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Background: Failure to rescue (FTR) is mortality after at least 1 postoperative complication. We investigated the impact of nighttime intensivist staffing and FTR after cardiac surgery., Methods: We included patients who underwent cardiac surgery to examine FTR, defined as mortality in those who experienced a Society of Thoracic Surgeons-defined major complication. Era 2 (July 2021-June 2023) and era 1 (July 2016-June 2021) were characterized by the presence and absence of nighttime intensivists staffing, respectively. Complications and FTR rates, daily intensive care unit (ICU) census, and relative value units (RVUs) were compared., Results: Among 5654 patients, 17% (284 of 1661) in era 2 had at least 1 complication vs 19% (769 of 3993) in era 1 (P = .057). Among patients with complications, FTR incidence was 8% (22 of 284) in era 2 vs 19% (145 of 769) in era 1 (P < .001). The daily average ICU census did not change (12.3 in era 2 vs 12.0 in era 1, P = .386). Comparing mean annual RVUs during the 2 fiscal years in era 2 (35,613 per year) with what would have been expected based on the last 2 fiscal years of era 1 (26,744 per year), a significant increase of +8870 per year was observed (95% CI, 3876-13,863, P = .028). Multivariable analyses found no difference in the risk of major complications comparing era 2 vs era 1 (odds ratio, 1.04; 95% CI, 0.89-1.23; P = .602), and a 59% reduction in FTR risk in era 2 vs era 1 (odds ratio, 0.41; 95% CI, 0.25-0.67; P < .001)., Conclusions: Nighttime ICU coverage reduced FTR rates in postcardiotomy patients while complication rates and ICU census remained stable. Furthermore, the increase in RVUs suggested an economically sustainable model., Competing Interests: Disclosures The authors have no conflicts of interest to disclose., (Copyright © 2025 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This study investigated the potential of machine learning (ML) as a substitute for polynomial regression in conventional response surface methodology (RSM) for decolorizing textile wastewater via a UV/H 2 O 2 process. While polynomial regression offers limited adaptability, ML models provide superior flexibility in capturing nonlinear responses but are prone to overfitting, particularly with constrained RSM datasets. In this study, we evaluated decision tree (DT), random forest (RF), multilayer perceptron (MLP), and extreme gradient boosting (XGBoost) models with respect to a quadratic regression model. Our observations indicated that the ML models achieved higher R 2 values, demonstrating better adaptability. However, when provided with additional data, the polynomial regression displayed a moderate predictability, whereas MLP and XGBoost exhibited indications of overfitting, while DT and RF remained robust. Both ANalysis Of VAriance (ANOVA) and SHapley Additive exPlanations (SHAP) analyses consistently emphasized the significance of operational factors (H 2 O 2 concentration, reaction time, UV light intensity) in decolorization. The findings underscore the need for cautious validation when substituting ML models in RSM and highlight the complementary value of ML (particularly SHAP analysis) alongside conventional ANOVA for analyzing factor significance. This study offered significant insights into replacing polynomial regression with ML models in RSM., 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.)

Low pulse pressure (PP) in venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is a marker of cardiac dysfunction and has been associated with acute brain injury (ABI) as continuous-flow centrifugal pump may lead to endothelial dysregulation. We retrospectively analyzed adults (≥18 years) receiving "peripheral" VA-ECMO for cardiogenic shock in the Extracorporeal Life Support Organization Registry (January 2018-July 2023). Acute brain injury (our primary outcome) included central nervous system (CNS) ischemia, intracranial hemorrhage, brain death, and seizures. Multivariable logistic regressions were performed to examine whether PP ≤10 mm Hg was associated with ABI. Of 9,807 peripheral VA-ECMO patients (median age = 57.4 years, 67% = male), 8,294 (85%) had PP >10 mm Hg versus 1,513 (15%) had PP ≤10 mm Hg. Patients with PP ≤10 mm Hg experienced ABI more frequently versus PP >10 mm Hg (15% versus 11%, p < 0.001). After adjustment, PP ≤10 mm Hg was independently associated with ABI (adjusted odds ratio [aOR] = 1.25, 95% confidence interval [CI] = 1.06-1.48, p = 0.01). Central nervous system ischemia and brain death were more common in patients with PP ≤10 versus PP >10 mm Hg (8% versus 6%, p = 0.008; 3% versus 1%, p < 0.001). Pulse pressure ≤10 mm Hg was associated with CNS ischemia (aOR = 1.26, 95% CI = 1.02-1.56, p = 0.03) but not intracranial hemorrhage (aOR = 1.14, 95% CI = 0.85-1.54, p = 0.38). Early low PP (≤10 mm Hg) at 24 hours of ECMO support was associated with ABI, particularly CNS ischemia, in peripheral VA-ECMO patients., Competing Interests: Disclosure: D.B. receives research support from and consults for LivaNova. He has been on the medical advisory boards for Abiomed, Xenios, Medtronic, Inspira and Cellenkos. He is the President-elect of the Extracorporeal Life Support Organization (ELSO) and the Chair of the Executive Committee of the International ECMO Network (ECMONet), and he writes for UpToDate. S.-M.C. is supported by NHLBI (1K23HL157610) and Hyperfine (SAFE MRI ECMO study). The other authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Objective: To investigate the relationship between nutrient intake and peripheral artery disease (PAD) using machine learning (ML) methods., Methods: Data from NHANES (1999-2004) were analyzed, including demographic, clinical, and dietary information. Nutrient intake was assessed through 24-hour dietary recalls using CADI and AMPM methods. PAD was defined as an Ankle-Brachial Index (ABI) <0.9. Six ML models-Extreme Gradient Boosting (XGBoost), Random Forest (RF), Naive Bayes Classifier (NB), Support Vector Machine (SVM), Logistic Regression (LR), and Decision Tree (DT)-were trained on a 70/30 train-test split, with missing data imputed and sample imbalance addressed via SMOTE. Model performance was evaluated using AUROC, accuracy, sensitivity, specificity, precision, recall, and F1 score. SHAP analysis was used to identify key features. In addition, to further enhance the interpretability of the model, we applied SHAP analysis to identify the features that have a significant impact on PAD prediction. This approach allowed us to determine the contribution of different variables to the model's output, providing deeper insights into how each feature influences the prediction of PAD outcomes., Results: Of 31,126 participants, 4,520 met inclusion criteria (mean age 61.2 ± 13.5 years; 48.8% male), and 441 (9.7%) had ABI <0.9. XGBoost outperformed other models, achieving an AUROC of 0.913 (95% CI, 0.891-0.936) and F1 score of 0.932. With SMOTE, its AUROC improved to 0.926 (95% CI, 0.889-0.936) and F1 score to 0.937. SHAP analysis identified Vitamin C, saturated fatty acids, selenium, phosphorus, and protein intake as key predictors of PAD., Conclusions: This is the first study to apply ML algorithms to examine nutrient intake and PAD in a general population. Vitamin C and phosphorus showed negative correlations with PAD, while saturated fatty acids, protein, and selenium exhibited positive associations., (Copyright © 2025. Published by Elsevier Inc.)

The adsorption of radioactive iodine is a critical concern in nuclear safety and environmental protection due to its hazardous nature and long half-life. Covalent organic frameworks (COFs) have emerged as promising materials for capturing radioactive iodine owing to their tunable porosity, high surface area, and versatile functionalization capabilities. This review provides a comprehensive overview of the application of COFs in the adsorption of radioactive iodine. We begin by discussing the sources, properties, and hazards of radioactive iodine, as well as traditional capture techniques and their limitations. We then delve into the intrinsic structures of COFs, focusing on their porosity, conjugated frameworks, and hydrogen bonding, which are pivotal for effective iodine adsorption. The review further explores various functionalization strategies, including electron-rich COFs, flexible COFs, ionic COFs, COF nanosheets, and quasi-3D COFs, highlighting how these modifications enhance the adsorption performance. Finally, we conclude with an outlook on future research directions and potential applications, underscoring the significance of continued innovation in this field. This review aims to provide valuable insights for researchers and practitioners seeking to develop advanced materials for the efficient capture of radioactive iodine.

The use of cardiac devices, including mechanical circulatory support (MCS), cardiac implantable electronic devices (CIEDs), and pacing wires, has increased and significantly improved survival in patients with severe cardiac failure. However, these devices are frequently associated with acute brain injuries (ABIs) including ischemic strokes, intracranial hemorrhages, seizures, and hypoxic-ischemic brain injury which contribute substantially to morbidity and mortality. Computed tomography (CT) and magnetic resonance imaging (MRI), the standard imaging modalities for ABI diagnosis, can pose significant challenges in this patient population due to the risks associated with patient transportation and the incompatibility of ferromagnetic components of certain cardiac devices with high magnetic field of the MRI. This review discusses the application of Ultralow-field portable MRI (ULF-pMRI), which operates at much lower magnetic field (0.064 T), with the potential to allow safe bedside imaging of critically ill patients. In this review, we detail the clinical studies and research findings defining the safety, feasibility, and diagnostic utility of ULF-pMRI in detecting ABI in the critically ill. We further discuss the potential broader applications of ULF-pMRI, as a standard diagnostic tool for neurocritical care in patients with cardiac devices. The integration of such technology into current practice promises to enhance diagnostic accuracy, improve patient outcomes, and optimize healthcare resources., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2025.)

Objectives: In the randomized phase III TASUKI-52 trial, nivolumab with carboplatin, paclitaxel, and bevacizumab significantly prolonged the progression-free survival (PFS) of treatment-naive patients with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC). Here, we report the long-term outcomes of patients treated with nivolumab plus carboplatin, paclitaxel, and bevacizumab with 3 years of follow-up., Methods: Patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 mutations were randomized (1:1) to receive either nivolumab or placebo, in addition to carboplatin, paclitaxel, and bevacizumab, every 3 weeks. Treatment was continued for a maximum of six cycles. The endpoints included PFS, overall survival (OS), and safety. Exploratory analyses included efficacy and safety in subgroups., Results: A total of 550 patients were randomized to the nivolumab arm (n = 275) and placebo arm (n = 275). At the minimum follow-up of 36.1 months, PFS was consistently longer in the nivolumab arm than in the placebo arm (median, 10.6 vs. 8.2 months; hazard ratio [HR], 0.59; 95 % confidence interval [CI], 0.47-0.73; P < 0.0001), with PFS rates of 20.2 % vs. 4.9 %. The median OS was 31.6 months (95 % CI, 26.8-36.5) in the nivolumab arm and 24.7 months (95 % CI, 21.1-28.0) in the placebo arm (HR, 0.71; 95 % CI, 0.57-0.88), with OS rates of 44.2 % and 32.3 %, respectively. Of note, PFS and OS favored the nivolumab arm across patients with different PD-L1 expression levels, and regardless of baseline brain metastasis status. Grade 3-4 treatment-related adverse events occurred in 76.2 % and 74.9 % of the patients in the nivolumab and placebo arms, respectively, while no new safety concerns were identified., Conclusion: Nivolumab, in addition to carboplatin, paclitaxel, and bevacizumab, remained to demonstrate significantly longer PFS and long-term OS benefit compared with placebo in the first-line treatment of patients with nonsquamous NSCLC. The extended follow-up identified no new safety signals., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors declared support for the current study from Ono and Bristol Myers Squibb (BMS). KHL reports grants from Merck Serono; consulting fees from Merck Sharp & Dohme (MSD), Pfizer, Eli Lilly, Yuhan, AstraZeneca, and BMS. SS reports grants from Ono, BMS, AnHeart Therapeutics, AstraZeneca, Chugai, MSD, Daiichi Sankyo, Nippon Boehringer Ingelheim, AbbVie, Amgen, Taiho, Takeda, and Clinipace; and honoraria from AstraZeneca, Chugai, Ono, BMS, MSD, Nippon Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Novartis, Kyowa Kirin, Takeda, Nippon Kayaku, Merck, Amgen, AbbVie, Otsuka, Thermo Fisher Scientific, and Towa Pharmaceutical. J-HK reports grants from Ono; consulting fees from Daiichi Sankyo, Boehringer Ingelheim, Merck Serono, and AstraZeneca; honoraria from Boehringer Ingelheim, Bayer, and Pfizer; participation on an advisory board of Novartis, Yuhan, Daiichi Sankyo, and BeiGene. HRK received honoraria from AstraZeneca, Bristol Myers Squibb, Genentech/Roche, stock ownership in Bridgebio Therapeutics; served as a consultation or advisory role for Bayer, AstraZeneca, Bristol Myers Squibb, Takeda, and Yuhan; and received research funding from the Yonsei Lee Youn Jae Fellowship outside of the current work. NI reports grants from Chugai, Nippon Boehringer Ingelheim, and Taiho; and honoraria from Chugai, Taiho, and AstraZeneca. TH reports honoraria from Ono and BMS. TY reports grants from Novartis, AbbVie, Amgen, Daiichi Sankyo, AstraZeneca, MSD, Chugai, Astellas, Medpace, Boehringer Ingelheim, BMS, Ono, and Merck; honoraria from Novartis, Daiichi Sankyo, AstraZeneca, MSD, Chugai, BMS, Ono, Takeda, Pfizer, Eli Lilly, and Merck; and participation on an advisory board in Novartis, MSD, Amge, Chugai, Pfizer, and Boehringer Ingelheim. HT reports grants from Ono, AstraZeneca, Chugai, MSD, BMS, Daiichi Sankyo, Eli Lilly, Takeda, Taiho, Merck, Boehringer Ingelheim, Amgen, and AbbVie; honoraria for lecture from Ono, AstraZeneca, Chugai, MSD, BMS, Daiichi Sankyo, Eli Lilly, Takeda, Taiho, Merck, Boehringer Ingelheim, Sun Pharmaceutical, Eisai, and Novartis. C-TY reports honoraria for lecture from AstraZeneca, Pfizer, Ono, MSD, Pfizer, Eli Lilly, and Roche; support from Takeda for attending a meeting and travel; and serving as the president of Taiwan Lung Cancer Society. TI reports payment for expert testimony from AstraZeneca, Chugai, BMS, Ono, and MSD. MN reports consulting fees from Ono and BMS; honoraria for lecture from Ono, Chugai, Taiho, BMS, Daiichi Sankyo, Eli Lilly, AstraZeneca, MSD, AbbVie, Takeda, Pfizer, Boehringer Ingelheim, Novartis, Nippon Kayaku, Merck, and Janssen. YO reports grants from AstraZeneca, Chugai, Eli Lilly, Kirin, Sumitomo, Pfizer, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen, and Loxo; honoraria from AstraZeneca, Chugai, Eli Lilly, Ono, BMS, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho, Nippon Kayaku, Kyowa Hakko Kirin, Eisai, and Daiichi Sankyo; payment for expert testimony from AstraZeneca, Chugai, Ono, BMS, Kyorin, Celltrion, Amgen, Nippon Kayaku, Boehringer Ingelheim, AnHeart Therapeutics, and PharmaMar; participation on an advisory board in Haihe Biopharma; and leaderships in Japanese Society of Medical Oncology, Japan Lung Cancer Society, and Japan Clinical Oncology Group. TT reports honoraria from Ono, Chugai, Eli Lilly, Cmic ShiftZero, Taiho, and Nihon Kayaku. NY reports grands from Boehringer Ingelheim, Taiho, Chugai, Shionogi, Eli Lilly Japan, Daiichi Sankyo, Tsumura, Nippon Kayaku, Asahi Kasei Pharma, Janssen, Sanofi, Amgen, Novartis, Astellas, MSD, Eisai, BMS, AbbVie, and Tosoh; honoraria from MSD, AstraZeneca, Amgen, Ono, Otsuka, Guardant Health Japan, Tsumura, Kyowa Kirin, Kyorin, Glaxo Smith Kline, Sanofi, Daiichi Sankyo, Taiho, Takeda, Chugai, Eli Lilly Japan, Nippon Kayaku, Boehringer Ingelheim, Novartis, Pfizer, BMS, Miyarisan, Merck, and Janssen; participation on an Advisory board of AstraZeneca, Eli Lilly Japan, and Takeda. HA reports grants from Amgen and Chugai; honoraria from Amgen, AstraZeneca K.K., Boehringer Ingelheim Japan, BMS, Chugai, Eli Lilly Japan K.K., MSD K.K., Nippon Kayaku, Novartis Pharma K.K., Ono, Pfizer, Takeda, and Taiho; participation on an advisory board in Amgen, Janssen Pharmaceutical K.K., and Sandoz. ST reports employment in Ono. KN reports honoraria from Amgen, MSD K.K., Ono, Nippon Boehringer Ingelheim, Novartis Pharma K.K., Pfizer Japan, BMS, Eli Lilly Japan K.K., Chugai, Daiichi Sankyo, AstraZeneca K.K., Parexel International, PRA Health Science, EPS, Kissei, Taiho, PPD-SNBL K.K., SymBio Pharmaceuticals, IQVIA Services Japan, K.K., Syneos Health Clinical K.K., Nippon Kayaku, EP-CRSU, Mebix, Janssen Pharmaceutical K.K., Astellas, Bayer Yakuhin, Eisai, Mochida Pharmaceutical, Labcorp Development Japan K.K. (Covance Japan Inc.), Japan Clinical Research Operations, Takeda, GlaxoSmithKline K.K., Sanofi K.K., Sysmex Corporation, Medical Research Support, Otsuka, SRI, Pfizer R&D Japan GK., CMIC, Eisai, Shionogi, Kobayashi, and Ascent Development Services; consulting fees from Eli Lilly Japan K.K., and Ono; honoraria from Ono, Amgen, Nippon Kayaku, AstraZeneca K.K., Chugai, Eli Lilly Japan K.K., MSD K.K., Pfizer Japan, Nippon Boehringer Ingelheim, Taiho, Bayar Yakuhin, Cmic ShiftZero K.K., Life Technologies Japan, Neo Communication, Daiichi Sankyo, Incyte Biosciences Japan, Merch Biopharma, Kyowa Kirin, Takeda, 3H Clinical Trial, Care Net, Medical Review, Medical Mobile Communication, Yodosha, Nikkei Business Publications, Japan Clinical Research Operations, Cmic, Novartis, Taiyo, Janssen Pharmaceutical K.K., and BMS K.K.; and a patent matter with Daiichi Sankyo., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Phase separation of specific proteins into liquid-like condensates is a key mechanism for forming membrane-less organelles, which organize diverse cellular processes in space and time. These protein condensates hold immense potential as biomaterials capable of containing specific sets of biomolecules with high densities and dynamic liquid properties. Despite their appeal, methods to manipulate protein condensate materials remain largely unexplored. Here, we present a one-pot assembly method to assemble coalescence-resistant protein condensates, ranging from a few μm to 100 nm in sizes, with surface-stabilizing protein cages. We discover that large protein cages (~30 nm), finely tuned to interact with condensates, efficiently localize on condensate surfaces and prevent the merging (coalescence) of condensates during phase separation. We precisely control condensate diameters by modulating condensate/cage ratios. In addition, the 3D structures of intact protein condensates with interfacial cages are visualized with cryo-electron tomography (ET). This work offers a versatile platform for designing size-controlled, surface-engineered protein condensate materials., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

A major goal of cancer biology is to understand the mechanisms driven by somatically acquired mutations. Two distinct methodologies-one analyzing mutation clustering within protein sequences and 3D structures, the other leveraging protein-protein interaction network topology-offer complementary strengths. We present NetFlow3D, a unified, end-to-end 3D structurally-informed protein interaction network propagation framework that maps the multiscale mechanistic effects of mutations. Built upon the Human Protein Structurome, which incorporates the 3D structures of every protein and the binding interfaces of all known protein interactions, NetFlow3D integrates atomic, residue, protein and network-level information: It clusters mutations on 3D protein structures to identify driver mutations and propagates their impacts anisotropically across the protein interaction network, guided by the involved interaction interfaces, to reveal systems-level impacts. Applied to 33 cancer types, NetFlow3D identifies 2 times more 3D clusters and incorporates 8 times more proteins in significantly interconnected network modules compared to traditional methods., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: This study aimed to explore the characteristics, overall anxiety and depression status, and influencing factors of only-child and non-only-child students by examining a medical student population in the post-COVID-19 era., Study Design: This study was a cross-sectional design., Methods: An online questionnaire survey was administered among medical students. The psychological problems related to depression and anxiety were measured using Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder Scale (GAD-7), respectively, which were scored via a Likert-4 scale. Statistical analysis was employed to explore the characteristics and overall differences between only-child and non-only-child students, along with the factors affecting their anxiety and depression., Results: A total of 1688 participants were enrolled. No significant differences were observed in the prevalence of anxiety (χ 2  = 1.154, P = 0.283) and depression (χ 2  = 0.313, P = 0.576) between only-child and non-only-child students. School level, single status, and desire for only child status are associated with anxiety and depression in the two groups. Region and loneliness are merely related to anxiety and depression among only-child students, while gender, willingness to apply for medical school, and equal treatment are associated with anxiety and depression among non-only-child students., Conclusion: Our study found the factors that are associated with depression or anxiety inthe only-child and non-only-child medical students jointly and separately, which could provide a new theoretical basis for the psychological intervention of medical students, that is, to identify the high risk factors of depression and anxiety from the perspective of only child and non-only child., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Lactobacillus reuteri is a well-known probiotic with beneficial effects, such as anti-insulin resistance, anti-inflammatory, and improvement of the intestinal barrier. However, the underlying mechanisms remain unclear. Here, we found that gavage of L. reuteri improved the intestinal barrier and glucose homeostasis in HFD-fed mice. Analysis of lipid metabolomics reveals a significant increase in eicosatrienoic acid (ETA) levels in mouse feces after L. reuteri gavage. We found that ETA maintain intestinal barrier integrity and improve glucose homeostasis by promoting GLP-1 secretion. Mechanistically, by using CD36 inhibitor in vivo and CD36 knockdown STC-1 cells in vitro , we elucidate that ETA activates intestinal CD36-activated PLC/IP3R/Ca 2+ signaling to promote GLP-1 secretion. In vivo administration of GLP-1R inhibitor and in vitro intestinal organoid experiments demonstrate that GLP-1 upregulates the PI3K/AKT/HIF-1α pathway by GLP-1R and increases intestinal tight junction protein expressions, which in turn enhance the intestinal barrier integrity, reduce serum LPS level, attenuate inflammation in white adipose tissue (WAT), and ultimately improve glucose homeostasis in HFD and db/db mice. Our study elucidates for the first time the mechanism by which L. reuteri and its enriched metabolite ETA inhibit WAT inflammation by ameliorating the intestinal barrier, ultimately improving glucose homeostasis, and provides a new treatment strategy for T2D.

Background: Anti-citrullinated peptide antibodies (ACPA)-negative (ACPA-) rheumatoid arthritis (RA) presents significant diagnostic and therapeutic challenges due to the absence of specific biomarkers, underscoring the need to elucidate its distinctive cellular and metabolic profiles for more targeted interventions., Methods: Single-cell RNA sequencing data from peripheral blood mononuclear cells (PBMCs) and synovial tissues of patients with ACPA- and ACPA+ RA, as well as healthy controls, were analyzed. Immune cell populations were classified based on clustering and marker gene expression, with pseudotime trajectory analysis, weighted gene co-expression network analysis (WGCNA), and transcription factor network inference providing further insights. Cell-cell communication was explored using CellChat and MEBOCOST, while scFEA enabled metabolic flux estimation. A neural network model incorporating key genes was constructed to differentiate patients with ACPA- RA from healthy controls., Results: Patients with ACPA- RA demonstrated a pronounced increase in classical monocytes in PBMCs and C1QChigh macrophages (p < 0.001 and p < 0.05). Synovial macrophages exhibited increased heterogeneity and were enriched in distinct metabolic pathways, including complement cascades and glutathione metabolism. The neural network model achieved reliable differentiation between patients with ACPA- RA and healthy controls (AUC = 0.81). CellChat analysis identified CD45 and CCL5 as key pathways facilitating macrophage-monocyte interactions in ACPA- RA, prominently involving iron-mediated metabolite communication. Metabolic flux analysis indicated elevated beta-alanine and glutathione metabolism in ACPA- RA macrophages., Conclusion: These findings underscore that ACPA-negative rheumatoid arthritis is marked by elevated classical monocytes in circulation and metabolic reprogramming of synovial macrophages, particularly in complement cascade and glutathione metabolism pathways. By integrating single-cell RNA sequencing with machine learning, this study established a neural network model that robustly differentiates patients with ACPA- RA from healthy controls, highlighting promising diagnostic biomarkers and therapeutic targets centered on immune cell metabolism., Competing Interests: The authors declare that this research was conducted without any commercial or financial relationships that could present a potential conflict of interest., (Copyright © 2025 Jiang, Hu, Huang, Ho, Wang and Kang.)

The carbon dioxide removal (CDR) capacity of macroalgae, a crucial component in climate regulation, has gained increasing attention. However, accurately estimating the CDR potential of macroalgae in natural conditions remains challenging, necessitating the use of multiple independent methods to reduce the uncertainties in these estimates. In this study, we compared two methods for estimating net ecosystem production (NEP), a key parameter in determining CDR potential: 1) NEP Chem. , derived from seawater carbonate chemistry and 2) NEP Biol. , based on photorespiratory measurements using benthic tent incubation. This study, conducted in a macroalgal forest dominated by Ecklonia cava, involved simultaneous measurements of NEP Chem. and NEP Biol. over a course of one year. Our findings revealed that NEP Biol. was 1.23 times higher than NEP Chem. , with an annual rate of 3.69 tons CO 2 ha -1  yr -1 . These results suggest that both independent methods are reliable and can be used complementarily to improve the accuracy of NEP measurements, thereby enhancing estimates of the CDR potential of macroalgae., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests of personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease soon to become the second leading cause of cancer deaths in the US. Beside surgery, current therapies have narrow clinical benefits with systemic toxicities. FOLFIRINOX is the current standard of care, one component of which is 5- Fluorouracil (5-FU), which causes serious gastrointestinal and hematopoietic toxicities and is vulnerable to resistance mechanisms. Recently, we have developed polymeric fluoropyrimidines (F10, CF10) which unlike 5-FU, are, in principle, completely converted to the thymidylate synthase inhibitory metabolite FdUMP, without generating appreciable levels of ribonucleotides that cause systemic toxicities while displaying much stronger anti-cancer activity. Here, we confirm the potency of CF10 and investigate enhancement of its efficacy through combination with inhibitors in vitro targeting replication stress, a hallmark of PDAC cells. CF10 is 308-times more potent as a single agent than 5-FU and was effective in the nM range in primary patient derived models. Further, we find that activity of CF10, but not 5-FU, is enhanced through combination with inhibitors of ATR and Wee1 that regulate the S and G2 DNA damage checkpoints and can be reversed by addition of dNTPs indicative of CF10 acting, at least in part, through inducing replication stress. Our results indicate CF10 has the potential to supersede the established benefit of 5-FU in PDAC treatment and indicate novel combination approaches that should be validated in vivo and may be beneficial in established regimens that include 5-FU.

Background: Influenza remains a significant public health challenge, with vaccination being a substantial way to prevent it. Cell-cultured influenza vaccines have emerged to improve on the drawbacks of egg-based vaccines, but there are few studies focusing on T cell immunity with both types of vaccines. Therefore, we studied the following 2022-2023 seasonal influenza vaccines with a standard dose and high dose: cell-based (C&#95;sd and C&#95;hd) and egg-based (E&#95;sd and E&#95;hd) vaccines., Methods: Along with a saline control group, C&#95;sd, C&#95;hd, E&#95;sd, and E&#95;hd vaccines were administered to BALB/c mice, followed by a challenge with the A/Victoria/2570/2019 (H1N1) strain., Results: After the challenge, four out of five mice in the saline group died by day 7 post-infection (P.I.). None of the vaccinated groups experienced over 20% weight loss or any deaths. On day 7 P.I., the lung viral load in the saline group (mean log value of 4.17) was higher than that in the vaccinated groups, with the C&#95;sd group showing the lowest viral load (mean log value of 3.47). The C&#95;sd group showed a significantly high response in macrophage 1 (M1), IFN-γ+ T cells, and tissue-resident memory (T RM ) T cells compared with the E&#95;sd group on day 2 P.I. These M1, IFN-γ+ T cells, and T RM cells showed similar trends ( p < 0.01). In terms of humoral immunity, only the E&#95;hd group showed HAI titers above 40 for all four strains before and after the challenge., Conclusions: The high levels of T cells in the cell-cultured vaccines suggest, pending further real-world research, that these vaccines may offer advantages.

Background: Early detection of acute brain injury (ABI) at the bedside is critical in improving survival for patients with extracorporeal membrane oxygenation (ECMO) support. We aimed to examine the safety of ultra-low-field (ULF; 0.064-T) portable magnetic resonance imaging (pMRI) in patients undergoing ECMO and to investigate the ABI frequency and types with ULF-pMRI., Methods: This was a multicenter prospective observational study (SAFE MRI ECMO study [Assessing the Safety and Feasibility of Bedside Portable Low-Field Brain Magnetic Resonance Imaging in Patients on ECMO]; NCT05469139) from 2 tertiary centers (Johns Hopkins, Baltimore, MD and University of Texas-Houston) with specially trained intensive care units. Primary outcomes were safety of ULF-pMRI during ECMO support, defined as completion of ULF-pMRI without significant adverse events., Results: Of 53 eligible patients, 3 were not scanned because of a large head size that did not fit within the head coil. ULF-pMRI was performed in 50 patients (median age, 58 years; 52% male), with 34 patients (68%) on venoarterial ECMO and 16 patients (32%) on venovenous ECMO. Of 34 patients on venoarterial ECMO, 11 (22%) were centrally cannulated and 23 (46%) were peripherally cannulated. In venovenous ECMO, 9 (18%) had single-lumen cannulation and 7 (14%) had double-lumen cannulation. Of 50 patients, adverse events occurred in 3 patients (6%), with 2 minor adverse events (ECMO suction event; transient low ECMO flow) and one serious adverse event (intra-aortic balloon pump malfunction attributable to electrocardiographic artifacts). All images demonstrated discernible intracranial pathologies with good quality. ABI was observed in 22 patients (44%). Ischemic stroke (36%) was the most common type of ABI, followed by intracranial hemorrhage (6%) and hypoxic-ischemic brain injury (4%). Of 18 patients (36%) with both ULF-pMRI and head computed tomography within 24 hours, ABI was observed in 9 patients with a total of 10 events (8 ischemic, 2 hemorrhagic events). Of the 8 ischemic events, pMRI observed all 8, and head computed tomography observed only 4 events. For intracranial hemorrhage, pMRI observed only 1 of them, and head computed tomography observed both (2 events)., Conclusions: Our study demonstrates that ULF-pMRI can be performed in patients on ECMO across different ECMO cannulation strategies in specially trained intensive care units. The incidence of ABI was high, seen in 44% of ULF-pMRI studies. ULF-pMRI imaging appears to be more sensitive to ABI, particularly ischemic stroke, compared with head computed tomography., Competing Interests: None.

Endometriosis is a chronic inflammatory, estrogenic disorder caused by endometrial tissue growth places other than uterine lumen, resulting in infertility and severe pelvic pain. Thymol, an extract of Thymus vulgaris , processes diverse biological properties, including anti-inflammatory, local anesthetic, decongestant, and antiseptic effects. However, the efficacy of thymol in treating endometriosis has still not been explored. Herein, this research aimed to investigate the role of thymol in the treatment of endometriosis using a murine model and Ishikawa cells. Thirty C57BL/6 mice were administered 17β-E2 (100 ng/mouse) subcutaneously for three consecutive days to induce synchronous estrus. On the last day of injection, the mice underwent surgical induction of endometriosis. After that, the mice were divided into three groups, i.e., Control (CTRL), Thymol 30 mg/kg and Thymol 60 mg/kg, receiving oral administration of either saline or thymol (30 mg/kg/d or 60 mg/kg/d, as 0.1 mL/kg/d, respectively) for a three-week duration. Each group consisted of ten mice and was evenly divided into estrus and diestrus according to the vaginal cytology on the last day of treatment. Thymol significantly ( p < 0.05) reduced the weight and volume of ectopic tissue, hindered cell proliferation, and stimulated apoptosis compared to the CTRL group. Additionally, in the thymol-treated group, the levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) , interleukin (IL)-1β , and IL-6 , as well as the numbers of neutrophils and macrophages, were significantly ( p < 0.05) decreased. Moreover, a novel role of thymol in rebalancing estrogen and progesterone (E 2 -P 4 ) signaling was explored, and it was distributed in the ectopic endometrium. Next, the role of thymol on Ishikawa cells was determined. The results demonstrated that thymol significantly ( p < 0.05) suppressed the E 2 -induced proliferation of Ishikawa cells. Furthermore, molecular docking analyses suggested that thymol potentially binds to ESR1-like estrogens, indicating its antagonistic activity against estrogens. The estrogen receptor 1 (ESR1) and its target gene expression exhibited significant ( p < 0.05) downregulation, while progesterone receptor (PGR) and target genes were markedly ( p < 0.05) upregulated following thymol treatment in the ectopic endometrium. Most importantly, our data revealed the minimal impact of thymol treatment on the eutopic endometrium and its crucial role in supporting pregnancy, thus indicating the safety of thymol in treating endometriosis. Overall, our study suggests that thymol holds promising therapeutic implications for endometriosis by virtue of its anti-inflammatory properties and ability to antagonize estrogen activity.

Background: Varicella can lead to severe complications in immunocompromised children, including those undergoing hematopoietic stem cell transplantation (HSCT) or chemotherapy. Preventing primary varicella zoster virus (VZV) infection is crucial in these populations to mitigate morbidity and mortality. This study aimed to evaluate the immunogenicity and safety of the live attenuated MAV/06 varicella vaccine in pediatric patients post-HSCT and post-chemotherapy. Additionally, it sought to compare fluorescent-antibody-to-membrane-antigen (FAMA) and enzyme-linked immunosorbent assay (ELISA) titers to establish effective cut-off levels for protection against varicella., Methods: The FAMA assay was conducted at the Vaccine Bio Research Institute, and a VARICELLA-ZOSTER ELISA (Vircell, Granada, Spain) kit, which relies on lysate from whole cells infected with VZV, was used to determine VZV IgG. A prospective cohort study was conducted with 76 pediatric patients under 18 years old who tested negative for VZV IgG via ELISA. Patients post-HSCT and post-chemotherapy were included. Participants received the MAV/06 varicella vaccine, and serologic responses were evaluated using ELISA and FAMA., Results: The median age of participants was 9.8 years, with acute lymphoid leukemia and acute myeloid leukemia being the most common underlying disease. Post-dose 1, the seropositive rate was 56.1% by ELISA and 97.2% by FAMA. Based on the FAMA seropositive cut-off ≥1:4, post-dose 1 geometric mean titers (GMTs) of seropositive patients in the post-HSCT group were 14.7 (95% CI, 11.3-19.1) versus 20.2 (95% CI, 13.0-31.3) in the post-chemotherapy group ( p = 0.690). Based on a FAMA seropositive cut-off ≥1:16, the post-dose 1 GMT of patients considered seropositive in the post-HSCT group was 19.3 (95% CI, 15.6-24.0) versus 34.1 (95% CI, 21.0-55.4) in the post-chemotherapy group ( p = 0.116), and post-dose 2 FAMA titers of 76.1 (95% CI, 14.6-398.1) in the post-HSCT group and 64.0 (95% CI, 11.4-358.1) in the post-HSCT group ( p = 0.853) were observed. In patients with lower baseline FAMA titers (1:4 to 1:8), 66.7% in the post-HSCT group and 71.5% in the post-chemotherapy group achieved a greater than four-fold increase in FAMA titers post-dose 1, while those with higher baseline titers (≥1:16) did not. There were no serious adverse events or vaccine-related rashes occurring in any of the patients., Conclusion: The MAV/06 varicella vaccine is immunogenic in pediatric patients post-HSCT and post-chemotherapy, particularly when administered in a two-dose schedule using a cut-off FAMA titer of <1:16.

Nowadays, aggregation-caused quenching (ACQ) of organic molecules in aqueous media seriously restricts their analytical and biomedical applications. In this work, hydrogen bond (H-bond) was utilized to resist the ACQ effect of 2,5,8-triamino-1,3,4,6,7,9,9b-heptaazaphenalene (Melem) as an advanced electrochemiluminescence (ECL) luminophore, whose ECL process was carefully studied in an aqueous K 2 S 2 O 8 system coupled with electron paramagnetic resonance (EPR) measurements. Notably, the H-bond-induced Melem assemblies (Melem-H) showed 16.6-fold enhancement in the ECL signals as compared to the Melem aggregates (Melem-A), combined by elaborating the enhanced mechanism. On such basis, the effective ECL signal transduction was in situ achieved through the specific recognition of the double-stranded DNA embedded in Melem-H assemblies (Me-dsDNA) with spike protein (SP) of coronavirus disease 2019 (COVID-19). For that, such an ECL biosensor showed a wider linear range (1.0-125.0 pg mL -1 ) with a lower limit of detection (LOD) down to 0.45 pg mL -1 , which also displayed acceptable results in analysis of human nasal swab samples. Therefore, the work provides a distinctive insight on addressing the ACQ effect and broadening the application scope of the organic emitter and offers a simple platform for biomedical detection.

Oocytes and early embryos are exposed to many uncontrollable factors that trigger endoplasmic reticulum (ER) stress during in vitro culture. Prevention of ER stress is an effective way to improve the oocyte maturation rate and oocyte quality. Increasing evidence suggests that dietary intake of sufficient n-3 polyunsaturated fatty acids (PUFAs) is associated with health benefits, particularly in the domain of female reproductive health. We found that supplementation of eicosatrienoic acid (ETA) during in vitro maturation (IVM) of oocyte significantly downregulated ER stress-related genes. Mitochondria-associated membranes (MAMs) are communications areas between the ER and mitochondria. Inositol 1,4,5-trisphosphate receptor (IP3R) is a key calcium channels in MAMs and, participates in the regulation of many cellular functions. Notably, the MAM area was significantly decreased in ETA-treated oocytes. CDGSH iron sulfur domain 2 (CISD2) is presents in MAMs, but its role in oocytes is unknown. ETA treatment significantly increased CISD2 expression, and siRNA-mediated knockdown of CISD2 blocked the inhibitory effect of ETA on IP3R. Transcriptomic sequencing and immunoprecipitation experiments showed that ETA treatment significantly decreased expression of the E3 ubiquitin ligase PRKN. PRKN induced ubiquitination and degradation of CISD2, indicating that the PRKN-mediated ubiquitin-proteasome system regulates CISD2. In conclusion, our study reveals the mechanism by which ETA supplementation during IVM alleviates mitochondrial calcium overload under ER stress conditions by decreasing PRKN-mediated ubiquitination of CISD2 and facilitating inhibition of IP3R by CISD2/BCL-2. This improves oocyte quality and subsequent embryo developmental competence prior to implantation., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the authors., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Venoactive drugs (VADs) based on Vitis vinifera extract are widely used in Korea. However, studies on the clinical effects and head-to-head comparisons with other groups of VADs are limited. This trial aimed to evaluate whether Vitis vinifera seed extract was noninferior to the micronized purified flavonoid fraction (MPFF) in relieving venous symptoms and improving quality of life in patients with chronic venous disease., Methods: In this double-blind prospective randomized trial, patients from 13 hospitals, who were diagnosed with venous incompetence by duplex ultrasound and classified as clinical class 1, 2, or 3 in the Clinical, Etiological, Anatomical, and Pathophysiological classifications were enrolled. The primary outcome was the change in the Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) score at 8 weeks from baseline. Secondary outcomes included changes in the Aberdeen Varicose Vein Questionnaire, visual analog scale, and Venous Clinical Severity Score at 4 and 8 weeks from baseline. Moreover, the change in leg circumferences was measured at 8 weeks and compared to baseline., Results: In total, 303 patients were enrolled and randomly assigned to receive either Vitis vinifera seed extract (n = 154) or MPFF (n = 149). The CIVIQ-20 scores at 8 weeks were significantly reduced compared to those at baseline in both groups. No significant intergroup difference in the change of CIVIQ-20 at 8 weeks from baseline was observed (-8.31 ± 14.63 vs. -10.35 ± 14.38, P = 0.29, 95% confidence interval -1.65 to 5.72). The lower limit of the 95% confidence interval was within the predefined noninferiority margin of 6.9. Furthermore, the Aberdeen Varicose Vein Questionnaire, visual analog scale, and Venous Clinical Severity Score scores significantly decreased at 4 and 8 weeks after randomization compared with baseline in both groups. No significant differences were observed in the reduction of each score between groups. The calf circumference measured at 8 weeks was significantly reduced compared to that at baseline in patients receiving Vitis vinifera seed extract., Conclusions: Vitis vinifera seed extract was noninferior to MPFF in relieving venous symptoms and improving the quality of life in patients with chronic venous disease., (Copyright © 2024. Published by Elsevier Inc.)

We consider the effects of an external periodic forcing on a spatially extended system that consists of identical phase oscillators coupled with transmission delays on a ring. Analyzing the continuum limit N→∞ of the model system along the Ott-Antonsen invariant manifold, we obtain the stability diagram for two regimes, called the forced and drifting entrainments. The former exhibits a spatially homogeneous solution trying to lock onto the drive, of which the stability boundary is rigorously determined. The latter represents a spatially organized group of oscillators that entrain one another at a frequency different from that of the drive. We show that in the drifting entrainment the external driving triggers the occurrence of unusual twisted states, characterized by nonuniform phase gradient as well as by the traveling wave of the order parameter amplitude. Moreover, it is found that by increasing or decreasing the forcing strength one can effectively switch between twisted states with different winding numbers. Our theoretical and numerical results for the reduced system are supported by the direct numerical simulations of the model system., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Topologically associating domains (TADs) are chromatin domains in the eukaryotic genome. TADs often comprise several sub-TADs. The boundaries of TADs and sub-TADs are enriched in CTCF, an architectural protein. Deletion of CTCF-binding motifs at one boundary disrupts the domains, often resulting in a transcriptional decrease in genes inside the domains. However, it is not clear how TAD and sub-TAD affect each other in the domain formation. Unaffected gene transcription was observed in the β-globin locus when one boundary of TAD or sub-TAD was destroyed. Here, we disrupted β-globin TAD and sub-TAD by deleting CTCF motifs at both boundaries in MEL/ch11 cells. Disruption of TAD impaired sub-TAD, but sub-TAD disruption did not affect TAD. Both TAD and sub-TAD disruption compromised the β-globin transcription, accompanied by the loss of enhancer-promoter interactions. However, histone H3 occupancy and H3K27ac were largely maintained across the β-globin locus. Genome-wide analysis showed that putative enhancer-promoter interactions and gene transcription were decreased by the disruption of CTCF-mediated topological domains in neural progenitor cells. Collectively, our results indicate that there is unequal relationship between TAD and sub-TAD formation. TAD is likely not sufficient for gene transcription, and, therefore, sub-TAD appears to be required. TAD-dependently formed sub-TADs are considered to provide chromatin environments for enhancer-promoter interactions enabling gene transcription., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

HEPN-MNT, a type VII TA module, comprises the HEPN toxin and the MNT antitoxin, which acts as a nucleotidyltransferase that transfers the NMP moiety to the corresponding HEPN toxin, thereby interfering with its toxicity. Here, we report crystal structures of the Legionella pneumophila HEPN-MNT module, including HEPN, AMPylated HEPN, MNT, and the HEPN-MNT complex. Our structural analysis and biochemical assays, suggest that HEPN is a metal-dependent RNase and identify its active site residues. We also elucidate the oligomeric state of HEPN in solution. Interestingly, L. pneumophila MNT, which lacks a long C-terminal α4 helix, controls the toxicity of HEPN toxin via a distinct binding mode with HEPN. Finally, we propose a comprehensive regulatory mechanism of the L. pneumophila HEPN-MNT module based on structural and functional studies. These results provide insight into the type VII HEPN-MNT TA system., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: While left ventricular (LV) venting reduces LV distension in cardiogenic shock patients on venoarterial extracorporeal membrane oxygenation (VA-ECMO), it may also amplify risk of acute brain injury (ABI). We investigated the hypothesis that LV venting is associated with increased risk of ABI. We also compared ABI risk of the two most common LV venting strategies, percutaneous microaxial flow pump (mAFP) and intra-aortic balloon pump (IABP)., Methods: The Extracorporeal Life Support Organization registry was queried for patients on peripheral VA-ECMO for cardiogenic shock (2013-2024). ABI was defined as hypoxic-ischemic brain injury, ischemic stroke, or intracranial hemorrhage. Secondary outcome was hospital mortality. We compared no LV venting with 1) LV venting, 2) mAFP, and 3) IABP using multivariable logistic regression. To compare ABI risk of mAFP vs. IABP, propensity score matching was performed., Results: Of 13,276 patients (median age=58.2, 69.9% male), 1,456 (11.0%) received LV venting (65.5% mAFP and 29.9% IABP), and 525 (4.0%) had ABI. After multivariable regression, LV-vented patients had increased odds of ABI (adjusted odds ratio (aOR)=1.76, 95% CI=1.29, 2.37, p<0.001) but no difference in mortality (aOR=1.08, 95% CI=0.91-1.28, p=0.39) compared to non-LV-vented patients. In the propensity- matched cohort of IABP (n=231) vs. mAFP (n=231) patients, there was no significant difference in odds of ABI (aOR=1.35, 95%CI=0.69-2.71, p=0.39) or mortality (aOR=0.88, 95%CI=0.58-1.31, p=0.52)., Conclusions: LV venting was associated with increased odds of ABI but not mortality in patients receiving peripheral VA-ECMO for cardiogenic shock. There was no difference in odds of ABI or mortality for IABP vs. mAFP patients., Clinical Perspective: In patients receiving peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) for cardiogenic shock, left ventricular venting is associated with increased odds of acute brain injury (ABI) but not mortality. However, mode of venting-intra-aortic balloon pump (IABP) or percutaneous microaxial flow pump (mAFP)-does not appear to impact either odds of ABI or mortality. These findings highlight a link between venting strategies and neurological outcomes in this high-risk population. Clinicians must weigh the benefits of venting against ABI risk when managing neurocritically ill patients, though our findings provide reassurance clinicians that both IABP and mAFP may offer comparable neurologic safety profiles.

Background: Neck pain and primary headache disorders are highly prevalent in populations and clinical cohorts. Medication-overuse headache (MOH) is a treatable secondary headache, mainly developing in migraine sufferers, that accounts for the majority of patients presenting to headache clinics. Nevertheless, the association between neck pain and MOH has not been reported. This study evaluated the prevalence and clinical course of neck pain in patients with MOH before and after MOH treatment., Methods: We analyzed 635 MOH patients enrolled in a nationwide, prospective, multicenter MOH registry. Demographics and clinical data were collected at baseline and 3 months to evaluate changes in the status and severity of neck pain and headache. Severity of neck pain was graded into 4 groups, and severe neck pain was defined as grade 3 or 4., Results: Among 635 patients with MOH, 366 (57.6%) reported neck pain at baseline. MOH patients with neck pain had an earlier onset of their primary headache disorder (23.4 ± 12.7 vs. 26.2 ± 13.3 years, p = 0.007). Although monthly headache days were comparable between the patients with neck pain and those without neck pain, the neck pain group had higher levels of anxiety (7.4 ± 5.8 vs. 6.4 ± 5.4, p = 0.017), more severe cutaneous allodynia (2.4 ± 3.3 vs. 1.8 ± 3.0, p = 0.038), and poorer quality of life (171.7 ± 70.4 vs. 184.0 ± 68.9, p = 0.029). At 3 months, 456 (71.8%) were followed-up, and 257 (56.4%) were recovered from MOH. Compared to the baseline, the proportion of severe neck pain (40.4% vs. 19.4%, p < 0.001) was decreased. The proportion of severe neck pain was much lower in patients with recovery from MOH compared to those without (4.7% vs. 15.1%, p < 0.001)., Conclusions: Neck pain in MOH patients was associated with earlier onset of headache, higher levels of anxiety and allodynia, and poorer quality of life. Improvement in neck pain improvement was linked to recovery from MOH. These findings suggest the potential importance of integrating and management of neck pain into clinical practice for MOH., (© 2024. The Author(s).)

Polycystic ovary syndrome (PCOS) is a common metabolic and endocrine disorder characterized by abnormal elevation in hormone levels, with currently lacking effective treatment options. N-3 polyunsaturated fatty acids (PUFA) have broad pharmacological activity and play a beneficial role in the development of PCOS. In this study, we observed that n-3 PUFA-eicosatrienoic acid (ETA) improves the estrous cycle and ovarian morphology in dehydroepiandrosterone (DHEA)-induced PCOS mice, particularly serum hormone levels. Additionally, it suppresses the expression of CYP19A1 and E2 synthesis in human granulosa-like tumor cell line (KGN) cells. Further investigation revealed that ETA significantly upregulates the expression of CD36, cAMP, P-PKA, and FOXO1 in KGN cells and mouse ovaries to lower E2 levels. This conclusion was supported by inhibiting CD36 and FOXO1 at both the mouse and cellular levels. Additionally, ETA treatment decreased the expression of ESR1, Kiss1, Gnrh in the hypothalamus, and GnRHR, Lhβ, Egr1, Pitx1, Sf1 in the pituitary of PCOS mice. No differences were observed after ETA treatment in the CD36 and FOXO1 inhibitor groups, indicating that ETA improves PCOS mice by regulating the hypothalamic-pituitary axis through E2 synthesis inhibition. In summary, we have elucidated for the first time the mechanism by which CD36 regulates E2 synthesis in ovarian granulosa cells and demonstrated that ETA activates the CD36 receptor to inhibit E2 synthesis through the cAMP/PKA/FOXO1/CYP19A1 signaling pathway, thereby improving hormonal imbalance and treating PCOS. This provides a new strategy for the effective prevention and treatment of PCOS., 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.)

Carbapenems and colistin are vital antimicrobials used to treat Enterobacteriaceae-caused infections. The present study aimed to characterize the coexistence mechanism of carbapenem and colistin resistance in an Escherichia coli isolated from retail chicken meat. A total of 4 E. coli isolates co-harboring carbapenem resistance gene bla NDM (2 E. coli isolates with bla NDM-5 and 2 with bla NDM-9 ) and colistin resistance gene mcr-1. Antimicrobial susceptibility testing exhibited that all the 4 E. coli strains had multidrug resistance profile and consistent with the resistance genes they carried. MLST showed that 3 E. coli isolates belonged to a pathogenic E. coli lineage ST354, which is closely associated with human infections and pose a serious threat to public health. Whole genome sequencing (WGS) showed that 4 mcr-1-positive plasmids with sizes of 60.4 kb to 67.4 kb all belonged to the IncI2 type. A total of 5 bla NDM -harboring plasmids ranged from 99.0 kb to 138.3 kb, among which 4 plasmids belonged to unknow type and only pCS5L-NDM belonged to IncFIA/IncFIB group of hybrid plasmids, a novel carrier for bla NDM . Comparative analysis exhibited that the mcr-1 or bla NDM -carrying plasmids of E. coli strains from chicken meat showed high identity with that from Enterobacteriaceae of human origin, which indicated the risk of mcr-1 or bla NDM dissemination from retail meat to human. The simultaneous occurrence of mcr-1 and bla NDM in E. coli emphasizes the significant of antimicrobial resistance surveillance in retail meat., Competing Interests: DISCLOSURES The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Competing Interests: Declarations. Conflict of interest: No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. The authors have no conflict of interest relevant to this article to declare.

Cadmium (Cd), a carcinogen, is released from industrial activities like metal refineries and battery runoff, with significant contamination reported near zinc smelters in Korea. This study addresses the issue using an efficient, economical adsorption process with waste-derived biochar-based adsorbents known for high Cd removal. Poultry manure (PM), typically used as fertilizer, can lead to environmental pollution if mismanaged; therefore, it was pyrolyzed to produce biochar. The resulting poultry manure biochar (PMBC) was produced on a large scale (15 ton/day), demonstrating feasibility for large-scale implementation. The effectiveness of PMBC as an adsorbent for Cd was evaluated using wastewater discharged from a zinc smelter. The Cd adsorption capacity of PMBC (60.39 mg/g) was lower than that (302.0 mg/g) of hen manure biochar produced at a laboratory scale in our previous study but was comparable to other biochars reported in the literature. Response surface methodology analysis indicated that reaction time, dose, and agitation significantly influenced Cd removal by PMBC, whereas pH had a negligible impact. Notable contributions to Cd adsorption include the release of K + from PMBC and the presence of O-containing functional groups. Under continuous flow conditions with real wastewater, Cd was not detected in the effluent for the initial 8 h, and PMBC sustained a removal efficiency of 40.77% until saturation was reached. The results from wastewater treatment and large-scale biochar production offer valuable insights into the potential of biochar as a medium for addressing environmental issues in real-world applications., 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.)

Objective: Annuloplasty is the most common strategy for repair of functional tricuspid regurgitation (FTR) but is not effective in patients with massive/torrential FTR or leaflet tethering. To address the deficits of tricuspid annuloplasty, TRicuspid Anterior and Posterior Patch (TRAPP) repair was developed, which is a pericardial patch augmentation of the anterior and posterior leaflets., Methods: To test this repair, a previously validated ex vivo model in an explanted porcine heart was used, wherein annular and leaflet geometry were evaluated using a 3-dimensional structured light scanner at 4 time points: (1) baseline, (2) induction of FTR, (3) annuloplasty repair, and (4) patch repair., Results: Compared with the regurgitant tricuspid valve, annuloplasty reduced annular circumference (13.7 to 9.5 cm) and area (13.7 vs 6.1 cm 2 ), whereas TRAPP repair did not alter annular dimensions (circumference: 13.7 vs 13.5 cm; area: 13.7 vs 13.6 cm 2 ). Annuloplasty increased leaflet tenting angles (anterior: 53.5° vs 41.0°; posterior: 59.7° vs 48.2°; septal: 38.9° vs 31.4°) whereas TRAPP repair relieved anterior and posterior leaflet tenting (anterior: 28.9° vs 41.0°; posterior: 34.9° vs 48.2°; septal: 33.2° vs 31.4°) and restored geometry comparable to the native tricuspid valve. Central coaptation lengths were greater with TRAPP repair than with annuloplasty for all 3 leaflets (anterior: 12.7 vs 9.5 mm; posterior: 12.2 vs 8.2 mm; septal: 7.4 vs 4.6 mm)., Conclusions: Compared with annuloplasty, TRAPP repair yielded greater coaptation length, resolved leaflet tethering, and resulted in a larger annular area that may facilitate durable repair of advanced FTR, which previously would have required replacement., 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.

Pediatric patients who have undergone hematopoietic stem cell transplantation (HSCT) or chemotherapy are at increased risk for severe influenza complications, necessitating annual vaccination. This study evaluated the immunogenicity and antibody persistence of the 2021-2022 seasonal quadrivalent influenza vaccine in pediatric patients post-HSCT or chemotherapy, compared to healthy controls. A prospective cohort study included 80 pediatric participants divided into three groups: chemotherapy ( n = 33), HSCT ( n = 27), and healthy controls ( n = 20). All participants were vaccinated with the 2021-2022 GC FLU Quadrivalent vaccine. Hemagglutination inhibition (HI) assays measured seroprotection rates (SPR), geometric mean titers (GMT), and seroconversion rates (SCR) for the four vaccine antigens (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) at one, three, and six months post-vaccination. At one month post-vaccination, all groups met the 70% SPR threshold for A/H1N1 and A/H3N2, but not for B/Victoria. For B/Yamagata, the SPR was low in the chemotherapy and HSCT groups (18.18% and 33.33%, respectively), compared to 80.00% in controls ( p < 0.0001 and p = 0.0015). While A/H1N1 and A/H3N2 GMTs were protective in all groups, only controls achieved protective levels for B/Yamagata. Over time, the control group maintained >70% SPR for A/H1N1 up to six months, but the chemotherapy and HSCT groups declined by three and six months, respectively. For A/H3N2, the SPR in controls dropped below 70% at three months, while it remained above 70% in the chemotherapy and HSCT groups until three months. None of the groups achieved protective GMTs for B strains at three or six months. Pediatric patients post-HSCT or chemotherapy demonstrated a comparable immune response to healthy controls for A/H1N1 and A/H3N2, but the rapid decline in A/H1N1 antibody levels suggests the need for ongoing monitoring and adjusted vaccination schedules. The poor response to B antigens, particularly B/Yamagata, underscores the need for improved vaccination strategies in these vulnerable populations.

Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Jian Yang reports was provided by 10.13039/501100001809National Natural Science Foundation of China. Jian Yang reports equipment, drugs, or supplies was provided by the 10.13039/100009110Natural Science Foundation of Xinjiang Uygur Autonomous Region, China. Xiao-li Ma reports equipment, drugs, or supplies was provided by the Xinjiang Uygur Autonomous Region Tianshan Talent Youth Top Talent Project, China. Reports a relationship with that includes:. Has patent pending to. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Abbreviations:ATPAdenosine TriphosphateCCK-8Cell Counting Kit-8CCCPCarbonyl cyanide 3-chlorophenylhydrazoneDCFH-DA2,7-Dichlorodihydrofluorescein diacetateDRP1Dynamin-related protein 1;EX527SelisistatFFAFree fatty acidHepG2Hepatocellular carcinoma cellsIC50Half maximal inhibitory concentrationNRF1Recombinant Nuclear Respiratory Factor 1OAOleic acidOPA1Optic atrophy 1PAPalmitic acidPGC-1αPeroxisome proliferator-activated receptor gamma coactivator 1-alphaPMSFPhenylmethylsulfonyl fluorideROSReactive oxygen spicesSIRT-1Sirtuin-1SREBP1Sterol-regulatory element binding protein 1TFAMMitochondrial transcription factorATGTriglyceride, (© 2024 The Authors.)

To assist the translation of genetic findings to disease pathobiology and therapeutics discovery, we present an ensemble deep learning framework, termed PIONEER (Protein-protein InteractiOn iNtErfacE pRediction), that predicts protein-binding partner-specific interfaces for all known protein interactions in humans and seven other common model organisms to generate comprehensive structurally informed protein interactomes. We demonstrate that PIONEER outperforms existing state-of-the-art methods and experimentally validate its predictions. We show that disease-associated mutations are enriched in PIONEER-predicted protein-protein interfaces and explore their impact on disease prognosis and drug responses. We identify 586 significant protein-protein interactions (PPIs) enriched with PIONEER-predicted interface somatic mutations (termed oncoPPIs) from analysis of approximately 11,000 whole exomes across 33 cancer types and show significant associations of oncoPPIs with patient survival and drug responses. PIONEER, implemented as both a web server platform and a software package, identifies functional consequences of disease-associated alleles and offers a deep learning tool for precision medicine at multiscale interactome network levels., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The BRAF gene is an important signaling molecule in human cells that is involved in the regulation of cell growth, differentiation, and survival. When the BRAF gene mutates, it can lead to abnormal activation of the signaling pathway, which promotes cell proliferation, inhibits cell apoptosis, and ultimately contributes to the occurrence and development of cancer. BRAF mutations are widely present in various cancers, including malignant melanoma, thyroid cancer, colorectal cancer, non-small cell lung cancer, and hairy cell leukemia, among others. BRAF is an important target for the treatment of various solid tumors, and targeted combination therapies, represented by BRAF inhibitors, have become one of the main treatment modalities for a variety of BRAF-mutation-positive solid tumors. Dabrafenib plus trametinib, as the first tumor-agnostic therapy, has been approved by the US Food and Drug Administration for the treatment of adult and pediatric patients aged 6 years and older harboring a BRAF V600E mutation with unresectable or metastatic solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. This is also the first time a BRAF/MEK inhibitor combination has been approved for use in pediatric patients. As research into the diagnosis and treatment of BRAF mutations advances, standardizing the detection of BRAF mutations and the clinical application of BRAF inhibitors becomes increasingly important. Therefore, we have established a universal and systematic strategy for diagnosing and treating solid tumors with BRAF mutations. In this expert consensus, we (1) summarize the epidemiology and clinical characteristics of BRAF mutations in different solid tumors, (2) provide recommendations for the selection of genetic testing methods and platforms, and (3) establish a universal strategy for the diagnosis and treatment of patients with solid tumors harboring BRAF mutations., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Context: Conventional MRI is incompatible with extracorporeal membrane oxygenation (ECMO) cannulas and pumps. Ultra-low-field portable MRI (ULF-pMRI) with 0.064 Tesla may provide a solution, but its safety and compatibility is unknown., Hypothesis: ULF-pMRI does not cause significant displacement and heating of ECMO cannulas and does not affect ECMO pump function., Methods and Models: ECMO cannulas in various sizes were tested ex vivo using phantom models to assess displacement force and heating according to the American Society for Testing and Materials criteria. ECMO pump function was assessed by pump flow and power consumption. In vivo studies involved five female domestic pigs (20-42 kg) undergoing different ECMO configurations (peripheral and central cannulation) and types of cannulas with an imaging protocol consisting of T2-weighted, T1-weighted, FLuid-Attenuated Inversion Recovery, and diffusion-weighted imaging sequences., Results: Phantom models demonstrated that ECMO cannulas, both single lumen with various sizes (15-24-Fr) and double lumen cannula, had average displacement force less than gravitational force within 5 gauss safety line of ULF-pMRI and temperature changes less than 1°C over 15 minutes of scanning and ECMO pump maintained stable flow and power consumption immediately outside of the 5 gauss line. All pig models showed no visible motion due to displacement force or heating of the cannulas. ECMO flow and the animals' hemodynamic status maintained stability, with no changes greater than 10%, respectively., Interpretation and Conclusions: ULF-pMRI is safe and feasible for use with standard ECMO configurations, supporting its clinical application as a neuroimaging modality in ECMO patients., Competing Interests: Dr. Cho is supported by the National Heart, Lung, and Blood Institute (1K23HL157610). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Objective: This study was designed to investigate the clinical, pathological, endoscopic, and imaging characteristics of gastrointestinal metastasis in patients with lung cancer., Methods: The clinical data of 20 patients with primary lung cancer with gastrointestinal metastasis., Results: This study included sixteen men and four women, ranging in age from 31 to 75 years. The time interval from the diagnosis of lung cancer to the detection of gastrointestinal metastasis ranged from 13 to 142 months. The most common sites of metastasis were the small intestine (eight cases), colon (four cases), and upper gastrointestinal tract (eight cases). The major symptoms included obstruction, perforation, abdominal pain, abdominal distension, anorexia, and anemia. The predominant pathological type was poorly differentiated adenocarcinoma (seventeen cases). A single ulcer was mostly seen on endoscopy, and some cases showed a slight depression of the intestinal wall. The CT and PET-CT scan revealed bowel wall thickening, intraluminal polypoid masses, and intestinal perforation., Conclusion: Gastrointestinal metastasis of lung cancer is mainly observed in the small intestine, colon, and stomach, and is often detected when severe complications such as gastrointestinal obstruction and perforation occurred. Regular evaluation of gastrointestinal conditions during lung cancer diagnosis and treatment is recommended to improve the diagnostic accuracy and prevent misdiagnosis., Competing Interests: The authors declare that they have no competing interests in this work., (© 2024 Liao et al.)

Novel clinical trial designs are conducted in the precision medicine era. This study aimed to evaluate biomarker-driven, adaptive phase II trials in precision oncology, focusing on infrastructure, efficacy, and safety. We systematically reviewed and analyzed the target studies. EMBASE and PubMed searches from 2015 to 2023 generated 29 eligible trials. Data extraction included infrastructure, biomarker screening methodologies, efficacy, and safety profiles. Government agencies, cancer hospitals, and academic societies with accumulated experiences led investigator-initiated precision oncology clinical trials (IIPOCTs), which later guided sponsor-initiated precision oncology clinical trials (SIPOCTs). Most SIPOCTs were international studies with basket design. IIPOCTs primarily used the central laboratory for biomarker screening, but SIPOCTs used both central and local laboratories. Most of the studies adapted next-generation sequencing and/or immunohistochemistry for biomarker screening. Fifteen studies included an independent central review committee for outcome investigation. Efficacy assessments predominantly featured objective response rate as the primary endpoint, with varying results. Nine eligible studies contributed to the United States Food and Drug Administration's marketing authorization. Safety monitoring was rigorous, but reporting formats lacked uniformity. Health-related quality of life and patient-reported outcomes were described in some protocols but rarely reported. Our results reveal that precision oncology trials with adaptive design rapidly and efficiently evaluate anticancer drugs' efficacy and safety, particularly in specified biomarker-driven cohorts. The evolution from IIPOCT to SIPOCT has facilitated fast regulatory approval, providing valuable insights into the precision oncology landscape.

Importance: EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs)., Objective: To investigate CNS activity with lazertinib, a third-generation EGFR TKI., Design, Setting, and Participants: This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022., Exposure: Lazertinib, 240 mg, once daily., Main Outcomes and Measures: The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety., Results: Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2., Conclusions and Relevance: In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment., Trial Registration: ClinicalTrials.gov Identifier: NCT05326425.

Purpose: Staphylococcus aureus is a Gram-positive bacterium that most frequently acquires antibiotic resistance. As an opportunistic pathogen, it can cause conditions such as bacteremia, sepsis, and myocarditis. Due to the social need for a vaccine against methicillin-resistant Staphylococcus aureus (MRSA), many research groups have been designing and studying vaccines for decades. In this study, we developed a multivalent vaccine and evaluated its efficacy by applying a novel adjuvant, β-glucan., Materials and Methods: A vaccine composed of four pore-forming toxins from S. aureus was administered to rabbits 3 times, after which they were challenged with S. aureus USA 300 LAC strain. We measured changes in the rabbits' body weight to monitor systemic adverse reactions and analyzed the total immunoglobulin G antibody titer against the four antigens using enzyme-linked immunosorbent assay. For each rabbit, the number of abscesses and colony-forming units (CFU) in the kidneys were measured., Results: In all vaccinated groups, strong antibody responses against the four antigens were observed. After challenging with MRSA, the vaccinated groups showed less weight change compared to the non-vaccinated groups (average 5.7% versus 13.5%). Additionally, the number of renal abscesses was significantly lower in the vaccinated groups, with three individuals in group 1 (four antigens adjuvanted with β-glucan&#95;PK1) showing no abscess formation. The number of bacteria identified in the kidneys was also statistically significantly lower in the vaccinated group compared to the non-vaccinated group., Conclusion: We demonstrated that the four toxoid antigens we selected can protect against S. aureus infection in a rabbit model and that β-glucan could be used as an immune enhancer. Overall, our study shows that new antigen combinations can induce protective immunity in animal models and that a toxin-based vaccine can help control bacterial colonization., Competing Interests: No potential conflict of interest relevant to this article was reported., (© Korean Vaccine Society.)

The increasing presence of pharmaceuticals and personal care products (PPCPs) in aquatic systems pose significant environmental concerns. This study addresses this issue by synthesizing quaternized mesoporous SBA-15 (Q SBA ) with varied alkyl chain lengths of C1Q SBA , C8Q SBA , and C18Q SBA . Q SBA utilizes dual mechanisms: hydrophobic interactions via the alkyl chain and electrostatic attraction/ion exchange via the ammonium group. Diclofenac (DCF) and acetaminophen (ACT) were selected as target PPCPs due to their contrasting dissociation properties and hydrophobicity, which are the main characteristics of PPCPs. The adsorption of DCF and ACT revealed that longer alkyl chains enhanced the adsorption capacity of ACT through hydrophobic interactions, whereas dissociated DCF (DCF - ) adsorption was superior owing to its high hydrophobicity (log Kow = 4.5) and electrostatic attraction. pH levels between 6 and 8 resulted in a high affinity for DCF - . Notably, among the three alkyl chains, only C18Q SBA exhibited the most effective adsorption for DCF - . These PPCPs adsorption trends were confirmed through molecular simulations of adsorption under conditions in which competing ions coexisted. The molecular simulations show that while DCF - has lower adsorption energy than Cl - , OH - , and H 3 O + ions in Q SBA , enhancing its adsorption under various pH conditions. Conversely, ACT exhibits a higher adsorption energy, which reduces its adsorption efficiency. This suggests the potential application of Q SBA with long alkyl chains in the treatment of highly hydrophobic and negatively charged PPCPs. Furthermore, this study emphasizes the importance of simulating adsorption under competing ion conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

As one of the grave environmental hazards, soil salinization seriously limits crop productivity, growth, and development. When plants are exposed to salt stress, they suffer a sequence of damage mainly caused by osmotic stress, ion toxicity, and subsequently oxidative stress. As sessile organisms, plants have developed many physiological and biochemical strategies to mitigate the impact of salt stress. These strategies include altering root development direction, shortening the life cycle, accelerating dormancy, closing stomata to reduce transpiration, and decreasing biomass. Apart from being a prime energy source, light is an environmental signal that profoundly influences plant growth and development and also participates in plants' response to salt stress. This review summarizes the regulatory network of salt tolerance by light signals in plants, which is vital to further understanding plants' adaptation to high salinity. In addition, the review highlights potential future uses of genetic engineering and light supplement technology by light-emitting diode (LED) to improve crop growth in saline-alkali environments in order to make full use of the vast saline land., Competing Interests: The authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Skin identity is controlled by intrinsic features of the epidermis and dermis and their interactions. Modifying skin identity has clinical potential, such as the conversion of residual limb and stump (nonvolar) skin of amputees to pressure-responsive palmoplantar (volar) skin to enhance prosthesis use and minimize skin breakdown. Greater keratin 9 ( KRT9 ) expression, higher epidermal thickness, keratinocyte cytoplasmic size, collagen length, and elastin are markers of volar skin and likely contribute to volar skin resiliency. Given fibroblasts' capacity to modify keratinocyte differentiation, we hypothesized that volar fibroblasts influence these features. Bioprinted skin constructs confirmed the capacity of volar fibroblasts to induce volar keratinocyte features. A clinical trial of healthy volunteers demonstrated that injecting volar fibroblasts into nonvolar skin increased volar features that lasted up to 5 months, highlighting a potential cellular therapy.

Background: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME)., Methods: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance., Results: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice., Conclusions: This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

The present study aimed to identify the metabolites associated with the physiological activity of kimchi-derived lactic acid bacteria (LAB). A clear difference was observed between the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging rates when the pyruvate content was high (273.5 ng/µL; radical removal speed 6.50% per min) and the rates when the pyruvate content had decreased (131.9 ng/µL; radical removal speed 3.63% per min). Additionally, the characteristics of LAB antioxidant activity (increase in ABTS radical scavenging activity with reaction time, low level of 2,2-diphenyl-1-picrylhydrazyl radical scavenging activity) were similar to those of pyruvate-derived activity. Hydrogen peroxide content (WiKim0124, 2.08 → 0.26; WiKim0121, 0.99 → 0.47; WiKim39, 1.93 → 0.24) and lactate dehydrogenase activity (WiKim0124, 1.53 → 0.00; WiKim0121, 0.73 → 0.01; WiKim39, 1.72 → 0.02) decreased more in heat-killed LAB than in non-heat-killed LAB. Accordingly, this resulted in increased pyruvate content and the inhibitory activity of lipid peroxide production increased by 2-3 times. Our findings indicate that pyruvate is one of the major metabolites regulating LAB physiological activity. PRACTICAL APPLICATION: The safety of utilizing live probiotics remains a topic of debate. To mitigate associated risks, there is a growing interest in non-viable microorganisms or microbial cell extracts for use as probiotics. Various methods can be employed for probiotic inactivation. Heat treatment typically emerges as the preferred choice for inactivating probiotic strains in many instances. The present study shows the distinctions between inactivating lactic acid bacteria (LAB) through heat treatment and non-heat treatment. It may serve as a valuable reference for selecting an appropriate inactivation method for LAB in industrial processes., (© 2024 The Author(s). Journal of Food Science published by Wiley Periodicals LLC on behalf of Institute of Food Technologists.)

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)