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Thorium, a predominant actinide in the Earth's crust, presents significant environmental and health risks due to its radioactive nature. These risks are particularly pronounced during the mining and processing of monazite for rare earth elements (REEs), which contain substantial thorium concentrations. Current instrumental analysis methods for thorium, offer high accuracy but require laborious sample preparations and expensive instruments, making them unsuitable for on-site analysis. Herein, we present a class of color-tunable luminescent lanthanide-based metal-organic frameworks (Ln-MOFs) as fluorochromic sensors for Th 4+ cations. Utilizing a heterobimetallic Eu 3+ /Tb 3+ doping strategy, the luminescence colors of Eu x Tb 1-x -BDC-OH can be finely tuned from red, to orange, and to green. More intriguingly, the higher Lewis acidity of Th 4+ facilitates the transformation of Eu x Tb 1-x -BDC-OH into a UiO-type Th-MOF via a dissolution-recrystallization mechanism. This process results in a gradual reduction of characteristic Ln 3+ emissions and the emergence of blue color ligand-based fluorescence, thereby leading to selective fluorochromic responses with increasing Th 4+ concentrations and enabling visible detection of Th 4+ cations. Additionally, a custom-built portable optoelectronic device is fabricated, which directly converts luminescence colors into red-green-blue (RGB) values. This device enables easy quantification of Th 4+ concentrations without the need for complex instrumentation., (© 2024 Wiley-VCH GmbH.)

Porous metal-organic frameworks (MOFs) have shown great potential as adsorbents for capturing radioiodine, a major fission product generated during the reprocessing of nuclear fuel. However, studies exploring the correlation between the structure of MOFs and iodine uptake capacity remain notably rare. In this study, we introduce a new strategy for enhancing the iodine adsorption efficiency of MOFs by strategically varying the position of functional groups on the organic linkers. Employing ligand-functionalized UiO-67 MOFs, our findings reveal that ortho -amino substitution of UiO-67- o -NH 2 , proximal to the node of the dicarboxylate linker, markedly accelerates adsorption kinetics of iodine vapor in comparison to meta -amino substitution of UiO-67- m -NH 2 , where the amino groups are oriented away from the node. In contrast, UiO-67- m -NH 2 exhibits a higher adsorption capacity of 2.19 g/g, compared to 1.91 g/g for UiO-67- o -NH 2 , attributable to its higher porosity. Furthermore, a competitive I 2 /H 2 O vapor adsorption study demonstrated that UiO-67- o -NH 2 exhibits faster adsorption kinetics and higher selectivity for iodine in the presence of water vapor compared to UiO-67- m -NH 2 . Additionally, the crucial influence of positional isomerism on enhancing iodine adsorption has been corroborated through Raman spectroscopy, X-ray photoelectron spectroscopy, and density functional theory calculations. These analyses reveal that the nitrogen atom positioned at the ortho site demonstrates a stronger affinity for iodine molecules compared to the nitrogen atom at the meta site, thereby improving adsorption kinetics.

Background: Vitamin K (VK), an essential fat-soluble nutrient, exists in two primary forms, vitamin K1 (VK1), and vitamin K2 (VK2). VK1 plays an essential role in blood coagulation, while VK2 plays a crucial role in managing bone calcification, supporting bone strength and health. However, comprehensive epidemiological data on VK remains sparse, particularly in children. This study aims to evaluate the levels and characteristics of VK in children of Wenzhou area, China., Methods: A total of 3,342 children undergoing routine physical examinations in the outpatient department from December 2020 to August 2022 were recruited. The levels of VK (including VK1 and menaquinones (MK-4), a major form of VK2) and 25-hydroxy vitamin D (25(OH)D) in fasting serum samples from these children were measured using high-performance liquid chromatography-tandem mass spectrometry. The study analyzed the levels and distribution of VK and 25(OH)D across different sex, age, and weight groups, and explored their potential related factors., Results: The median serum levels of MK-4 and VK1 were 0.12 (0.07, 0.21) ng/ml and 0.33 (0.18, 0.57) ng/ml, respectively. The reference ranges of MK-4 and VK1 were 0.01-0.58 ng/ml and 0.03-1.48 ng/ml, respectively. The median serum 25(OH)D level was 21.26 (17.30, 25.35) ng/ml. Moreover, there were no significant variations in the levels of MK-4 and VK1 across different age and sex groups. The level of MK-4 in the underweight group was significantly higher than that in the normal weight group. MK-4 level reached its peak in summer, while the VK1 concentration was at its lowest. Furthermore, a very weak positive correlation was revealed between MK-4 and VK1 levels., Conclusion: In this study, we defined the median values and reference ranges of MK-4 and VK1 in a sample of Chinese children aged 0-18 years. MK-4 levels were higher in underweight children. Both MK-4 and VK1 levels exhibited seasonal variations. Further research is needed to explore the factors affecting MK-4 and VK1 levels., (© 2024. The Author(s).)

Human adenovirus type 7 (HAdV-7) is a prominent pathogen that causes severe pneumonia in children in China. However, the interaction between HAdV-7 infection and host metabolism is still poorly understood. To gain a comprehensive understanding of the metabolic interplay between host cells and the virus, we analysed the energy and lipid metabolism profiles of the HAdV-7-infected lung cancer cell line A549 by ultrahigh-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (ESI-QTRAP-MS/MS). Our study revealed significant alterations in various metabolic processes, including the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid metabolism, nucleotide metabolism, and lipid metabolism, in A549 cells after HAdV-7 infection. Moreover, HAdV-7 infection stimulated enhanced synthesis of membrane lipids in A549 cells. These findings emphasize the crucial role of metabolism in viral infection and suggest that modulating host cell metabolism could be a promising approach for targeted drug development and infection control., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond., Competing Interests: Declaration of interests P.R.C., F.L., J. Lin, and H. Zhang are listed as inventors on a patent application (PCT/CN2021/130337) filed on this work through Peking University., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study explores the relationship between m6A modification and ferroptosis in intrahepatic cholangiocarcinoma (ICC) and its impact on cisplatin resistance. We established cisplatin-resistant cells. CCK-8 and Transwell assays were conducted to evaluate the effects of METTL3 on drug resistance, migration, and invasion. RT-qPCR and Western blotting were used to measure target gene expression and the effects of overexpression and suppression. RIP, luciferase reporter assay, and other experiments were utilized to investigate the interaction between METTL3 and NRF2. Additionally, rescue experiments were performed to confirm the role of the METTL3/NRF2 axis in tumor drug resistance. METTL3 was found to be highly expressed in cisplatin-resistant cells, enhancing m6A modification levels, stabilizing NRF2 mRNA, and increasing NRF2 protein expression to inhibit ferroptosis. These findings indicate that the METTL3/NRF2 axis inhibits ferroptosis in cisplatin-resistant cells, thereby promoting chemotherapy resistance in ICC. This provides a potential direction for future research and treatment of ICC.

Background: Fat mass index (FMI) is a body composition indicator that reflects body fat content. Laparoscopic sleeve gastrectomy (LSG) is widely performed in patients with obesity., Objective: This study aimed to evaluate the value of the FMI in predicting weight loss effect and quality of life early after LSG., Material and Methods: From January 2014 to July 2022, the clinical data and computed tomography (CT) images of patients who underwent LSG at a tertiary referral teaching hospital were analyzed. Body composition indicators were calculated using the SliceOmatic software. Achieving initial body mass index within 6 months postoperatively was defined as early eligible weight loss (EEWL). The relationship between body composition and EEWL was analyzed., Results: A total of 243 patients were included. Receiver operating characteristic (ROC) curve analysis showed that the predictive value of the FMI for EEWL in patients after LSG was higher than that of other indicators (all P < 0.05; area under the curve = 0.813). The best FMI cut-off point was 13.662. Accordingly, the patients were divided into the high-FMI group and low-FMI group. The %EWL and BMI of patients in the low-FMI group at 1, 3, 6, 9, 12, and 24 months after surgery were better than those in the high-FMI group (all P < 0.001). Patients in the low-FMI group had higher BAROS (Bariatric Analysis and Reporting Outcome System) scores than those in the high-FMI group (P < 0.001)., Conclusion: Compared with other body composition indicators, FMI can effectively predict the early effect of weight loss and quality of life after LSG., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Knee osteoarthritis (KOA) is one of the leading causes of disability. Polydatin has a potential effect on KOA treatment but the therapeutic mechanism is not clear. This study aims to investigate the therapeutic action of polydatin in KOA and its mechanism in activating autophagy via the AMP-activated protein kinase (AMPK)/mTOR signaling pathway., Methods: After a KOA rat model was established by anterior cruciate ligament transection surgery, model rats were treated with polydatin 40 mg/kg for 30 days. Subsequently, cartilage tissues were collected, and hematoxylin-eosin (HE), Safranin-O, and TUNEL staining, and western blotting were performed to evaluate the pathological damage and autophagy-related protein expression. Then, human chondrocyte C28/I2 cells were stimulated with lipopolysaccharide (LPS), and the effects of polydatin on C28/I2 cell viability, apoptosis, and autophagy-related protein expression were detected by MTT, Flow Cytometry, and western blot. In addition, an AMPK inhibitor (Dorsomorphin 2HCl) was used to probe the cell proliferation and apoptosis of polydatin-administered C28/I2 cells., Results: Polydatin ameliorated the pathological damage in rat cartilage tissues and inhibited cell apoptosis in KOA rats. Meanwhile, in C28/I2 cells, polydatin promoted viability and reduced apoptosis. In addition, the protein expression of collagen II, LC3II/LC3I, Beclin-1, and p-AMPK/AMPK were upregulated, and p62 and p-mTOR/mTOR were downregulated by polydatin treatment. Interestingly, relative results showed that the protective effect of polydatin in LPS-stimulated-C28/I2 cells was blocked by the AMPK/mTOR inhibitor, dorsomorphin 2HCl., Conclusion: Our research showed that polydatin reduced apoptosis and activated autophagy both in vivo and in vitro by the AMPK/mTOR signaling pathway to protect against KOA, which provided the basis for further investigation into the potential therapeutic impact of polydatin on KOA., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Background: Accurate preoperative prediction of cervical lymph node metastasis (LNM) for papillary thyroid carcinoma (PTC) patients is essential for disease staging and individualized treatment planning, which can improve prognosis and facilitate better management., Purpose: To establish a fully automated deep learning-enabled model (FADLM) for automated tumor segmentation and cervical LNM prediction in PTC using ultrasound (US) video keyframes., Methods: The bicentral study retrospective enrolled 518 PTC patients, who were then randomly divided into the training (Hospital 1, n = 340), internal test (Hospital 1, n = 83), and external test cohorts (Hospital 2, n = 95). The FADLM integrated mask region-based convolutional neural network (Mask R-CNN) for automatic thyroid primary tumor segmentation and ResNet34 with Bayes strategy for cervical LNM diagnosis. A radiomics model (RM) using the same automated segmentation method, a traditional radiomics model (TRM) using manual segmentation, and a clinical-semantic model (CSM) were developed for comparison. The dice similarity coefficient (DSC) was used to evaluate segmentation performance. The prediction performance of the models was validated in terms of discrimination and clinical utility with the area under the receiver operator characteristic curve (AUC), heatmap analysis, and decision curve analysis (DCA). The comparison of the predictive performance among different models was conducted by DeLong test. The performances of two radiologists compared with FADLM and the diagnostic augmentation with FADLM's assistance were analyzed in terms of accuracy, sensitivity and specificity using McNemar's x 2 test. The p-value less than 0.05 was defined as a statistically significant difference. The Benjamini-Hochberg procedure was applied for multiple comparisons to deal with Type I error., Results: The FADLM yielded promising segmentation results in training (DSC: 0.88 ± 0.23), internal test (DSC: 0.88 ± 0.23), and external test cohorts (DSC: 0.85 ± 0.24). The AUCs of FADLM for cervical LNM prediction were 0.78 (95% CI: 0.73, 0.83), 0.83 (95% CI: 0.74, 0.92), and 0.83 (95% CI: 0.75, 0.92), respectively. It all significantly outperformed the RM (AUCs: 0.78 vs. 0.72; 0.83 vs. 0.65; 0.83 vs. 0.68, all adjusted p-values < 0.05) and CSM (AUCs: 0.78 vs. 0.71; 0.83 vs. 0.62; 0.83 vs. 0.68, all adjusted p-values < 0.05) across the three cohorts. The RM offered similar performance to that of TRM (AUCs: 0.61 vs. 0.63, adjusted p-value = 0.60) while significantly reducing the segmentation time (3.3 ± 3.8 vs. 14.1 ± 4.2 s, p-value < 0.001). Under the assistance of FADLM, the accuracies of junior and senior radiologists were improved by 18% and 15% (all adjusted p-values < 0.05) and the sensitivities by 25% and 21% (all adjusted p-values < 0.05) in the external test cohort., Conclusion: The FADLM with elaborately designed automated strategy using US video keyframes holds good potential to provide an efficient and consistent prediction of cervical LNM in PTC. The FADLM displays superior performance to RM, CSM, and radiologists with promising efficacy., (© 2024 American Association of Physicists in Medicine.)

Surfactin, a lipopeptide biosurfactant produced by Bacillus spp., has emerged as a promising bioactive compound due to its potent inhibitory effects on bacterial and viral pathogens. This showcases its potential as a non-antibiotic strategy for managing infectious diseases. Our investigation reveals that surfactin administration significantly promotes weight gain and improves immune organ indices in mice, reflecting enhanced immunity and gut health. Surfactin augments phagocytic function in peritoneal macrophages and boosts proliferative responses in splenic lymphocytes post-chicken red blood cell immunization. Furthermore, it increases intestinal villi height, indicative of superior nutrient absorption. It elevates mucin secretion and expression of intestinal mucosal proteins, such as secretory IgA, Muc1, and Muc2, and tight junction proteins claudin-1, occludin, and Zo-1 in the jejunum and colon. Crucially, surfactin modifies the gut microbiota composition by reducing Escherichia coli populations and ameliorating cyclophosphamide-induced gut dysbiosis. Our data suggest that oral surfactin could be a valuable therapeutic modality to alleviate immune suppression and gut damage, proposing a new pathway for immunomodulatory treatment., Importance: The potential of surfactin as a microbial surfactant extends beyond its surfactant properties, impacting immune regulation and gut health. As the need for alternatives to traditional antibiotics continues to grow, surfactin's ability to enhance host defense mechanisms against common pathogens without directly targeting them with antibiotics offers a strategic advantage. Understanding how surfactin shapes the immune landscape and the gut microbiome can inform innovative interventions against immunosuppression and intestinal impairment, particularly in contexts such as cyclophosphamide-induced toxicity.

Maternal low protein diet around pregnancy reduces the primordial follicles in offspring ovary. Resolving cellular and molecular mechanisms associated with low protein diet is therefore urgently needed for the guidance of dietary interventions. Here, we utilized single-cell and spatial RNA-seq to create transcriptomic atlases of offspring ovaries from maternal low protein diet mice. Analysis of cell type specific low protein diet associated transcriptional changes revealed increased unfolded protein and decreased oxidative phosphorylation defense as a hallmark of low protein diet effects. Altered pathways included hedgehog signaling in granulosa cells, BMP signaling in theca cells and PTN signaling in early theca cells. Notably, the disordered follicular cell function and ovarian microenvironment may closely corelated with decreased follicular number and quality. Collectively, our findings depict the transcriptomic atlases of the offspring ovary derived from maternal low protein diet group and provide candidate molecular mechanisms underlying the complex ovarian cell changes conferred by low protein diet., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

For single-atom catalysts (SACs), the dopants situated near the metal site have demonstrated a significant impact on the catalytic properties. However, the effect of dopants situated further away from the metal centers and their working mechanisms remain to be elucidated. Herein, we conduct density functional theory-driven studies on regulating the peripheral nitrogen dopants in graphene-based SACs, with a particular focus on Ir1 SAC, for propane dehydrogenation (PDH). It is found that increasing the distance between the N dopant and the Ir1 site results in a different energy change for the reaction process compared to the dense doping model with only first and second-shell N species. The proposed stochastic doping models demonstrate statistically that increasing the N dopant in farther shells not only enhances the activity of Ir1 but also maintains a high selectivity for propene, which is verified by experimental tests. The modulation of the d-band center of Ir1 by stochastic N dopants effectively modifies the binding strength of reaction intermediates, thereby enabling the optimization of the potential energy surface of PDH. These results deepen the understanding of dopant states around metal sites and provide an important implication for the doping engineering in heterogeneous catalysis., (© 2024 Wiley‐VCH GmbH.)

Dual-atom catalysts (DACs) are promising for applications in electrochemical CO 2 reduction due to the enhanced flexibility of the catalytic sites and the synergistic effect between dual atoms. However, precisely controlling the atomic distance and identifying the dual-atom configuration of DACs to optimize the catalytic performance remains a challenge. Here, the Ni and Fe atomic pairs were constructed on nitrogen-doped carbon support in three different configurations: NiFe-isolate, NiFe-N bridge, and NiFe-bonding. It was found that the NiFe-N bridge catalyst with NiN 4 and FeN 4 sharing two N atoms exhibited superior CO 2 reduction activity and promising stability when compared to the NiFe-isolate and NiFe-bonding catalysts. A series of characterizations and density functional theory calculations suggested that the N-bridged NiFe sites with an appropriate distance between Ni and Fe atoms can exert a more pronounced synergy. It not only regulated the suitable adsorption strength for the *COOH intermediate but also promoted the desorption of *CO, thus accelerating the CO 2 electroreduction to CO. This work provides an important implication for the enhancement of catalysis by the tailoring of the coordination structure of DACs, with the identification of distance effect between neighboring dual atoms., (© 2024 Wiley-VCH GmbH.)

Ethnopharmacological Relevance: The use of lavender as sleep aid or hypnotic agent can be traced back as early as ancient Romans and Greeks. Yet, objective experimental data on whether and how lavender enhances sleep duration or/and sleep quality remain lacking., Aim of the Study: We aimed to characterize the sleep-wake regulating effects of lavender in the mouse and to demonstrate the brain targets and neural circuits involved., Materials and Methods: A self-made precise odor delivery system combined with chronic polysomnographic recordings was employed to assess the sleep-wake effects of inhalation with lavender essential oil (LEO, extracted from lavender) and its different constituents during the light and dark phases in free-moving C57BL/6J mice. Neuroviral labeling, in situ hybridization and pharmacogenetics were combined to identify the neural circuits and targets involved. Finally, an insomniac model of DL-4-Chlorophenylalanine (PCPA)-treated mice was established to examine the sleep-inducing potential of LEO., Results: We found that inhalation of LEO with a concentration at 25.0% during the light (inactive) phase significantly shortened the latency to non-rapid eye movement (NREM) sleep, increased the total amount of NREM sleep at the expense of wakefulness (W), and enhanced cortical EEG slow wave activities, notably delta power spectra density. We further identified linalool, d-limonene, 1,8-cineole, linalyl acetate and terpinene-4-ol as the major effective sleep-promoting monomer components. Importantly, we found that LEO no longer produced any of the above sleep-promoting effect following either nasal injection of zinc sulfate which interrupts the olfactory pathway, or pharmacogenetics silencing of central amygdala GABAergic neurons. Finally, LEO reestablished NREM sleep with short latency in PCPA-treated insomniac mice, effects comparable with those induced by a potent sedative diazepam., Conclusions: We have characterized the quantitative and qualitative sleep-promoting effects of LEO and its effective components via the olfactory pathway and central amygdala GABA neuronal targets. The hypnotic property of LEO is reinforced by its ability to restore sleep in insomnia. Our study thus establishes a neurobiological basis for aromatherapy of sleep disorders using lavender., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is a major cause of cancer-related death worldwide and an effective screening strategy for diagnosis of early-stage CRC is highly desired. Although extracellular vesicles (EVs) are expected to become some of the most promising tools for liquid biopsy of early disease diagnosis, the existing EV-based proteomics methods for practical application in clinical samples are limited by technical challenges in high-throughput isolation and detection of EVs. In the current study, we have developed a simplified and efficient EV-based proteomics strategy for early diagnosis of CRC. DSPE-functionalized beads were specifically designed that enabled direct capture of EVs from plasma samples in 10 minutes with good reproducibility and comprehensive proteome coverage. The single-pot, solid-phase-enhanced sample-preparation (SP3) technology was then combined with data-independent acquisition mass spectrometry (DIA-MS) for in-depth analysis and quantification of EV proteomes. From a cohort with 30 individuals including 11 healthy controls, 8 patients with adenomatous polyp and 11 patients with early-stage CRC, our streamlined workflow reproducibly quantified over 800 proteins from their plasma-derived EV samples, from which dysregulated protein signatures for molecular diagnosis of CRC were revealed. We selected a panel of 10 protein markers to train a machine learning (ML) model, which resulted in accurate prediction of polyp and early-stage CRC in an independent and single-blind validation cohort with excellent diagnostic ability of 89.3% accuracy. Our simplified and efficient clinical proteomic strategy will serve as a valuable tool for fast, accurate, and cost-effective diagnosis of CRC that can be easily extended to other disease samples for discovery of unique EV-based biomarkers., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

There is an increasing demand for p-type semiconductors with scalable growth, excellent device performance, and back-end-of-line (BEOL) compatibility. Recently, tellurium (Te) has emerged as a promising candidate due to its appealing electrical properties and potential low-temperature production. So far, nearly all of the scalable production and integration of Te with complementary metal oxide semiconductor (CMOS) technology have been based on physical vapor deposition. Here we demonstrate wafer-scale atomic layer-deposited (ALD) TeO x /Te heterostructure thin-film transistors with high uniformity and integration compatibility. The wafer-scale uniformity of the film is evidenced by spatial Raman mappings and statistical electrical analysis. Furthermore, surface accumulation-induced good ohmic contact has been observed and explained by the unique band alignment of the charge neutrality level inside the Te valence band. These results demonstrate ALD TeO x /Te as a promising p-type semiconductor for monolithic three-dimensional integration in BEOL CMOS applications incorporated with well-established n-type ALD oxide semiconductors.

In this study, a feasibility of γ radiation detection using complementary metal-oxide semiconductor (CMOS) image sensors with a neural network algorithm to extract the γ rays interacted pixels has been investigated. The responses characteristics of the CMOS imaging sensor to γ-ray is studied by placed in a γ fields produced by standard 60 Co or 137 Cs isotope sources. The supported preview frame rate of the CMOS image sensor is 25 fps, establishing the functional relationship between the gray level histograms and the dose rate through the neural network, the high energy γ-ray from 60 Co and 137 Cs source radiation dose rate in µSv/h level can be detected using the CMOS imaging sensor. The results show that the proposed method can effectively identify the number of photon particles which detected by the radiation monitoring system based on CMOS image sensor, and infer that the CMOS imaging sensor with a radiation signal extraction algorithm can be used as a dose warner for radiation protection purpose., (© 2024. The Author(s).)

Objective: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood., Design: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21 -floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms., Results: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1 + cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy., Conclusions: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD., Competing Interests: Declaration of competing interest None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Since the onset of COVID-19, respiratory diseases have emerged as a focal concern within the field of public health. This study aims to reveal the prevalence of acute respiratory infectious diseases by screening antipyretic, antiviral, and antibiotic biomarkers through wastewater analysis. Samples were collected over a seven-day period each year in 2022, 2023, and 2024 from a northern city in China, assessing the concentrations of two antipyretics (paracetamol and ibuprofen), one antiviral drug (oseltamivir), eleven antibiotics, and three pathogens (influenza A, influenza B, and Mycoplasma pneumoniae). The usage of most antipyretics and antibiotics was higher in 2023 and 2024, primarily due to the outbreak of COVID-19 in 2023 and the prevalence of influenza A, influenza B, and Mycoplasma pneumoniae in 2024. The prevalence assessed using antipyretics (2.68 %) and pathogens (2.70 %) demonstrated a high degree of consistency, whereas the prevalence estimated using antibiotics and antiviral drugs was only 0.53 % and 0.36 %, respectively. Antibiotics are generally used to treat a broad spectrum of bacterial infections rather than targeting a specific pathogen, so their presence in wastewater may not directly reflect the prevalence of a particular disease. In contrast, antipyretics and specific pathogens exhibit a stronger correlation, suggesting that they may serve as more reliable biomarkers than antiviral and antibiotic drugs. The research findings offer alternative biomarkers, such as antipyretics, aside from pathogens, for the assessment of acute respiratory infectious diseases., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The performance of 3D printed thermoplastics largely depends on the ink formulation, which is composed of tremendous chemical space as an increased number of monomers, making it very difficult to identify an optimum one with desired properties. To tackle this challenge, we demonstrate a virtual experimentation platform that is enabled by a physics-informed machine learning algorithm. As a case study, the algorithm was trained based on a multilayer perceptron (MLP) model to predict the experimental stress-strain curves of the 3D printed thermoplastics given the ink compositions made of six monomers. To solve the issue of experimental data scarcity, we first reduced the dimensions of the curves to eight principal components (PCs), which serve as the outputs of the model. In addition, we incorporated the physics-informed descriptors into the input dataset. These two strategies afford the model with a prediction accuracy of R 2 of 0.97 and an RMSE value of 1.01 for fracture strength, and an R 2 of 0.95 and a RMSE of 0.40 for toughness. To perform virtual experimentation, the well-trained model was then utilized to predict 100 000 sets of the PCs from the randomly given 100 000 ink formulations. The PC sets were then converted back to the corresponding stress-strain curves. To validate the prediction results, some of the virtual experiments were performed. The results showed a good match between the predicted and experimental curves. This methodology offers a general and efficient pathway to virtual experimentation for establishing the correlation between the complex input variables and the output performance metrics of new materials.

Lung cancer is the leading cause of cancer deaths worldwide. Brain metastasis of lung cancer, which counts for nearly 50% of late-stage lung cancer patients, is a sign of a really poor prognosis. However, the presence of blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) limits the penetration of drugs from the blood into the brain and thus restricts their accumulation in brain tumors. Systematic delivery of drugs into brain and brain tumor lesion using BBB and BBTB penetrating vehicles represents a promising strategy to overcome the BBB and BBTB limitations. Hence, we validated one of our previously identified BBB/BBTB penetrating peptide and its drug conjugate form for the treatment of lung cancer brain metastasis. With in vitro experiment, we first validated that the receptor LRP1, which mediated the peptide penetration of the BBB, was expressed on lung cancer cells and thus can be targeted by the peptide to overcome BBTB. With this delivery peptide, we constructed peptide-paclitaxel conjugate (the PDC) and in vitro validation showed that the PDC can across the BBB and efficiently kill lung cancer cells. We therefore constructed mouse lung cancer brain metastasis xenograft. In vivo anti-tumor validations showed that the PDC efficiently inhibited the proliferation of the brain resident lung cancer cells and significantly expanded the survival of the mouse xenograft, with no visible damages to the organs. Overall, our study provided potential therapeutic drugs for the treatment of lung cancer brain metastasis that may be clinically effective in the near future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The efficient utilization of methane, a vital component of natural gas, shale gas and methane hydrate, holds significant importance for global energy security and environmental sustainability. However, converting methane into value-added oxygenates presents a formidable challenge due to its inert nature. Direct selective oxidation of methane (DSOM) under mild conditions is essential for reducing energy consumption and carbon emissions compared with traditional indirect routes. Achieving total selectivity in methane hydroxylation remains elusive due to the competitive CO 2 formation. This feature article highlights recent advancements in methane hydroxylation using thermo-, photo-, and electro-catalytic systems. Through strategically designing the structure of catalysts to control the reactive oxygen species and optimizing reaction parameters, significant progress has been made in enhancing oxygenate selectivity and minimizing overoxidation. A comprehensive understanding of the mechanisms underlying methane hydroxylation with total selectivity offers insights for improving catalyst design and reaction parameter optimization, promoting sustainable methane utilization.

In vivo astrocyte-to-neuron (AtN) conversion induced by overexpression of neural transcriptional factors has great potential for neural regeneration and repair. Here, we demonstrate that a single neural transcriptional factor, Dlx2, converts mouse striatal astrocytes into neurons in a dose-dependent manner. Lineage-tracing studies in Aldh1l1-CreERT2 mice confirm that Dlx2 can convert striatal astrocytes into DARPP32 + and Ctip2 + medium spiny neurons (MSNs). Time-course studies reveal a gradual conversion from astrocytes to neurons in 1 month, with a distinct intermediate state in between astrocytes and neurons. Interestingly, when Dlx2-infected astrocytes start to lose astrocytic markers, the other local astrocytes proliferate to maintain astrocytic levels in the converted areas. Unexpectedly, although Dlx2 efficiently reprograms astrocytes into neurons in the gray matter striatum, it also induces partial reprogramming of astrocytes in the white matter corpus callosum. Such partial reprogramming of white matter astrocytes is associated with neuroinflammation, which can be suppressed by the addition of NeuroD1. Our results highlight the importance of investigating AtN conversion in both the gray matter and white matter to thoroughly evaluate therapeutic potentials. This study also unveils the critical role of anti-inflammation by NeuroD1 during AtN conversion., (© 2024 The Author(s). Developmental Neurobiology published by Wiley Periodicals LLC.)

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome's set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate-release (IR) tablets, modified-release (MR) tablets, and IR solution. A once daily MR microsphere formulation was developed for use in pediatric patients. Demonstration of bioequivalence (BE) between the 10 mg once daily (q.d.) MR microsphere formulation and 5 mg twice daily (b.i.d.) IR solution is needed to enable the exposure-response analyses-based bridging to support regulatory approval. To assess BE between MR microsphere and IR solution, an innovative approach was utilized with physiologically-based pharmacokinetic (PBPK) virtual BE trials (VBE) in lieu of a clinical BE trial. A PBPK model was developed to characterize the absorption of different formulations of tofacitinib using Simcyp ADAM module. VBE trials were conducted by simulating PK profiles using the verified PBPK model and integrating the clinically observed intrasubject coefficient of variation (ICV) where BE was assessed with a predetermined sample size and prespecified criteria. The VBE trials demonstrated BE between IR solution 5 mg b.i.d. and MR microsphere 10 mg q.d. after a single dose on day 1 and after multiple doses on day 5. This research presents an innovative approach that incorporates clinically observed ICV in PBPK model-based VBE trials, which could reduce unnecessary drug exposure to healthy volunteers and streamline new formulation development strategies., (© 2024 Pfizer Inc. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Textbook outcome (TO) is widely recognized as a comprehensive prognostic indication for patients with gastric cancer (GC). This study aims to develop a modified TO (mTO) for elderly patients with GC., Methods: Data from the elderly patients (aged ≥ 65 years) in two Chinese tertiary referral hospitals were analyzed. 1389 patients from Fujian Medical University Union Hospital were assigned as the training cohort and 185 patients from Affiliated Hospital of Putian University as the validation cohort. Nomogram was developed by the independent prognostic factors of Overall Survival (OS) based on Cox regression., Results: In the training cohort, laparoscopic surgery was significantly correlated with higher TO rate (P < 0.05). Cox regression analysis revealed that surgical approach was also an independent factor of OS (P < 0.001), distinct from the traditional TO. In light of these findings, TO parameters were enhanced by the inclusion of surgical approach, rendering a modified TO (mTO). Further analysis showed that mTO, tumor size, pTNM staging, and adjuvant chemotherapy were independent prognostic factors associated with OS (all P < 0.05). Additionally, the nomogram incorporating these four indicators accurately predicted 1-, 3-, and 5-year OS in the training cohort, with AUC values of 0.793, 0.814, and 0.807, respectively, and exhibited outstanding predictive performance within the validation cohort., Conclusion: mTO holds a robust association with the prognosis of elderly patients with GC, meriting intensified attention in efforts aimed at enhancing surgical quality. Furthermore, the predictive model incorporating mTO demonstrates excellent predictive performance for elderly patients with GC., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract: Objective: The objective of this study is to assess and compare the efficacy of oXiris with conventional continuous renal replacement therapy (CRRT) in managing severe abdominal infections. Methods: A retrospective analysis encompassing cases from 2017 to 2023 was conducted at the Department of Critical Care Medicine within the First Affiliated Hospital of Fujian Medical University. Parameters including heart rate (HR), mean arterial pressure (MAP), oxygenation index, lactate (Lac), platelet count, neutrophil ratio, procalcitonin, C-reactive protein (CRP), interleukin 6 (IL-6), norepinephrine dosage, Acute Physiology and Chronic Health Evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA) were recorded prior to treatment initiation, at 24 h, and 72 h after treatment for both the oXiris and conventional CRRT groups. In addition, the duration of respiratory support, CRRT treatment, length of stay in the intensive care unit (ICU), total hospitalization period, and mortality rates at 14 and 28 days for both groups were recorded. Results: 1) Within the conventional CRRT group, notable enhancement was observed solely in Lac levels at 24 h after treatment compared with pretreatment levels. In addition, at 72 h after treatment, improvements were evident in HR, Lac, CRP, and IL-6 levels. 2) Conversely, the oXiris group exhibited improvements in HR, MAP, Lac, oxygenation index, neutrophil ratio, and IL-6 at 24 h after treatment when compared with baseline values. In addition, reductions were observed in APACHE II and SOFA scores. At 72 h after treatment, all parameters demonstrated enhancement except for platelet count. 3) Analysis of the changes in the indexes (Δ) between the two groups at 24 h after treatment revealed variances in HR, MAP, Lac, norepinephrine dosage, CRP levels, IL-6 levels, APACHE II scores, and SOFA scores. 4) The Δ indexes at 72 h after treatment indicated more significant improvements following oXiris treatment for both groups, except for procalcitonin. 5) The 14-day mortality rate (24.4%) exhibited a significant reduction in the oXiris group when compared with the conventional group (43.6%). However, no significant difference was observed in the 28-day mortality rate between the two groups. 6) Subsequent to multifactorial logistic regression analysis, the results indicated that oXiris treatment correlated with a noteworthy decrease in the 14-day and 28-day mortality rates associated with severe abdominal infections, by 71.3% and 67.6%, respectively. Conclusion: oXiris demonstrates clear advantages over conventional CRRT in the management of severe abdominal infections. Notably, it reduces the fatality rates, thereby establishing itself as a promising and potent therapeutic option., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Objective: In this study, we investigated the safety and practicability of ultra-fast track anesthesia (UFTA) for endoscopic thoracic sympathectomy (ETS)., Methods: A total of 72 patients with palmar hyperhidrosis undergoing ETS were randomly divided into three groups: the UFTA group (group I), the group undergoing single-lumen tracheal intubation with local infiltration anesthesia technique (group II), and the group undergoing single-lumen tracheal intubation with routine anesthesia (group III). Mean arterial pressure (MAP) and heart rate (HR) were recorded for all three groups at the following six time points: Before anesthetics administration (T0), the time of intubating or inserting laryngeal mask airway (T1), the time of incising skin (T2), the time of disconnecting of the right sympathetic nerve (T3), the time of disconnecting of the left sympathetic nerve (T4), the time of withdrawing the tracheal tube or laryngeal mask airway (T5), and the time of transferring the patient to a post-anesthesia care unit (PACU) (T6). The three groups were compared from the following perspectives: surgery duration; anesthesia recovery duration, that is, the duration from discontinuation of anesthesia to extubating the tracheal tube; the dose of propofol and remifentanil per kilogram body mass per unit time interval (the time at the end of the procedure, which lasted from anesthesia induction to incision suturing); and the visual analog scale (VAS) in the resting state in the PACU., Results: Based on pairwise comparisons, the average HR and average MAP values of the three groups differed significantly from T2 to T6 (p < 0.05). As demonstrated by the correlation analysis between remifentanil and propofol with HR and MAP, the doses of the total amount of remifentanil and propofol were lower, and group I used less remifentanil and propofol than group II. No patient in group I experienced throat discomfort following surgery. Patients in groups II and III experienced a range of postoperative discomfort. The VAS scores of groups I and II were significantly lower than those of group III, with group I lower than group II., Conclusion: When utilized in ETS, UFTA can provide effective anesthesia for minor traumas. It is safe, effective, and consistent with the enhanced recovery philosophy of fast-track surgery departments., (© 2024 The Author(s). Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Background: Investigating oncogenes and the mechanisms driving oncogenic processes in human tumors is imperative for the development of efficient therapies. Peroxidasin (PXDN) has been reported to play a critical role in tissue development and homeostasis. However, the role of PXDN in the occurrence and development of Nasopharyngeal Carcinoma (NPC) remains unknown., Methods: Data from multiple databases, including GEO and TCGA, were used to analyze the expression levels of PXDN. Taking nasopharyngeal carcinoma as an example, in vitro experiments were conducted to explore the biological functions of PXDN. Overexpression of stable cell lines was achieved through lentiviral infection, cell proliferation was examined using CCK8 and BrdU incorporation assays, and clone formation experiments were performed to assess cell growth. Transwell and wound healing assays were employed to evaluate cell invasion and migration abilities. Additionally, immunofluorescence staining with multiple targets was used to analyze the immune microenvironment of the tumor tissues. Co-culture experiments, followed by clone formation and CFSE incorporation assays, were conducted to observe the impact of NPC stable cell lines on T cells. Flow cytometry was performed to detect surface markers and cytokines in T cells after co-culture to assess T cell function., Results: PXDN was highly expressed in multiple tumors, and its high expression and mutation profile were correlated with poor survival. Functionally, PXDN plays a crucial role in promoting oncogenic processes by enhancing NPC cell proliferation and metastasis. Mechanistically, PXDN activates extracellular matrix (ECM) signaling pathways while simultaneously inhibiting T-cell infiltration and activation, thereby facilitating cancer progression., Conclusion: We characterized PXDN as a valuable biomarker for pan-cancer diagnosis and prognosis. We also uncovered new oncogenic roles for PXDN in promoting cancer progression and regulating T-cell immunosuppressive function in NPC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Xiao, Chen, Xiao, Lin, Cai, Zeng, Ye, Yu, Yuan and Li.)

Background: In laparoscopic proximal gastrectomy (LPG), the prolapse of the hepatic left lateral lobe near the lesser curvature and esophageal hiatus can obstruct the field of vision and operation. Therefore, it is necessary to retract or obstruct the hepatic left lateral lobe to ensure a clear field of vision., Aim: To investigate the safety and clinical efficacy of the modified hepatic left lateral lobe inversion technique for LPG., Methods: A retrospective analysis was conducted on the clinical data of 13 consecutive patients with early-stage upper gastric adenocarcinoma or adenocarcinoma of the esophagogastric junction treated with LPG from January to December 2023 at the Department of Gastrointestinal Surgery, Second Affiliated Hospital of Fujian Medical University. The modified hepatic left lateral lobe inversion technique was used to expose the surgical field in all patients, and short-term outcomes were observed., Results: In all 13 patients, the modified hepatic left lateral lobe inversion technique was successful during surgery without the need for re-retraction or alteration of the liver traction method. There were no instances of esophageal hiatus occlusion, eliminating the need for forceps to assist in exposure. There was no occurrence of intraoperative hepatic hemorrhage, hepatic vein injury, or hepatic congestion. No postoperative digestive complications of Clavien-Dindo grade ≥ II occurred within 30 days after surgery, except for a single case of pulmonary infection. Some patients experienced increases in alanine aminotransferase and aspartate aminotransferase levels on the first day after surgery, which significantly decreased by the third day and returned to normal by the seventh day after surgery., Conclusion: The modified hepatic left lateral lobe inversion technique has demonstrated satisfactory results, offering advantages in terms of facilitating surgical procedures, reducing surgical trauma, and protecting the liver., Competing Interests: Conflict-of-interest statement: All authors report no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Independent and valid prognostic predictors for locally advanced gastric cancer (LAGC) patients with non-elevated serum tumor markers (Triple-negative: CA199 < 37U/ml, CEA < 5 µg/ml and CA125 < 35U/ml) before and after neoadjuvant chemotherapy (NACT) remain unclear., Methods: A total of 352 LAGC patients treated with NACT(NLAGC) from two centers were included. Of the 156 were Triple-negative patients. CA72-4 trajectory groupings was defined as longitudinal changes in CA72-4 levels before and after NACT to identify different potential subgroups and to compare recurrence-free survival (RFS) and overall survival (OS) among subgroups. The predictive performance of the nomogram-trajectory was evaluated using the area under the receiver operating characteristic curve(AUC), decision curve analysis, and C-index., Results: In the Triple-negative patients, the Stable group had significantly worse 3-year OS than the Normal, Elevated, and Descend groups(3-year OS: 53.9% vs. 77.9% vs. 73.5% vs. 87.7%;P = 0.002). Cox multivariate analysis showed that CA72-4 trajectory groupings (Stable group: HR:3.442, 95%CI[1.574-7.528], P = 0.002) was an independent prognostic risk factor. In addition, the C-index and AUC values based on the nomogram-trajectory were significantly higher than those of ypTNM staging (C-index: 0.788 vs. 0.719,P < 0.001;AUC: 0.800 vs. 0.667,P < 0.001). Furthermore, The survival analysis revealed that the 3-year OS of the Low-Risk group of nomogram scores was significantly better than that of the High-Risk group(3-year OS:84.7% vs. 29.1%). And the Low-Risk group had the lower cumulative risk of recurrence (P < 0.001)., Conclusion: The CA72-4 trajectory groupings were an independent prognostic factor for NLAGC Triple-negative patients. The predictive efficacy of the Nomogram-trajectory was significantly better than the ypTNM., (© 2024. The Author(s).)

Progress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The IL-2 cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and antiinflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexing with anti-IL-2 antibodies that bias the cytokine toward immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multiprotein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine toward immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared with natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, and its pathogenesis is believed to be associated with an imbalance between commensal organisms and the intestinal immune system. This imbalance is significantly influenced by the intestinal microbiota and metabolites and plays a critical role in maintaining intestinal mucosal homeostasis. However, disturbances in the intestinal microbiota cause dysregulated immune responses and consequently induce intestinal inflammation. Recent studies have illustrated the roles of the intestinal microbiota in the pathogenesis of IBD and underscored the potential of precision diagnosis and therapy. This work summarises recent progress in this field and particularly focuses on the application of the intestinal microbiota and metabolites in the precision diagnosis, prognosis assessment, treatment effectiveness evaluation, and therapeutic management of IBD., Competing Interests: None declared. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author Z.L. was blinded from reviewing and making decisions on this manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the West China School of Medicine & West China Hospital of Sichuan University.)

Aging of epidermal keratinocytes profoundly impacts skin health, contributing to changes in appearance, barrier function, and susceptibility to diseases. Despite its significance, the molecular mechanisms underlying epidermal aging remain elusive. In this study, a reversible immortalized cell line was established by expressing SV40T in keratinocytes using the Tet-Off lentiviral system. Inducing a senescent phenotype by terminating SV40T expression revealed a significant reduction in mitotic ability, as well as characteristics of cellular aging. RNA sequencing analysis revealed alterations in gene expression and signaling pathways including DNA repair dysfunction, notably senescence-associated secretory phenotype (SASP)-related genes, such as MMP1, SERPINB2 and VEGFA. Our study provides insights into the molecular mechanisms of epidermal aging, offering potential therapeutic targets and highlighting the role of SASP in the aging process.

Objective: To analyze the factors influencing recurrent urinary tract infections (UTIs) in children and explore predictive factors and intervention measures., Methods: Data of 158 children with UTIs treated at the Longyan First Affiliated Hospital of Fujian Medical University from January 2020 to June 2023 were analyzed. Among them, 122 children without recurrent UTIs were included in a non-recurrent group, while the remaining 36 were included in a recurrent group. The quality of life prior to treatment and six weeks after treatment, the immunoglobulin A (IgA) and immunoglobulin G (IgG) levels after treatment, the relationship between the quality of life after six weeks of treatment and the levels of IgA and IgG were analyzed. Multivariate logistic regression analysis was conducted to identify factors impacting the recurrence of UTIs, and receiver operating characteristic (ROC) curves were generated to predict recurrent UTIs based on independent risk factors., Results: Before treatment, no notable difference was observed in Short Form 36 Health Survey (SF-36) scores between the non-recurrent group and the recurrent group (P>0.05). After treatment, the SF-36 scores notably increased in the non-recurrent group (P<0.0001), while there was no notable increase in the recurrent group (P>0.05). However, the difference in SF-36 scores after treatment was significant between the two groups (P<0.0001). In addition, there was a significantly positive correlation between IgA levels and quality of life after 6 weeks of treatment (P<0.05). The recurrent group showed significantly lower IgA and IgG levels than the non-recurrent group (P<0.05). Multivariate logistic regression analysis identified anemia, urinary system malformation, constipation, decreased IgA level, and decreased IgG level as independent risk factors for recurrent UTIs in children. ROC curves-based analysis of independent risk factors demonstrated that urinary system malformation had a better performance in predicting recurrent UTIs in children than the other four factors., Conclusion: Urinary system malformation, constipation, anemia, decreased IgA and IgG levels are all identified as independent risk factors for recurrent UTIs in children, and urinary system malformation is a better predictor for recurrent UTIs in children than the other four factors., Competing Interests: None., (AJTR Copyright © 2024.)

Background: Childhood maltreatment (CM) is increasingly recognized as a significant risk factor for major depressive disorder (MDD), yet the neural mechanisms underlying the connection between CM and depression are not fully understood. This study aims to deepen our understanding of this relationship through neuroimaging, exploring how CM correlates with depression., Methods: The study included 56 MDD patients (33 with CM experiences and 23 without) and 23 healthy controls. Participants were assessed for depression severity, CM experiences, and underwent resting-state functional MRI scans. Independent Component Analysis was used to examine differences in functional connectivity (FC) within the Default Mode Network (DMN) among the groups., Results: MDD patients with CM experiences exhibited significantly stronger functional connectivity in the left Superior Frontal Gyrus (SFG) and right Anterior Cingulate Cortex (ACC) within the DMN compared to both MDD patients without CM experiences and healthy controls. FC in these regions positively correlated with Childhood Trauma Questionnaire scores. Receiver Operating Characteristic (ROC) curve analysis underscored the diagnostic value of FC in the SFG and ACC for identifying MDD related to CM. Additionally, MDD patients with CM experiences showed markedly reduced FC in the left medial Prefrontal Cortex (mPFC) relative to MDD patients without CM experiences, correlating negatively with Childhood Trauma Questionnaire scores., Conclusion: Our findings suggest that increased FC in the ACC and SFG within the DMN is associated with CM in MDD patients. This enhanced connectivity in these brain regions is key to understanding the predisposition to depression related to CM., 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 Lin, Huang, Wu, Zhou, Qiao, Xie and Hu.)

Factor XII (FXII) is the zymogen of the plasma protease FXIIa that activates the intrinsic coagulation pathway and the kallikrein kinin-system. The role of FXII in inflammation has been obscure. Here, we report a single-domain antibody (nanobody, Nb) fused to the Fc region of a human immunoglobulin (Nb-Fc) that recognizes FXII in a conformation-dependent manner and interferes with FXIIa formation. Nb-Fc treatment inhibited arterial thrombosis in male mice without affecting hemostasis. In a mouse model of extracorporeal membrane oxygenation (ECMO), FXII inhibition or knockout reduced thrombus deposition on oxygenator membranes and systemic microvascular thrombi. ECMO increased circulating levels of D-dimer, alkaline phosphatase, creatinine and TNF-α and triggered microvascular neutrophil adherence, platelet aggregation and their interaction, which were substantially attenuated by FXII blockade. Both Nb-Fc treatment and FXII knockout markedly ameliorated immune complex-induced local vasculitis and anti-neutrophil cytoplasmic antibody-induced systemic vasculitis, consistent with selectively suppressed neutrophil migration. In human blood microfluidic analysis, Nb-Fc treatment prevented collagen-induced fibrin deposition and neutrophil adhesion/activation. Thus, FXII is an important mediator of inflammatory responses in vasculitis and ECMO, and Nb-Fc provides a promising approach to alleviate thrombo-inflammatory disorders., (© 2024. The Author(s).)

In mammalian ovary, the primordial follicle pool serves as the source of developing follicles and fertilizable ova. To maintain the normal length of female reproductive life, the primordial follicles must have adequate number and be kept in a quiescent state before menopause. However, the molecular mechanisms underlying primordial follicle survival are poorly understood. Here, we provide genetic evidence showing that lacking protein phosphatase 4 (PPP4) in oocytes, a member of PP2A-like subfamily, results in infertility in female mice. A large quantity of primordial follicles has been depleted around the primordial follicle pool formation phase and the ovarian reserve is exhausted at about 7 months old. Further investigation demonstrates that depletion of PPP4 causes the abnormal activation of mTOR, which suppresses autophagy in primordial follicle oocytes. The abnormal primordial follicle oocytes are eventually erased by pregranulosa cells in the manner of lysosome invading. These results show that autophagy prevents primordial follicles over loss and PPP4-mTOR pathway governs autophagy during the primordial follicle formation and dormant period., (© 2024. The Author(s).)

Crustal accretion at mid-ocean ridges governs the creation and evolution of the oceanic lithosphere. Generally accepted models 1-4 of passive mantle upwelling and melting predict notably decreased crustal thickness at a spreading rate of less than 20 mm year -1 . We conducted the first, to our knowledge, high-resolution ocean-bottom seismometer (OBS) experiment at the Gakkel Ridge in the Arctic Ocean and imaged the crustal structure of the slowest-spreading ridge on the Earth. Unexpectedly, we find that crustal thickness ranges between 3.3 km and 8.9 km along the ridge axis and it increased from about 4.5 km to about 7.5 km over the past 5 Myr in an across-axis profile. The highly variable crustal thickness and relatively large average value does not align with the prediction of passive mantle upwelling models. Instead, it can be explained by a model of buoyant active mantle flow driven by thermal and compositional density changes owing to melt extraction. The influence of active versus passive upwelling is predicted to increase with decreasing spreading rate. The process of active mantle upwelling is anticipated to be primarily influenced by mantle temperature and composition. This implies that the observed variability in crustal accretion, which includes notably varied crustal thickness, is probably an inherent characteristic of ultraslow-spreading ridges., (© 2024. The Author(s).)

Background: Learning curves have been used in the field of robotic gastrectomy (RG). However, it should be noted that the previous study did not comprehensively investigate all changes related to the learning curve. This study aims to establish a learning curve for radical RG and evaluate its effect on the short-term outcomes of patients with gastric cancer., Methods: The clinicopathological data of 527 patients who underwent RG between August 2016 and June 2021 were retrospectively analyzed. Learning curves related to the operation time and postoperative hospital stay were determined separately using cumulative sum (CUSUM) analysis. Then, the impact of the learning curve on surgical efficacy was analyzed., Results: Combining the CUSUM curve break points and technical optimization time points, the entire cohort was divided into three phases (patients 1-100, 101-250, and 251-527). The postoperative complication rate and postoperative recovery time tended to decrease significantly with phase advancement ( P <0.05). More extraperigastric examined lymph nodes (LN) were retrieved in phase III than in phase I (I vs. III, 15.12±6.90 vs. 17.40±7.05, P =0.005). The rate of LN noncompliance decreased with phase advancement. Textbook outcome (TO) analysis showed that the learning phase was an independent factor in TO attainment ( P <0.05)., Conclusion: With learning phase advancement, the short-term outcomes were significantly improved. It is possible that our optimization of surgical procedures could have contributed to this improvement. The findings of this study facilitate the safe dissemination of RG in the minimally invasive era., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Talaromyces marneffei (T. marneffei), a kind of endemic opportunistic pathogen, was previously thought to occur in HIV-positive individuals and non-HIV hosts with impaired immune function. However, the infection of T. marneffei in patient with normal immune function was rarely reported., Case Presentation: We report a case of severe pneumonia caused by T. marneffei in an immunocompetent and HIV-negative patient, which was rapidly confirmed by metagenomics next-generation sequencing (mNGS) and treated successfully. The patient was a previously healthy 63-year-old male, who was admitted to hospital with fever for 11 days, cough and sputum for 1 week, and chest distress for 4 days. The infection of T. marneffei was quickly determined by alveolar lavage under bedside bronchoscope and mNGS test., Results: Patient's condition improved rapidly after voriconazole treatment, and he was evaluated as a HIV-negative case of T. marneffei infection with normal immune function. This is a sporadic case of T. marneffei in non-endemic areas, and mNGS played a very important role in the treatment of the disease. The patient's immune function was relatively normal which was rare in clinical practice., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Ling-Yan Ye, Xu-Ling Zhao, Jia-Jia Qin, Jian Lin.)

This study investigates the impact of chronic ankle instability (CAI) on athletes' lower extremity mechanics during bounce drop-jump landings with divided attention. Thirty Division I physical education voluntarily participated in the study. They performed two sets of bounce drop jumps: one set with a divided attention task and the other without. The obtained data were analysed using a paired t-test to compare the outcomes between the divided attention (DA) and non-divided attention (NDA) tasks. Athletes with CAI, during the DA task, displayed higher vertical landing forces, increased ankle inversion velocity, and greater range of motion of the ankle, knee, and hip in the frontal and transverse planes. They also exhibited insufficient neuromuscular preparation of the rectus femoris muscle. Notably, distinct kinematic alterations were observed in the ankle, knee, and hip joints regarding frontal and transverse lower-extremity kinematics. The findings suggest that athletes with CAI experience decreased activation of the rectus femoris muscle, which may impact their dynamic postural stability from pre-landing to ascending phases. Furthermore, the results indicate that individuals with CAI closely replicate the injury mechanisms encountered during a drop-jump landing task with divided attention. These insights offer valuable information about the real-time challenges faced by athletes with CAI.

Cytokine-mediated STAT5 protein activation is vital for lymphocyte development and function. In vitro tyrosine phosphorylation of a C-terminal tyrosine is critical for activation of STAT5A and STAT5B; however, the importance of STAT5 tyrosine phosphorylation in vivo has not been assessed. Here we generate Stat5a and Stat5b tyrosine-to-phenylalanine mutant knockin mice and find they have greatly reduced CD8 + T-cell numbers and profoundly diminished IL-2-induced proliferation of these cells, and this correlates with reduced induction of Myc, pRB, a range of cyclins and CDKs, and a partial G1→S phase-transition block. These mutant CD8 + T cells also exhibit decreased IL-2-mediated activation of pERK and pAKT, which we attribute in part to diminished expression of IL-2Rβ and IL-2Rγ. Our findings thus demonstrate that tyrosine phosphorylation of both STAT5A and STAT5B is essential for maximal IL-2 signaling. Moreover, our transcriptomic and proteomic analyses elucidate the molecular basis of the IL-2-induced proliferation of CD8 + T cells., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The results of existing lower extremity robotics studies are conflicting, and few relevant clinical trials have examined short-term efficacy. In addition, most of the outcome indicators in existing studies are scales, which are not objective enough. We used the combination of objective instrument measurement and scale to explore the short-term efficacy of the lower limb A3 robot, to provide a clinical reference., Aim: To investigate the improvement of lower limb walking ability and balance in stroke treated by A3 lower limb robot., Methods: Sixty stroke patients were recruited prospectively in a hospital and randomized into the A3 group and the control group. They received 30 min of A3 robotics training and 30 min of floor walking training in addition to 30 min of regular rehabilitation training. The training was performed five times a week, once a day, for 2 wk. The t -test or non-parametric test was used to compare the three-dimensional gait parameters and balance between the two groups before and after treatment., Results: The scores of basic activities of daily living, Stroke-Specific Quality of Life Scale, FM balance meter, Fugl-Meyer Assessment scores, Rivermead Mobility Index, Stride speed, Stride length, and Time Up and Go test in the two groups were significantly better than before treatment (19.29 ± 12.15 vs 3.52 ± 4.34; 22.57 ± 17.99 vs 4.07 ± 2.51; 1.21 ± 0.83 vs 0.18 ± 0.40; 3.50 ± 3.80 vs 0.96 ± 2.08; 2.07 ± 1.21 vs 0.41 ± 0.57; 0.89 ± 0.63 vs 0.11 ± 0.32; 12.38 ± 9.00 vs 2.80 ± 3.43; 18.84 ± 11.24 vs 3.80 ± 10.83; 45.12 ± 69.41 vs 8.41 ± 10.20; 29.45 ± 16.62 vs 8.68 ± 10.74; P < 0.05). All outcome indicators were significantly better in the A3 group than in the control group, except the area of the balance parameter., Conclusion: For the short-term treatment of patients with subacute stroke, the addition of A3 robotic walking training to conventional physiotherapy appears to be more effective than the addition of ground-based walking training., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The performance of a pulse oximeter based on photoelectric detection is greatly affected by motion noise (MA) in the photoplethysmographic (PPG) signal. This paper presents an algorithm for detecting motion oxygen saturation, which reconstructs a motion noise reference signal using ensemble of complete adaptive noise and empirical mode decomposition combined with multi-scale permutation entropy, and eliminates MA in the PPG signal using a convex combination least mean square adaptive filters to calculate dynamic oxygen saturation. The test results show that, under simulated walking and jogging conditions, the mean absolute error (MAE) of oxygen saturation estimated by the proposed algorithm and the reference oxygen saturation are 0.05 and 0.07, respectively, with means absolute percentage error (MAPE) of 0.05% and 0.07%, respectively. The overall Pearson correlation coefficient reaches 0.971 2. The proposed scheme effectively reduces motion artifacts in the corrupted PPG signal and is expected to be applied in portable photoelectric pulse oximeters to improve the accuracy of dynamic oxygen saturation measurement.