Search

Abstract Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

Oral administration is the most simple, noninvasive, convenient treatment. With the increasing demands on the targeted drug delivery, the traditional oral treatment now is facing some challenges: 1) biologics how to implement the oral treatment and ensure the bioavailability is not lower than the subcutaneous injections; 2) How to achieve targeted therapy of some drugs in the gastrointestinal tract? Based on these two issues, drug delivery microrobots have shown great application prospect in oral drug delivery due to their characteristics of flexible locomotion or driven ability. Therefore, this paper summarizes various drug delivery microrobots developed in recent years and divides them into four categories according to different driving modes: magnetic-controlled drug delivery microrobots, anchored drug delivery microrobots, self-propelled drug delivery microrobots and biohybrid drug delivery microrobots. As oral drug delivery microrobots involve disciplines such as materials science, mechanical engineering, medicine, and control systems, this paper begins by introducing the gastrointestinal barriers that oral drug delivery must overcome. Subsequently, it provides an overview of typical materials involved in the design process of oral drug delivery microrobots. To enhance readers' understanding of the working principles and design process of oral drug delivery microrobots, we present a guideline for designing such microrobots. Furthermore, the current development status of various types of oral drug delivery microrobots is reviewed, summarizing their respective advantages and limitations. Finally, considering the significant concerns regarding safety and clinical translation, we discuss the challenges and prospections of clinical translation for various oral drug delivery microrobots presented in this paper, providing corresponding suggestions for addressing some existing challenges.

Abstract Background The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. Methods To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. Results We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. Conclusion The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

Abstract In the era of data‐driven transportation development, traffic forecasting is crucial. Established studies either ignore the inherent spatial structure of the traffic network or ignore the global spatial correlation and may not capture the spatial relationships adequately. In this work, a Dynamic Spatial‐Temporal Network (DSTN) based on Joint Latent Space Representation (JLSR) is proposed for traffic forecasting. Specifically, in the spatial dimension, a JLSR network is developed by integrating graph convolution and spatial attention operations to model complex spatial dependencies. Since it can adaptively fuse the representation information of local topological space and global dynamic space, a more comprehensive spatial dependency can be captured. In the temporal dimension, a Stacked Bidirectional Unidirectional Gated Recurrent Unit (SBUGRU) network is developed, which captures long‐term temporal dependencies through both forward and backward computations and superimposed recurrent layers. On these bases, DSTN is developed in an encoder‐decoder framework and periodicity is flexibly modeled by embedding branches. The performance of DSTN is validated on two types of real‐world traffic flow datasets, and it improves over baselines.

Abstract Background Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. Methods By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. Results UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. Conclusion This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.

Objectives: Combination therapy of lenvatinib and immune checkpoint inhibitors (CLICI) has emerged as a promising approach for managing unresectable hepatocellular carcinoma (HCC). However, the response to such treatment is observed in only a subset of patients, underscoring the pressing need for reliable methods to identify potential responders. Materials & methods: This was a retrospective analysis involving 120 patients with unresectable HCC. They were divided into training (n = 72) and validation (n = 48) cohorts. We developed an interpretable deep learning model using multiphase computed tomography (CT) images to predict whether patients will respond or not to CLICI treatment, based on the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). We evaluated the models' performance and analyzed the impact of each CT phase. Critical regions influencing predictions were identified and visualized through heatmaps. Results: The multiphase model outperformed the best biphase and uniphase models, achieving an area under the curve (AUC) of 0.802 (95% CI = 0.780–0.824). The portal phase images were found to significantly enhance the model's predictive accuracy. Heatmaps identified six critical features influencing treatment response, offering valuable insights to clinicians. Additionally, we have made this model accessible via a web server at http://uhccnet.com/ for ease of use. Conclusions: The integration of multiphase CT images with deep learning-generated heatmaps for predicting treatment response provides a robust and practical tool for guiding CLICI therapy in patients with unresectable HCC.

Cotton breeding for the development of early-maturing varieties is an effective way to improve multiple cropping indexes and alleviate the conflict between grains and cotton in the cultivated fields in China. In the present study, we aimed to identify upland cotton quantitative trait loci (QTLs) and candidate genes related to early-maturity traits, including whole growth period (WGP), flowering timing (FT), node of the first fruiting branch (NFFB), height of the node of the first fruiting branch (HNFFB), and plant height (PH). An early-maturing variety, CCRI50, and a late-maturing variety, Guoxinmian 11, were crossed to obtain biparental populations. These populations were used to map QTLs for the early-maturity traits for two years (2020 and 2021). With BSA-seq analysis based on the data of population 2020, the candidate regions related to early maturity were found to be located on chromosome D03. We then developed 22 polymorphic insertions or deletions (InDel) markers to further narrow down the candidate regions, resulting in the detection of five and four QTLs in the 2020 and 2021 populations, respectively. According to the results of QTL mapping, two candidate regions (InDel_G286-InDel_G144 and InDel_G24-InDel_G43) were detected. In these regions, three genes (GH_D03G0451, GH_D03G0649, and GH_D03G1180) have non-synonymous mutations in their exons and one gene (GH_D03G0450) has SNP variations in the upstream sequence between CCRI50 and Guoxinmian 11. These four genes also showed dominant expression in the floral organs. The expression levels of GH_D03G0451, GH_D03G0649 and GH_D03G1180 were significantly higher in CCRI50 than in Guoxinmian 11 during the bud differentiation stages, while GH_D03G0450 showed the opposite trend. Further functional verification of GH_D03G0451 indicated that the GH_D03G0451-silenced plants showed a delay in the flowering time. The results suggest that these are the candidate genes for cotton early maturity, and they may be used for breeding early-maturity cotton varieties.

The beer industry is one of the most rapidly developing industries in Chinese beverage alcohol industry, in which the production of raw materials and processing of beer are closely related to the quality of products and industrial development. The control of Deoxynivalenol (DON) from contamination of raw materials or processing of beer is one of the most critical and interesting research areas. This paper analyzes the contamination of DON, which is an important mycotoxin that affects the quality and safety of beer. Combined with the migration and transformation of DON during the key stages of beer processing, the measures for controlling DON in beer processing are elaborated from three major methods of physics, chemistry and biology, which provides the theoretical basis for controlling DON contamination and improving the quality of beer.

Abstract Background Left atrial appendage aneurysm is a rare cardiac mass, with only a few cases reported. There are usually no specific symptoms, and a few patients visit the doctor with symptoms. Case presentation A 20-year-old male presented to our hospital with a “pericardial cyst found by medical evaluation in another hospital for 2 years.” Cardiac ultrasound performed at clinics of our hospital suggested a cystic dark area in the left ventricular lateral wall and the anterior lateral wall, consistent with a pericardial cyst and mild mitral regurgitation. After further relevant examinations and ruling out contraindications, an excision of the left atrial appendage aneurysm was performed under general anesthesia and cardiopulmonary bypass with beating—heart. The postoperative pathological results identified that: (left atrial appendage) fibrocystic wall-like tissue with a focal lining of the flat epithelium, consistent with a benign cyst. Conclusion Left atrial appendage aneurysms are rare and insidious. They are usually found by chance during medical evaluations. If the location is not good or the volume is too large, then compression symptoms or arrhythmia, thrombosis and other concomitant symptoms will occur. Surgical resection is presently the only effective radical cure for a left atrial appendage aneurysm.

To address the issue of low gas extraction efficiency in driving roadway of broken soft and low permeability coal seams in Huainan mining area, a model of segmented cluster fracturing gas management in horizontal wells at the roof of coal seams was proposed. The crack expansion process of hydraulic fracturing in horizontal wells of coal seam roof was studied using numerical simulation and physical similarity simulation methods. The gas production effect of segmented and clustered fracturing was investigated using productivity simulation, and a comparative analysis of residual gas content between fracturing in clusters and without clustering was conducted. The numerical simulation results of crack extension shown that, the cracks in the horizontal wells at the roof of coal seam could expand to the coal seam and open up the coal seam completely. Due to the plasticity of the coal seam was greater than that of the sandy mudstone at the roof, a wider fracturing crack was formed in the coal seam than at the roof. The physical similarity simulation results of crack extension shown that, considering the development of the mudstone pseudo-roof, when the horizontal drilling was placed in the sandstone at the roof of the broken soft coal seam, and under reasonable vertical distances and high-displacement fracturing fluid construction, if coal seam developed a relatively thin mudstone pseudo-roof, the fractures could extend through the interface of direct roof and pseudo roof (siltstone- mudstone interface) and the interface of pseudo-roof and coal seam (mudstone-coal seam interface) along the shot hole aperture and into the underlying coal seam. The fractures extended to form a curved and irregular step-like pattern, which can achieve the goal of fracturing and reforming the broken soft coal seam. However, when the coal seam developed a thick mudstone pseudo-roof, it had a blocking effect on hydraulic fracturing, making it difficult for the cracks to open up the underlying coal seam. The productivity simulation results shown that, under the same stratigraphic environment and construction conditions, after 3 years of extraction, single-stage non-cluster fracturing could produce a larger gas extraction impact range. However, the gas content of driving roadway could not be uniformly reduced, and there was a gas extraction gap between the fractured segments. Fracturing in clusters produced a smaller gas extraction impact, but it could more evenly reduce the gas content in driving roadway. After the engineering verification in the Panxie coal mine in Huainan, with a construction discharge of 10 m3/min, the longest fracture length could reach up to 193.8 m, the maximum height of fracture was 27.0 m, and the daily gas production of a single well reached 1 490 m3/d. The gas extraction volume of 2 years was 31×104 m3, indicating that the segmented and cluster fracturing technology of horizontal wells at the coal seam roof was an effective model for efficient gas extraction in the driving roadway of broken soft and low-permeability coal seams in Huainan area.

Abstract The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca2+ and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.

Abstract Objectives This study aimed to identify the risk factors for postoperative atrial fibrillation in patients with valvular atrial fibrillation, and establish predictive models of atrial fibrillation recurrence. Methods Overall, 224 patients who underwent radiofrequency ablation of atrial fibrillation from November 2014 to November 2020 were included. The statistical package for social sciences, X-tile, and R-studio were used for statistical analysis. Results Patients were divided into training and validation sets according to a ratio of 3:1. The training set was analysed using univariate and multivariate Cox regression analysis and showed that preoperative uric acid > 401 μmol/L (P = 0.006), B-type natriuretic peptide > 202 ng/L (P = 0.042), hypersensitivity C-reactive protein > 6.1 mg/L (P = 0.026), erythrocyte sedimentation rate > 7.0 mm/h (P = 0.016), preoperative left atrial diameter > 48 mm (P = 0.031) were significantly correlated with the recurrence of atrial fibrillation after radiofrequency ablation in patients with valvular atrial fibrillation. In the training set, a Cox regression model of the five related factors was established using the R language. The C-index of the model was 0.82, and the area under the receiver operating characteristic curve was 0.831 (P

Abstract Janus group-III chalcogenide monolayers and based heterostructures with breaking vertical structural symmetry offer additional prospects in the upcoming high-performance photoelectric devices. We studied the geometrical, electronic, and photoelectric properties of Janus group-III chalcogenide monolayers and heterostructures. The most energy favorable stacking design of ten vertical heterostructures are considered. The results showed that the Janus Se-In-Ga-S and S-In-Ga-Se monolayers exhibit semiconducting characteristics with the band gaps of 1.295 eV and 1.752 eV, respectively. Furthermore, the different stacking configurations and surface termination at interface can realize the transition of band alignment between type I and type II due to the interlayer coupling. Moreover, we systematically investigated the photoelectric properties of Janus group-III chalcogenide heterostructures and predicated an optimized power conversion efficiency of 16.2%. These findings can aid in comprehending the customized characteristics of Janus group-III chalcogenide heterostructures, offering theoretical guidance for creating innovative photoelectric devices.

Abstract Aims This study compared the prevalences of metabolic syndrome and of cardiac or kidney comorbidities among patients with hepatocellular carcinoma (HCC) associated with metabolic dysfunction-related fatty liver disease (MAFLD), chronic infection with hepatitis B or C virus (HBV or HCV), or the combination of MAFLD and chronic HBV infection. Methods Medical records were retrospectively analyzed for patients with HCC who underwent hepatectomy between March 2013 and March 2023. Patients with HCC of different etiologies were compared in terms of their clinicodemographic characteristics and laboratory data before surgery. Results Of the 2422 patients, 1,822 (75.2%) were chronically infected with HBV without MAFLD and HCV, 415 (17.2%) had concurrent MAFLD and chronic HBV infection but no HCV infection, 121 (5.0%) had MAFLD without hepatitis virus infection, and 64 (2.6%) were chronically infected with HCV in the presence or absence of MAFLD and HBV infection. Compared to patients chronically infected with HBV without MAFLD and HCV, those with MAFLD but no hepatitis virus infection showed significantly lower prevalence of cirrhosis, ascites, portal hypertension, alpha-fetoprotein concentration ≥ 400 ng/mL, tumor size > 5 cm, multinodular tumors and microvascular invasion. Conversely, they showed significantly higher prevalence of metabolic syndrome, hypertension, type 2 diabetes, abdominal obesity, history of cardiovascular disease, T-wave alterations, hypertriglyceridemia and hyperuricemia, as well as higher risk of arteriosclerotic cardiovascular disease. Compared to patients with MAFLD but no hepatitis virus infection, those with concurrent MAFLD and chronic infection with HBV showed significantly higher prevalence of cirrhosis, ascites and portal hypertension, but significantly lower prevalence of hypertension and history of cardiovascular disease. Compared to patients with other etiologies, those chronically infected with HCV in the presence or absence of MAFLD and HBV infection, showed significantly higher prevalence of cirrhosis, portal hypertension, ascites, and esophagogastric varices. Conclusion Patients with HCC associated with MAFLD tend to have a background of less severe liver disease than those with HCC of other etiologies, but they may be more likely to suffer metabolic syndrome or comorbidities affecting the heart or kidneys.

ABSTRACT: A novel ratiometric electrochemical aptasensor based on split aptamer and Au-reduced graphene oxide (Au-rGO) nanomaterials was proposed to detect aflatoxin M1 (AFM1). In this work, Au-rGO nanomaterials were coated on the electrode through the electrodeposition method to increase the aptamer enrichment. We split the aptamer of AFM1 into 2 sequences (S1 and S2), where S1 was immobilized on the electrode due to the Au-S bond, and S2 was tagged with methylene blue (MB) and acted as a response signal. A complementary strand to S1 (CS1) labeled with ferrocene (Fc) was introduced as another reporter. In the presence of AFM1, CS1 was released from the electrode surface due to the formation of the S1-AFM1-S2 complex, leading to a decrease in Fc and an increase in the MB signal. The developed ratiometric aptasensor exhibited a linear range of 0.03 μg L−1 to 2.00 μg L−1, with a detection limit of 0.015 μg L−1 for AFM1 detection. The ratiometric aptasensor also showed a linear relationship from 0.2 μg L−1 to 1.00 μg L−1, with a detection limit of 0.05 μg L−1 in natural milk after sample pretreatment, indicating the successful application of the developed ratiometric aptasensor. Our proposed strategy provides a new way to construct aptasensors with high sensitivity and selectivity.

Abstract More than 70% of the potash fertilizer globally is produced by the froth flotation process, in which 4-dodecylmorpholine (DMP) serves as a reverse flotation agent. As the potash fertilizer production rapidly rises, the increased DMP levels in discharged brine pose a threat to the production of high-value chemicals. In this paper, composite particles of basic magnesium sulfate@TiO2 (BMS@TiO2) were prepared using a simple and mild loading method. These particles were utilized for the adsorption and photocatalytic degradation of DMP in brine. Compared with normal powdered materials, the granular BMS@TiO2 in this study can be easily separated from liquid, and the degradation intermediates will not enter the brine without causing secondary pollution. BMS@TiO2 consists of 5·1·7 phase (5Mg(OH)2·MgSO4·7H2O) whisker clusters embedding 2.3% TiO2. The adsorption equilibrium of DMP on BMS@TiO2 particles was achieved through hydrogen bonding and pore interception with the adsorption capacity of approximately 5 mg g−1 after 6 h. The photodegradation efficiency of DMP adsorbed on BMS@TiO2 reached about 92% within 16 h, which is compared with that of pure TiO2 nanoparticles. Additionally, excellent stability and recyclability of BMS@TiO2 were also observed in five cycle tests of adsorption and photocatalytic degradation of DMP, and the possible photocatalytic degradation pathways and mechanism of DMP are proposed following molecular electrostatic potential analysis. This work provides a sustainable and environmentally friendly approach for eliminating organic micropollutants from water environments.

Abstract Background Sinus of Valsalva aneurysm (SVA) is a rare cardiac anomaly which can be congenital or acquired. Patients with SVA are commonly asymptomatic when the occupying effect of SVA is insignificant, while ruptured SVA usually causes severe symptoms including heart failure and myocardial ischemia. Case presentation We present an unusual case of a 64-year-old female manifesting with exertional dyspnea as well as angina pectoris for three months. Echocardiography and cardiac computed tomographic angiography confirmed unruptured left-coronary and non-coronary SVAs. The left anterior descending artery and left circumflex artery were stretched and compressed by the SVA which causing myocardial ischemia. The patient finally received aortic root replacement (Bentall procedure) and got symptom relieved. Conclusions Giant unruptured SVA originating from left coronary sinus is extremely rare. Our case highlights that giant SVA should be considered in cases with angina pectoris. Echocardiography and coronary computed tomographic angiography are useful and important for diagnosis. Surgery is highly recommended in patients with SVA.

Abstract We show that the bosonic sector of the N = (1, 0), 6D Salam-Sezgin gauged supergravity model possesses a T-duality symmetry upon a circle reduction to D = 5. We then construct a simple magnetic rotating string solution with two equal angular momenta. Applying the T-duality transformation to this solution, we obtain the general boosted rotating dyonic black string solutions whose global structures and thermodynamic quantities are also analyzed. Owing to the fact that the solutions are not asymptotically flat, we find that there are two distinct globally-different non-extremal solutions with two different sets of thermal dynamic variables, with both satisfying the thermodynamic first law and the corresponding Small relations. However, their BPS limit becomes the same and we show that it preserves one quarter of supersymmetry by directly solving the corresponding Killing spinor equations.

Abstract Solid tumors are complex ecosystems with heterogeneous 3D structures, but the spatial intra-tumor heterogeneity (sITH) at the macroscopic (i.e., whole tumor) level is under-explored. Using a phylogeographic approach, we sequence genomes and transcriptomes from 235 spatially informed sectors across 13 hepatocellular carcinomas (HCC), generating one of the largest datasets for studying sITH. We find that tumor heterogeneity in HCC segregates into spatially variegated blocks with large genotypic and phenotypic differences. By dissecting the transcriptomic heterogeneity, we discover that 30% of patients had a “spatially competing distribution” (SCD), where different spatial blocks have distinct transcriptomic subtypes co-existing within a tumor, capturing the critical transition period in disease progression. Interestingly, the tumor regions with more advanced transcriptomic subtypes (e.g., higher cell cycle) often take clonal dominance with a wider geographic range, rejecting neutral evolution for SCD patients. Extending the statistical tests for detecting natural selection to many non-SCD patients reveal varying levels of selective signal across different tumors, implying that many evolutionary forces including natural selection and geographic isolation can influence the overall pattern of sITH. Taken together, tumor phylogeography unravels a dynamic landscape of sITH, pinpointing important evolutionary and clinical consequences of spatial heterogeneity in cancer.

Abstract Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1β, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1β expression, which thereby alleviate IL-1β-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

Utilising both morphological and molecular analyses, this study unveils Mazus jiangshiense sp. nov., a novel addition to the Mazaceae family, discovered in Shaowu County, Fujian Province, China. The comprehensive description and illustrations provided here are a result of a meticulous exploration of its morphological features. While bearing a resemblance to M. gracilis, this new-found species is distinguished by three distinct characteristics: its stems are delicately soft, its leaves possess a membranous quality and the ovary is notably villous at the apex. Integration of molecular evidence, derived from the nuclear ribosomal DNA (nrITS) and three plastid DNA sequences (rps16, rbcL and trnL-trnF), unequivocally supports the classification of M. jiangshiense as a distinct species. Notably, the molecular analysis positions it as a sister species to M. spicatus, underscoring the phylogenetic relationships within the genus Mazus. Our research not only introduces M. jiangshiense as a novel taxonomic entity, but also provides a nuanced understanding of its morphological differences and molecular affinities, enriching our comprehension of the diversity and evolutionary relationships of Mazaceae.

Abstract Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence‐associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.

Peritoneal dialysis (PD) is currently one of the effective methods for treating end-stage renal disease (ESRD). However, long-term exposure to high concentration glucose in peritoneal dialysis environment could lead to peritoneal fibrosis (PF), impaired peritoneal filtration function, decreased peritoneal dialysis efficiency, and even withdrawal from peritoneal dialysis in patients. Considerable evidence suggests that peritoneal fibrosis after peritoneal dialysis is related to crucial factors such as mesothelial-to-mesenchymal transition (MMT), inflammatory response, and angiogenesis, etc. In our review, we summarize the pathophysiological mechanisms and further illustrate the future strategies against PF.

BackgroundStroke is the leading cause of acquired disability and the second leading cause of death worldwide. Its rate of incidence, disability, mortality, and recurrence is high, and the patients experience various symptoms of discomfort, which not only affect their rehabilitation function but also reduce their ability to perform daily activities and their quality of life. Nowadays, with the improvement of China’s medical standards, patients are increasingly attentive to their quality of life and health status. However, diagnostic techniques and effective treatments for patients with stroke are still limited but urgently required. ObjectiveThis study aimed to evaluate the quality of life during hospitalization using a stroke patient-reported outcomes (PROs) scale and additionally to recognize potential factors and risk indicators that may impact recurrent events, facilitating early intervention measures. MethodsThis is a registry-based, retrospective observational cross-sectional study on patients with stroke. A convenient sampling method was used to select various indicators of patients. The Stroke-PRO scale was then used to assess patients’ conditions across physical, psychological, social, and therapeutic domains. Multiple linear regression analysis was applied to identify factors influencing stroke PROs, while correlation analysis was conducted to explore the relationship between these outcomes and blood lipid levels. ResultsThe mean Stroke-PRO score in this study was 4.09 (SD 0.29) points. By multiple linear regression analysis, residence, occupation, physical exercise, Barthel index, Braden scale, National Institutes of Health Stroke Scale scores at admission, and stroke type were the risk factors for reported outcomes of patients with stroke (P

Abstract Extremely low‐frequency (ELF) electromagnetic (EM) waves adeptly propagate in harsh cross‐medium environments, overcoming rapid decay that hinders high‐frequency counterparts. Traditional antennas, however, encounter challenges concerning size, efficiency, and power. Here, drawing inspiration from nature, we present a groundbreaking piezo‐actuated, bionic flapping‐wing magnetic‐dipole resonator (BFW‐MDR), operating in the electro‐mechano‐magnetic coupling mechanism, designed for efficient ELF EM wave transmission. The unique rigid‐flexible hybrid flapping‐wing structure magnifies rotation angles of anti‐phase magnetic dipoles by tenfold, leading to constructive superposition of emitted magnetic fields. Consequently, the BFW‐MDR exhibits a remarkable quality factor of 288 and an enhanced magnetic field emission of 514 fT at 100 meters with only 6.9 mW power consumption, surpassing traditional coil antennas by three orders of magnitude. The communication rate is doubled by the ASK+PSK modulation method. Its robust performance in cross‐medium communication, even amidst various interferences, underscores its potential as a highly efficient antenna for underwater and underground applications.

Abstract Our current knowledge regarding the distribution patterns of ancient and recent recycled materials, as well as the origin of intraplate basalts in the eastern Asia Big Mantle Wedge (BMW), is limited. To address this, we conducted a detailed geochemical analysis of olivine melt inclusions (OLMI) in nephelinite samples. The normal OLMIs detected in our investigation exhibit geochemical features that closely resemble those of the hosting nephelinite, indicating a consistent association with a carbonated mantle source. Additionally, we identified a distinct group of anomalous OLMIs that displayed different geochemical characteristics from the hosting nephelinite but showed similarities to regional alkali basalts sourced from pyroxenite. The observed geochemical diversity in the nephelinite OLMIs suggests an interaction between deeply derived carbonated melts originating from the flattened Pacific slab in the mantle transition zone and pyroxenite in the lithospheric mantle. Carbonated fluid‐fluxed melting is key to basalt formation in the BMW.

Mechanical stress has been viewed as one of the key risk factors in accelerating the intervertebral disc degeneration process. The goal of the present study was to employ a repeated strike loading bovine caudal disc system to elucidate the pathophysiological impacts of cumulative mechanical stress on the disc. The discs in the model groups were subjected to two different mechanical stresses: one strike loading or repeated strike loading. The following indices were analyzed: histological morphology, glycosaminoglycan release, disc height, cell viability, apoptosis-related protein expression, and catabolism-related gene expression. Both mechanical stress modes induced degenerative changes in the discs by day 11, such as clefts and delamination of the annulus fibrosus; they increased glycosaminoglycan release. Cell viability was significantly decreased and catabolic gene expression was significantly up-regulated in the degenerative loading group and repeated strike loading group by day 9. These alterations remained evident in the annulus fibrosus tissue of the repeated strike loading group on day 11. Our data suggests that the repeated strike loading model adopted in this study could lead to degenerative changes in the disc organ model. Annulus fibrosus cells displayed a more noticeable response to mechanical stress damage and a slower recovery process, suggesting that the annulus fibrosus serves as a pivotal factor in disc degeneration due to mechanical stress injuries. The study also indicates that due to the gradual self-repair of intervertebral disc cells after injury, it is necessary to apply repeated strike loading on the disc at specific intervals when researching the repair of chronic disc injuries.

This study investigated the synthesis of α-hemihydrate gypsum (α-HH) through semi-liquid autoclaving of phosphogypsum (PG) using various carboxylic acids as modifying agents. The impact of carboxyl group spatial location, auxiliary functional group type, and the number of carboxyl groups within the carboxylic acid modifiers on the mechanical strength and crystal morphology of α-HH was analyzed using scanning electron microscopy (SEM), strength testing, and molecular dynamics simulations. The results revealed a significant influence of the carboxylic acid molecular structure on the α-HH crystal morphology. Monocarboxylic acids and dicarboxylic acids with a long carbon chain length between carboxyl groups exhibited preferential adsorption on the (200), (110), and (−110) crystal planes, promoting crystal growth along the c-axis. In contrast, hydroxyl groups and cis double bonds in the modifier structure induced selective adsorption on the (001) plane, hindering growth along the c-axis. Conversely, trans double bonds favored adsorption on the (200), (110), and (−110) planes, enhancing growth along the c-axis. Based on these observations, screening principles for carboxylic acid modifiers were established, suggesting that: 1) the number of carboxyl groups should exceed 2; 2) the optimal carbon atom spacing between carboxyl groups is 3; and 3) auxiliary functional groups such as hydroxyl groups and cis double bonds should be introduced. Modifiers like citric acid, ethylene diamine tetraacetic acid (EDTA), and pyromellitic acid, within concentration ranges of 0.05%–0.1%, 0.1%–0.15%, and 0.05%–0.1%, respectively, yielded α-HH with flexural strengths exceeding 4 MPa and compressive strengths greater than 35 MPa, demonstrating the validity of these principles.

Abstract Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are neurodegenerative disorders caused by the accumulation of misfolded alpha‐synuclein protein. Developing effective vaccines against synucleinopathies is challenging due to the difficulty of stimulating an immune‐specific response against alpha‐synuclein without causing harmful autoimmune reactions, selectively targeting only pathological forms of alpha‐synuclein. Previous attempts using linear peptides and epitopes without control of the antigen structure failed in clinical trials. The immune system was unable to distinguish between native alpha‐synuclein and its amyloid form. The prion domain of the fungal HET‐s protein was selected as a scaffold to introduce select epitopes from the surface of alpha‐synuclein fibrils. Four vaccine candidates were generated by introducing specific amino acid substitutions onto the surface of the scaffold protein. The approach successfully mimicked the stacking of the parallel in‐register beta‐sheet structure seen in alpha‐synuclein fibrils. All vaccine candidates induced substantial levels of IgG antibodies that recognized pathological alpha‐synuclein fibrils derived from a synucleinopathy mouse model. Furthermore, the antisera recognized pathological alpha‐synuclein aggregates in brain lysates from patients who died from DLB, MSA, or PD, but did not recognize linear alpha‐synuclein peptides. Our approach, based on the rational design of vaccines using the structure of alpha‐synuclein amyloid fibrils and strict control over the exposed antigen structure used for immunization, as well as the ability to mimic aggregated alpha‐synuclein, provides a promising avenue toward developing effective vaccines against alpha‐synuclein fibrils.

Abstract Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate‐lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia‐related CKD. In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia‐related CKD mice. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia‐related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene, which was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p‐FAK or p‐AKT1 phosphorylation, and concurrent inhibiting of p‐FAK while activating p‐AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.

Abstract Epidermal electrophysiology is a non‐invasive method used in research and clinical practices to study the electrical activity of the brain, heart, nerves, and muscles. However, electrode/tissue interlayer materials such as ionically conducting pastes can negatively affect recordings by introducing lateral electrode‐to‐electrode ionic crosstalk and reducing spatial resolution. To overcome this issue, biocompatible, anisotropic‐conducting interlayer composites (ACI) that establish an electrically anisotropic interface with the skin are developed, enabling the application of dense cutaneous sensor arrays. High‐density, conformable electrodes are also microfabricated that adhere to the ACI and follow the curvilinear surface of the skin. The results show that ACI significantly enhances the spatial resolution of epidermal electromyography (EMG) recording compared to conductive paste, permitting the acquisition of single muscle action potentials with distinct spatial profiles. The high‐density EMG in developing mice, non‐human primates, and humans is validated. Overall, high spatial‐resolution epidermal electrophysiology enabled by ACI has the potential to advance clinical diagnostics of motor system disorders and enhance data quality for human‐computer interface applications.

Abstract Feeding faba beans to freshwater fish could crisp its muscle texture to avoid softening. However, the dynamic crisping mechanism was unclear. Herein, a 120‐day feeding trial was conducted to systemically investigate the textural crisping mechanism of crisp grass carp (CGC) via molecular‐level, gene/protein expression analysis. In the early crisping stage (0–30 days), the total antioxidant capacity significantly decreased (by 16.79%), TUNEL staining and qRT‐PCR results revealed that apoptosis occurred, which was induced by oxidative stress validating by proteomics. Meanwhile, the content of dityrosine and hydroxylysyl pyridinoline rose, thereby substantially increasing the hardness and chewiness of CGC by 37.51% and 40.84%, respectively. With further crisping (30–90 days), Masson staining exhibited collagen gradually filling the gap between myofibrils, the content and cross‐linking degree of collagen further increased, finally elevating the hardness and chewiness of CGC. This study laid a theoretical foundation for producing and supplying aquatic raw materials with different texture characteristics.

Citrus fruits are the largest fruit crop in China. Post-harvest green mold is one of the major diseases that affect the quality and safety of citrus fruits, as it poses a risk of mycotoxins contamination. Current research primarily focuses on the infection mechanism of Penicillium digitatum, while other important Penicillium plays a significant role in citrus infection and toxin production. The mycotoxins produced can pose a serious threat to food safety. In this review, we provide an overview of the infection and toxin producing mechanisms of the main green mold fungi affecting citrus post-harvest, analyze the current research trends and directions in the field of citrus green mold disease, aiming to reduce the risk of fungal toxin contamination and promote quality improvement and efficiency in the citrus industry, providing new research perspectives for enhancing citrus quality and supporting industry development.

Abstract Fish scales, considered as low-value by-products, contain peptides and hydroxyapatite that can be applied to produce peptide chelated calcium directly. This study developed a sustainable and one-pot fabrication method for the peptide-chelated calcium from fish scale hydrolysates (FSP-Ca). During pepsin hydrolysis, the releases of peptides (FSP), calcium, and phosphate from fish scales occurred simultaneously, and the chelation was also effectively performed. After a 6-h hydrolysis, the yield of FSP was 46.18%, and the dissolution rate of calcium was 49.53%. Under the optimal conditions (pH 7, chelation time of 25 min, and chelation temperature of 48 °C), a high chelation rate of 86.16% was obtained, with a calcium content of 81.8 mg/g. The results of UV absorption, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM) confirmed the successful chelation between FSP and calcium derived from fish scales. The –NH2, –COO–, N–H, C=O, C–H, and –OH groups in FSP participated in the formation of FSP-Ca. Graphical Abstract

Abstract Background Telomere length has long been recognized as a valuable biomarker of aging and is inversely correlated with chronological age. Various lifestyle factors have been implicated in telomere shortening or preservation; however, the association between lifestyle factors and telomere length remains controversial. To address this issue, we conducted a Mendelian randomization (MR) analysis to investigate the potential causal associations between multiple lifestyle factors and telomere length. Methods Independent genetic variants strongly associated with lifestyle factors (tobacco smoking, sleep duration, insomnia, and physical activity) were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for telomere length was obtained from a GWAS comprising 472,174 European ancestries. Univariable and multivariable MR analyses were performed to assess the relationships. Results The genetic liability to lifetime smoking was robustly associated with shorter telomere length (odd ratio [OR]: 0.882; 95% confidence interval [CI]: 0.847–0.918). Genetically predicted insomnia was also linked to shorter telomere length (OR: 0.972; 95% CI: 0.959–0.985), while no significant association was observed between sleep duration and telomere length. Furthermore, a suggestive association was found between moderate-to-vigorous physical activity and longer telomere length (OR: 1.680; 95% CI: 1.115–2.531). In multivariable MR analyses, adjusting for potential mediators such as body mass index, type 2 diabetes, alcohol consumption, and alcohol use disorder, the associations of lifetime smoking and insomnia with telomere length remained robust. Conclusion Our findings suggest that smoking and insomnia may contribute to telomere shortening, while physical activity may play a role in telomere length maintenance. These findings underscore the importance of managing positive risk factors and adopting a healthy lifestyle to promote telomere health.

Abstract Formulas containing intact cow milk protein are appropriate alternatives when human milk (HM) is not feasible. However, for babies with a physician‐diagnosed cow milk protein allergy (CMPA), hydrolyzed formulas are needed. We conducted a 3‐month, open‐label, nonrandomized concurrent controlled trial (ChiCTR2100046909) between June 2021 and October 2022 in Qingdao City, China. In this study, CMPA toddlers were fed with a partially hydrolyzed formula containing synbiotics (pHF, n = 43) and compared with healthy toddlers fed a regular intact protein formula (IF, n = 45) or HM (n = 21). The primary endpoint was weight gain; the secondary endpoints were changes in body length and head circumference of both CMPA and healthy toddlers after 3‐month feeding; and the exploratory outcomes were changes in gut microbiota composition. After 3 months, there were no significant group differences for length‐for‐age, weight‐for‐age, or head circumference‐for‐age Z scores. In the gut microbiota, pHF feeding increased its richness and diversity, similar to those of IF‐fed and HM‐fed healthy toddlers. Compared with healthy toddlers, the toddlers with CMPA showed an increased abundance of phylum Bacteroidota, Firmicutes, class Clostridia, and Bacteroidia, and a decreased abundance of class Negativicutes, while pHF feeding partly eliminated these original differences. Moreover, pHF feeding increased the abundance of short‐chain fatty acid producers. Our data suggested that this pHF partly simulated the beneficial effects of HM and shifted the gut microbiota of toddlers with CMPA toward that of healthy individuals. In conclusion, this synbiotic‐containing pHF might be an appropriate alternative for toddlers with CMPA.

Abstract Background The objective of this study was to examine and analyze differential methylation profiles in order to investigate the influence of hyper-methioninemia (HM) on the development of diabetic nephropathy (DN). Male Wistar rats, aged eight weeks and weighing 250–300 g, were randomly assigned into four groups: a control group (Healthy, n = 8), streptozocin-induced rats (STZ group, n = 8), HM + STZ group (n = 8), and the Tangshen Formula (TSF) treatment group (TSF group, n = 8). Blood glucose levels and other metabolic indicators were monitored before treatment and at four-week intervals until 12 weeks. Total DNA was extracted from the aforementioned groups, and DNA methylation landscapes were analyzed via reduced representative bisulfite sequencing. Results Both the STZ group and HM + STZ group exhibited increased blood glucose levels and urinary albumin/creatinine ratios in comparison with the control group. Notably, the HM + STZ group exhibited a markedly elevated urinary albumin/creatinine ratio (411.90 ± 88.86 mg/g) compared to the STZ group (238.41 ± 62.52 mg/g). TSF-treated rats demonstrated substantial reductions in both blood glucose levels and urinary albumin/creatinine ratios in comparison with the HM + STZ group. In-depth analysis of DNA methylation profiles revealed 797 genes with potential therapeutic effects related to TSF, among which approximately 2.3% had been previously reported as homologous genes. Conclusion While HM exacerbates DN through altered methylation patterns at specific CpG sites, TSF holds promise as a viable treatment for DN by restoring abnormal methylation levels. The identification of specific genes provides valuable insights into the underlying mechanisms of DN pathogenesis and offers potential therapeutic targets for further investigation.

Abstract Background Entecavir and tenofovir disoproxil fumarate (TDF) are standard first-line treatments to prevent viral reactivation and hepatocellular carcinoma (HCC) in individuals chronically infected with the hepatitis B virus (HBV), but the long-term efficacy of the two drugs remains controversial. Also unclear is whether the drugs are effective at preventing viral reactivation or HCC recurrence after hepatectomy to treat HBV-associated HCC. This trial will compare recurrence-free survival, overall survival, viral indicators and adverse events in the long term between patients with HBV-associated HCC who receive entecavir or TDF after curative resection. Methods This study is a randomized, open-label trial. A total of 240 participants will be randomized 1:1 into groups receiving TDF or entecavir monotherapy. The two groups will be compared in terms of recurrence-free and overall survival at 1, 3, and 5 years after surgery; adverse events; virological response; rate of alanine transaminase normalization; and seroreactivity at 24 and 48 weeks after surgery. Discussion This study will compare long-term survival between patients with HBV-associated HCC who receive TDF or entecavir monotherapy. Numerous outcomes related to prognosis will be analyzed and compared in this study. Trial registration ClinicalTrials.gov NCT02650271. Registered on January 7, 2016.

Abstract We obtain a class of dyonic black string solutions in 6D Salam-Sezgin model. We then calculate various thermodynamic quantities associated with this solution. Interestingly, for the thermodynamic quantities to be well defined, the temperature is bounded from above. However, the mass and entropy can still grow without any upper bound, reaching infinity at the maximal temperature. The quantization condition obeyed by various charges is also analyzed. In particular, we find that the Dirac quantization condition selects one particular sign choice for the magnetic string charges.

Abstract Background Most bone defects caused by bone disease or trauma are accompanied by infection, and there is a high risk of infection spread and defect expansion. Traditional clinical treatment plans often fail due to issues like antibiotic resistance and non-union of bones. Therefore, the treatment of infected bone defects requires a strategy that simultaneously achieves high antibacterial efficiency and promotes bone regeneration. Results In this study, an ultrasound responsive vanadium tetrasulfide-loaded MXene (VSM) Schottky junction is constructed for rapid methicillin-resistant staphylococcus aureus (MRSA) clearance and bone regeneration. Due to the peroxidase (POD)-like activity of VS4 and the abundant Schottky junctions, VSM has high electron–hole separation efficiency and a decreased band gap, exhibiting a strong chemodynamic and sonodynamic antibacterial efficiency of 94.03%. Under the stimulation of medical dose ultrasound, the steady release of vanadium element promotes the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). The in vivo application of VSM in infected tibial plateau bone defects of rats also has a great therapeutic effect, eliminating MRSA infection, then inhibiting inflammation and improving bone regeneration. Conclusion The present work successfully develops an ultrasound responsive VS4-based versatile sonosensitizer for robust effective antibacterial and osteogenic therapy of infected bone defects.

In the human body, almost all cells interact with extracellular matrices (ECMs), which have tissue and organ-specific compositions and architectures. These ECMs not only function as cellular scaffolds, providing structural support, but also play a crucial role in dynamically regulating various cellular functions. This comprehensive review delves into the examination of biofabrication strategies used to develop bioactive materials that accurately mimic one or more biophysical and biochemical properties of ECMs. We discuss the potential integration of these ECM-mimics into a range of physiological and pathological in vitro models, enhancing our understanding of cellular behavior and tissue organization. Lastly, we propose future research directions for ECM-mimics in the context of tissue engineering and organ-on-a-chip applications, offering potential advancements in therapeutic approaches and improved patient outcomes.

AbstractThe precautionary principle is a widely recognized approach in policy-making across various fields, emphasizing preventive action in situations of uncertain potential harm. However, its full potential remains unrealized due to implementation challenges. Our study analyzes policies related to face mask usage during the COVID-19 pandemic, characterized by significant uncertainty, time pressure, and potentially catastrophic consequences. We explore the challenges of balancing urgency against unforeseen negative consequences and determining the appropriate level of caution amid rapidly evolving scientific knowledge. To enhance the precautionary principle’s effectiveness, we argue for integrating additional principles: transparency, fairness, and adaptability. Transparency fosters public trust and informed decision-making through clear communication of policy rationales, uncertainties, and tradeoffs. Fairness ensures the equitable distribution of policy intervention benefits and burdens, considering vulnerable populations’ needs. Adaptability involves revising policies based on new information or changing circumstances, maintaining effectiveness and relevance. Our examination aims to provide insights and recommendations for improving the precautionary principle’s utility in policy-making, particularly where timely, informed action is crucial.

Background Neutrophil-to-lymphocyte ratio (NLR) has been suggested to be a prognostic marker for various diseases, but whether NLR dynamics (ΔNLR) is related to mortality and disease severity in patients with septic acute kidney injury (AKI) has not been determined.Methods Between August 2013 and August 2021, septic AKI patients at our center were retrospectively enrolled. ΔNLR was defined as the difference between the NLR at septic AKI diagnosis and at hospital admission. The relationship between the ΔNLR and mortality was evaluated by Kaplan–Meier curves, Cox proportional hazards, and cubic spline analyses. The prediction values were compared by area under the receiver-operating characteristic curve (AUROC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses.Results Of the 413 participants, the mean age was 63 ± 17 years, and 134 were female (32.4%). According to the median value, patients in the high-ΔNLR group had significantly greater 90-d mortality (74.4% vs. 46.6%, p

Efficient drug delivery across the blood-brain barrier is imperative for treating glioblastoma (GBM). This study utilized the GBM cell membrane to construct a biomimetic targeted nanosystem (GMNPs@AMD/RAPA) that hierarchically releases the CXCR4 antagonist AMD3100 and the mTOR pathway inhibitor rapamycin (RAPA) for reprogramming the tumor immune microenvironment and suppressing the progression of GBM. By initially inhibiting the CXCL12/CXCR4 axis, the tumor microenvironment (TME) was reprogrammed to enhance the infiltration of cytotoxic T lymphocytes (CTLs) into the TME while suppressing tumor cell survival, proliferation, and angiogenesis. Subsequently, through further cellular uptake and degradation of the nanoparticles, the mTOR pathway inhibitor RAPA was released, further suppressing the tumor progression. This study successfully combined chemotherapy and immunotherapy, achieving effective synergistic therapeutic effects, and suppressing the progression of GBM.

Abstract The evolution of gas hydrates influenced by the seawater environment is unknown. We present a model of structural transformation from sI hydrate to sII hydrate due to the influence of seawater environment and vent fluid in nature through in situ experiments of gas hydrate formation in the Haima cold seep area. The in situ experimental results indicate that gas hydrates preferentially form as sI hydrates even in cold seep environments where C2+ hydrocarbons are present. During subsequent evolution, the sI hydrates could restructured at the effect of seawater environment and vent fluid, causing transformation to sII hydrates under the influence of hydrate stability. The supply of gas and direct contact with seawater environment are critical factors for structural transformation. Such structural transformation is the result of gas hydrates seeking thermodynamic stability and may be common in active cold seep areas.

Diabetic foot ulcer (DFU) is a highly morbid complication in patients with diabetes mellitus, necessitating the development of innovative pharmaceuticals to address unmet medical needs. Sodium ion (Na+) is a well-established mediator for membrane potential and osmotic equilibrium. Recently, Na+ transporters have been identified as a functional regulator of regeneration. However, the role of Na+ in the intricate healing process of mammalian wounds remains elusive. Here, we found that the skin wounds in hyponatremic mice display a hard-to-heal phenotype. Na+ ionophores that were employed to increase intracellular Na+ content could facilitate keratinocyte proliferation and migration, and promote angiogenesis, exhibiting diverse biological activities. Among of them, monensin A emerges as a promising agent for accelerating the healing dynamics of skin wounds in diabetes. Mechanistically, the elevated mitochondrial Na+ decelerates inner mitochondrial membrane fluidity, instigating the production of reactive oxygen species (ROS), which is identified as a critical effector on the monensin A-induced improvement of wound healing. Concurrently, Na+ ionophores replenish H+ to the mitochondrial matrix, causing an enhancement of mitochondrial energy metabolism to support productive wound healing programs. Our study unfolds a new role of Na+, which is a pivotal determinant in wound healing. Furthermore, it directs a roadmap for developing Na+ ionophores as innovative pharmaceuticals for treating chronic dermal wounds in diabetic patients.

Abstract Digital PCR (dPCR) holds immense potential for precisely detecting nucleic acid markers essential for personalized medicine. However, its broader application is hindered by high consumable costs, complex procedures, and restricted multiplexing capabilities. To address these challenges, an all‐in‐one dPCR system is introduced that eliminates the need for microfabricated chips, offering fully automated operations and enhanced multiplexing capabilities. Using this innovative oscillation‐induced droplet generation technique, OsciDrop, this system supports a comprehensive dPCR workflow, including precise liquid handling, pipette‐based droplet printing, in situ thermocycling, multicolor fluorescence imaging, and machine learning‐driven analysis. The system's reliability is demonstrated by quantifying reference materials and evaluating HER2 copy number variation in breast cancer. Its multiplexing capability is showcased with a quadruplex dPCR assay that detects key EGFR mutations, including 19Del, L858R, and T790M in lung cancer. Moreover, the digital stepwise melting analysis (dSMA) technique is introduced, enabling high‐multiplex profiling of seven major EGFR variants spanning 35 subtypes. This innovative dPCR system presents a cost‐effective and versatile alternative, overcoming existing limitations and paving the way for transformative advances in precision diagnostics.

Spinal cord injury (SCI) is a complex problem in modern medicine. Fibroblast activation and fibroscarring after SCI impede nerve recovery. Non-coding RNA plays an important role in the progression of many diseases, but the study of its role in the progression of spinal fibrosis is still emerging. Here, we investigated the function of circular RNAs, specifically antisense to the cerebellar degeneration-related protein 1 (CDR1as), in spinal fibrosis and characterized its molecular mechanism and pathophysiology. The presence of CDR1as in the spinal cord was verified by sequencing and RNA expression assays. The effects of inhibition of CDR1as on scar formation, inflammation and nerve regeneration after spinal cord injury were investigated in vivo and in vitro. Further, gene expression of miR-7a-5p and protein expression of transforming Growth Factor Beta Receptor II (TGF-βR2) were measured to evaluate their predicted interactions with CDR1as. The regulatory effects and activation pathways were subsequently verified by miR-7a-5p inhibitor and siCDR1as. These results indicate that CDR1as/miR-7a-5p/TGF-βR2 interactions may exert scars and nerves functions and suggest potential therapeutic targets for treating spinal fibrotic diseases.

ObjectiveThis study aimed to evaluate the impact of early rhythm control (ERC) on the occurrence of cardiocerebrovascular events in patients diagnosed with atrial fibrillation detected after stroke (AFDAS).MethodsA systematic search was conducted across nine databases from inception to October 15, 2023 to identify clinical trials comparing ERC with usual care interventions in AFDAS patients. The primary outcome assessed was recurrent stroke, with secondary outcomes including all-cause mortality, adverse events related to arrhythmias, and dementia.ResultsAnalysis of five studies, consisting of two randomized clinical trials (RCTs) involving 490 patients and three cohort studies involving 95,019 patients, revealed a reduced rate of recurrent stroke [odds ratio (OR) = 0.30, 95% confidence interval (CI) 0.11–0.80, P = 0.016 in RCTs; OR = 0.64, 95% CI 0.61–0.68, P