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Amitriptyline (AMI), one of the widely used tricyclic antidepressants (TCAs), has become a pharmaceutical contaminant frequently detected in aquatic ecosystems. However, the impacts of AMI exposure and underlying mechanisms on fish are still limited. In this study, adult zebrafish (F0) were exposed to AMI at 0 (control), 0.8, and 8 μg/L for 14 days. Subsequently, the exposed zebrafish were paired for spawning, and their offspring (F1) were reared in an AMI-free medium until 5 days post-fertilization (dpf). This study aimed to assess variations in behaviors and neurotransmitter levels in both the F0 (at the end of the 14-day exposure) and F1 generations (at 5 dpf). As a result, waterborne AMI exposure significantly reduced the locomotor activity, frequency of body contact, and duration of chase in F0 zebrafish, and resulted in notable changes in monoamine neurotransmitter levels in their brains. Parental exposure to AMI significantly elevated the heart rate and eye movement but reduced the locomotor activity in the F1 zebrafish, also along with significant changes in monoamine neurotransmitters and acetylcholine. Furthermore, significant correlations between the changes in behavioral traits and neurotransmitter levels were identified in both F0 and F1 generations. Our findings confirm the critical role of monoamine modulation in the neurobehavioral toxicity of AMI on zebrafish and their offspring, and emphasize the importance of paying attention to its multigenerational effects on fish., 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 Inc.)

Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1β, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1β and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

A new transfer approach was proposed to share calibration models of the hexamethylenetetramine-acetic acid solution for studying hexamethylenetetramine concentration values across different near-infrared (NIR) spectrometers. This approach combines Savitzky-Golay first derivative (S_G_1) and orthogonal signal correction (OSC) preprocessing, along with feature variable optimization using an adaptive chaotic dung beetle optimization (ACDBO) algorithm. The ACDBO algorithm employs tent chaotic mapping and a nonlinear decreasing strategy, enhancing the balance between global and local search capabilities and increasing population diversity to address limitations observed in traditional dung beetle optimization (DBO). Validated using the CEC-2017 benchmark functions, the ACDBO algorithm demonstrated superior convergence speed, accuracy, and stability. In the context of a partial least squares (PLS) regression model for transferring hexamethylenetetramine-acetic acid solutions using NIR spectroscopy, the ACDBO algorithm excelled over alternative methods such as uninformative variable elimination, competitive adaptive reweighted sampling, cuckoo search, grey wolf optimizer, differential evolution, and DBO in efficiency, accuracy of feature variable selection, and enhancement of model predictive performance. The algorithm attained outstanding metrics, including a determination coefficient for the calibration set (R c 2 ) of 0.99999, a root mean square error for the calibration set (RMSEC) of 0.00195%, a determination coefficient for the validation set (R v 2 ) of 0.99643, a root mean squared error for the validation set (RMSEV) of 0.03818%, residual predictive deviation (RPD) of 16.72574. Compared to existing OSC, slope and bias correction (S/B), direct standardization (DS), and piecewise direct standardization (PDS) model transfer methods, the novel strategy enhances the accuracy and robustness of model predictions. It eliminates irrelevant background information about the hexamethylenetetramine concentration, thereby minimizing the spectral discrepancies across different instruments. As a result, this approach yields a determination coefficient for the prediction set (R p 2 ) of 0.96228, a root mean squared error for the prediction set (RMSEP) of 0.12462%, and a relative error rate (RER) of 17.62331, respectively. These figures closely follow those obtained using DS and PDS, which recorded R p 2 , RMSEP, and RER values of 0.97505, 0.10135%, 21.67030, and 0.98311, 0.08339%, 26.33552, respectively. Unlike conventional methods such as OSC, S/B, DS, and PDS, this novel approach does not require the analysis of identical samples across different instruments. This characteristic significantly broadens its applicability for model transfer, which is particularly beneficial for transferring specific measurement samples., 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.)

Burn injuries cause severe pain, infection risks, psychological distress, financial burdens, and mortality, necessitating effective care. Aloe vera, a traditional burn remedy, shows wound-healing potential, but its analgesic effects and efficacy with varying burn severity are uncertain. This study aims to investigate A. vera's effect on wound healing, pain management, and infection prevention in patients with burns. A systematic search on PubMed, Embase, and CENTRAL was performed on October 9, 2023, for randomized controlled trials (RCTs). The risk of bias was examined using the Cochrane risk-of-bias tool (version 2), and the meta-analysis was carried out using a random-effects model. The primary outcome was wound-healing time, with secondary outcomes examining pain severity and wound infection. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence for each outcome. Nine RCTs were included in the current study, of which 6 provided data on the primary outcome. Aloe vera significantly reduced mean wound-healing time compared to other topicals (mean difference [MD] -3.76 days; 95% CI, -5.69 to -1.84). Additionally, the meta-analysis of the secondary outcomes found no significant differences in pain reduction (MD -0.76 points; 95% CI, -1.53 to 0.01) and wound infection risk (risk ratio 1.10; 95% CI, 0.34-3.59) between A. vera and control groups. In conclusion, A. vera expedites wound healing in patients with second-degree burns without increased infection risk compared to other antimicrobial agents. The analgesic effects on burn injuries remain uncertain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association. 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.)

Ceramic capacitors, known for their exceptional energy-storage performance (ESP), are crucial components in high-pulsed power systems. However, their ESP is significantly constrained by breakdown strength (E b ), which is influenced by interfacial polarization. This study delves into the physics, characterization, and application of interfacial polarization. The findings indicate that key factors affecting ESP, such as grain size, relaxor factor, and bandgap, are intrinsically linked to interfacial polarization, establishing it as the most critical determinant of ESP. To demonstrate the practical applications of interfacial polarization engineering, lead-free ceramics of (1-x)(0.94Bi 0.5 Na 0.5 TiO 3 -0.06BaTiO 3 )-xCa 0.7 Bi 0.2 (Sn 0.5 Ti 0.5 )O 3 (abbreviated as (BNT-BT)-xCBST is designed, where x = 0, 0.1, 0.15, 0.2, and 0.25). The (BNT-BT)-0.25CBST sample, with a thickness of 120 µm, achieved an ultrahigh recoverable energy-storage density (W rec ) of 12.2 J cm -3 and a high efficient (η) of 88.8%, along with excellent temperature/frequency stability and outstanding charge/discharge performance. The remarkable ESP is attributed to the suppression of interfacial polarization, which significantly enhances E b . This work highlights the pivotal role of interfacial polarization engineering in the development of energy-storage ceramics with superior comprehensive performance., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

While tobacco smoking is a risk factor in the development of oral squamous cell carcinoma (OSCC), only a fraction of smokers develop the disease. Compelling evidence shows that microbial community composition is associated with carcinogenesis, suggesting that the microbiome may play a role in cancer development of smokers. We previously showed that black raspberry (BRB) protects against OSCC induced by the tobacco constituent dibenzo[def,p]chrysene (DBP) altering genetic and epigenetic markers in a manner consistent with its cancer preventive activity. In the present study, we conducted a mouse experiment to investigate the effects of BRB and DBP individually and in combination on the oral and gut microbiota. DBP-induced DNA damage in the mouse oral cavity which is an essential step for the development of OSCC in mice. 16S rRNA gene sequencing revealed that BRB significantly increased microbial diversity and shifted microbiome composition in the gut and oral cavity, whereas DBP had no significant effect. In both gut and oral microbiota, Akkermansia muciniphila was significantly reduced after BRB treatment; however, this was not consistent with pure culture in vitro assays suggesting that the impact of BRB on A. muciniphila may be mediated through indirect mechanisms including the host or other microbes. Indeed BRB, but not DBP, was found to modulate the growth kinetics of human gut microbes in vitro including lactic acid bacteria and Bacteroides spp. The results of the current study further emphasize the interplay of microbiome and environmental factors in the development and prevention of OSCC.

Polygenic risk scores (PRSs) are promising for risk stratification but have mainly been developed in European populations. This study developed single- and multi-ancestry PRSs for lung adenocarcinoma (LUAD) in East Asian (EAS) never-smokers using genome-wide association study summary statistics from EAS (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. A multi-ancestry PRS, developed using CT-SLEB, was strongly associated with LUAD risk (odds ratio=1.71, 95% confidence interval (CI):1.61,1.82), with an area under the receiver operating curve value of 0.640 (95% CI:0.629,0.653). Individuals in the highest 20% of the PRS had nearly four times the risk compared to the lowest 20%. Individuals in the 95 th percentile of the PRS had an estimated 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41. Our study underscores the potential of multi-ancestry PRS approaches to enhance LUAD risk stratification in EAS never-smokers.

Background and Aims: Colorectal cancer (CRC) incidence and mortality of China account for nearly 30% of the global attributable fraction. We aimed to estimate the yield and effectiveness of two-sample fecal immunochemical test (FIT)-based screening program in China., Methods: Eligible individuals were invited for two-sample FIT between 2007 and 2021, with positive ones (cutoff: 40 μg/g before 2013, and 20 μg/g thereafter) referred for colonoscopy. Participation rates, detection rates, and positive predictive values (PPVs) were calculated. Participants were classified into: FIT+ / colonoscopy compliers, FIT+ / colonoscopy non-compliers, and FIT- as controls. We compared CRC incidence and mortality, and calculated the age reaching comparable risk., Results: Among 246,349 invitees, 150,524 (61.10%) participated in two-sample FIT, with 16,994 (11.29%) identified as FIT+; 12,816 (75.41%) underwent colonoscopy, yielding a detection rate and PPV of 0.57% and 6.70% for advanced neoplasia. Median follow-up was 10.58 years. Compared with FIT- participants, CRC incidence and mortality were relatively similar among FIT+ / colonoscopy compliers with hazard ratio (HR) and 95% confidence interval (CI) of 0.94 (0.75-1.19) and 1.62 (1.09-2.41), but higher among non-compliers with HR and 95% CI of 3.52 (2.85-4.34) and 4.41 (2.96-6.55). Taking CRC incidence and mortality risk of FIT- participants at age 50.0 as the benchmark, FIT+ / colonoscopy compliers reached same risk at 50.6 and 46.1 years, while non-compliers at age 38.0 and 37.9 years, respectively., Conclusions: Two-sample FIT could effectively identify high-risk populations, and colonoscopy compliance is associated with a lower risk of CRC incidence and mortality. This strategy might facilitate CRC screening practice in countries with large populations., (Copyright © 2024. Published by Elsevier Inc.)

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N 2 -substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC 50  = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models., 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 Masson SAS. All rights reserved.)

Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), shows superior lung cancer treatment efficacy. However, osimertinib-induced severe hypersensitivity, including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), is frequently observed in Asian populations and hinders cancer treatment., Objective: We investigated the genetic HLA predisposition and immune pathomechanism of osimertinib-induced hypersensitivity., Methods: We enrolled 17 patients with osimertinib-induced delayed hypersensitivity (7 with severe SJS/TEN and 10 with mild maculopapular exanthema [MPE]), 98 osimertinib-tolerant subjects, and 2123 general population controls. HLA genotyping, drug-induced lymphocyte activation test (LAT), and surface plasmon resonance (SPR) assay were performed., Results: HLA-B*51:02 was present in 83.3% of osimertinib-induced SJS/TEN patients but only in 3.3% of the general population controls (P = 2.8×10 -7 , Pc=6.9×10 -6 , odds ratio [OR]=146), and 0% of osimertinib-tolerant controls (P = 6.5×10 -8 , Pc=1.6×10 -6 , OR=707). The association of HLA-B*51:01 and HLA-A*24:02 with osimertinib-induced MPE patients, rather than with osimertinib-tolerant subjects (P = 0.002, OR=15.7 for HLA-B*51:01; P = 0.003, OR=9.5 for HLA-A*24:02), was identified as a phenotype-specific association. Granulysin-the SJS/TEN-specific cytotoxic protein-was significantly higher in SJS/TEN patients' plasma (39.8±4.5 ng/ml, P<0.001) and in in vitro LAT (sensitivity=83.3%, P<0.01) compared to the tolerant controls. Patients with osimertinib-induced hypersensitivity appeared to tolerate alternative EGFR-TKIs. SPR results also confirmed that HLA-B*51:02 protein has a higher binding affinity for osimertinib and lower or no affinity for other EGFR-TKIs., Conclusions: HLA-B*51:02 frequently occurs in Asian populations and is strongly associated with osimertinib-induced SJS/TEN. Our findings suggest HLA-B*51:02 screening as a preemptive test to reduce osimertinib-induced severe hypersensitivity., (Copyright © 2024. Published by Elsevier Inc.)

Photodynamic Therapy (PDT) offers a promising minimally invasive treatment for breast cancer, but its efficacy is limited by the hostile tumor microenvironment (TME), including hypoxia and high glutathione (GSH) levels. Although various strategies to improve oxygen concentration or reduce reactive oxygen species (ROS) resistance for enhanced PDT have been explored, they typically require intricate design and complex synthesis of multifunctional nanocarriers. Thus, this study introduces a facile K 2 FeO 4 -induced strategy to enhance PDT efficiency in breast cancer through the tumor in situ synthesis of Fe 2 O 3 and O 2 . Inspired by the successful application of K 2 FeO 4 in ecological remediation and hemostasis, K 2 FeO 4 reacts with GSH, biological system, H 2 O 2 , and water, to generate Fe 2 O 3 and O 2 . Intratumoral injection of K 2 FeO 4 improves the TME, followed by Ce6 administration to enhance PDT through synergistic ferroptosis. This approach boosts PDT efficacy significantly by increasing ROS generation, lipid peroxidation, and inhibiting GSH and GPX4. Proteomic analysis revealed alterations in key pathways, including endocytosis and energy metabolism. This K 2 FeO 4 -PDT strategy creates a positive feedback loop by enhancing oxidative stress, providing an interesting and promising approach to PDT., (© 2024 Wiley‐VCH GmbH.)

Objective: To investigate the value of 18 F-FDG PET/CT-based intratumoral and peritumoral radiomics in predicting the efficacy of neoadjuvant chemotherapy (NAC) for breast cancer., Methods: 190 patients who met the inclusion and exclusion criteria from 2017 to 2022 were studied. Features were extracted from the PET/CT intratumoral and peritumoral regions, feature selection was performed through the correlation analysis, t-tests, and least absolute shrinkage and selection operator regression (LASSO). Four classifiers, support vector machine (SVM), k-nearest neighbor (KNN), logistic regression (LR), and naive bayes (NB) were used to build the prediction models. The receiver operating characteristic (ROC) curves were plotted to measure the predictive performance of the models. Concurrent stratified analysis was conducted to establish subtype-specific features for each molecular subtype., Results: Compared to intratumoral features alone, intratumoral + peritumoral features achieved higher AUC values in each classifier. The SVM model constructed with intratumoral + peritumoral features achieved the highest AUC values in both the train and test set (train set: 0.95 and test set: 0.83). Subtype-specific features improve performance in predicting the efficacy of NAC (luminal group: 0.90; HER2 + group: 0.86; triple negative group: 0.92)., Conclusion: Intratumoral and peritumoral radiomics models based on 18 F-FDG PET/CT can reliably forecast the efficacy of NAC, thereby assisting clinical decision-making., (© 2024. The Author(s).)

Background: Combination therapy is required for the treatment of moderate acne vulgaris. However, patient compliance in applying multiple topical formulations is poor., Objective: To assess the efficacy and safety of a fixed-dose combination gel with adapalene 0.1% and clindamycin 1% (adapalene-clindamycin) relative to adapalene 0.1% monotherapy and clindamycin 1% monotherapy in patients with moderate facial acne vulgaris., Methods: This was a randomized, controlled, assessor-blind, phase III study conducted in patients with moderate facial acne vulgaris., Results: A total of 1617 patients were enrolled. At week 12, patients in the adapalene-clindamycin gel treatment group showed a significant reduction in the percentage change from baseline in total lesion count (- 66.85%), compared with adapalene alone (- 50.82%) or clindamycin gel alone (- 57.61%). The difference in the least square means of the adapalene-clindamycin gel group and adapalene group, or clindamycin gel group was - 16.08% (95% CI - 19.95% to - 12.21%) and - 9.38% (95% CI - 13.25% to - 5.51%;), respectively. At week 12, 19.28% of participants who received adapalene-clindamycin gel achieved at least 2-grade improvement in IGA, versus 7.74% with adapalene gel (OR 3.05, 95% CI 1.93, 4.80) and 14.77% with clindamycin gel (OR 1.42, 95% CI 0.97, 2.07). The study also achieved all its secondary endpoints. Adverse event rates were mostly mild to moderate and comparable across the three treatment groups., Conclusion: Adapalene 0.1%-clindamycin 1% combination gel is well tolerated and demonstrated superior efficacy over 0.1% adapalene gel monotherapy and 1% clindamycin gel monotherapy for the treatment of moderate acne vulgaris., Trial Registration: ClinicalTrials.gov identifier NCT03615768., Competing Interests: Declarations Conflict of Interest Dr. Benjamin Xiao Yi Li is the Chairman & CEO of Zhaoke Ophthalmology Limited, and Director of Zhaoke Pharmaceutical (Hefei) Company Limited and Lee’s Pharmaceutical (Hong Kong) Limited. Xiang Rong DAI, and Xiao Hui YU are the staffs employed by Zhaoke Pharmaceutical (Hefei) Company Limited. Qiu Ju YIN is the staff employed by Zhaoke (Guangzhou) Ophthalmology Pharmaceutical Limited; The other authors declare no conflict of interest. Ethics Approval The trial was conducted in accordance with the Good Clinical Practice guidelines and complies with the Declaration of Helsinki. The protocol and informed consent form were reviewed and approved by a properly constituted institutional review board/independent ethics committee/research ethics board before study commencement. The names of the approving ethics committees are listed in Supplementary Table 1., (© 2024. The Author(s).)

As an emerging pollutant frequently detected in aquatic ecosystems, the toxicity of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-quinone) on fish has been confirmed, but insight into the mechanisms underlying those adverse effects is still limited. Thus, we exposed zebrafish embryos to 6PPD-quinone at 0, 0.25, 2.5, and 25 μg/L until 120 h post-fertilization (hpf), and investigated the variations in their development, behavior, monoamine neurotransmitter levels, and transcriptional profile. Exposure to 6PPD-quinone notably elevated the heart rate of zebrafish at 48 hpf (at 2.5 and 25 μg/L) and 72 hpf (at 0.25, 2.5, and 25 μg/L). In the dark-light transition test, the locomotor activity of zebrafish larvae exposed to 6PPD-quinone significantly increased, especially in the dark periods. Exposure to 6PPD-quinone also altered the dopamine level and its turnover in zebrafish, which exhibited significant correlations to their locomotor activity. RNA sequencing identified 394 differentially expressed genes (DEGs), most of which have the molecular function of binding and catalytic activity. Five DEGs were predicted as the key driver genes in the protein-protein interaction networks associated with circadian rhythm (i.e., npas2), protein processing in endoplasmic reticulum (i.e., hsp90b1 and pdia4), and estrogen signaling pathway (i.e., hsp90aa1.1 and hsp90aa1.2). Our findings provide more insights into mechanisms underlying the toxicity of 6PPD-quinone to teleosts and highlight the necessity to assess its potential risks to aquatic ecosystems., 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.)

Mental fatigue is defined as a decline in the ability and efficiency of mental activities. A lot of research suggests that the transition from alertness to fatigue is accompanied by alterations in correlation patterns among various brain regions. However, conventional methods for detecting mental fatigue seldom emphases inter-channel connectivity in the spatial domain. To fill this gap, this paper explores the spatial inter-channel connectivity in alertness and fatigue, employing spectral graph convolutional networks (GCN) for mental fatigue detection. We utilized Pearson correlation coefficients (PCC) to establish temporal connections and magnitude-squared coherence (MSC) for spectral connections. Topological features of the brain network were then analysed. To enhance the learning of spatial inter-channel connectivity, a dual-graph strategy transforms edge features into node features, serving as inputs to the spectral GCN. By simultaneously learning PCC and MSC features, the model results indicate significant differences in some brain network characteristics between alert and fatigue states. It confirms that the synchronicity of brain operations differs in the alert state compared to mental fatigue, and indicates that fatigue states can influence correlation patterns among different brain regions. Our approach is evaluated on a self-designed experimental dataset containing 7 subjects, demonstrating a classification accuracy of 89.59 % in group-level experiments and 95.24 % at the subject level. Additionally, on the public dataset SEED-VIG containing 23 subjects, our method achieves an accuracy of 86.58 %. In summary, this paper proposes a neural network approach based on a dynamic functional connectivity network. The network integrates both temporal and spectral connections with the goal of simultaneously learning spatial inter-channel connectivity in time and frequency domains. This effectively accomplishes fatigue state detection, highlighting that fatigue significantly influences correlations among different brain regions., 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 clinical outcomes of patients with anaplastic lymphoma kinase-positive (ALK+) advanced lung adenocarcinoma vary according to real-world data., Objective: In this study, we aimed to investigate the treatment discontinuation (TTD) and overall survival (OS) of patients with ALK+ advanced lung adenocarcinoma treated with first-line ALK-TKIs in Taiwan., Patients and Methods: This retrospective study evaluated all advanced lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2020 who had ALK rearrangement and received ALK-TKI treatment, using data from Taiwan's National Health Insurance Research Database (NHIRD). The TKI treatment sequences were classified into first generation (G1: crizotinib), second generation (G2: ceritinib, alectinib, brigatinib), and third generation (G3: lorlatinib)., Results: A total of 587 patients were analyzed, with a median age of 60.0 years, 91 (15.5%) aged ≥ 74 years, 293 (49.9%) female, 397 (67.6%) never smoked, and 534 (91.0%) with stage IV disease. Patients who received next-generation ALK-TKIs during the treatment course had longer median time to ALK-TKI TTD and OS. The TTD of the G1, G1+2, G1+2+3, G2, and G2+3 groups was 7.5 (5.4-11.1), 40.6 (29.4-not calculated (NC)), 50.3 (41.3-NC), 34.3 (29.2-43.0), and 36.3 (22.4-NC) months, respectively (p < 0.001). The median OS of the patients in the G1, G1+2, G1+2+3, G2, and G2+3 groups was 10.6 (7.5-14.6), not reached (NR) (NC-NC), NR (NC-NC), 43.0 (36.3-NC), and NR (30.3-NC) months, respectively (p < 0.001). Compared with treatment with crizotinib alone, the multivariate analysis revealed that treatment with next-generation TKIs was independently associated with longer TTD (G1+2 (hazard ratio (HR), 0.24; 95% CI 0.17-0.33; p < 0.001), G1+2+3 or G1+3 (HR, 0.17; 95% confidence interval (CI), 0.10-0.28; p < 0.001), G2 (HR, 0.26; 95% CI 0.19-0.36; p < 0.001), and G2+3 (HR, 0.25; 95% CI 0.14-0.44; p < 0.001)) and median OS (G12 (HR, 0.24; 95% CI 0.17-0.35; p < 0.001), G1+2+3 or G1+3 (HR, 0.09; 95% CI 0.04-0.21; p < 0.001), G2 (HR, 0.22; 95% CI 0.15-0.31; p < 0.001), and G2+3 (HR, 0.20; 95% CI 0.10-0.42; p < 0.001))., Conclusions: For patients with ALK+ NSCLC, treatments including next-generation ALK-TKIs were independently associated with longer survival outcomes., Competing Interests: Declarations Funding This study was funded by Pfizer (tracking no. 75046155), the Ministry of Health and Welfare (MOHW112-TDU-B-222-124019), and Formatting the Risk Prediction Models for Never-Smoking Lung Cancer (FORMOSA). Conflict of interest Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, Cheng-Hsiang Chu, Sheng-Yi Lin, Sung-Liang Yu, Wen-Chung Lee, Tsang-Wu Liu, and Gee-Chen Chang declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Ethics approval The study was approved by the Institutional Review Board (IRB) of CSMUH, Taiwan (IRB no. CS1-22160). Consent to participate Not applicable. Consent for publication All authors reviewed the manuscript and approved the version for publication. Availability of data and material The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Code availability Not applicable. Author contributions Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, and Gee-Chen Chang contributed to the study conception and design. Material preparation and data collection were performed by Jia-Jun Wu and Chun-Ju Chiang. The analysis of the data was done by Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, and Gee-Chen Chang. The writing of the original draft was performed by Zhe-Rong Zheng, Jia-Jun Wu, Chun-Ju Chiang, Tzu-I Chen, Kun-Chieh Chen, Cheng-Hsiang Chu, Sheng-Yi Lin, Sung-Liang Yu, Wen-Chung Lee, Tsang-Wu Liu, and Gee-Chen Chang. Jia-Jun Wu and Gee-Chen Chang revised the manuscript critically for important intellectual content., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Electroluminochromic (ELC) materials have garnered significant research interest because of their potential applications in lighting, displaying, and sensing. These materials exhibit reversible modulation of photoluminescence under low-voltage stimuli. Here five phosphorescent iridium(III) complexes are reported featuring viologen-substituted 2-phenylpyridine (Vppy) ligands acting as electroactive components. Four of the complexes are bis-cyclometalated and coordinated with either neutral bipyridine derivatives or negatively charged 2-picolinate. The remaining complex is heteroleptic tris-cyclometalated, containing one Vppy and two 2-phenylquinoline ligands. Upon photoexcitation, the bis-cyclometalated complexes exhibit orange to red phosphorescence originating from mixed triplet metal-to-ligand charge transfer ( 3 MLCT) and intraligand ( 3 IL) dπ(Ir)/π(Vppy) → π*(Vppy) state, whereas the tris-cyclometalated complex is non-emissive due to a low Ir(IV/III) oxidation potential favoring oxidative quenching by the viologen pendants. When the cationic viologens are electrochemically reduced to their neutral form, the bis-cyclometalated complexes show a remarkable blue-shift in their phosphorescence maxima due to increased energy levels of the Vppy molecular orbitals. In the case of the tris-cyclometalated complex, reduction of the viologen groups interrupts the quenching process, leading to a luminescence turn-on. These complexes are used to develop ELC devices, which exhibit reversible luminescence response in terms of color or on-off switching under a low voltage of 2 V., (© 2024 Wiley‐VCH GmbH.)

Background: Psoriasis is a chronic inflammatory skin disease that affects a significant proportion of the global population. The involvement of S-adenosine homocysteine hydrolase (AHCY) in psoriasis and its impact on DNA methylation have not been extensively studied., Objective: This study aimed to investigate the role of AHCY and its impact on DNA methylation in psoriasis pathogenesis., Methods: In the present study, we investigated the expression of AHCY in psoriatic lesions and assessed its association with the severity of the disease. Moreover, knockdown experiments were conducted to elucidate the impact of AHCY on psoriatic symptoms, keratinocyte proliferation, and aberrant differentiation. Furthermore, alterations in DNA methylation patterns resulting from AHCY knockdown were analyzed., Results: Our findings revealed that AHCY was upregulated in psoriatic lesions and exhibited a positive correlation with disease severity. Knockdown of AHCY alleviated psoriatic symptoms, inhibited keratinocyte proliferation, and prevented abnormal differentiation. Moreover, AHCY knockdown led to reduced levels of DNA methylation and alterations in methylation patterns. Notably, differential methylation was observed at specific gene loci associated with psoriasis-related inflammation., Conclusion: This study highlights the potential role of AHCY in psoriasis development through its influence on DNA methylation. The findings underscore the complex interaction among AHCY, epigenetic modifications, and inflammation in the pathogenesis of psoriasis. Consequently, AHCY may serve as a promising therapeutic target for psoriasis treatment., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2024 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

The promotion of health and provision of care services for new recruits are issues of constant concern for military leaders and healthcare providers, as they are crucial to maintaining and operating military forces. The enhancement of military personnel's empowerment has been recognized as a core value in promoting health perception. However, the pathways between military personnel's sense of empowerment and health perception have not been thoroughly explored. The primary aim of this study is to examine the predictive power of different dimensions of empowerment (personal, interpersonal, and socio-political) on new recruits' health perception, and to further observe differences among subgroups, which will help us grasp the nuances of future health intervention measures. The research data were extracted from the "Military Career Development Study," analyzing personal empowerment data from Wave 1 (W1) and perceived health data from Wave 2 (W2) (N = 2,232). In terms of analytical methods, five ML classifiers, including Decision Tree, Random Forest, Support Vector Machine, AdaBoost, and k-Nearest Neighbors (KNN) algorithms, were used for prediction in both the full sample and subsamples (gender and socioeconomic status). Results show that among the five ML classifiers, the Decision Tree performed best overall, achieving a prediction accuracy of 95.4%. The results by gender show that the ML models perform best for both males and females with the Decision Tree and Random Forest methods. For the Decision Tree, the accuracy rates were 94.9% for males and 95.1% for females; the F1 scores were 92.9% for males and 93.2% for females. For the Random Forest, the accuracy rates were 94.9% for males and 95.4% for females; the F1 scores were 92.7% for males and 93.2% for females. Regarding SES, the Decision Tree and Random Forest methods performed best. In the SES Low group, both methods achieved a prediction accuracy of 95.6% and an F1 score of 93.7%; in the SES high group, they achieved a prediction accuracy of 95.4% and an F1 score of 93.3%. However, the contribution of different dimensions of empowerment features varied significantly among subgroups. These findings can provide important information on the differences in health perception among military personnel., (© 2024 International Association of Applied Psychology.)

Cysteine (Cys) not only plays an indispensable role in maintaining the redox balance in organisms, but is also an important nutrient in the food industry. Fluorescence-based detection systems have emerged as an effective method to track the locations and concentrations of different species. To achieve efficient monitoring of Cys in both food samples and biological systems, a novel lipid droplet (LD) targeted fluorescent probe (namely NIT-Cys) was constructed for the turn-on detection of Cys, characterized by a large Stokes shift (142 nm), a short response time (<8 min), and a low Cys detection limit (39 nM). Furthermore, the NIT-Cys probe has been successfully used not only to quantify the amounts of Cys in selected food samples, but also to enable the visualization of endogenous Cys in acetaminophen (APAP)-induced drug-induced liver injury cells, zebrafish larvae and mice models. Consequently, the work presented here provides an efficient tool for monitoring Cys., 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.)

Ultrasensitive analysis of organic molecules is crucial for various fundamental research and applications. State-of-the-art techniques for this purpose can achieve detection limits of several hundred ppq (parts-per-quadrillion), while a higher sensitivity is pursued constantly. To achieve this goal, we develop femtosecond laser assisted chemical ionization for mass spectrometry. This technique combines the advantages of femtosecond laser ionization and chemical ionization, either of which enables subppt (parts-per-trillion) mass spectrometry analysis of organic molecules. The results demonstrate that the developed ionization technique, when employed in mass spectrometry, can surpass femtosecond laser ionization by more than 3 orders of magnitude in sensitivity, while still maintaining good versatility and the ability to work under ambient conditions. This work paves the way for subppq analysis of organic molecules in gas phase and even in ambient environments, which can open up new research fields for trace substance analysis in atmospheric environment, clinical diagnosis, biomedical studies, etc.

Janus transition metal dichalcogenides (TMDs) are a novel class of 2D materials with unique mirror asymmetry. Plasma-assisted synthesis at room temperature is favored for producing Janus TMDs due to its energy efficiency and prevention of alloying. However, current methods require stringent control over growth conditions, risking defects or unintended materials. A robust plasma-assisted (RPA) synthesis strategy is introduced, incorporating a built-in tube with a suitable inner diameter into the plasma-assisted system. This innovation creates a mild, uniform plasma atmosphere, allowing for broader variations in growth parameters without significantly affecting Janus MoSSe's morphology and characteristics. This approach simplifies the synthesis process and enhances the success rate of Janus TMD production. Additionally, methods are explored to enhance the photoluminescence (PL) of Janus MoSSe. Releasing MoSSe from the growth substrate and annealing it removes strain and unintentional doping, improving PL performance. MoSSe on hexagonal boron nitride (h-BN) flakes after annealing shows a 32-fold increase in PL intensity. Bis(trifluoromethane) sulfonimide (TFSI) treatment of MoSSe results in a remarkable 70-fold increase in PL intensity, a 2.5-fold extension in exciton lifetime, and quantum yield (QY) reaching up to ≈31.2%. These findings provide critical insights for optimizing the luminescence properties of 2D Janus materials, advancing Janus optoelectronics., (© 2024 Wiley‐VCH GmbH.)

The intermitochondrial cement (IMC) is a prominent germ granule that locates among clustered mitochondria in mammalian germ cells. Serving as a key platform for Piwi-interacting RNA (piRNA) biogenesis; however, how the IMC assembles among mitochondria remains elusive. Here, we identify that Tudor domain-containing 1 (TDRD1) triggers IMC assembly via phase separation. TDRD1 phase separation is driven by the cooperation of its tetramerized coiled-coil domain and dimethylarginine-binding Tudor domains but is independent of its intrinsically disordered region. TDRD1 is recruited to mitochondria by MILI and sequentially enhances mitochondrial clustering and triggers IMC assembly via phase separation to promote piRNA processing. TDRD1 phase separation deficiency in mice disrupts IMC assembly and piRNA biogenesis, leading to transposon de-repression and spermatogenic arrest. Moreover, TDRD1 phase separation is conserved in vertebrates but not in invertebrates. Collectively, our findings demonstrate a role of phase separation in germ granule formation and establish a link between membrane-bound organelles and membrane-less organelles., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fluoride (F) pollution in soils, which can be caused by long-term application of phosphate fertilizers, has serious socio-economic and ecological impacts. Therefore, it is important to find economically viable and environmentally friendly remediation technologies that mitigating the potential hazards of F-contaminated soil while maintaining crop yields. In this study, a soil incubation experiment was carried out to investigate the effects of two different organic manures at various amounts on soil F content and soil properties. We demonstrated that organic manure application at a rate of 5% was optimal to control the content of available fluoride (AE-F) in soil. Organic manure decreased the AE-F content and increased the residual or organically bound content. Furthermore, organic manure application also increased the contents of carbohydrates, proteins, and amides, which can anchor AE-F to the dissolved organic matter (DOM) in soil through physicochemical reactions, thereby reducing the migration of F. Moreover, after organic manure application, complex humus compounds were formed through microbial action, thus reducing the bioavailability of soil F. In summary, the application of organic manures can reduce the accumulation of soil AE-F, thereby reducing the absorption of F by crops in F-contaminated soil and alleviating the potential risk of F contamination., 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.)

Background: Bevacizumab is extensively used in the treatment of advanced non-small-cell lung cancer (NSCLC). Numerous clinical trials have proven the clinical efficacies of bevacizumab biosimilars (BB)., Objective: Our study aimed to compare the clinical outcomes between bevacizumab reference product (RP) and BB among advanced NSCLC patients in a real-world setting., Design: We retrospectively analyzed stage IV metastatic NSCLC patients who were treated with bevacizumab as part of a combination therapy. Patients were categorized into chemotherapy (CT) and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) groups. We compared the patients' characteristics, treatment efficacy, and adverse events between RP and BB in the two treatment groups., Methods: From January 2020 to July 2022, a total of 171 patients who underwent combination therapy with bevacizumab were screened. Seventy-nine of these patients met the study's inclusion criteria and were enrolled in the final analysis. We utilized the Kaplan-Meier method to estimate progression-free survival (PFS) and the log-rank test to compare PFS between groups. The Cox proportional hazards model was used to identify predictors of PFS., Results: Within the CT cohort, 34 patients were treated with RP in combination with platinum and pemetrexed, and 25 patients received a combination regimen with BB. The median PFS was 6.9 months in the RP group and 8.9 months in the BB group ( p  = 0.255). Within the EGFR-TKI cohort, 20 patients with EGFR -mutant NSCLC received first-line treatment with EGFR-TKI plus bevacizumab. Of these patients, 9 were treated with a combination regimen that included RP, and 11 patients received EGFR-TKI in combination with BB. The median PFS was 18.4 months for the RP group and 13.6 months for the BB group ( p  = 0.363)., Conclusion: In our advanced NSCLC patients, we found no difference in clinical outcomes when receiving treatment with RP or BB. Given a combination regimen, BB was as effective as RP together with either CT or EGFR-TKIs., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Heavy metal pollution in soil and groundwater is difficult to detect in time because of its long-term accumulation. This poses a severe hazard to the ecosystem security in polluted areas. Considering the Tongyang River Basin of the Chaohu Lake water system as the research object, various pollution evaluation methods, Geographic Information System (GIS) source analysis models, adsorption and desorption experiments, and mathematical models were used. Based on the data of the heavy metal content in the soil and river sediments in the study area, regional heavy metal pollution evaluation, spatial distribution characteristics, source identification, and lake loss analysis were conducted to evaluate the current situation of environmental pollution, pollution sources, and migration and transformation of heavy metals in the basin. The results show that the heavy metals in the soil of the basin are mainly distributed from the southwest to the northeast and the island distribution to the east of Tongyang Town. The Cd, Cu, Zn, and Pb concentrations are higher in the sediment than in the soil. The Unmix analytical model was established. The natural source of heavy metals in the Tongyang River Basin and the composite pollution source of traffic-production and life showed a high correlation. According to the one-dimensional steady-state model, the concentrations of the heavy metals are in the following descending order: Zn, Cr, Pb, Cu, Ni, and Cd. The amounts of these elements entering the lake annually are 1993.04, 1028.1, 372.47, 301.72, 308.80, and 19.46 kg, respectively (a total of 4023.6 kg)., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The NOD2 signaling pathway, which plays an important role in the mechanisms of inflammatory bowel disease (IBD) development, has been closely associated with ubiquitination. It was revealed in this study that NOD2 receptor activation could obviously affect the expression of 19 ubiquitination-related genes, with N4BP3 being the most prominently expressed and upregulated. In addition, N4BP3 knockdown was found to reduce the mRNA levels of MDP-induced inflammatory factors, while N4BP3 overexpression elevated their mRNA levels as well as the levels of phospho-ERK1/2, phospho-JNK, phospho-P38 and phospho-NF-κB P65 proteins. Immunoprecipitation tests showed that N4BP3 could pull down RIPK2 and promote its K63-linked ubiquitination. In human tissue specimen assays and mouse experiments, we found that the expression of N4BP3 was significantly elevated in Crohn's disease (CD) patients and IBD mice, and N4BP3 knockdown reduced the dextran sulfate sodium-induced pathological score and the expression of inflammatory factors in the mouse colon tissue. In conclusion, N4BP3 is able to interact with RIPK2 and promote its K63-linked ubiquitination, to further promote the NOD2-MAPK/NF-κB pathway, thereby increasing promoting the release of inflammation factors and the degree of IBD inflammation., (© 2024. The Author(s).)

Cultivated strawberry (Fragaria × ananassa) is a popular, economically important fruit. The ripening of the receptacle (pseudocarp), the main edible part, depends on endogenously produced abscisic acid (ABA) and is suppressed by the high level of auxin produced from achenes (true fruit) during early development. However, the mechanism whereby auxin regulates receptacle ripening through inhibiting ABA biosynthesis remains unclear. Here, we identified AUXIN RESPONSE FACTOR 2 (FaARF2), which showed decreased expression with reduced auxin content in the receptacle, leading to increased ABA levels and accelerated ripening. Dual-luciferase, yeast one-hybrid, and electrophoretic mobility shift assays demonstrated that FaARF2 could bind to the AuxRE element in the promoter of 9-CIS-EPOXYCAROT-ENOID DIOXYGENASE 1 (FaNCED1), a key ABA biosynthetic gene, to suppress its transcriptional activity. Transiently overexpressing FaARF2 in the receptacles decreased FaNCED1 expression and ABA levels, resulting in inhibition of receptacle ripening and of development of quality attributes, such as pigmentation, aroma, and sweetness. This inhibition caused by overexpressing FaARF2 was partially recovered by the injection of exogenous ABA; conversely, transient silencing of FaARF2 using RNA interference produced the opposite results. The negative targeting of FaNCED1 by FaARF2 is a key link between auxin-ABA interactions and regulation of strawberry ripening., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: Fine particulate matter (PM 2.5 ) is a recognized risk factor for respiratory and cardiovascular diseases, but the association between PM 2.5 and rheumatoid arthritis (RA) is still controversial. Additionally, evidence on the relationship of green space with RA is scarce. This study aimed to investigate the separate and combined associations of PM 2.5 and green space with risk of RA., Methods: Our study involved 30,684 participants from the Yinzhou cohort in Ningbo, China. PM 2.5 concentrations were determined using a land-use regression model. Residential green space was assessed using the Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) from satellite images. We employed the Cox proportional hazard model to evaluate the relationships of PM 2.5 and green space with RA., Results: During the 176,894 person-years of follow-up period, 354 cases of RA were identified. Hazard ratio (HR) and the corresponding 95% confidence interval (95% CI) for every interquartile range (IQR) increase in PM 2.5 were 1.23 (95% CI: 1.02, 1.49). Compared with lower exposure to residential green space, individuals living in areas with more green space had a decreased risk of RA (HR was 0.80 (95% CI: 0.70, 0.92), 0.80 (95% CI: 0.70, 0.92), and 0.79 (95% CI: 0.70, 0.89) for 250m, 500m, and 1000m NDVI buffers, respectively). Similar results were observed for the association between EVI and RA. Furthermore, a significant multiplicative interaction was observed between PM 2.5 and green space (NDVI 250m and EVI 250m). No mediating effect of PM 2.5 on the relationship between green space and RA was observed., Conclusion: Our findings indicated that living in areas with higher green space was linked to a reduced risk of RA, whereas living in areas with higher PM 2.5 was associated with an increased risk of RA. The beneficial effect of high green space may be offset by exposure to PM 2.5 ., Competing Interests: Declaration of Competing Interest ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Inc.)

The development of novel antibacterial agents from plant sources is emerging as a successful strategy to combat antibiotic resistance in pathogens. In this study, we systemically investigated the antibacterial activity and underlying mechanisms of baicalin against methicillin-resistant Staphylococcus aureus (MRSA) and Stenotrophomonas maltophilia . Our results showed that baicalin effectively restrained bacterial proliferation, compromised the integrity of cellular membranes, increased membrane permeability, and triggered oxidative stress within bacteria. Transcriptome profiling revealed that baicalin disrupted numerous biological pathways related to antibiotic resistance, biofilm formation, cellular membrane permeability, bacterial virulence, and so on. Furthermore, baicalin demonstrated a synergistic antibacterial effect when combined with ampicillin against both MRSA and S . maltophilia . In conclusion, baicalin proves to be a potent antibacterial agent with significant potential for addressing the challenge of antibiotic resistance in pathogens.

Background: Actinic keratoses (AK) may progress into squamous cell carcinoma. Many combination therapies were used to improve the clearance rate. However, there are limited studies on the efficacy and safety of lesion-directed Liquid nitrogen cryotherapy combined with field-directed photodynamic therapy (PDT)., Objective: This study is aimed to determine the efficacy and safety of Liquid nitrogen cryotherapy combined with PDT in Chinese patients with actinic keratosis., Methods: A total of 61 patients with AK were selected at the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College between August 2018 and August 2023. They were randomly divided into PDT plus Liquid nitrogen cryotherapy group (LN-PDT) and control PDT group (C-PDT) with 30 patients and 31 patients, respectively. 27 patients in the LN-PDT group and 28 patients in the C-PDT group completed the clinical sessions. Efficacy, adverse effects, and cosmetic outcomes were recorded and compared between the two groups., Results: 3 months after the final treatment, the clearance rates for total AK lesions were 97.4 % (449/461) in the LN-PDT group and 93.4 % (456/488) in the C-PDT group (P < 0.05). For grade I AK lesions, the clearance rates were 99.2 % (234/237) for the LN-PDT group and 98.3 % (237/241) for the C-PDT group (P >0.05). For grade II lesions, the clearance rates were 97.5 % (156/160) for the LN-PDT group and 91.9 % (172/186) for the CPDT group (P < 0.05). For grade III lesions, the clearance rates of the LN-PDT and C-PDT groups were 87.5 % (58/64) and 78.7 % (47/61), respectively (P < 0.05). The two groups had no significant differences in pain, erythema, edema, hyperpigmentation and scarring. Cosmetic outcomes mainly were excellent or good in both groups with no significant difference., Conclusion: Liquid nitrogen cryotherapy combined with PDT showed higher efficacy on grade II and grade III AK lesions than PDT alone. The two groups have similar adverse effects and cosmetic outcomes., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Although there is enough pooled evidence supporting the positive association between family history of colorectal cancer (CRC) in first-degree relatives (FDRs) and the risk of CRC, synthesized data on its association with the risk of other colorectal neoplasia are lacking. Therefore, we aimed to systematically assess this issue., Methods: We searched PubMed, Web of Science, and Embase from database inception through May 9, 2024, to identify observational studies investigating the association between family history of CRC in FDRs and the risk of colorectal neoplasia (excepting CRC). Adenoma, nonadvanced adenoma (NAA), advanced adenoma (AA), and advanced neoplasia (AN) were further chosen as main outcomes because of data availability. Random-effects model was used for data synthesis. Subgroup meta-analyses were performed to evaluate the robustness of results., Results: Of 5,172 initial records screened, 75 studies (with 931,515 participants) were identified for analysis. Family history of CRC in FDRs was associated with increased risk of adenoma (pooled odds ratio [OR] 1.67, 95% confidence interval [CI] 1.46-1.91), NAA (pooled OR 1.35, 95% CI 1.21-1.51), AA (pooled OR 1.66, 95% CI 1.46-1.88), and AN (pooled OR 1.58, 95% CI 1.44-1.73). The positive associations persisted in all examined subgroups. The risk of adenoma (pooled OR 4.18, 95% CI 1.76-9.91), AA (pooled OR 2.42, 95% CI 1.72-3.40), and AN (pooled OR 2.00, 95% CI 1.68-2.38) was more evident among individuals with 2 or more affected FDRs., Discussion: Family history of CRC is associated with increased risk of adenoma, NAA, AA, and AN totally, and in all available subgroups. The findings further strengthen the necessity and importance of an intensified screening strategy for individuals with a positive family history of CRC, which is very useful for related health resource allocation and policymaking., (Copyright © 2024 by The American College of Gastroenterology.)

Using LC-MS/MS analysis we previously showed for the first time (Carcinogenesis 43:746-753, 2022) that levels of DNA damage-induced by benzo[a]pyrene (B[a]P), an oral carcinogen and tobacco smoke (TS) constituent, were significantly higher in buccal cells of smokers than those in non-smokers; these results suggest the potential contribution of B[a]P in the development of oral squamous cell carcinoma (OSCC) in humans. Treating cancers, including OSCC at late stages even with improved targeted therapies, continues to be a major challenge. Thus interception/prevention remains a preferable approach for OSCC management and control. In previous preclinical studies we and others demonstrated the protective effects of black raspberry (BRB) against carcinogen-induced DNA damage and OSCC. Thus, to translate preclinical findings we tested the hypothesis, in a Phase 0 clinical study, that BRB administration reduces DNA damage induced by B[a]P in buccal cells of smokers. After enrolling 27 smokers, baseline buccal cells were collected before the administration of BRB lozenges (5/day for 8 weeks, 1 gm BRB powder/lozenge) at baseline, at the middle and the end of BRB administration. The last samples were collected at four weeks after BRB cessation (washout period). B[a]P-induced DNA damage (BPDE-N2-dG) was evaluated by LC-MS/MS. BRB administration resulted in a significant reduction in DNA damage: 26.3% at the midpoint (p = 0.01506) compared to baseline, 36.1% at the end of BRB administration (p = 0.00355), and 16.6% after BRB cessation (p = 0.007586). Our results suggest the potential benefits of BRB as a chemopreventive agent against the development of TS-initiated OSCC., (© The Author(s) 2024. Published by Oxford University Press. 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.)

Renal cell carcinoma (RCC) is the most common malignant tumor in the urinary system, accounting for 80 % to 90 % for all renal malignancies. Traditional diagnostic methods like magnetic resonance imaging (MRI) and computed tomography (CT) lack the sensitivity and specificity as they lack specific biomarkers. These limitations impede effective monitoring of tumor recurrence. This study aims to employ Attenuated Total Reflection (ATR)-Fourier transform infrared (FTIR) spectroscopy, an optical technology sensitive to molecular groups, to analyze the potential optical biomarkers in urine and plasma samples from RCC patients pre- and post-surgery. The results reveal distinctive spectral information from both plasma and urine samples. Post-surgery urine spectra exhibit complexity compared to plasma, showing reduced content at 1072 cm -1 , 1347 cm -1 and 1654 cm -1 bands, while increased content at 1112 cm -1 , 1143 cm -1 , 1447 cm -1 , 3334 cm -1 and 3420 cm -1 bands. Utilizing machine learning models such as eXtreme Gradient Boosting (XGBoost), support vector machine (SVM), partial least squares (PLS), and artificial neural network (ANN), the study evaluated plasma and urine samples pre- and post-surgery. Remarkably, the XGBoost method excelled in distinguishing between tumor conditions and recovery, achieving an impressive AUC value of 0.99. These results underscore the potential of ATR-FTIR technology in identifying RCC optical biomarkers, with XGBoost showing promise as a valuable screening tool for RCC recurrence diagnosis., 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.)

Thimerosal (THI) has become a significant source of organic mercury pollutants in aquatic ecosystems, but there is limited information regarding its adverse effects on fish. In this study, zebrafish embryos were exposed to THI at 0 (control), 5.0, and 50 ng/L from 0-5 days post fertilization (dpf), and variations in their survival, development, behavior, free amino acid contents, and the biochemical responses involved in monoaminergic systems were examined. Although THI exposure did not significantly affect the survival, heart rate, or hatching time of zebrafish embryos, it substantially increased swimming velocity (136-154 % of the control) and reduced exploratory behavior (141-142 % of the control) in zebrafish larvae at 5 dpf. Exposure also significantly altered the amino acid contents (51-209 % of the control) and monoamine levels (70-154 % of the control) in zebrafish larvae, some of which displayed significant correlations with behavioral traits. THI significantly elevated dopamine receptor gene expression and monoamine oxidase activity in zebrafish larvae. Adding extra phenylalanine or tryptophan to the E3 medium facilitates the recovery of zebrafish larvae from the abnormal behaviors induced by THI. These findings reveal for the first time that THI exposure at the level of ng/L is sufficient to induce neurobehavioral toxic effects in the early life stages of zebrafish, and disrupting amino acid homeostasis is a critical underlying mechanism. This study provides valuable insights into the toxicity of THI to fish and highlights the importance of assessing its potential risks to aquatic ecosystems., 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: This retrospective study aimed to evaluate the short-term recovery and cost-effectiveness of bilateral unicompartmental knee arthroplasty (UKA) compared to staged unilateral UKA. The study analyzed postoperative pain scores, medical costs, and complications in patients with knee osteoarthritis who underwent these procedures., Methods: A total of 226 patients who received either unilateral UKA (Group A, n  = 170) or bilateral UKA (Group B, n  = 56) using the mobile-bearing UKA were included in the study. Patient demographics, surgical details, postoperative pain scores, knee range of motion, length of hospital stay, self-controlled analgesic use, total medical costs, and complications were retrospectively collected from medical records., Results: The demographic characteristics were comparable between the groups. Group B had a longer surgical time and higher medical costs than Group A. However, there were no significant differences in hospital stay, pain scores, or knee range of motion between the two groups. Complications were infrequent and not significantly different. Insert dislocation and loosening were the most common complications. Patient-controlled analgesia effectively reduced pain scores in Group A but not in Group B., Conclusion: Bilateral UKA does not significantly affect hospital stay, postoperative pain, or complications compared to unilateral UKA. Although bilateral UKA requires longer surgical time and incurs higher costs, it offers the potential benefit of reducing anesthesia-related complications and overall health insurance expenditures. This study recommends bilateral UKA as a suitable option for patients with bilateral knee osteoarthritis, given its comparable short-term outcomes and potential cost-saving advantages., Level of Evidence: III., 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., (© 2024 Tu, Shih, Wang and Chen.)

Impact-protective materials are gaining importance because of the widespread occurrence of impact damage. Hydrogels have emerged as promising candidates owing to their lightweight and flexible nature. However, achieving soft impact-resistant hydrogels with exceptional stiffness, strength, and toughness remains a challenge. Inspired by the Bouligand structure found in the smasher dactyl club of stomatopods, we propose a straightforward multiscale hierarchical structural design strategy. This strategy integrates self-assembly and salting-out techniques to enhance the impact resistance of soft hydrogels. Rigid cellulose nanocrystals (CNCs) self-assemble into Bouligand-like structures within soft poly(vinyl alcohol) (PVA) matrix via supramolecular interactions. This rational structural design combines the CNC Bouligand structure with a cross-linked network of soft PVA crystalline domains, resulting in a composite hydrogel with impressive mechanical properties: high tensile fracture strength (30.2 MPa), elastic modulus (62.7 MPa), and fracture energy (75.6 kJ m -2 ), surpassing those of other tough hydrogels. Moreover, the multiscale hierarchical structure facilitates various energy dissipation mechanisms, including crack twisting, tortuous crack paths, and PVA chain orientation, resulting in notable force attenuation (80.4%) in the composite hydrogel. This biomimetic design strategy opens new avenues for developing soft and lightweight impact-resistant materials.

Diazepam (DZP) is a universally detected emerging pollutant in aquatic ecosystems. Although the sex-dependent effects of DZP on fish have been properly established, the underlying mechanisms remain unclear. In this study, zebrafish of both sexes were separately exposed to DZP (8 μg/L) for 21 days, and the alteration of the behaviors, brain amino acid neurotransmitter contents, and transcriptomic profiles were investigated. Although DZP exposure showed a sedative effect on both sexes, significantly reduced cumulative duration of high mobility and willingness to encounter the opposite sex were only observed in females. However, DZP significantly enhanced the brain levels of glutamate and glutamine in males but not in females. Transcriptome analysis identified more different expression genes (DEGs) in females (322 up-regulated and 311 down-regulated) than in males (138 up-regulated genes and 38 down-regulated). The DEGs in both sexes were significantly enriched in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway of the synaptic vesicle cycle, indicating a possible pathway for the sedative effects of DZP on zebrafish. DZP exhibited different or even opposing regulatory patterns on gene expression in the brains of females and males, providing some insights into its sex-dependent impacts on the behaviors and brain neurotransmitter contents in zebrafish. Moreover, enrichment analysis also suggested that DZP exposure may affect the oocyte maturation in female zebrafish, which highlights the need to study its reproductive and transgenerational toxicity to fish species., 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.)

Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2) has been related to transcriptional inhibition and chromatin compaction. Nevertheless, the biological functions and mechanisms of L3MBTL2 are undefined in breast cancer (BRCA). Here, we revealed that L3MBTL2 is responsible for the decline of Nischarin (NISCH), a well-known tumor suppressor, in BRCA, and explored the detailed mechanism. Knockdown of L3MBTL2 reduced monoubiquitination of histone H2A at lysine-119 (H2AK119ub), leading to reduced binding to the NISCH promoter and increased expression of NISCH. Meanwhile, the knockdown of L3MBTL2 decreased proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of BRCA cells, and increased apoptosis, which were abated by NISCH knockdown. Nucleolar transcription factor 1 (UBTF) induced the transcription of L3MBTL2 in BRCA, and the suppressing effects of UBTF silencing on EMT in BRCA cells were also reversed by NISCH knockdown. Knockdown of UBTF slowed tumor progression and attenuated lung tumor infiltration, whereas simultaneous knockdown of NISCH accelerated EMT and increased tumor lung metastasis. Taken together, our results show that L3MBTL2, transcriptionally activated by UBTF, exerts oncogenic functions in BRCA, by catalyzing H2AK119Ub and reducing expression of NISCH., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Self-assembled graphene films at air-liquid interface have great potential for multiple applications. However, the large size and ultrathin thickness for graphene-based films are hardly achieved simultaneously because of poor assembly ability of graphene oxide (GO) and cautious film transfer process (FTP). Herein, the ethanol-based binary solution with supramolecular clusters and weak polarity is introduced to enhance the assembly performance of GO. In this regime, GO film is formed within 52 s, and its formation temperature can be as low as -20 °C. More importantly, the attractive force between the formed GO film and this binary solution is 62% lower than that between GO film and traditional aqueous solution. On this basis, for the first time a spontaneous separation of the self-assembled GO film from solution is reported, and the air‒floating graphene films (AGFs) with nanoscale thickness and centimeter-scale diameter are prepared without FTP. By means of this separation behavior, the in situ growth AGFs sensors are fabricated, and they express fast response and ultrahigh sensitivity to imperceptible change in temperature and disturbances that are hardly recognized by common sensors. Therefore, a new accessible strategy is demonstrated to prepare ultrathin graphene macrofilms, which can be the excellent candidates for multifunctional, ultrasensitive sensors., (© 2024 Wiley‐VCH GmbH.)

Oleanolic acid is an active ingredient from natural products with anti-breast cancer activity. However, the poor solubility in water and low bioavailability have limited its effectiveness in clinic. To improve the anticancer activity of oleanolic acid, we synthesized a novel oleanolic quaternary ammonium (QDT), which, driven by electrostatic interactions, was introduced into heparin and coated with chitosan to obtain a QDT/heparin/chitosan nanoaggregate (QDT/HEP/CS NAs). QDT/HEP/CS NAs showed the negative zeta potential (-35.01 ± 4.38 mV), suitable mean particle size (150.45 ± 0.68 nm) with strip shape, and high drug loading (36 %). The coated chitosan had strong anti-leakage characteristics toward QDT under physiological conditions. More importantly, upon sustained release in tumor cells, QDT could significantly decrease the mitochondrial membrane potential and induce apoptosis of breast cancer cells. Further in vivo antitumor study on 4 T1 tumor-bearing mice confirmed the enhanced anticancer efficacy of QDT/HEP/CS NAs via upregulation of caspase-3, caspase-9 and cytochrome C, which was attributed to the high accumulation in tumor via the enhanced permeability and retention effect. Moreover, QDT/HEP/CS NAs significantly enhanced the biosafety and biocompatibility of QDT in vitro and in vivo. Collectively, the development of QDT/HEP/CS NAs with high antitumor activity, favorable biodistribution and good biocompatibility provided a safe, facile and promising strategy to improve the anti-cancer effect of traditional Chinese medicine ingredients., 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.)

Actuators based on shape memory polymers and composites incorporating nanomaterial additives have been extensively studied; achieving both high output stress and precise shape change by low-cost, scalable methods is a long-term-desired yet challenging task. Here, conventional polymers (polyurea) and carbon nanotube (CNT) fillers are combined to fabricate reinforced composite fibers with exceptional actuation performance, by a wet-spinning method amenable for continuous production. It is found that a thermal-induced shrinkage step could obtain densified strong fibers, and the presence of CNTs effectively promotes the tensile orientation of polymer molecular chains, leading to much improved mechanical properties. Consequently, the CNT/ polyurea composite fibers exhibit stresses as high as 33 MPa within 0.36 s during thermal actuation, and stresses up to 22 MPa upon electrical stimulation enabled by the built-in conductive CNT networks. Utilizing the flexible thin fibers, various shape change behavior are also demonstrated including the conversion between different structures/curvatures, and recovery of predefined simple patterns. This high-performance composite fibers, capable of both thermal and electrical actuation and produced by low-cost materials and fabrication process, may find many potential applications in wearable devices, robotics, and biomedical areas., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Background/Objectives : Various surgical approaches have been proposed for treating adjacent segment disease (ASD) after lumbar fusion. However, studies using oblique lumbar interbody fusion (OLIF) to treat ASD are lacking. The current study assessed the postoperative outcomes of single-level OLIF for ASD, comparing the results with those for patients undergoing transforaminal lumbar interbody fusion (TLIF). Methods : Patients who underwent single-level OLIF or TLIF for lumbar ASD were retrospectively included. Clinical outcomes, that is, the results of assessments using the Euroqol 5-Dimension quality of life scale (EQ-5D), the Oswestry Disability Index, and the visual analog scale, were evaluated. Radiologic parameters, including disc height (DH), segmental lordosis (SL), segmental coronal angle (SCA), lumbar lordosis, and pelvic incidence-lumbar lordosis mismatch, were also assessed. Results : A total of 65 patients were enrolled: 32 in the OLIF group and 33 in the TLIF group. The median follow-up time was 24.0 months in both groups. The clinical outcomes and radiologic parameters significantly improved in both groups postoperatively. According to intergroup comparisons, the OLIF group had significantly less blood loss and superior improvement in radiologic parameters (DH, SL, and SCA) whereas the TLIF group had significantly shorter operation times. For the OLIF patients who did not undergo posterior decompression, the operation time was similar to that of the TLIF group, but the surgical blood loss and length of hospital stay were significantly reduced compared with the TLIF group. Conclusions : Compared with TLIF, OLIF provides similar clinical outcomes, leads to less surgical blood loss, and has superior radiologic parameters; however, the operation time is significantly longer. OLIF without posterior decompression may be a superior option to TLIF for certain patients.

Backgrounds: Glioma stands as one of the most formidable brain tumor types, with patient outcomes remaining bleak even in the face of advancements in treatment modalities. FBXW4, a constituent of the F-box and WD repeat domain-containing protein family, is recognized for its participation in diverse cellular activities, including those related to tumor dynamics. Yet, the therapeutic relevance and specific role of FBXW4 in the context of glioma are not well defined. This study aims to elucidate the functional dynamics and significance of FBXW4 in glioma cases., Methods: This research undertook a comprehensive analysis of FBXW4's expression patterns and clinical relevance in glioma by harnessing data from the TCGA and GTEx databases., Results: The investigation revealed a distinct downregulation of FBXW4 in glioma tissues compared to normal brain counterparts, with a pronounced correlation between FBXW4 levels and disease severity. Intriguingly, FBXW4 expression inversely related to WHO tumor grades, with the most advanced grade IV gliomas exhibiting the lowest FBXW4 levels, whereas grade II tumors demonstrated the highest. Cases presenting with IDH1/2 mutations or 1p/19q codeletions were also associated with elevated FBXW4 levels. Furthermore, diminished FBXW4 expression aligned with an increased risk of mortality., Conclusions: The findings suggest that FBXW4 holds promise as a prognostic marker and a potential therapeutic avenue in glioma management. Nonetheless, future research is imperative to decode the intricate signaling pathways involving FBXW4 and to understand its broader clinical ramifications in glioma treatment paradigms., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2024 Kun Chen et al.)

Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system and is characterized by abnormal hypersensitivity to stimuli and nociceptive responses to non-noxious stimuli, affecting approximately 7-10% of the general population. However, current first-line drugs like non-steroidal anti-inflammatory agents and opioids have limitations, including dose-limiting side effects, dependence, and tolerability issues. Therefore, developing new interventions for the management of NP is urgent. In this study, we discovered that the high-frequency terahertz stimulation (HFTS) at approximately 36 THz effectively alleviates NP symptoms in mice with spared nerve injury. Computational simulation suggests that the frequency resonates with the carbonyl group in the filter region of Kv1.2 channels, facilitating the translocation of potassium ions. In vivo and in vitro results demonstrate that HFTS reduces the excitability of pyramidal neurons in the anterior cingulate cortex likely through enhancing the voltage-gated K + and also the leak K + conductance. This research presents a novel optical intervention strategy with terahertz waves for the treatment of NP and holds promising applications in other nervous system diseases., Competing Interests: WP, PW, CT, HZ, KC, HS, YT, AL, ZZ, YY, KW, CC, YW, TC No competing interests declared, (© 2024, Peng, Wang, Tan et al.)

Background: Air pollution and outdoor light at night (LAN) have been reported to be related to type 2 diabetes (T2D). However, their interaction with risk of T2D remains uncertain. Therefore, our study aimed to explore the relationship between outdoor LAN, air pollution and incident T2D., Methods: Our study included a cohort of 24,147 subjects recruited from 2015 to 2018 in Ningbo, China. Land use regression models were used to evaluate particulate matter with a diameter ≤2.5 μm (PM 2.5 ), ≤10 μm (PM 10 ) and nitrogen dioxide (NO 2 ). Satellite images data with a spatial resolution of 500m was used to estimate outdoor LAN levels. T2D new cases were identified by medical records based on health information system. Cox proportional hazards models were used to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs). Moreover, we investigated the multiplicative and additive interactions between air pollution and outdoor LAN., Results: During 108,908 person-years of follow-up period, 1016 T2D incident cases were identified. The HRs (95% CIs) were 1.22 (1.15, 1.30) for outdoor LAN, 1.20 (1.00, 1.45) for PM 2.5 , 1.23 (1.11, 1.35) for PM 10 and 1.19 (1.04, 1.37) for NO 2 in every interquartile range increase, respectively. Furthermore, significant interactions were observed between outdoor LAN and NO 2 ., Conclusions: Our findings indicated that air pollution and outdoor LAN were positively associated with T2D. Moreover, we observed an interaction between outdoor LAN and NO 2 suggesting that stronger associations for outdoor LAN and T2D in areas with higher levels of NO 2 , and for NO 2 and T2D in areas with higher levels of outdoor LAN., 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.)

Case: A 22-year-old man with habitual dislocation of the patella (HDP), characterized by lateral dislocation in flexion with spontaneous relocation with extension, presented with right knee pain and inability to actively extend. Imaging revealed lateral patellar dislocation, flat articular surface of the patella, and trochlear dysplasia. His symptoms persisted despite physical therapy. A 4-directional patellar stabilization surgery, incorporating lateral release, medial tibial tuberosity osteotomy, quadriceps muscle lengthening, and medial patellofemoral ligament reconstruction, was performed, with significant improvement in pain and function postoperatively., Conclusion: The procedure could be feasible in cases of severe HDP when conservative measures failed to relieve the patient's symptoms., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/C436)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

Polymethyl methacrylate (PMMA) based biomaterials have been widely utilized in clinics. However, currently, PMMA catalyzed by benzoyl peroxide (BPO) exhibits disquieting disadvantages including an exothermic polymerization reaction and a lack of bioactivity. Here, we first designed three industrial-scale synthesis methods for high-purity butoxydibutylborane (BODBB), achieving purity levels greater than 95% (maximum: 97.6%) and ensuring excellent fire safety. By utilizing BODBB as a catalyst, the highest polymerization temperature of PMMA bone cement (PMMA-BODBB) reached only 36.05 °C, ensuring that no thermal damage occurred after implantation. Compared to PMMA catalyzed by BPO and partially oxidized tributylborane (TBBO, catalyst of Super Bond C&B), PMMA-BODBB exhibited superior cell adhesion, proliferation, and osteogenesis, attributed to the reduced release of free radicals and toxic monomer, and moderate bioactive boron release. After injection into a 5 mm defect in the rat cranial bone, PMMA-BODBB demonstrated the highest level of osteointegration. This work not only presents an industrial-scale synthesis of high-purity BODBB, but also offers an innovative PMMA biomaterial system with intrinsic biocompatibility and osseointegration, paving the way for the next generation of PMMA-based biomaterials with broader applications.

Background: Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death., Methods: Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank., Results: After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant., Conclusions: The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field., 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 Zhang, Shi, Li, Huang, Chen and Yao.)