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Background: Mongolian cattle are local breeds in northern China with excellent adaptability to harsh environmental conditions. Adipose tissues play essential roles in tolerance to cold and disease, but the associated cellular and molecular mechanisms are unclear., Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed on the adipose tissues from the subcutaneous (SAT), greater omentum (OAT) and perirenal (PAT) of 3 healthy cattle. The adipogenic trajectory was analyzed, and the functional roles of gene of interest were verified in vitro., Results: There were different cell subpopulations in adipose tissues. The lipid-deposition adipocytes identified by the PTGER3 marker exhibited outstanding characteristics in SAT. In PAT and OAT, aldosterone was expressed to provide clues for the differential brown adipocytes. Among the DEGs by comparing OAT with SAT and PAT with OAT, C3 was significantly expressed in most of the cell populations in SAT. G0S2, LIPE, LPIN1, PTGER3 and RGCC took part in the adipogenic trajectory from preadipocyte commitment to mature adipocytes. S100A4 expression affected Ca 2+ signaling and the expression of UCP1 ~ 3, FABP4 and PTGER3., Conclusion: The cell heterogeneity and genes expressed in adipose tissues of Mongolian cattle not only determine the endocrine and energy storage, but contribute to adapt to cold and disease resistance., (© 2024. The Author(s).)

Background: It is still being determined if prophylaxis (PR) has superior cost effectiveness compared with on-demand (OD) treatment for moderate or severe hemophilia A (HA) children in China., Objective/purpose: To evaluate the cost-effectiveness of PR and OD treatment for children with moderate or severe HA without inhibitors in China., Methods: A retrospective cost-effectiveness study was conducted on 640 HA children (373 and 267 children were on the PR and OD treatment, respectively) from January 2021 to November 2022. The Markov model was used to estimate the economic and clinical outcomes and would run for 17 yearly cycles with the initial age at 2 years. The transfer probabilities were extracted from the data of "Hemophilia Home Care Center" and the literature published. All patients' drug costs were collected from the data of "Hemophilia Home Care Center". One-way and probabilistic sensitivity analyses were conducted on the data to evaluate the robustness of the results., Results/findings: PR was consistently associated with higher overall quality-adjusted life years (QALYs) compared with OD treatment (9.59 QALYs vs. 6.85 QALYs). The incremental cost-effectiveness ratio (ICER) of PR compared with the OD treatment was calculated to be approximately US$12,151.35 (RMB¥81,778.55) per QALY gained. This amount was lower than the willingness-to-pay (WTP) threshold of US$38,212.74 (RMB¥257,171.71). One-way sensitivity analysis found that the results were sensitive to the cost of OD and PR treatments., Conclusions/implications: This study indicated that PR is cost-effective compared with OD treatment for children with moderate or severe HA without inhibitors in China., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Although the strigolactone (SL) signaling pathway and SL-mediated anthocyanin biosynthesis have been reported, the molecular association between SL signaling and anthocyanin biosynthesis remains unclear. In this study, we identified the SL signal transduction pathway associated with anthocyanin biosynthesis and the crosstalk between gibberellin (GA) and SL signaling in apple (Malus × domestica). ELONGATED HYPOCOTYL5 (HY5) acts as a key node integrating SL signaling and anthocyanin biosynthesis, and the SL-response factor AGAMOUS-LIKE MADS-BOX9 (AGL9) promotes anthocyanin biosynthesis by activating HY5 transcription. The SL signaling repressor SUPPRESSOR OF MAX2 1-LIKE8 (SMXL8) interacts with AGL9 to form a complex that inhibits anthocyanin biosynthesis by downregulating HY5 expression. Moreover, the E3 ubiquitin ligase PROTEOLYSIS1 (PRT1) mediates the ubiquitination-mediated degradation of SMXL8, which is a key part of the SL signal transduction pathway associated with anthocyanin biosynthesis. In addition, the GA signaling repressor REPRESSOR-of-ga1-3-LIKE2a (RGL2a) mediates the crosstalk between GA and SL by disrupting the SMXL8-AGL9 interaction that represses HY5 transcription. Taken together, our study reveals the regulatory mechanism of SL-mediated anthocyanin biosynthesis and uncovers the role of SL-GA crosstalk in regulating anthocyanin biosynthesis in apple., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Submerged macrophytes can overgrow and negatively affect freshwater ecosystems. This study aimed to investigate the use of chlormequat (CQ) to regulate submerged Vallisneria natans growth as well as its impact on the microbial community of epiphytic biofilms. V. natans height under CQ dosages of 20, 100, and 200 mg/L decreased within 21 days by 12.57%, 30.07%, and 44.62%, respectively, while chlorophyll content increased by 1.94%, 20.39%, and 38.83%. At 100 mg/L, CQ reduced the diversity of bacteria in the biofilm attached to V. natans leaves but increased the diversity of the eukaryotic microbial community. CQ strongly inhibited Cyanobacteria; compared with the control group, the treatment group experienced a significant reduction from 36.54% to 2.61%. Treatment significantly inhibited Gastrotricha and Rotifera, two dominant phyla of eukaryotes in the leaf biofilm, reducing their relative abundances by 17.41% and 6.48%, respectively. CQ significantly changed the leaf biofilm microbial community correlation network. The treatment group exhibited lower modularity (2.012) compared with the control group (2.249); however, the central network of the treated group contained a higher number of microbial genera (13) than the control group (4), highlighting the significance of eukaryotic genera in the network. The results obtained from this study provide invaluable scientific context and technical understanding pertinent to the restoration of submerged macrophytes within aquatic ecosystems. PRACTITIONER POINTS: Chlormequat reduced the plant height but increased leaf chlorophyll content. Chlormequat reduced biofilm bacterial diversity but increased eukaryotic diversity. Chlormequat affected the bacterial-fungal association networks in biofilms., (© 2024 Water Environment Federation.)

Deep learning methods have recently achieved remarkable performance in vessel segmentation applications, yet require numerous labor-intensive labeled data. To alleviate the requirement of manual annotation, transfer learning methods can potentially be used to acquire the related knowledge of tubular structures from public large-scale labeled vessel datasets for target vessel segmentation in other anatomic sites of the human body. However, the cross-anatomy domain shift is a challenging task due to the formidable discrepancy among various vessel structures in different anatomies, resulting in the limited performance of transfer learning. Therefore, we propose a cross-anatomy transfer learning framework for 3D vessel segmentation, which first generates a pre-trained model on a public hepatic vessel dataset and then adaptively fine-tunes our target segmentation network initialized from the model for segmentation of other anatomic vessels. In the framework, the adaptive fine-tuning strategy is presented to dynamically decide on the frozen or fine-tuned filters of the target network for each input sample with a proxy network. Moreover, we develop a Gaussian-based signed distance map that explicitly encodes vessel-specific shape context. The prediction of the map is added as an auxiliary task in the segmentation network to capture geometry-aware knowledge in the fine-tuning. We demonstrate the effectiveness of our method through extensive experiments on two small-scale datasets of coronary artery and brain vessel. The results indicate the proposed method effectively overcomes the discrepancy of cross-anatomy domain shift to achieve accurate vessel segmentation for these two datasets.

Objective: This study aimed to investigate the relationship between physical exercise and depression among college students, focusing on the mediating role of self-esteem and positive psychological capital., Methods: Group psychological measurements were conducted on 579 students using various scales, including the Physical Activity Rating Scale (PARS-3), Self-Esteem Scale (SES), Positive Psychological Capital Questionnaire (PPQ), and Self-rating Depression Scale (SDS). The data was analyzed using SPSS 26.0 and bootstrap methods to test and analyze the effects., Results: A negative correlation between physical exercise and depressive mood, with physical exercise significantly predicting college students' depressive mood. Additionally, physical exercise was found to positively predict self-esteem and positive psychological capital, both of which are negatively predictive of depressive mood. Self-esteem and positive psychological capital were identified as significant mediators between physical exercise and depressive mood, with three mediating paths: physical exercise, self-esteem, and depressed mood (Path 1), exhibited an indirect effect of 0.017, with the bootstrap 95% confidence interval excluding 0 (LLCI = -0.051, ULCI = -0.004) and accounting for 8.30% of the total effect. Physical exercise, positive psychological capital, and depression emotion (Path 2), had an indirect effect of 0.049, with the bootstrap 95% confidence interval also not containing 0 (LLCI = -0.088, ULCI = -0.011) and contributing to 23.90% of the total effect. Physical exercise, self-esteem, positive psychological capital, depressed mood (Path 3), demonstrated an indirect effect of 0.006, with the bootstrap 95% confidence interval excluding 0 (LLCI = -0.011, ULCI = -0.001) and representing 2.90% of the total effect., Conclusion: Physical exercise negatively predicts depressive mood among college students and has a mediating effect through self-esteem and positive psychological capital, creating a chain-like impact on their depressive symptoms., 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 Wei, Lai, Tan, Ou, Feng, Xu and Ai.)

Introduction: Gene regulatory networks (GRNs) reveal the intricate interactions between and among genes, and understanding these interactions is essential for revealing the molecular mechanisms of cancer. However, existing algorithms for constructing GRNs may confuse regulatory relationships and complicate the determination of network directionality., Methods: We propose a new method to construct GRNs based on causal strength and ensemble regression (CSER) to overcome these issues. CSER uses conditional mutual inclusive information to quantify the causal associations between genes, eliminating indirect regulation and marginal genes. It considers linear and nonlinear features and uses ensemble regression to infer the direction and interaction (activation or regression) from regulatory to target genes., Results: Compared to traditional algorithms, CSER can construct directed networks and infer the type of regulation, thus demonstrating higher accuracy on simulated datasets. Here, using real gene expression data, we applied CSER to construct a colorectal cancer GRN and successfully identified several key regulatory genes closely related to colorectal cancer (CRC), including ADAMDEC1 , CLDN8 , and GNA11 ., Discussion: Importantly, by integrating immune cell and microbial data, we revealed the complex interactions between the CRC gene regulatory network and the tumor microenvironment, providing additional new biomarkers and therapeutic targets for the early diagnosis and prognosis of CRC., 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, Du, Wang and Ai.)

Redox transformation of mercury (Hg) is critical for Hg exchange at the air-water interface. However, the superoxide radicals (O 2 •─ ) contribution of microalgal-fungal symbiotic systems in lake water to Hg(II) reduction is mainly unknown. Here, we studied the enhanced potential for O 2 •─ production by the coupling effect between microalgae and fungi. The relationships between microenvironment, microorganisms, and O 2 •─ production were also investigated. Furthermore, the implication of O 2 •─ for Hg(II) reduction was explored. The results showed that the coupling effect of microalgae and fungi enhanced O 2 •─ generation in the symbiotic systems, and the O 2 •─ generation peaked on day 4 in the lake water at 160.51 ± 13.06-173.28 ± 18.21 μmol/kg FW (fresh weight). In addition, O 2 •- exhibited circadian fluctuations that correlated with changes in dissolved oxygen content and redox potential on the inter-spherical interface of microalgal-fungal consortia. Partial least squares path modeling (PLS-PM) indicates that O 2 •─ formation was primarily associated with microenvironmental factors and microbial metabolic processes. The experimental results suggest that O 2 •─ in the microalgal-fungal systems could mediate Hg(II) reduction, promoting Hg conversion and cycling. The findings highlight the importance of microalgae and fungal symbiotic systems in Hg transformation in aquatic environments., 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.)

Highly integrated energy systems are on the rise due to increasing global demand. To capture the underlying physics of such interdisciplinary systems, we need a modern framework that unifies all forms of energy. Here, we apply modified Lagrangian mechanics to the description of multi-energy systems. Based on the minimum entropy production principle, we revisit fluid mechanics in the presence of both mechanical and thermal dissipations and propose using exergy flow as the unifying Lagrangian across different forms of energy. We illustrate our theoretical framework by modeling a one-dimensional system with coupled electricity and heat. We map the exergy loss rate in real space and obtain the total exergy changes. Under steady-state conditions, our theory agrees with the traditional formula but incorporates more physical considerations such as viscous dissipation. The integral form of our theory also allows us to go beyond steady-state calculations and visualize the local, time-dependent exergy flow density everywhere in the system. Expandable to a wide range of applications, our theoretical framework provides the basis for developing versatile models in integrated energy systems.

Background: Gastrointestinal cancer cells display both morphology and physiology diversity, thus posing a significant challenge for precise representation by a single data model. We conducted an in-depth study of gastrointestinal cancer heterogeneity by integrating and analyzing data from multiple modalities., Methods: We used a modified Canny algorithm to identify edges from tumor images, capturing intricate nonlinear interactions between pixels. These edge features were then combined with differentially expressed mRNA, miRNA, and immune cell data. Before data integration, we used the K-medoids algorithm to pre-cluster individual data types. The results of pre-clustering were used to construct the kernel matrix. Finally, we applied spectral clustering to the fusion matrix to identify different tumor subtypes. Furthermore, we identified hub genes linked to these subtypes and their biological roles through the application of Weighted Gene Co-expression Network Analysis (WGCNA) and Gene Ontology (GO) enrichment analysis., Results: Our investigation categorized patients into three distinct tumor subtypes and pinpointed hub genes associated with each. Genes MAGI2-AS3 , MALAT1 , and SPARC were identified as having a differential impact on the metastatic and invasive capabilities of cancer cells., Conclusion: By harnessing multimodal features, our study enhances the understanding of gastrointestinal tumor heterogeneity and identifies biomarkers for personalized medicine and targeted treatments., Competing Interests: The authors declare no conflicts of interest.

Stroke leads to persistently high risk for recurrent vascular events caused by systemic atheroprogression that is driven by endothelial cell (EC) activation. However, whether and how stroke induces sustained pro-inflammatory and proatherogenic endothelial alterations in systemic vessels remain poorly understood. We showed that brain ischemia induces persistent activation, the upregulation of adhesion molecule VCAM1, and increased senescence in peripheral ECs until 4 weeks after stroke onset. This aberrant EC activity resulted from sustained Notch1 signaling, which was triggered by increased circulating Notch1 ligands DLL1 and Jagged1 after stroke in mice and humans. Consequently, this led to increased myeloid cell adhesion and atheroprogression by generating a senescent, pro-inflammatory endothelium. Notch1- or VCAM1-blocking antibodies and the genetic ablation of endothelial Notch1 reduced atheroprogression after stroke. Our findings revealed a systemic machinery that induces the persistent activation of peripheral ECs after stroke, which paves the way for therapeutic interventions or the prevention of recurrent vascular events following stroke., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Detecting dopamine (DA) in biological samples is vital to understand its crucial role in numerous physiological processes, such as motion, cognition, and reward stimulus. In this work, p-type graphene on sapphire, synthesized via chemical vapor deposition, serves as substrate for the preparation of p-type Cu 2-x S films through solid-phase sulfurization. The optimized Cu 2-x S/graphene heterostructure, prepared at 250 °C using a 15-nm copper film sulfurized for 2 h, exhibits superior electron transfer performance, ideal for electrochemical sensing. It is confirmed that the spontaneous charge transfer from graphene to Cu 2-x S, higher Cu(II)/Cu(I) ratio (~ 0.8), and the presence of well-defined nanocrystalline structures with an average size of ~ 35 nm in Cu 2-x S significantly contribute to the improved electron transfer of the heterostructure. The electrochemical sensor based on Cu 2-x S/graphene heterostructure demonstrates remarkable sensitivity towards DA, with a detection limit as low as 100 fM and a dynamic range greater than 10 9 from 100 fM to 100 μM. Additionally, it exhibits excellent selectivity even in the presence of uric acid and ascorbic acid 100 times higher, alongside notable storage and measurement stability and repeatability. Impressively, the sensor also proves capable of detecting DA concentrations as low as 100 pM in rat serum, showcasing its potential for clinically relevant analytes and promising applications in sensitive, selective, reliable, and efficient point-of-care diagnostics., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background Aims: Partial hepatectomy (PHx)-induced liver regeneration causes the increase in relative blood flow rate within the liver, which dilates hepatic sinusoids and applies mechanical stretch on liver sinusoidal endothelial cells (LSECs). Heparin-binding EGF-like growth factor (HB-EGF) is a crucial growth factor during liver regeneration. We aimed to investigate whether this sinusoidal dilation-induced stretch promotes HB-EGF secretion in LSECs and what the related molecular mechanism is., Approach Results: In vivo PHx, ex vivo liver perfusion and in vitro LSEC mechanical stretch were applied to detect HB-EGF expression in LSECs and hepatocyte proliferation. Knockdown or inhibition of mechanosensitive proteins were used to unravel the molecular mechanism in response to stretch. This stretch triggers amplitude- and duration-dependent HB-EGF up-regulation in LSECs, which is mediated by Yes-associated protein (YAP) nuclear translocation and binding to TEAD. This YAP translocation is achieved in two ways: On one hand, F-actin polymerization-mediated expansion of nuclear pores promotes YAP entry into nucleus passively. On the other hand, F-actin polymerization up-regulates the expression of BAG family molecular chaperone regulator 3 (BAG-3), which binds with YAP to enter nucleus cooperatively. In this process, β1-integrin serves as a target mechanosensory in stretch-induced signaling pathways. This HB-EGF secretion-promoted liver regeneration after 2/3 PHx is attenuated in endothelial cell-specific Yap1-deficient mice., Conclusions: Our findings indicate that mechanical stretch-induced HB-EGF up-regulation in LSECs via YAP translocation can promote the hepatocyte proliferation during liver regeneration through a mechanocrine manner, which deepens the understanding of the mechanical-biological coupling in liver regeneration., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Aims: Proper arteriogenesis after tissue ischaemia is necessary to rebuild stable blood circulation; nevertheless, this process is impaired in type 2 diabetes mellitus (T2DM). Raptor is a scaffold protein and a component of mammalian target of rapamycin complex 1 (mTORC1). However, the role of the endothelial Raptor in arteriogenesis under the conditions of T2DM remains unknown. This study investigated the role of endothelial Raptor in ischaemia-induced arteriogenesis during T2DM., Methods and Results: Although endothelial mTORC1 is hyperactive in T2DM, we observed a marked reduction in the expression of endothelial Raptor in two mouse models and in human vessels. Inducible endothelial-specific Raptor knockout severely exacerbated impaired hindlimb perfusion and arteriogenesis after hindlimb ischaemic injury in 12-week high-fat diet fed mice. Additionally, we found that Raptor deficiency dampened vascular endothelial growth factor receptor 2 (VEGFR2) signalling in endothelial cells (ECs) and inhibited VEGF-induced cell migration and tube formation in a PTP1B-dependent manner. Furthermore, mass spectrometry analysis indicated that Raptor interacts with neuropilin 1 (NRP1), the co-receptor of VEGFR2, and mediates VEGFR2 trafficking by facilitating the interaction between NRP1 and Synectin. Finally, we found that EC-specific overexpression of the Raptor mutant (loss of mTOR binding) reversed impaired hindlimb perfusion and arteriogenesis induced by endothelial Raptor knockout in high-fat diet fed mice., Conclusion: Collectively, our study demonstrated the crucial role of endothelial Raptor in promoting ischaemia-induced arteriogenesis in T2DM by mediating VEGFR2 signalling. Thus, endothelial Raptor is a novel therapeutic target for promoting arteriogenesis and ameliorating perfusion in T2DM., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The Chinese Haemophilia Individualized Prophylaxis Study (CHIPS), which was launched in 2016, reported a significant reduction in haemarthrosis over a one-year study. However, its long-term efficacy requires verification. This paper summarizes the clinical outcomes of 18 severe haemophilia A (SHA) patients who completed one year on the CHIPS and 3 more years of follow-up., Methods: Clinical follow-up was based on the CHIPS protocol (from July 2018 to July 2021). Escalation was based on index joint bleeding, and serial ultrasound (greyscale and colour Doppler) examinations of the index joints (both sides of the ankles, knees and elbows) were conducted every 6 months via a scoring system., Results: A total of 18 SHA patients completed the 3-year study. Fifteen patients dropped out due to the financial crisis during the COVID-19 pandemic in China. The median age was 5.4 (range 4.3-6.9) years. A significant reduction in haemarthrosis was achieved, with mean annual bleeding rates reduced from 18.9 ± 2.8 to 1.7 ± 0.4 (p < 0.001), annual joint bleeding rates from 3.1 ± 0.7 to1.2 ± 0.3 (p < 0.028). 5 out of 8 target joint resolved. Sixteen doses were escalated. At study exit, the heterogeneous treatment outcomes of the SHA boys were 5 at step 4 (20-25 lU/kg, every other day), 10 at step 3 (15-20 IU/kg, 3×/week), 2 at step 2 (10-15 lU/kg, 3×/week) and 1 at step 1 (10-15 lU/kg, 2×/week). The mean FVIII consumption was 2964 IU/kg/year, with savings. The quality of life improved, with Canadian Haemophilia Outcomes-Kids Life Assessment Tool (CHO-KLAT, Chinese Version 2.0) scores ranging from 68.8 to 78.8. There was no change in the ultrasound score., Conclusion: Our follow-up data on the 18 SHA boys after completing one year on the CHIPS verify the long-term efficacy of the CHIPS for haemarthrosis reduction, joint health preservation, improvement in the quality of life of the boys and cost savings., 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 Ltd.)

Background: Inferring the shape and position of coronary artery poses challenges when using fluoroscopic image guidance during percutaneous coronary intervention (PCI) procedure. Although angiography enables coronary artery visualization, the use of injected contrast agent raises concerns about radiation exposure and the risk of contrast-induced nephropathy. To address these issues, dynamic coronary roadmapping overlaid on fluoroscopic images can provide coronary visual feedback without contrast injection., Purpose: This paper proposes a novel cardio-respiratory motion compensation method that utilizes cardiac state synchronization and catheter motion estimation to achieve coronary roadmapping in fluoroscopic images., Methods: For more accurate cardiac state synchronization, video frame interpolation is applied to increase the frame rate of the original limited angiographic images, resulting in higher framerate and more adequate roadmaps. The proposed method also incorporates a multi-length cross-correlation based adaptive electrocardiogram (ECG) matching to address irregular cardiac motion situation. Furthermore, a shape-constrained path searching method is proposed to extract catheter structure from both fluoroscopic and angiographic image. Then catheter motion is estimated using a cascaded matching approach with an outlier removal strategy, leading to a final corrected roadmap., Results: Evaluation of the proposed method on clinical x-ray images demonstrates its effectiveness, achieving a 92.8% F1 score for catheter extraction on 589 fluoroscopic and angiographic images. Additionally, the method achieves a 5.6-pixel distance error of the coronary roadmap on 164 intraoperative fluoroscopic images., Conclusions: Overall, the proposed method achieves accurate coronary roadmapping in fluoroscopic images and shows potential to overlay accurate coronary roadmap on fluoroscopic image in assisting PCI., (© 2024 American Association of Physicists in Medicine.)

The aquatic ecosystem has been extensively investigated as a hotspot for the spread of antibiotic resistance genes (ARGs); yet, the evolution and distribution of ARGs profiles in submerged macrophytes biofilms and surrounding water remained unclear. In this study, the dynamic distribution and seasonal variations of microbial communities and ARGs profiles were investigated, alongside their assembly processes and mutual interactions. Bacitracin and multidrug resistance genes were predominant, constituting more than 60% of the total ARGs abundance. The deterministic processes (<65%), influenced by the physicochemical properties of the river environment, governed the assembly and composition of ARGs profiles, exhibiting significant seasonal variation. The peak diversity (21 types) and abundance (0.316 copy ratios) of ARGs were detected during the summer. Proteobacteria and Actinobacteria were the dominant bacterial phyla, accounting for 38.41-85.50% and 4.03-27.09% of the microbial community, respectively. Furthermore, Proteobacteria, especially genera such as Acinetobacter, Burkholderia, and Pseudomonas, with various resistance sequences, were the primary carriers of multiple ARGs. Notably, the genetic exchanges between biofilms and surrounding water facilitated the further propagation of high-risk ARGs, posing greater ecological risks. Redundancy analysis indicated that the total nitrogen and temperature in water determined the fate of pathogenic-resistant species. These findings provided theoretical support for the mitigation of ARGs contamination in aquatic environments., 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.)

Virtual culinary medicine education interventions have the potential to improve dietary behaviors, nutrition knowledge, cooking skills, and health outcomes for ethnically diverse individuals with type 2 diabetes. The purpose of this study is to describe the adaptation of the Nourishing the Community through Culinary Medicine (NCCM) program for virtual delivery, and the protocol for pilot testing this intervention. The intervention includes five 90-min virtual NCCM sessions streamed live from a Teaching Kitchen. Feasibility outcomes are recruitment, retention, acceptability, and satisfaction. Short-term effectiveness outcomes are measured through self-administered questionnaires, including perceived health, average daily servings of fruits and vegetables, frequency of healthy food consumption, shopping, cooking, and eating behaviors, cooking self-efficacy, diabetes self-management, perceived barriers to healthy eating, and nutrition knowledge. Demographics and biometric outcomes are sourced from the patient's electronic medical records including glycosylated hemoglobin (HbA1c), Body Mass Index, and blood pressure. We will conduct a single-arm pilot study to test the feasibility and short-term effectiveness of NCCM program with individuals with type 2 diabetes., Competing Interests: JM is employed by the company Suvida Healthcare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Macias-Navarro, McWhorter, Guevara, Bentley, Sharma, Torres, Ai and Heredia.)

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been associated with potential cardiovascular benefits, partly attributed to their bioactive metabolites. However, the underlying mechanisms responsible for these advantages are not fully understood. We previously reported that metabolites of the cytochrome P450 pathway derived from eicosapentaenoic acid (EPA) mediated the atheroprotective effect of ω-3 PUFAs. Here, we show that 17,18-epoxyeicosatetraenoic acid (17,18-EEQ) and its receptor, sphingosine-1-phosphate receptor 1 (S1PR1), in endothelial cells (ECs) can inhibit oscillatory shear stress- or tumor necrosis factor-α-induced endothelial activation in cultured human ECs. Notably, the atheroprotective effect of 17,18-EEQ and purified EPA is circumvented in male mice with endothelial S1PR1 deficiency. Mechanistically, the anti-inflammatory effect of 17,18-EEQ relies on calcium release-mediated endothelial nitric oxide synthase (eNOS) activation, which is abolished upon inhibition of S1PR1 or G q signaling. Furthermore, 17,18-EEQ allosterically regulates the conformation of S1PR1 through a polar interaction with Lys34 Nter . Finally, we show that Vascepa, a prescription drug containing highly purified and stable EPA ethyl ester, exerts its cardiovascular protective effect through the 17,18-EEQ-S1PR1 pathway in male and female mice. Collectively, our findings indicate that the anti-inflammatory effect of 17,18-EEQ involves the activation of the S1PR1-G q -Ca 2+ -eNOS axis in ECs, offering a potential therapeutic target against atherosclerosis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia., Methods: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t 1/2 ), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used., Result: Compared with standard-collected blood samples, prolonged APTT results ( P -values < 0.01) and decreased FVIII activity ( P -values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P  < 0.0001) and FVIII-S level(r = 0.68, P  < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P  < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t 1/2 , lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group., Conclusion: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.

Reactive oxygen species (ROS) play crucial roles in element cycling and pollutant dynamics, but their variations and mechanisms in the rhizosphere of submerged macrophytes are poorly investigated. This study investigated the light-dark cycle fluctuations and periodic variations in ROS, redox-active substances, and microbial communities in the rhizosphere of Vallisneria natans. The results showed sustained production and significant diurnal fluctuations in the O 2 •- and •OH from 27.6 ± 3.7 to 61.7 ± 3.0 μmol/kg FW and 131.0 ± 6.8 to 195.4 ± 8.7 μmol/kg FW, respectively, which simultaneously fluctuated with the redox-active substances. The ROS contents in the rhizosphere were higher than those observed in non-rhizosphere sediments over the V. natans growth period, exhibiting increasing-decreasing trends. According to the redundancy analysis results, water-soluble phenols, fungi, and bacteria were the main factors influencing ROS production in the rhizosphere, showing contribution rates of 74.0, 17.3, and 4.4 %, respectively. The results of partial least squares path modeling highlighted the coupled effects of redox-active substances and microbial metabolism. Our findings also demonstrated the degradation effect of ROS in rhizosphere sediments of submerged macrophytes. This study provides experimental evidence of ROS-related rhizosphere effects and further insights into submerged macrophytes-based ecological restoration., 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.)

Detecting coronary stenosis accurately in X-ray angiography (XRA) is important for diagnosing and treating coronary artery disease (CAD). However, challenges arise from factors like breathing and heart motion, poor imaging quality, and the complex vascular structures, making it difficult to identify stenosis fast and precisely. In this study, we proposed a Quantum Diffusion Model with Spatio-Temporal Feature Sharing to Real-time detect Stenosis (STQD-Det). Our framework consists of two modules: Sequential Quantum Noise Boxes module and spatio-temporal feature module. To evaluate the effectiveness of the method, we conducted a 4-fold cross-validation using a dataset consisting of 233 XRA sequences. Our approach achieved the F1 score of 92.39% with a real-time processing speed of 25.08 frames per second. These results outperform 17 state-of-the-art methods. The experimental results show that the proposed method can accomplish the stenosis detection quickly and accurately.

Background: Region-specific immune environments in the epididymis influence the immune responses to uropathogenic Escherichia coli (UPEC) infection, a relevant cause of epididymitis in men. Toll-like receptors (TLRs) are essential to orchestrate immune responses against bacterial infections. The epididymis displays region-specific inflammatory responses to bacterial-derived TLR agonists, such as lipopolysaccharide (LPS; TLR4 agonist) and lipoteichoic acid (LTA; TLR2/TLR6 agonist), suggesting that TLR-associated signaling pathways could influence the magnitude of inflammatory responses in epididymitis., Objectives: To investigate the expression and regulation of key genes associated with TLR4 and TLR2/TLR6 signaling pathways during epididymitis induced by UPEC, LPS, and LTA in mice., Material and Methods: Epididymitis was induced in mice using UPEC, ultrapure LPS, or LTA, injected into the interstitial space of the initial segment or the lumen of the vas deferens close to the cauda epididymidis. Samples were harvested after 1, 5, and 10 days for UPEC-treated animals and 6 and 24 h for LPS-/LTA-treated animals. Ex vivo epididymitis was induced by incubating epididymal regions from naive mice with LPS or LTA. RT-qPCR and Western blot assays were conducted., Results: UPEC infection up-regulated Tlr2, Tlr4, and Tlr6 transcripts and their associated signaling molecules Cd14, Ticam1, and Traf6 in the cauda epididymidis but not in the initial segment. In these epididymal regions, LPS and LTA differentially modulated Tlr2, Tlr4, Tlr6, Cd14, Myd88, Ticam1, Traf3, and Traf6 expression levels. NFKB and AP1 activation was required for LPS- and LTA-induced up-regulation of TLR-associated signaling transcripts in the cauda epididymidis and initial segment, respectively., Conclusion: The dynamic modulation of TLR4 and TLR2/TLR6 signaling pathways gene expression during epididymitis indicates bacterial-derived antigens elicit an increased tissue sensitivity to combat microbial infection in a spatial manner in the epididymis. Differential activation of TLR-associated signaling pathways may contribute to fine-tuning inflammatory responses along the epididymis., (© 2024 American Society of Andrology and European Academy of Andrology.)

The E3 ubiquitin ligase MdSINA11 targets the jasmonate ZIM domain protein MdJAZ2 for ubiquitination and degradation through the 26S proteasome pathway, thereby initiating jasmonate signaling and jasmonic acid-triggered anthocyanin biosynthesis in apple., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Objectives: Type 2 diabetes (T2DM), a recognized risk factor for periodontitis, is characterized by insulin resistance. However, the molecular mechanisms concerning the role of insulin resistance in linking T2DM and periodontitis remain poorly elucidated due to the absence of an appropriate T2DM cell model. We aimed to explore an appropriate model of T2DM in human periodontal ligament stem cells (hPDLSCs) and uncover the involved mechanisms., Materials and Methods: hPDLSCs were incubated with common reagents for recapitulating insulin resistance state including high glucose (HG) (15, 25, 35, 45 mM), glucosamine (0.8, 8, 18, 28, 38 mM), or palmitic acid (PA; 100, 200, 400, 800 μM), combined with LPS for 48 h. The insulin signaling pathway, inflammation, and pyroptosis were detected by western blots and quantitative real-time polymerase chain reaction (RT-qPCR). The effects on osteogenesis were evaluated by alkaline phosphatase staining, alizarin red S staining, RT-qPCR, and western blots., Results: HG failed to recapitulate insulin resistance. Glucosamine was sufficient to induce insulin resistance but failed to trigger inflammation. In total, 100 and 200 μM PA exhibited the most proinflammatory, insulin resistance, and pyroptosis induced role, and inhibited the osteogenic differentiation of hPDLSCs., Conclusion: Palmitic acid is a promising candidate for developing T2DM model in hPDLSCs., (© 2023 Wiley Periodicals LLC.)

Development of low temperature catalytic pyrolysis technology for heated tobacco sheets is expected to increase the aroma of heated tobacco products and improve their overall smoking quality. In this study, the low temperature pyrolysis performances of heated tobacco sheets catalyzed by various anionic sodium salts were investigated using TG-DTG, Py-GC-MS technology and smoke routine chemical composition analysis. The results showed that the total weight loss between 100°C and 300°C increased by 7.8%-13.15% after adding various anionic sodium salts, among which, sodium acetate and sodium tartrate showed a relatively higher weight loss. The relative content of free hydroxyacetone, furfuryl alcohol, butyrolactone and megastigmatrienone in the pyrolysis gas increased, while the relative content of free nicotine decreased. With the change of anionic species, the catalytic decomposition ability of cellulose, lignin, and other substances may change, resulting in the distribution alteration of compounds in the pyrolysis gas. After adding sodium acetate and sodium citrate, the release of total particulate matter (TPM), glycerol, and nicotine in flue gas increased. Overall, the addition of sodium acetate and sodium citrate showed a higher low temperature pyrolysis performance of heated tobacco sheets. The research results in this paper provide data support for changing the low temperature catalytic pyrolysis performance of heated tobacco sheets by adjusting the type of anions in sodium salts., Competing Interests: Authors XZ, QW, DA, HT, ZZ, KC, YW, WQ, BoL, YN, and BiL were employed by China Tobacco Henan Industrial Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Wang, Ai, Tian, Zhang, Cao, Wang, Qi, Li, Niu, Meng, Gao and Li.)

Importance: It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS 200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS 40 regimen)., Objective: To compare the efficacy of the LD-ITI-IS 200 regimen with that of the LD-ITI-IS 40 regimen for SHA patients with high-titer inhibitors., Methods: A prospective cohort study on patients receiving LD-ITI-IS 200 compared to those receiving LD-ITI-IS 40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS 200 regimen and ≥40 BU/mL in the LD-ITI-IS 40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected., Results: We enrolled 30 patients on LD-ITI-IS 200 and 64 patients on LD-ITI-IS 40 , with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS 200 regimen compared to the LD-ITI-IS 40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS 200 vs. LD-ITI-IS 40 ) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS 200 than for LD-ITI-IS 40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS 200 regimen) and 28 IS-using (on LD-ITI-IS 40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months)., Interpretation: In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL., Competing Interests: Man‐Chiu Poon declares no conflict of interest for this work. However, he has otherwise received an honorarium for events sponsored by Takeda and for attending advisory Board meetings for KVR Pharm, Novo Nordisk, Octapharma, and Sobi. The other authors declare no conflict of interest., (© 2024 Chinese Medical Association. Pediatric Investigation published by John Wiley & Sons Australia, Ltd on behalf of Futang Research Center of Pediatric Development.)

Lipotoxicity refers to the accumulation of lipids in tissues other than adipose tissue (body fat). It is one of the major pathophysiological mechanisms responsible for the progression of diabetes complications such as non-alcoholic fatty liver disease and diabetic nephropathy. Accumulating evidence indicates that lipotoxicity also contributes significantly to the toxic effects of diabetes on periodontitis. Therefore, we reviewed the current in vivo, in vitro, and clinical evidence of the detrimental effects of lipotoxicity on periodontitis, focusing on its molecular mechanisms, especially oxidative and endoplasmic reticulum stress, inflammation, ceramides, adipokines, and programmed cell death pathways. By elucidating potential therapeutic strategies targeting lipotoxicity and describing their associated mechanisms and clinical outcomes, including metformin, statins, liraglutide, adiponectin, and omega-3 PUFA, this review seeks to provide a more comprehensive and effective treatment framework against diabetes-associated periodontitis. Furthermore, the challenges and future research directions are proposed, aiming to contribute to a more profound understanding of the impact of lipotoxicity on periodontitis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Periodontal tissue destruction in periodontitis is a consequence of the host inflammatory response to periodontal pathogens, which could be aggravated in the presence of type 2 diabetes mellitus (T2DM). Accumulating evidence highlights the intricate involvement of macrophage-mediated inflammation in the pathogenesis of periodontitis under both normal and T2DM conditions. However, the underlying mechanism remains elusive. Alpha-2-glycoprotein 1 (AZGP1), a glycoprotein featuring an MHC-I domain, has been implicated in both inflammation and metabolic disorders. In this study, we found that AZGP1 was primarily colocalized with macrophages in periodontitis tissues. AZGP1 was increased in periodontitis compared with controls, which was further elevated when accompanied by T2DM. Adeno-associated virus-mediated overexpression of Azgp1 in the periodontium significantly enhanced periodontal inflammation and alveolar bone loss, accompanied by elevated M1 macrophages and pyroptosis in murine models of periodontitis and T2DM-associated periodontitis, while Azgp1 -/- mice exhibited opposite effects. In primary bone marrow-derived macrophages stimulated by lipopolysaccharide (LPS) or LPS and palmitic acid (PA), overexpression or knockout of Azgp1 markedly upregulated or suppressed, respectively, the expression of macrophage M1 markers and key components of the NLR Family Pyrin Domain Containing 3 (NLRP3)/caspase-1 signaling. Moreover, conditioned medium from Azgp1 -overexpressed macrophages under LPS or LPS+PA stimulation induced higher inflammatory activation and lower osteogenic differentiation in human periodontal ligament stem cells (hPDLSCs). Furthermore, elevated M1 polarization and pyroptosis in macrophages and associated detrimental effects on hPDLSCs induced by Azgp1 overexpression could be rescued by NLRP3 or caspase-1 inhibition. Collectively, our study elucidated that AZGP1 could aggravate periodontitis by promoting macrophage M1 polarization and pyroptosis through the NLRP3/casapse-1 pathway, which was accentuated in T2DM-associated periodontitis. This finding deepens the understanding of AZGP1 in the pathogenesis of periodontitis and suggests AZGP1 as a crucial link mediating the adverse effects of diabetes on periodontal inflammation., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. Here, to explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3 and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely, thymosin beta 4, thymosin beta 10 and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, has a poor prognosis and lacks effective treatment strategies. Here, the study discovered that TNBC shows a decreased expression of epithelial transcription factor ovo-like 2 (OVOL2). The loss of OVOL2 promotes fatty acid oxidation (FAO), providing additional energy and NADPH to sustain stemness characteristics, including sphere-forming capacity and tumor initiation. Mechanistically, OVOL2 not only suppressed STAT3 phosphorylation by directly inhibiting JAK transcription but also recruited histone deacetylase 1 (HDAC1) to STAT3, thereby reducing the transcriptional activation of downstream genes carnitine palmitoyltransferase1 (CPT1A and CPT1B). PyVT-Ovol2 knockout mice develop a higher number of primary breast tumors with accelerated growth and increased lung-metastases. Furthermore, treatment with FAO inhibitors effectively reduces stemness characteristics of tumor cells, breast tumor initiation, and metastasis, especially in OVOL2-deficient breast tumors. The findings suggest that targeting JAK/STAT3 pathway and FAO is a promising therapeutic strategy for OVOL2-deficient TNBC., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Accurately reconstructing 4D critical organs contributes to the visual guidance in X-ray image-guided interventional operation. Current methods estimate intraoperative dynamic meshes by refining a static initial organ mesh from the semantic information in the single-frame X-ray images. However, these methods fall short of reconstructing an accurate and smooth organ sequence due to the distinct respiratory patterns between the initial mesh and X-ray image. To overcome this limitation, we propose a novel dual-stage complementary 4D organ reconstruction (DSC-Recon) model for recovering dynamic organ meshes by utilizing the preoperative and intraoperative data with different respiratory patterns. DSC-Recon is structured as a dual-stage framework: 1) The first stage focuses on addressing a flexible interpolation network applicable to multiple respiratory patterns, which could generate dynamic shape sequences between any pair of preoperative 3D meshes segmented from CT scans. 2) In the second stage, we present a deformation network to take the generated dynamic shape sequence as the initial prior and explore the discriminate feature (i.e., target organ areas and meaningful motion information) in the intraoperative X-ray images, predicting the deformed mesh by introducing a designed feature mapping pipeline integrated into the initialized shape refinement process. Experiments on simulated and clinical datasets demonstrate the superiority of our method over state-of-the-art methods in both quantitative and qualitative aspects.

Reaction of [CuH(PPh 3 )] 6 with 1 equiv. of Tl(OTf) results in formation of [Cu 6 TlH 6 (PPh 3 ) 6 ][OTf] ([1]OTf]), which can be isolated in good yields. Variable-temperature 1 H NMR spectroscopy, in combination with density functional theory (DFT) calculations, confirms the presence of a rare Tl-H orbital interaction. According to DFT, the 1 H chemical shift of the Tl-adjacent hydride ligands of [1] + includes 7.7 ppm of deshielding due to spin-orbit effects from the heavy Tl atom. This study provides valuable new insights into a rare class of metal hydrides, given that [1][OTf] is only the third isolable species reported to contain a Tl-H interaction., (© 2024 Wiley-VCH GmbH.)

Various infections trigger a storm of proinflammatory cytokines in which IL-6 acts as a major contributor and leads to diffuse alveolar damage in patients. However, the metabolic regulatory mechanisms of IL-6 in lung injury remain unclear. Polyriboinosinic-polyribocytidylic acid [poly(I:C)] activates pattern recognition receptors involved in viral sensing and is widely used in alternative animal models of RNA virus-infected lung injury. In this study, intratracheal instillation of poly(I:C) with or without an IL-6-neutralizing antibody model was combined with metabonomics, transcriptomics, and so forth to explore the underlying molecular mechanisms of IL-6-exacerbated lung injury. We found that poly(I:C) increased the IL-6 concentration, and the upregulated IL-6 further induced lung ferroptosis, especially in alveolar epithelial type II cells. Meanwhile, lung regeneration was impaired. Mechanistically, metabolomic analysis showed that poly(I:C) significantly decreased glycolytic metabolites and increased bile acid intermediate metabolites that inhibited the bile acid nuclear receptor farnesoid X receptor (FXR), which could be reversed by IL-6-neutralizing antibody. In the ferroptosis microenvironment, IL-6 receptor monoclonal antibody tocilizumab increased FXR expression and subsequently increased the Yes-associated protein (YAP) concentration by enhancing PKM2 in A549 cells. FXR agonist GW4064 and liquiritin, a potential natural herbal ingredient as an FXR regulator, significantly attenuated lung tissue inflammation and ferroptosis while promoting pulmonary regeneration. Together, the findings of the present study provide the evidence that IL-6 promotes ferroptosis and impairs regeneration of alveolar epithelial type II cells during poly(I:C)-induced murine lung injury by regulating the FXR-PKM2-YAP axis. Targeting FXR represents a promising therapeutic strategy for IL-6-associated inflammatory lung injury.

Background: The existing face matching method requires a point cloud to be drawn on the real face for registration, which results in low registration accuracy due to the irregular deformation of the patient's skin that makes the point cloud have many outlier points., Methods: This work proposes a non-contact pose estimation method based on similarity aspect graph hierarchical optimization. The proposed method constructs a distance-weighted and triangular-constrained similarity measure to describe the similarity between views by automatically identifying the 2D and 3D feature points of the face. A mutual similarity clustering method is proposed to construct a hierarchical aspect graph with 3D pose as nodes. A Monte Carlo tree search strategy is used to search the hierarchical aspect graph for determining the optimal pose of the facial 3D model, so as to realize the accurate registration of the facial 3D model and the real face., Results: The proposed method was used to conduct accuracy verification experiments on the phantoms and volunteers, which were compared with four advanced pose calibration methods. The proposed method obtained average fusion errors of 1.13 ± 0.20 mm and 0.92 ± 0.08 mm in head phantom and volunteer experiments, respectively, which exhibits the best fusion performance among all comparison methods., Conclusions: Our experiments proved the effectiveness of the proposed pose estimation method in facial augmented reality., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The heavy-metal ion critical role in γ-dicalcium silicate (γ-C 2 S) both in terms of solidification mechanism and hydration is still unclear. In this work, the solidification mechanism and the effect on initiating hydration of these three heavy-metal ions (Ba, Cd, and Cr) in γ-C 2 S is systemically studied by well-defined ab initio calculations. The calculated results show that the solid solution tendency of ions originates from the charge contribution, and the charge localization caused by the doping of Cr ions weakens the surface water adsorption. These insights will provide theoretical guidance for the low-carbon cement development by γ-C 2 S., Competing Interests: The authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Clear cell renal carcinoma (ccRCC), the most common subtype of renal cell carcinoma, has the high heterogeneity of a highly complex tumor microenvironment. Existing clinical intervention strategies, such as target therapy and immunotherapy, have failed to achieve good therapeutic effects. In this article, single-cell transcriptome sequencing (scRNA-seq) data from six patients downloaded from the GEO database were adopted to describe the tumor microenvironment (TME) of ccRCC, including its T cells, tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated fibroblasts (CAFs). Based on the differential typing of the TME, we identified tumor cell-specific regulatory programs that are mediated by three key transcription factors (TFs), whilst the TF EPAS1/HIF-2α was identified via drug virtual screening through our analysis of ccRCC's protein structure. Then, a combined deep graph neural network and machine learning algorithm were used to select anti-ccRCC compounds from bioactive compound libraries, including the FDA-approved drug library, natural product library, and human endogenous metabolite compound library. Finally, five compounds were obtained, including two FDA-approved drugs (flufenamic acid and fludarabine), one endogenous metabolite, one immunology/inflammation-related compound, and one inhibitor of DNA methyltransferase (N4-methylcytidine, a cytosine nucleoside analogue that, like zebularine, has the mechanism of inhibiting DNA methyltransferase). Based on the tumor microenvironment characteristics of ccRCC, five ccRCC-specific compounds were identified, which would give direction of the clinical treatment for ccRCC patients.

Appropriate DNA end synapsis, regulated by core components of the synaptic complex including KU70-KU80, LIG4, XRCC4, and XLF, is central to non-homologous end joining (NHEJ) repair of chromatinized DNA double-strand breaks (DSBs). However, it remains enigmatic whether chromatin modifications can influence the formation of NHEJ synaptic complex at DNA ends, and if so, how this is achieved. Here, we report that the mitotic deacetylase complex (MiDAC) serves as a key regulator of DNA end synapsis during NHEJ repair in mammalian cells. Mechanistically, MiDAC removes combinatorial acetyl marks on histone H2A (H2AK5acK9ac) around DSB-proximal chromatin, suppressing hyperaccumulation of bromodomain-containing protein BRD4 that would otherwise undergo liquid-liquid phase separation with KU80 and prevent the proper installation of LIG4-XRCC4-XLF onto DSB ends. This study provides mechanistic insight into the control of NHEJ synaptic complex assembly by a specific chromatin signature and highlights the critical role of H2A hypoacetylation in restraining unscheduled compartmentalization of DNA repair machinery., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Ki-67 expression levels in breast cancer have prognostic and predictive significance. Therefore, accurate Ki-67 evaluation is important for optimal patient care. Although an algorithm developed by the International Ki-67 in Breast Cancer Working Group (IKWG) improves interobserver variability, it is tedious and time-consuming. In this study, we simplify IKWG algorithm and evaluate its interobserver agreement among breast pathologists in Ki-67 evaluation., Methods: Six subspecialized breast pathologists (4 juniors, 2 seniors) assessed the percentage of positive cells in 5% increments in 57 immunostained Ki-67 slides. The time spent on each slide was recorded. Two rounds of ring study (R1, R2) were performed before and after training with the modified IKWG algorithm (eyeballing method at 400× instead of counting 100 tumor nuclei per area). Concordance was assessed using Kendall's and Kappa coefficients., Results: Analysis of ordinal scale ratings for all categories with 5% increments showed almost perfect agreement in R1 (0.821) and substantial in R2 (0.793); Seniors and juniors had substantial agreement in R1 (0.718 vs. 0.649) and R2 (0.756 vs. 0.658). In dichotomous scale analysis using 20% as the cutoff, the overall agreement was moderate in R1 (0.437) and R2 (0.479), among seniors (R1: 0.436; R2: 0.437) and juniors (R1: 0.445; R2: 0.505). Average scoring time per case was higher in R2 (71 vs. 37 s)., Conclusion: The modified IKWG algorithm does not significantly improve interobserver agreement. A better algorithm or assistance from digital image analysis is needed to improve interobserver variability in Ki-67 evaluation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated., Methods: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA., Results: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence., Conclusions: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA., Competing Interests: Disclosures None.

The segmentation of the orbit in computed tomography (CT) images plays a crucial role in facilitating the quantitative analysis of orbital decompression surgery for patients with Thyroid-associated Ophthalmopathy (TAO). However, the task of orbit segmentation, particularly in postoperative images, remains challenging due to the significant shape variation and limited amount of labeled data. In this paper, we present a two-stage semi-supervised framework for the automatic segmentation of the orbit in both preoperative and postoperative images, which consists of a pseudo-label generation stage and a semi-supervised segmentation stage. A Paired Copy-Paste strategy is concurrently introduced to proficiently amalgamate features extracted from both preoperative and postoperative images, thereby augmenting the network discriminative capability in discerning changes within orbital boundaries. More specifically, we employ a random cropping technique to transfer regions from labeled preoperative images (foreground) onto unlabeled postoperative images (background), as well as unlabeled preoperative images (foreground) onto labeled postoperative images (background). It is imperative to acknowledge that every set of preoperative and postoperative images belongs to the identical patient. The semi-supervised segmentation network (stage 2) utilizes a combination of mixed supervisory signals from pseudo labels (stage 1) and ground truth to process the two mixed images. The training and testing of the proposed method have been conducted on the CT dataset obtained from the Eye Hospital of Wenzhou Medical University. The experimental results demonstrate that the proposed method achieves a mean Dice similarity coefficient (DSC) of 91.92% with only 5% labeled data, surpassing the performance of the current state-of-the-art method by 2.4%., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Concurrent chemoradiotherapy is the standard nonoperative treatment for locally advanced esophageal squamous cell carcinoma. However, local recurrence is still the main failure pattern, accounting for more than half of all treatment failures, indicating that the sensitivity of radiotherapy still needs to be improved. This trial aimed at demonstrating whether PD-1 inhibitors followed by chemoradiotherapy could promote esophageal tumor vascular normalization, alleviate hypoxia, and thus enhance radiosensitivity and improve local control., Methods: We did a multicenter, single-arm, phase 2 trial in China. Patients with locally advanced esophageal cancer were enrolled in this study. In induction phase, patients received two cycles of sintilimab, paclitaxel and carboplatin once per 21 days. In concurrent phase, patients were treated with five cycles of carboplatin and paclitaxel once per week concurrent with radiotherapy of 50.4Gy delivered in 28 fractions. The primary endpoint was 2-year local control rate. Hypoxia and vessel normalization was assessed before and after induction phase using immunofluorescence and perfusion CT. This trial is registered with ClinicalTrials.gov (NCT03985046)., Findings: Seventy-five patients with esophageal cancer were enrolled in this study between October 2019 and April 2021. The median follow-up of surviving patients was 33.6 months (IQR 29.3-35.7). The 2-year local control rate was 81.7% (95% confidence interval, 72.7%-90.7%), which was much higher than that in concurrent chemoradiation only (71.3%) in previous studies. Vascular normalization and hypoxia alleviation were observed in both biopsy specimens and perfusion CT., Interpretation: The addition of induction immunotherapy to standard concurrent chemoradiotherapy could improve radiosensitivity for locally advanced esophageal cancer as non-surgical treatment. New treatment combination led to higher local control rate through promoting vascular normalization and alleviating hypoxia. Our findings suggest that induction immunotherapy followed by concurrent chemoradiotherapy could be a potential option in future treatment., Funding: National Natural Science Foundation of China and Shanghai Rising-Star Program., Competing Interests: We declare no competing interests., (© 2024 The Author(s).)

Feature matching of monocular laparoscopic videos is crucial for visualization enhancement in computer-assisted surgery, and the keys to conducting high-quality matches are accurate homography estimation, relative pose estimation, as well as sufficient matches and fast calculation. However, limited by various monocular laparoscopic imaging characteristics such as highlight noises, motion blur, texture interference and illumination variation, most exiting feature matching methods face the challenges of producing high-quality matches efficiently and sufficiently. To overcome these limitations, this paper presents a novel sequential coupling feature descriptor to extract and express multilevel feature maps efficiently, and a dual-correlate optimized coarse-fine strategy to establish dense matches in coarse level and adjust pixel-wise matches in fine level. Firstly, a novel sequential coupling swin transformer layer is designed in feature descriptor to learn and extract multilevel feature representations richly without increasing complexity. Then, a dual-correlate optimized coarse-fine strategy is proposed to match coarse feature sequences under low resolution, and the correlated fine feature sequences is optimized to refine pixel-wise matches based on coarse matching priors. Finally, the sequential coupling feature descriptor and dual-correlate optimization are merged into the Sequential Coupling Dual-Correlate Network (SeCo DC-Net) to produce high-quality matches. The evaluation is conducted on two public laparoscopic datasets: Scared and EndoSLAM, and the experimental results show the proposed network outperforms state-of-the-art methods in homography estimation, relative pose estimation, reprojection error, matching pairs number and inference runtime. The source code is publicly available at https://github.com/Iheckzza/FeatureMatching., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Automatic vessel segmentation is a critical area of research in medical image analysis, as it can greatly assist doctors in accurately and efficiently diagnosing vascular diseases. However, accurately extracting the complete vessel structure from images remains a challenge due to issues such as uneven contrast and background noise. Existing methods primarily focus on segmenting individual pixels and often fail to consider vessel features and morphology. As a result, these methods often produce fragmented results and misidentify vessel-like background noise, leading to missing and outlier points in the overall segmentation. To address these issues, this paper proposes a novel approach called the progressive edge information aggregation network for vessel segmentation (PEA-Net). The proposed method consists of several key components. First, a dual-stream receptive field encoder (DRE) is introduced to preserve fine structural features and mitigate false positive predictions caused by background noise. This is achieved by combining vessel morphological features obtained from different receptive field sizes. Second, a progressive complementary fusion (PCF) module is designed to enhance fine vessel detection and improve connectivity. This module complements the decoding path by combining features from previous iterations and the DRE, incorporating nonsalient information. Additionally, segmentation-edge decoupling enhancement (SDE) modules are employed as decoders to integrate upsampling features with nonsalient information provided by the PCF. This integration enhances both edge and segmentation information. The features in the skip connection and decoding path are iteratively updated to progressively aggregate fine structure information, thereby optimizing segmentation results and reducing topological disconnections. Experimental results on multiple datasets demonstrate that the proposed PEA-Net model and strategy achieve optimal performance in both pixel-level and topology-level metrics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Biliary interventional procedures require physicians to track the interventional instrument tip (Tip) precisely with X-ray image. However, Tip positioning relies heavily on the physicians' experience due to the limitations of X-ray imaging and the respiratory interference, which leads to biliary damage, prolonged operation time, and increased X-ray radiation., Methods: We construct an augmented reality (AR) navigation system for biliary interventional procedures. It includes system calibration, respiratory motion correction and fusion navigation. Firstly, the magnetic and 3D computed tomography (CT) coordinates are aligned through system calibration. Secondly, a respiratory motion correction method based on manifold regularization is proposed to correct the misalignment of the two coordinates caused by respiratory motion. Thirdly, the virtual biliary, liver and Tip from CT are overlapped to the corresponding position of the patient for dynamic virtual-real fusion., Results: Our system is respectively evaluated and achieved an average alignment error of 0.75 ± 0.17 mm and 2.79 ± 0.46 mm on phantoms and patients. The navigation experiments conducted on phantoms achieve an average Tip positioning error of 0.98 ± 0.15 mm and an average fusion error of 1.67 ± 0.34 mm after correction., Conclusion: Our system can automatically register the Tip to the corresponding location in CT, and dynamically overlap the 3D virtual model onto patients to provide accurate and intuitive AR navigation., Significance: This study demonstrates the clinical potential of our system by assisting physicians during biliary interventional procedures. Our system enables dynamic visualization of virtual model on patients, reducing the reliance on contrast agents and X-ray usage.

Background: Monocular depth estimation plays a fundamental role in clinical endoscopy surgery. However, the coherent illumination, smooth surfaces, and texture-less nature of endoscopy images present significant challenges to traditional depth estimation methods. Existing approaches struggle to accurately perceive depth in such settings., Method: To overcome these challenges, this paper proposes a novel multi-scale residual fusion method for estimating the depth of monocular endoscopy images. Specifically, we address the issue of coherent illumination by leveraging image frequency domain component space transformation, thereby enhancing the stability of the scene's light source. Moreover, we employ an image radiation intensity attenuation model to estimate the initial depth map. Finally, to refine the accuracy of depth estimation, we utilize a multi-scale residual fusion optimization technique., Results: To evaluate the performance of our proposed method, extensive experiments were conducted on public datasets. The structural similarity measures for continuous frames in three distinct clinical data scenes reached impressive values of 0.94, 0.82, and 0.84, respectively. These results demonstrate the effectiveness of our approach in capturing the intricate details of endoscopy images. Furthermore, the depth estimation accuracy achieved remarkable levels of 89.3 % and 91.2 % for the two models' data, respectively, underscoring the robustness of our method., Conclusions: Overall, the promising results obtained on public datasets highlight the significant potential of our method for clinical applications, facilitating reliable depth estimation and enhancing the quality of endoscopy surgical procedures., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest related to this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Endothelial cells (EC) play essential roles in retinal vascular homeostasis. This study aimed to characterize retinal EC heterogeneity and functional diversity using single-cell RNA sequencing. Systematic analysis of cellular compositions and cell-cell interaction networks identified a unique EC cluster with high inflammatory gene expression in diabetic retina; sphingolipid metabolism is a prominent aspect correlated with changes in retinal function. Among sphingolipid-related genes, alkaline ceramidase 2 (ACER2) showed the most significant increase. Plasma samples of patients with nonproliferative diabetic retinopathy (NPDR) with diabetic macular edema (DME) or without DME (NDME) and active proliferative DR (PDR) were collected for mass spectrometry analysis. Metabolomic profiling revealed that the ceramide levels were significantly elevated in NPDR-NDME/DME and further increased in active PDR compared with control patients. In vitro analyses showed that ACER2 overexpression retarded endothelial barrier breakdown induced by ceramide, while silencing of ACER2 further disrupted the injury. Moreover, intravitreal injection of the recombinant ACER2 adeno-associated virus rescued diabetes-induced vessel leakiness, inflammatory response, and neurovascular disease in diabetic mouse models. Together, this study revealed a new diabetes-specific retinal EC population and a negative feedback regulation pathway that reduces ceramide content and endothelial dysfunction by upregulating ACER2 expression. These findings provide insights into cell-type targeted interventions for diabetic retinopathy., (© 2024 by the American Diabetes Association.)

Glabridin is a natural isoflavone with estrogen receptor agonism and significant anti-tumor activity. Additionally, glabridin has a regulation effect on PI3K/AKT/mTOR pathway, but its exact target remains unclear. In this study, we evaluated the antitumor activity of glabridin against breast cancer and prostate cancer cells, and further clarified its targeting to PI3K. We found that glabridin could significantly inhibit the cell viability of human breast cancer and prostate cancer cell lines. It induced caspase activation cascade and cell apoptosis through decreasing the mitochondrial transmembrane potential and increasing the intracellular reactive oxygen species (ROS). Moreover, glabridin could attenuate epithelial-mesenchymal transition (EMT) progression by inhibiting cell migration. PharmMapper calculation showed that PI3Kγ might be the most potential target protein because of the highest Normal Fit score (0.9735) and z'-score (0.9797). Molecular docking and bio-layer interferometry (BLI) analysis further demonstrated the PI3Kγ targeting of glabridin. In vivo experiments showed that glabridin can effectively inhibit the tumor growth of breast cancer xenograft model, and does not show obvious hepatorenal toxicity. Moreover, glabridin could effectively promote the anti-proliferation and pro-apoptotic effects of tamoxifen on MDA-MB-231 cell and taxol on DU145 cell. Elucidating the targeting of glabridin to PI3K may lay a theoretical foundation for the structural derivatization of glabridin, which is expected to greatly promote the application and development of glabridin in the field of cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)