to regain forests and grasslands from former agricultural lands in Ningxia on tick population dynamics deserve further investigation., Competing Interests: 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., (© 2024 The Authors.)

The risk for suffering immune checkpoint inhibitors (ICIs)-associated myocarditis increases in patients with pre-existing conditions and the mechanisms remain to be clarified. Spatial transcriptomics, single-cell RNA sequencing, and flow cytometry are used to decipher how anti-cytotoxic T lymphocyte antigen-4 m2a antibody (anti-CTLA-4 m2a antibody) aggravated cardiac injury in experimental autoimmune myocarditis (EAM) mice. It is found that anti-CTLA-4 m2a antibody increases cardiac fibroblast-derived C-X-C motif chemokine ligand 1 (Cxcl1), which promots neutrophil infiltration to the myocarditic zones (MZs) of EAM mice via enhanced Cxcl1-Cxcr2 chemotaxis. It is identified that the C-C motif chemokine ligand 5 (Ccl5)-neutrophil subpopulation is responsible for high activity of cytokine production, adaptive immune response, NF-κB signaling, and cellular response to interferon-gamma and that the Ccl5-neutrophil subpopulation and its-associated proinflammatory cytokines/chemokines promoted macrophage (Mφ) polarization to M1 Mφ. These altered infiltrating landscape and phenotypic switch of immune cells, and proinflammatory factors synergistically aggravated anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. Neutralizing neutrophils, Cxcl1, and applying Cxcr2 antagonist dramatically alleviates anti-CTLA-4 m2a antibody-induced leukocyte infiltration, cardiac fibrosis, and dysfunction. It is suggested that Ccl5-neutrophil subpopulation plays a critical role in aggravating anti-CTLA-4 m2a antibody-induced cardiac injury in EAM mice. This data may provide a strategic rational for preventing/curing ICIs-associated myocarditis., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Several X-linked genes escape from X chromosome inactivation (XCI), while differences in escape across cell types and tissues are still poorly characterized. Here, we developed scLinaX for directly quantifying relative gene expression from the inactivated X chromosome with droplet-based single-cell RNA sequencing (scRNA-seq) data. The scLinaX and differentially expressed gene analyses with large-scale blood scRNA-seq datasets consistently identified the stronger escape in lymphocytes than in myeloid cells. An extension of scLinaX to a 10x multiome dataset (scLinaX-multi) suggested a stronger escape in lymphocytes than in myeloid cells at the chromatin-accessibility level. The scLinaX analysis of human multiple-organ scRNA-seq datasets also identified the relatively strong degree of escape from XCI in lymphoid tissues and lymphocytes. Finally, effect size comparisons of genome-wide association studies between sexes suggested the underlying impact of escape on the genotype-phenotype association. Overall, scLinaX and the quantified escape catalog identified the heterogeneity of escape across cell types and tissues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tunchang pigs, mainly distributed throughout Hainan Province of China, are well-known for their superior meat quality, crude feed tolerance, and adaptability to high temperatures and humidity. Runs of homozygosity (ROH) can provide valuable information about the inbreeding coefficient in individuals and selection signals that may reveal candidate genes associated with key functional traits. Runs of heterozygosity (ROHet) are commonly associated with balance selection, which can help us understand the adaptive evolutionary history of domestic animals. In this study, we investigated ROHs and ROHets in 88 Tunchang pigs. We also compared the estimates of inbreeding coefficients in individuals calculated based on four methods. In summary, we detected a total of 16 ROH islands in our study, and 100 genes were found within ROH regions. These genes were correlated with economically important traits such as reproduction (e.g., SERPIND1, HIRA), meat quality (e.g., PI4KA, TBX1), immunity (e.g., ESS2, RANBP1), adaption to heat stress (TXNRD2 and DGCR8), and crude food tolerance (TRPM6). Moreover, we discovered 18 ROHet islands harbouring genes associated with reproduction (e.g., ARHGEF12, BMPR2), immune system (e.g., BRD4, DNMT3B). These findings may help us design effective breeding and conservation strategies for this unique breed., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 ., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To enhance the DNA/RNA amplification efficiency and inhibitor tolerance of Bst DNA polymerase, four chimeric Bst DNA polymerase by fusing with a DNA-binding protein Sto7d and/or a highly hydrophobic protein Hp47 to Bst DNA polymerase large fragment. One of chimeric protein HpStBL exhibited highest inhibitor tolerance, which retained high active under 0.1 U/μL sodium heparin, 0.8 ng/μL humic acid, 2.5× SYBR Green I, 8 % (v/v) whole blood, 20 % (v/v) tissue, and 2.5 % (v/v) stool. Meanwhile, HpStBL showed highest sensitivity (93.75 %) to crude whole blood infected with the African swine fever virus. Moreover, HpStBL showed excellent reverse transcriptase activity in reverse transcription loop-mediated isothermal amplification, which could successfully detect 0.5 pg/μL severe acute respiratory syndrome coronavirus 2 RNA in the presence of 1 % (v/v) stools. The fusion of two domains with different functions to Bst DNA polymerase would be an effective strategy to improve Bst DNA polymerase performance in direct loop-mediated isothermal amplification and reverse transcription loop-mediated isothermal amplification detection, and HpStBL would be a promising DNA polymerase for direct African swine fever virus/severe acute respiratory syndrome coronavirus 2 detection due to simultaneously increased inhibitor tolerance and reverse transcriptase activity., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interest associated with this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

KRAS-G12C inhibitors has been made significant progress in the treatment of KRAS-G12C mutant cancers, but their clinical application is limited due to the adaptive resistance, motivating development of novel structural inhibitors. Herein, series of coumarin derivatives as KRAS-G12C inhibitors were found through virtual screening and rational structural optimization. Especially, K45 exhibited strong antiproliferative potency on NCI-H23 and NCI-H358 cancer cells harboring KRAS-G12C with the IC 50 values of 0.77 μM and 1.50 μM, which was 15 and 11 times as potent as positive drug ARS1620, respectively. Furthermore, K45 reduced the phosphorylation of KRAS downstream effectors ERK and AKT by reducing the active form of KRAS (KRAS GTP) in NCI-H23 cells. In addition, K45 induced cell apoptosis by increasing the expression of anti-apoptotic protein BAD and BAX in NCI-H23 cells. Docking studies displayed that the 3-naphthylmethoxy moiety of K45 extended into the cryptic pocket formed by the residues Gln99 and Val9, which enhanced the interaction with the KRAS-G12C protein. These results indicated that K45 was a potent KRAS-G12C inhibitor worthy of further study., 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.)

Marek's disease (MD), caused by the Marek's disease virus (MDV), is a common infectious tumor disease in chickens and was the first neoplastic disease preventable by vaccination. However, the vaccine cannot completely prevent virulent MDV infections, allowing both the vaccine and virulent MDV to coexist in the same chicken for extended periods. This study aims to investigate the changes in viral load of the very virulent strain Md5 and the rHVT-IBD vaccine in different chicken tissues using a real-time PCR assay. The results showed that the rHVT-IBD vaccine significantly reduced the viral load of MDV-Md5 in different organs, while the load of rHVT-IBD was significantly increased when co-infected with Md5. Additionally, co-infection with Md5 and rHVT-IBD in chickens not only changed the original viral load of both viruses but also affected the positive rate of Md5 at 14 days post-vaccination. The positive rate decreased from 100% to 14.29% (feather tips), 0% (skin), 33.33% (liver), 16.67% (spleen), 28.57% (thymus), 33.33% (bursa), and 66.67% (PBL), respectively. This study enhances our understanding of the interactions between HVT vector vaccines and very virulent MDV in chickens and provides valuable insights for the future development of MD vaccines., Competing Interests: All experiments involved in the manuscript were performed at Yangzhou University. The current addresses of all authors are listed and verified, and Nanchang Boehringer Ingelheim Animal Heath Co. Ltd provided us with the VAXXITEK vaccine used in the manuscript and technical support for the use of the vaccine. We declare no potential conflict of interest in the content of the study.

Background: Many patients with atrial fibrillation (AF) discontinued oral anticoagulation (OAC) therapy after successful catheter ablation. We aimed to determine the real-world risks and consequences of discontinuing OAC use after catheter ablation for AF., Methods: Patients who underwent successful catheter ablation for AF from January 2004 to December 2020 were divided into continued long-term OAC (On-OAC, n = 1062) and discontinued (Off-OAC, n = 1055) groups. The long-term outcomes including thromboembolic events, major bleeding, all-cause mortality and major adverse cardiovascular events (MACE), were compared between the two groups., Results: The CHA2DS2-VASc score was 3.44 ± 1.12. After a mean follow-up of 37.09 months, thromboembolism risk was higher and major bleeding risk was lower in the Off-OAC than in the On-OAC group (Both log-rank P < 0.001). CHA2DS2-VASc score-stratified subgroup analysis showed similar cumulative event rates between the two groups in men and women with scores of 2 and 3 (intermediate risk for stroke), respectively, (P > 0.05), except for a higher major bleeding rate in the On-OAC group (P = 0.002). Patients at high risk for stroke (men and women with scores ≥3 and ≥ 4) had better non-thromboembolic and non-MACE results (Both log-rank P < 0.05)., Conclusion: Men with a CHA2DS2-VASc score of 2 and women with a score of 3 had a relatively low incidence of stroke events after successful catheter ablation for AF and may be safe for anticoagulation cessation. Greater benefits from long-term OAC were observed in men with CHA2DS2-VASc score ≥3 and women with score ≥4., Competing Interests: 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., (© 2024 The Author(s).)

Bacterial RecJ exhibits 5'→3' exonuclease activity that is specific to ssDNA; however, archaeal RecJs show 5' or 3' exonuclease activity. The hyperthermophilic archaea Methanocaldococcus jannaschii encodes the 5'-exonuclease MjRecJ1 and the 3'-exonuclease MjRecJ2. In addition to nuclease activity, archaeal RecJ interacts with GINS, a structural subcomplex of the replicative DNA helicase complex. However, MjRecJ1 and MjRecJ2 do not interact with MjGINS. Here, we report the structural basis for the inability of the MjRecJ2 homologous dimer to interact with MjGINS and its efficient 3' hydrolysis polarity for short dinucleotides. Based on the crystal structure of MjRecJ2, we propose that the interaction surface of the MjRecJ2 dimer overlaps the potential interaction surface for MjGINS and blocks the formation of the MjRecJ2-GINS complex. Exposing the interaction surface of the MjRecJ2 dimer restores its interaction with MjGINS. The cocrystal structures of MjRecJ2 with substrate dideoxynucleotides or product dCMP/CMP show that MjRecJ2 has a short substrate binding patch, which is perpendicular to the longer patch of bacterial RecJ. Our results provide new insights into the function and diversification of archaeal RecJ/Cdc45 proteins., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)