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Abstract Lipid metabolism is a well-regulated process essential for maintaining cellular functions and energy homeostasis. Dysregulation of lipid metabolism is associated with various conditions, including cardiovascular diseases, neurodegenerative disorders, and metabolic syndromes. This review explores the mechanisms underlying lipid metabolism, emphasizing the roles of key lipid species such as triglycerides, phospholipids, sphingolipids, and sterols in cellular physiology and pathophysiology. It also examines the genetic and environmental factors contributing to lipid dysregulation and the challenges of diagnosing and managing lipid-related disorders. Recent advancements in lipid-lowering therapies, including PCSK9 inhibitors, ezetimibe, bempedoic acid, and olpasiran, provide promising treatment options. However, these advancements are accompanied by challenges related to cost, accessibility, and patient adherence. The review highlights the need for personalized medicine approaches to address the interplay between genetics and environmental factors in lipid metabolism. As lipidomics and advanced diagnostic tools continue to progress, a deeper understanding of lipid-related disorders could pave the way for more effective therapeutic strategies.

Abstract This study aimed to evaluate the diagnostic value of miR-193b-5p and miR-511-5p in sepsis and septic shock from the perspective of immune regulation. Initially, serum exosomal miRNA sequencing was conducted on patients with sepsis (n = 6), septic shock (n = 6), and healthy controls (n = 3). Using bioinformatics analysis, miR-193b-5p and miR-511-5p were identified as immune-related miRNAs differentiating sepsis from septic shock. Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to validate the identified miRNAs in a cohort of 90 participants, including 30 patients with sepsis, 30 with septic shock, and 30 general surgery patients serving as controls. The results indicated that miR-193b-5p expression level was significantly reduced in septic patients and septic shock patients compared with healthy controls. Both miR-193b-5p and miR-511-5p exhibited diagnostic potential, distinguishing sepsis from the control group, with area under the curve values of 0.797 and 0.795, respectively (P

Abstract Background Extracorporeal membrane oxygenation (ECMO) provides effective support for respiratory and circulatory functions and stands as an essential means in the management of life-threatening conditions. This study aimed to evaluate the safety and efficacy of a novel ECMO system in awake sheep models across various support durations. Methods Ten healthy Hu sheep were divided into venovenous (VV) and venoarterial (VA) groups, further categorized into short, medium, and long-term observation subgroups. Vital signs and blood indices were meticulously monitored. The integrity of heparin coatings and thrombosis in the ECMO system were assessed at indicated time points, followed by histopathological analysis. Results All ten sheep survived to their planned endpoints under awake ECMO, exhibiting stable vital signs without notable reductions in blood cells. With the support of ECMO, all sheep demonstrated a significant increase in partial pressure of oxygen (PO2) and maintained oxygen saturation (SO2) between 99.8 and 100%. The heparin coating remained relatively intact even after prolonged ECMO operation. Anatomical observations and pathological histology analyses of major organs revealed no apparent abnormalities. Conclusions In healthy Hu sheep models with different maintenance periods, the novel ECMO support in awake state demonstrated high safety and feasibility.

Abstract Background During oocyte maturation, DNA double-strand breaks (DSBs) can decrease oocyte quality or cause mutations. How DSBs are repaired in dividing oocytes and which factors influence DSB repair are not well understood. Results By analyzing DSB repair pathways in oocytes at different stages, we found that break-induced replication (BIR) and RAD51-mediated homology-directed repair (HDR) were highly active in germinal vesicle breakdown (GVBD) oocytes but suppressed in metaphase II (MII) oocytes and the BIR in oocytes was promoted by CDK1 activity. By culturing oocytes in different media, we found that high-energy media, such as DMEM, decreased CDK1 protein levels and suppressed BIR or HDR in MII oocytes. In contrast, 53BP1-mediated nonhomologous end joining (NHEJ) repair was inhibited in germinal vesicle (GV) and GVBD oocytes but promoted in MII oocytes, and NHEJ was not affected by DMEM medium and CDK1 activity. In addition, in DSB MII oocytes, polymerase theta-mediated end joining (TMEJ) was found to be suppressed by CDK1 activity and promoted by high-energy media. Conclusions In summary, MII oocytes exhibit high heterogeneity in DSB repair, which is regulated by both metabolic factors and CDK1 activity. These results not only expand our understanding of oocyte DSB repair but also contribute to the modification of in vitro maturation medium for oocytes.

Abstract Background In this study, we aimed to explore the association between baseline and early changes in the neutrophil-to-lymphocyte ratio (NLR) and the 30-day mortality rate in patients having anti-melanoma differentiation-associated gene 5 (MDA5)-positive dermatomyositis with interstitial lung disease (DM-ILD). Methods Overall, 263 patients with anti-MDA5 DM-ILD from four centers in China were analyzed. Multivariate logistic regression analysis was used to evaluate the impact of baseline NLR on the 30-day mortality rate in patients with anti-MDA5-positive DM-ILD. Furthermore, a generalized additive mixed model (GAMM) was applied to compare the NLR variations over time between 30-day survival group and non-survival group. Results Two hundred sixty-three patients with anti-MDA5-positive DM-ILD were divided into different groups based on their NLR and whether they survived or not within 30 days. The multivariate logistic regression analysis, accounting for confounding factors, identified an elevated baseline NLR as a prognostic indicator for 30-day mortality in patients with anti-MDA5-positive DM-ILD (hazard ratio 2.68, 95% confidence interval [CI] 1.18,6.00, P = 0.019). Furthermore, the GAMM results indicated that the NLR gradually increased more in the non-survival group compared with the survival group within 14 days of admission, with a daily average increase of 1.03 (β = 1.03; 95% CI, 0.75–1.31; P

Abstract Background Thaumatin-like proteins (TLPs) are crucial pathogenesis-related proteins that significantly contribute to plant defense rection. Fusarium oxysporum f. sp. cubense (Foc) causes Fusarium wilt of bananas, a serious threat to global production. However, the role of TLPs in disease resistance remains unclear. Results This study identified 49 TLP genes in banana, predominantly localized in the extracellular space, and distributed across 11 chromosomes. The ancestor–descendant relationship was explained, six genes remained remarkably conserved across species could represent the ancestral genes of the TLP gene family. Promoter regions, transcriptome and qRT-PCR analysis suggested that MaTLP16 might be involved in disease resistance. Furthermore, transcriptional silencing of MaTLP16 resulted in more severe leaf damage compared to the control, indicating that MaTLP16 is an important Foc resistance-related gene. Conclusion This study conducted a comprehensive genome-wide identification and systematic analysis of the TLP gene family in bananas. Our findings establish a foundation for further functional studies of MaTLP genes and highlight MaTLP16 as a strong candidate for use in breeding programs aimed at enhancing resistance to Musa diseases.

Abstract Background Neutrophil extracellular trap (NET) formation has been implicated as a pathogenic mechanism in both rheumatoid arthritis (RA) and interstitial lung disease (ILD). However, the role of NETs in RA-associated ILD (RA-ILD) and the mechanisms driving NET formation remain unclear. This study aimed to assess the involvement of NETs in RA-ILD and elucidate the underlying mechanisms. Methods Single-cell sequencing was used to identify changes in the quantity and function of neutrophils in the lung tissue of a zymosan A (ZYM)-induced interstitial pneumonia arthritis model. Additionally, nuclear receptor 4A3 (NR4A3) interference was performed in HL-60 cells to assess its impact on NET formation and the transformation of MRC-5 cells into myofibroblasts. The clinical relevance of plasma myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (Cit-H3), and cell-free DNA was evaluated in RA-ILD patients with different imaging types via a commercial enzyme-linked immunosorbent assay (ELISA). Results In the ZYM-treated SKG mouse model, which recapitulates key features of RA-ILD, an increased population of neutrophils in the lung tissue was primarily responsible for NET formation. Mechanistically, we found that interference with NR4A3 expression enhanced NET formation in HL-60 cells, which in turn promoted the differentiation of MRC-5 cells into myofibroblasts. Clinically, plasma MPO-DNA levels are elevated in patients with RA-nonspecific interstitial pneumonia (RA-NSIP), whereas Cit-H3 levels are elevated in RA-usual interstitial pneumonia (RA-UIP) patients compared with healthy subjects. ROC curve analysis further revealed that the combination of plasma MPO-DNA, rheumatoid factor (RF), and anti-citrullinated protein (anti-CCP) and the combination of Cit-H3, RF, and anti-CCP were superior diagnostic panels for NSIP and UIP in RA-ILD patients, respectively. Moreover, compared with those from healthy controls, neutrophils from patients with RA-UIP and RA-NSIP demonstrated a significantly increased ability to form NETs and induce the differentiation of MRC-5 cells into myofibroblasts. Specifically, RA-UIP patients exhibited a greater capacity for NET formation and the differentiation of MRC-5 cells into myofibroblasts than did RA-NSIP patients. Conclusions These findings suggest that targeting NETs may be a novel therapeutic approach for treating ILD in RA patients.

Abstract To address the challenge of reusing foaming agents in foam drainage gas production processes, we developed a redox-responsive surfactant with a straightforward preparation method based on molecular electrostatic interaction assembly. The redox response mechanism of the surfactant was investigated through surface tension, absorbance, particle size, and Zeta potential analyses. Results indicate that the minimum surface tension in the oxidized state can reach 26.4 mN∙m-1, and even after 6 repetitions, it remains at 28 mN∙m-1. In the oxidized state, the surfactant’s particle size can reach 310 nm, effectively stabilizing foam by reducing the liquid discharge rate of the liquid film through large micelles. Moreover, oxidized surfactants exhibit excellent dispersion and stability properties, with a Zeta potential of 28.7 mV. Even after 6 repetitions, the Zeta potential remains above 27.1 mV. Foaming performance tests demonstrate that the oxidation-reduction surfactant exhibits favorable foaming, stabilizing, and reusing effects. At 90 ℃, the initial and 5-minute foaming heights reached 131 mm and 94 mm, respectively. After 6 repetitions, these heights were 124 mm and 85 mm, respectively. The successful development of this treatment agent can effectively address on-site foam drainage needs and reduce the operational costs associated with foam drainage.

Abstract The development and modification of grouting materials constitute crucial factors influencing the effectiveness of grouting. Given the pivotal role of water in the hydration of cement-based composite materials and construction processes, this study proposes an exploratory approach using green, economical magnetized water technology to enhance the performance of cement grouts. The research systematically investigates the effects of magnetized water on the fundamental grouting properties (stability, rheological behavior, and stone body strength) of cement grouts, prepared under varying magnetization conditions (including magnetic intensity, water flow speed, and cycle times). Through the conduct of specific physicochemical tests on water, the study elucidates the mechanism through which magnetized water influences these properties. The results indicate that magnetized water positively impacts the stability of cement grouts, significantly reducing their absolute viscosity, apparent viscosity, plastic viscosity, and yield stress, thus markedly affecting the rheological characteristics of the cement grouts. Additionally, magnetized water notably enhances the flexural and compressive strength of the cement grout stone body, with a particularly significant improvement in early strength. From a quantum mechanics perspective, a magnetization mechanism based on the competition between the strengthening of hydrogen bonds between water molecule clusters and the weakening or breaking of hydrogen bonds within clusters is introduced, providing a theoretical basis for explaining the variability observed in water magnetization experiments.

Abstract Coal-burning fluorosis prevails in southwest China and other provinces. Although clay used as binder of briquettes was proven to cause coal-burning fluorosis, its enrichment processes remain unknown. The soils and rocks on typical geological units were sampled and simulation experiments were performed to detect the forming process of high-fluoride clay. The surface and mineral soils, farmland soils and rocks have fluoride levels of 157.9–1076.76, 334.58–1419.28, 227.52–1303.11 and 46.05–964.11 mg/kg respectively. Fluoride levels of surface soils, mineral horizon soils and farmland soils are significantly positively correlated, while those between soils and rocks are not significantly correlated. The soils overlying carbonates have substantially higher fluoride levels than those overlying non-carbonates although the carbonates have extremely lower fluoride levels. The fluoride levels in acid insoluble substances are significantly positively correlated with soil fluoride levels. The acid insoluble substances in carbonates have obviously higher fluoride levels than those in non-carbonates. High Ca(Mg) levels in carbonates restrict fluorine leaching into the water and facilitate fluorine deposition in soils. Fluoride enriches in soils with numerous Ca(Mg)CO3 leaching during carbonate weathering, which is a new insight into the cause of high-fluoride clay. An exposure pathway of fluoride is forwarded. The best prevention principle and policy are proposed.

The paper addresses the challenges of task migration and resource allocation in heterogeneous cloud–edge environments, where dynamic and stochastic conditions complicate efficient scheduling. To tackle this, the authors propose a novel scheduling algorithm combining soft actor–critic (SAC) agent with masked layer and graph convolutional network (GCN), namely MGSAC algorithm. MGSAC utilizes GCN to extract hidden structural features from the environment, enabling better adaptation to dynamic changes. Additionally, a learnable mask layer filters out ineffective actions, refining the selection of scheduling strategies and improving overall performance. By evaluating MGSAC on the real-world Bit-Brain dataset and simulating it using Cloud-Sim, experimental results demonstrate its superiority over existing algorithms in energy consumption, task response time, task migration time, and task Service-Level-Agreement violations rate, showcasing its effectiveness in real-world scenarios.

Abstract This study evaluated the ability of the triglyceride (TG) to high-density lipoprotein cholesterol (TG/HDL-C) ratio to identify individuals at risk of type 2 diabetes mellitus (T2DM) in the non-alcoholic fatty liver disease (NAFLD) population. We retrospectively studied 4,769 patients with NAFLD from the Affiliated Hospital of Hangzhou Normal University (2020–2023). Binary logistic regression models were used to evaluate the association between the TG/HDL-C ratio and lipid parameters with T2DM. TG/HDL-C ratio was positively associated with T2DM in patients with NAFLD, with an odds ratio (OR) of 2.72 (95% confidence interval, 2.23–3.31, p

Background Pneumococcal vaccines are effective in preventing pneumococcal diseases in adults. The evaluation of the antibodies persistence to the 23-valent pneumococcal polysaccharide vaccine (PPV23) could provide evidence on PPV23 revaccination.Research design and methods Adults aged ≥ 60 years were selected and vaccinated with PPV23 in Shanghai, and followed up for 5 years with blood samples collection of a 1-year interval. The geometric mean concentrations (GMC) of the IgG against 23 pneumococcal serotypes covered by PPV23 were detected using enzyme-linked immunosorbent assay. The antibodies to 23 pneumococcal serotypes among different groups was analyzed using statistical analysis.Results Overall, 517 participants completed all six visits over a 5-year period (2013–2018). The GMC of 23 serotypes in adults aged ≥ 60 years decreased slowly after PPV23 vaccination compared to baseline pre-vaccination (P

Background: Acting as mediators in cell-matrix and cell-cell communication, matricellular proteins play a crucial role in cancer progression. Thrombospondins (TSPs), a type of matricellular glycoproteins, are key regulators in cancer biology with multifaceted roles. Although TSPs have been implicated in anti-tumor immunity and epithelial-mesenchymal transition (EMT) in several malignancies, their specific roles to colon cancer remain elusive. Addressing this knowledge gap is essential, as understanding the function of TSPs in colon cancer could identify new therapeutic targets and prognostic markers. Methods: Analyzing 1981 samples from 10 high-throughput datasets, including six bulk RNA-seq, three scRNA-seq, and one spatial transcriptome dataset, our study investigated the prognostic relevance, risk stratification value, immune heterogeneity, and cellular origin of TSPs, as well as their influence on cancer-associated fibroblasts (CAFs). Utilizing survival analysis, unsupervised clustering, and functional enrichment, along with multiple correlation analyses of the tumor-microenvironment (TME) via Gene Set Variation Analysis (GSVA), spatial localization, Monocle2, and CellPhoneDB, we provided insights into the clinical and cellular implications of TSPs. Results: First, we observed significant upregulation of THBS2 and COMP in colon cancer, both of which displayed significant prognostic value. Additionally, we detected a significant positive correlation between TSPs and immune cells, as well as marker genes of EMT. Second, based on TSPs expression, patients were divided into two clusters with distinct prognoses: the high TSPs expression group (TSPs-H) was characterized by pronounced immune and stromal cell infiltration, and notably elevated T-cell exhaustion scores. Subsequently, we found that THBS2 and COMP may be associated with the differentiation of CAFs into pan-iCAFs and pan-dCAFs, which are known for their heightened matrix remodeling activities. Moreover, THBS2 enhanced CAFs communication with vascular endothelial cells and monocyte-macrophages. CAFs expressing THBS2 (THBS2+ CAFs) demonstrated higher scores across multiple signaling pathways, including angiogenic, EMT, Hedgehog, Notch, Wnt, and TGF-β, when compared to THBS2- CAFs. These observations suggest that THBS2 may be associated with stronger pro-carcinogenic activity in CAFs. Conclusions: This study revealed the crucial role of TSPs and the significant correlation between THBS2 and CAFs interactions in colon cancer progression, providing valuable insights for targeting TSPs to mitigate cancer progression.

Flood control operation, a non-engineering measure, can efficiently manage flood disasters within a river basin. However, numerous uncertainties exit in the real-time operation of flood control systems, creating risks in decision-making. As an efficient tool to mitigate these risks, risk management has garnered increasing attention in real-time flood control operation. This communication offers a series of suggestions for future research concerning risk management in real-time flood control operation, including risk assessment, risk diagnosis, and risk control methods.

Abstract Background Retinal vein occlusion (RVO) is a major cause of vision loss. The pathogenesis remains poorly defined although inflammation is known to play a critical role. In this study, we investigated the levels of complement proteins in the aqueous humour and plasma of RVO participants and the relationship between complement levels and retinal pathologies. Methods The plasma and aqueous humour were collected from 20 treatment-naive RVO and 20 cataract patients. Retinal lesions were examined by fundus stereoscopy and optical coherence tomography angiography. The levels of C1q, C2, C4, C4b, C3, C3b/iC3b, C5, C5a, CFB, CFD, CFI, CFH, and MBL in the plasma and aqueous humour were measured using the Luminex® x MAP® multiplex assay. Results RVO patients had significantly higher levels of C4, C4b, C3b/iC3b, CFB, and CFH in the plasma and aqueous humour compared to controls. The aqueous levels of C1q, C2, C5, C5a, and MBL were also significantly higher in RVO patients than in controls. CRVO patients had higher intraocular levels of C1q, C4, C5, CFI, CFH, and MBL than BRVO patients. C5a was below the detectable limit in the plasma in 18 cataracts and 16 RVO participants. The intraocular levels of C5a positively correlated with C1q, C2, C4, C3, C5, CFB, CFH, and MBL. The intraocular levels of CFD, CFI and MBL positively correlated with CRT, and the levels of C2, C3, C5, CFB, and MBL negatively correlated with the size of the foveal avascular zone. The plasma levels of C4b, C3b/iC3b, and CFD positively correlated with their counterparts in the aqueous humour in cataracts but not in RVO patients. The ratios of aqueous humour/plasma of C1q, C4, C4b, C3b/iC3b, C5, CFB, CFD, CFI, and CFH in the RVO patients were significantly higher than those in the cataract patients. Discussion and conclusions The intraocular complement activation in RVO is mediated by the classical and the alternative pathways and is largely independent of systemic complement activation. Intraocular complement activation may be related to retinal oedema and vascular remodeling in RVO patients.

Abstract Background Impoverished students constitute a group that cannot be overlooked in higher education. It is crucial for pharmaceutical universities worldwide to implement financial assistance programs that promote the development and success of students from poor families. Chinese universities have carried out active exploration of subsidized education, and made important achievements, but there are also problems, which are worth learning from. This study proposed a strategy to improve the core literacy of impoverished pharmaceutical students under the development-oriented funding system. Methods The study centers on clinical pharmacy students from a pharmaceutical college as the research subjects. A sequential explanatory mixed-methods approach was employed, with quantitative data collected through a survey questionnaire, supplemented by qualitative data collected through in-depth interviews. Data gathered from these two levels were integrated and subjected to statistical analysis. Results The quantitative survey yielded a total of 397 valid samples, most of whom were females (73.8%), mainly at undergraduate level (89.67%), and from non-urban area (73.81%). Five of them participated in further qualitative interviews. The combined data identified: (a) financial aid—most students were highly satisfied with the financial support; (b) psychological support—most of the students interviewed reported that the scholarship significantly improved their self-confidence and motivation; (c) academic guidance—funded students had clear expectations for career development and academic guidance, demonstrating a strong need for further professional study; and (d) employment assistance—most students wanted career guidance and career planning support. Conclusions The financial assistance in pharmaceutical colleges and universities should be enriched to resolve the worries of impoverished clinical pharmacy students through economic assistance, improve the moral cultivation with psychological assistance, strengthen their cultural and scientific literacy, and improve their knowledge and practical ability through academic assistance. Through the integration of pharmacy education, the vocational competence of clinical pharmacy students can be improved by employment assistance, and the reform of higher pharmacy education can be further promoted to improve the training quality of pharmaceutical talents.

Abstract Background Circulating microRNAs (miRNAs) are recently a rapidly increasing of interest as non-invasive biomarkers for diagnosis and prognosis of acute myocardial infarction (AMI). Previous studies revealed that several miRNAs exhibited the capacity for diagnosis and prognosis of AMI, the reasons why these circulating miRNAs are concerned as targets for investigation are quite cryptogenic, presumably due to the lack of clues provided by global surveillance at the transcriptome level, and the current data for some miRNAs are controversial and inconsistent among independent studies. Methods To comprehensively profiling the potential miRNAs for diagnosis and prognosis of AMI, we reported transcriptomes of circulating miRNAs in the plasma of 27 healthy controls, 64 AMI patients (37 STEMI and 27 NSTEMI) and 20 AMI patients who were subjected to reperfusion therapy. Meanwhile, the cTnI of AMI patients was parallel determined. Differentially-circulated miRNAs were analyzed between each group. All detected circulating miRNAs were examined by ROC analysis and then LASSO dimension reduction to obtain an optimal panel for diagnosis of AMI. A five-year period follow-up towards the AMI and reperfusion patients was performed, and the prognostic value of circulating miRNAs in these patients was estimated by using the Cox regression model, ROC and Kaplan-Meier curves. Results Comprehensive global differences of miRNAs transcriptome among AMI, reperfusion patients and healthy controls were identified. A total of 40 miRNAs, called high diagnostic performance miRNAs, including several previous well-studied miRNAs with AUC greater than 0.85 were shown to discriminate AMI with healthy controls. In addition, 29 miRNAs were analyzed to be strongly correlated with the plasma cTnI level, of which 20 overlapped with high diagnostic performance miRNAs. These overlapped miRNAs are over-represented in the pathways which actually reflect the pathological cause of myocardial infarction, as well as the regulation of gene expression and energetic pathway of cellular response to hypoxia. Finally, two miRNAs were analyzed to be significantly correlated to all-cause mortality. Conclusion This is the first time to survey plasma miRNAs for the development of AMI diagnostic and prognostic biomarkers at the transcriptome level. A subset of miRNAs exhibited potential diagnostic and prognostic merits for AMI.

The concept of precision nutrition was first proposed almost a decade ago. Current research in precision nutrition primarily focuses on comprehending individualized variations in response to dietary intake, with little attention being given to other crucial aspects of precision nutrition. Moreover, there is a dearth of comprehensive review studies that portray the landscape and framework of precision nutrition. This review commences by tracing the historical trajectory of nutritional science, with the aim of dissecting the challenges encountered in nutrition science within the new era of disease profiles. This review also deconstructs the field of precision nutrition into four key components: the proposal of the theory for individualized nutritional requirement phenotypes; the establishment of precise methods for measuring dietary intake and evaluating nutritional status; the creation of multidimensional nutritional intervention strategies that address the aspects of what, how, and when to eat; and the construction of a pathway for the translation and integration of scientific research into healthcare practices, utilizing artificial intelligence and information platforms. Incorporating these four components, this review further discusses prospective avenues that warrant exploration to achieve the objective of enhancing health through precision nutrition.

Skin aging is an increasingly prominent topic in the context of healthy aging. During the aging process, the skin’s barrier function diminishes, its water content decreases, wrinkles begin to form, and changes occur in the gut microbiota composition. However, the relationship between gut microbiota and skin aging remains unclear. In this study, we explored skin rejuvenation in aged mice through fecal microbiota transplantation (FMT) using feces from young mice. The results demonstrated enhanced water retention, thickened stratum corneum, increased collagen content, and improved epithelial cell differentiation in aged mice following FMT. Notably, FMT particularly increased the abundance of Lactobacillus and Lactococcus in aged mice, which were nearly undetectable in untreated aged mice. Non-targeted and targeted metabolomics analyses indicated that FMT significantly elevated levels of tryptophan (Trp) and its microbiota metabolites (e.g., indole-3-lactic acid (ILA)) in the feces and serum of aged mice. Both Trp and ILA appeared to rejuvenate aged skin by activating the aryl hydrocarbon receptor (AhR) to promote epidermal cell differentiation. In conclusion, FMT from young mice rejuvenated aged skin via Trp-metabolizing bacteria (Lactobacillus and Lactococcus) and Trp-derived metabolites, suggesting that interventions targeting Trp metabolites may effectively improve skin aging.

Intestinal stem cells (ISCs) initiate intestinal epithelial regeneration and tumorigenesis, and they experience rapid refilling upon various injuries for epithelial repair as well as tumor reoccurrence. It is crucial to reveal the mechanism underlying such plasticity for intestinal health. Recent studies have found that metabolic pathways control stem cell fate in homeostasis, but the role of metabolism in the regeneration of ISCs after damage has not been clarified. Here, we find that in a human colorectal cancer dataset, miR-29a and b (miR-29a/b) are metabolic regulators highly associated with intestinal tumorigenesis and worse prognostic value of radiotherapy. We also show that these two microRNAs are required for intestinal stemness maintenance in mice, and their expression is induced in regenerated ISCs after irradiation injury, resulting in skewed ISC fate from differentiation towards self-renewal. This upregulation of miR-29a/b expression in ISCs leads to suppression of fatty acid oxidation (FAO) and depression of oxidative phosphorylation, which in turn controls the balance between self-renewal and differentiation of ISCs. Deletion of miR-29a/b prevents these effects and thus impairs ISC-mediated epithelial recovery. Finally, we filter the potential targets of miR-29a/b and identify Hnf4g, a transcription factor, that drives this metabolic reprogramming through regulating FAO-related enzymes. Our work discovers an important metabolic mechanism of ISC-mediated regeneration and potentially pave the way for more targeted and effective therapeutic strategies for intestinal repair as well as tumor treatment.

Abstract Aims/Introduction To assess whether the sodium–glucose cotransporter 2 inhibitor, henagliflozin, improves cognitive impairment in patients with type 2 diabetes. Materials and Methods We carried out a prospective study on 290 patients with type 2 diabetes and cognitive impairment. Montreal Cognitive Assessment scores and plasma phosphorylated tau181 levels were used to assess cognition. The association between henagliflozin use and changes in cognition was examined using multivariable logistic regression analysis. Results Montreal Cognitive Assessment scores at enrollment and after 6 months were 21 (interquartile range [IQR]19–23) versus 22 (IQR 20–25; P 0.05) in the non‐sodium–glucose cotransporter 2 inhibitor group. Logistic regression analysis showed that henagliflozin treatment was associated with Montreal Cognitive Assessment score improvement independent of potential confounders (odds ratio [OR] 3.670, 95% confidence interval [CI] 2.224–6.056, P

Abstract With global climate change, ecosystems are affected, some of which are more vulnerable than others, such as alpine ecosystems. Microbes play an important role in environmental change in global ecosystems. Plants and microbes are tightly associated, and symbiotic or commensal microorganisms are crucial for plants to respond to stress, particularly for alpine plants. The current study of alpine and subalpine plant microbiome only stays at the community structure scale, but its ecological function and mechanism to help plants to adapt to the harsh environments have not received enough attention. Therefore, it is essential to systematically understand the structure, functions and mechanisms of the microbial community of alpine and subalpine plants, which will be helpful for the conservation of alpine and subalpine plants using synthetic microbial communities in the future. This review mainly summarizes the research progress of the alpine plant microbiome and its mediating mechanism of plant cold adaptation from the following three perspectives: (1) Microbiome community structure and their unique taxa of alpine and subalpine plants; (2) The role of alpine and subalpine plant microbiome in plant adaptation to cold stress; (3) Mechanisms by which the microbiome of alpine and subalpine plants promotes plant adaptation to low-temperature environments. Finally, we also discussed the future application of high-throughput technologies in the development of microbial communities for alpine and subalpine plants. The existing knowledge could improve our understanding of the important role of microbes in plant adaptation to harsh environments. In addition, perspective further studies on microbes’ function confirmation and microbial manipulations in microbiome engineering were also discussed.

Abstract The impact of climate change on medicinal plants has significantly altered their suitable environments, thereby affecting the quality of herbal medicines. Notopterygium franchetii (N. franchetii), a medicinal plant intricately linked to its natural habitat, exhibits substantial quality variations influenced by the ecological conditions of its native region. In this study, comprehensive field surveys were conducted to gather occurrence records and samples of N. franchetii. The Maxent model and ArcGIS software were employed to predict the suitable habitats of N. franchetii during different time periods. A high-performance liquid chromatography (HPLC) method was developed to establish the chemical fingerprints of 21 sample batches. Fourteen common peaks were subjected to cluster analysis, principal component analysis, and orthogonal partial least squares-discriminant analysis. The findings revealed quality variations correlated with their geographic origins, identifying peaks 10, 1, 14, 3, and 4 as crucial for quality differentiation. The study indicates that precipitation, temperature, and altitude significantly influence the distribution of N. franchetii. Under current climate conditions, the suitable habitat area for N. franchetii is estimated to be approximately 94,637.33 km2. However, projections under three future climate scenarios suggest a declining trend in suitable habitat areas. A quality zoning map of N. franchetii was developed, integrating a correlation model between chemical composition and environmental variables with the spatial analysis and visualization capabilities of ArcGIS. The high-quality regions for N. franchetii are predominantly located in the Gannan, Linxia, Dingxi, Longnan, and Wuwei districts. These research outcomes offer a valuable reference for identifying suitable cultivation areas and assessing the quality of N. franchetii in Gansu Province.

Abstract Background Previous studies have indicated that social connectedness can serve as a protective buffer against negative outcomes associated with online victimization. However, the role of social connectedness between Internet gaming disorder and somatic symptoms is still unclear. This study aims to examine the mediating effect of social connectedness on the association between Internet gaming disorder and somatic symptoms. Methods A cross-sectional design was utilized, using questionnaires for data collection and multi-stage stratified cluster sampling. The general demographic questionnaire, Nine-Item Internet Gaming Disorder Scale–Short Form, Social Connectedness Scale-Revised and Patient Health Questionnaire Physical Symptoms were used to collect data. We adopted Pearson’s correlation analysis and the PROCESS Macro Model in regression analysis to explore the relationships among Internet gaming disorder, social connectedness and somatic symptoms. Results Internet gaming disorder was positively correlated with somatic symptoms (r = 0.20, P

Abstract Background The prevalence of non-small cell lung cancer (NSCLC) is notably elevated in individuals diagnosed with idiopathic pulmonary fibrosis (IPF). Secreted phosphoprotein 1 (SPP1), known for its involvement in diverse physiological processes, including oncogenesis and organ fibrosis, has an ambiguous role at the intersection of IPF and NSCLC. Our study sought to elucidate the function of SPP1 within the pathogenesis of IPF and its subsequent impact on NSCLC progression. Methods Four GEO datasets was analyzed for common differential genes and TCGA database was used to analyze the prognosis. The immune infiltration was analyzed by TIMER database. SPP1 expression was examined in human lung tissues, the IPF fibroblasts and the BLM-induced mouse lung fibrosis model. Combined with SPP1 gene gain- and loss-of-function, qRT-PCR, Western blot, EdU and CCK-8 experiments were performed to evaluate the effects and mechanisms of SPP1 in IPF progression. Effect of SPP1 on NSCLC was detected by co-cultured IPF fibroblasts and NSCLC cells. Results Through bioinformatics analysis, we observed a significant overexpression of SPP1 in both IPF and NSCLC patient datasets, correlating with enhanced immune infiltration of cancer-associated fibroblasts in NSCLC. Elevated levels of SPP1 were detected in lung tissue samples from IPF patients and bleomycin-induced mouse models, with partial colocalization observed with α-smooth muscle actin. Knockdown of SPP1 inhibits TGF-β1-induced differentiation of fibroblasts to myofibroblasts and the proliferation of IPF fibroblasts. Conversely, SPP1 overexpression promoted IPF fibroblast proliferation via PI3K/Akt/mTOR pathway. Furthermore, IPF fibroblasts promoted NSCLC cell proliferation and activated the PI3K/Akt/mTOR pathway; these effects were attenuated by SPP1 knockdown in IPF fibroblasts. Conclusions Our findings suggest that SPP1 functions as a molecule promoting both fibrosis and tumorigenesis, positioning it as a prospective therapeutic target for managing the co-occurrence of IPF and NSCLC.

Abstract Background Childhood emotional maltreatment, non-suicidal self-injury and depression are prevalent among adolescents with mood disorders. While existing model indicated that childhood emotional maltreatment, functions of non-suicidal self-injury and depression are interrelated, not much is understood about the interplay of functions of non-suicidal self-injury in the relationship between childhood emotional maltreatment and depression. Thus, the goal of this research was to ascertain how functions of non-suicidal self-injury relate to childhood emotional maltreatment and depression. Methods The participants were adolescents with mood disorders from three hospitals in Sichuan Province, data was collected using self-administered questionnaires, including the Childhood Trauma Questionnaire, Ottawa Self-injury Inventory-Functions, and Childhood Depression Inventory. SPSS26.0 software and PROCESS v3.3 model 4 were used for analysis. Results In all, 235 adolescents (M age=14.8, SD = 1.62) participated in the research. The functions of non-suicidal self-injury (r = 0.289, P

Objective: The present study aims to examine whether secondhand smoke exposure (SHSE) in university students can affect three indices of self-satisfaction related to depression as indiced by appearance, weight, and freedom of life choice. Participants: We collected data from 740 nonsmoking students in the summer of 2018, of which 57.84% were exposed to secondhand smoke. Methods: Depressive symptoms, SHSE, smoking status, weight satisfaction, appearance satisfaction, and freedom of life choice were self-reported via a questionnaire. Results: The generalized linear analyses revealed that SHSE was linked to lower scores of perceived freedom of life choice but not significantly associated with weight nor appearance satisfaction. The mediation analyses indicated that perceived freedom of life choice fully mediated the association between SHSE and depressive symptoms. Conclusions: These findings shed light on the importance of SHSE and its effects on mental health in university students. Preventive strategies should therefore locally target university campuses.

Abstract Turbulence is of great importance for aviation safety, but its long‐term trend in China remains unclear due to the scarcity of in‐situ measurements. Here the national‐scale assessment of turbulence dissipation rate (ε) at flight cruising altitude (200 hPa) in China is conducted for the period from 2010 to 2022 using high‐resolution radiosonde measurements. Results show that both the intensity and frequency of turbulence exhibit a significant upward trend, particularly in the mid‐latitude regions. Furthermore, 12 other turbulence diagnostic parameters from ERA5 reanalysis show a similar increasing trend, corroborating the intensified trend in radiosonde‐derived turbulence. This more intensified and frequent turbulence is found to be closely associated with the increasing occurrence of jet streams, which could be attributed to the dynamic instability induced by the wind shear around jet streams. The findings help advance our understanding of turbulence trend and its underlying mechanism in the mid‐latitude regions under global warming.

IntroductionThis study aimed to identify suitable plants for remediating metal pollution in copper tailing soil and supporting ecological reclamation in Dongchuan, Yunnan, focusing on three major mining regions: Tangdan, Yinmin, and Lanniping.MethodsThe Nemerow comprehensive pollution index was employed to evaluate the metal contamination levels, and the enrichment and transfer capacities of the dominant plants for Cd, Cu, Pb, and Zn were analyzed to identify remediation candidates.ResultsThe findings revealed severe pollution in the copper tailing soil, with Cu as the primary pollutant, and with a pollution rate of 77.778%. A total of 96 plant species from 42 families and 87 genera were recorded, including 29 dominant species across 17 families and 26 genera, with herbs comprising 62.068% of the dominant types. Among the tested plants, Leucaena leucocephala, Rumex acetosa, Festuca rubra, and Salix balfouriana exhibited significantly higher metal enrichment and transfer capacities, rendering them for ecological restoration. Salix balfouriana with the highest comprehensive membership function score of 5.298 was identified as the preferred species for ecological restoration in the Dongchuan Cu tailing area. Correlation analysis revealed a positive relationship between the metal content in underground plant parts and both the total metal content and organic matter (OM) in the rhizosphere soil, whereas a negative correlation was observed with soil pH.DiscussionThe soil in the Dongchuan Cu tailing area is severely contaminated by metals, mainly Cu. Among the identified plants, S. balfouriana emerged as the most suitable candidate for metal accumulation. This study establishes a comprehensive theoretical framework for the application and promotion of phytoremediation technology in the Dongchuan copper tailings area.

Ischemic stroke is a leading cause of mortality and morbidity globally. Prompt intervention is essential for arresting disease progression and minimizing central nervous system damage. Although imaging studies play a significant role in diagnosing ischemic stroke, their high costs and limited sensitivity often result in diagnostic and treatment delays. Blood biomarkers have shown considerable promise in the diagnosis and prognosis of ischemic stroke. Serum markers, closely associated with stroke pathophysiology, aid in diagnosis, subtype identification, prediction of disease progression, early neurological deterioration, and recurrence. Their advantages are particularly pronounced due to their low cost and rapid results. Despite the identification of numerous candidate blood biomarkers, their clinical application requires rigorous research and thorough validation. This review focuses on various blood biomarkers related to ischemic stroke, including coagulation and fibrinolysis-related factors, endothelial dysfunction markers, inflammatory biomarkers, neuronal and axonal injury markers, exosomes with their circular RNAs and other relevant molecules. It also summarizes the latest methods and techniques for stroke biomarker detection, aiming to provide critical references for the clinical application of key stroke biomarkers.

BackgroundPatients with antimelanoma differentiation–associated gene 5 antibody–positive dermatomyositis–associated interstitial lung disease (anti-MDA5+DM-ILD) are susceptible to rapidly progressive interstitial lung disease (RP-ILD) and have a high risk of mortality. There is an urgent need for a reliable prediction model, accessible via an easy-to-use web-based tool, to evaluate the risk of death. ObjectiveThis study aimed to develop and validate a risk prediction model of 3-month mortality using machine learning (ML) in a large multicenter cohort of patients with anti-MDA5+DM-ILD in China. MethodsIn total, 609 consecutive patients with anti-MDA5+DM-ILD were retrospectively enrolled from 6 hospitals across China. Patient demographics and laboratory and clinical parameters were collected on admission. The primary endpoint was 3-month mortality due to all causes. Six ML algorithms (Extreme Gradient Boosting [XGBoost], logistic regression (LR), Light Gradient Boosting Machine [LightGBM], random forest [RF], support vector machine [SVM], and k-nearest neighbor [KNN]) were applied to construct and evaluate the model. ResultsAfter applying inclusion and exclusion criteria, 509 (83.6%) of the 609 patients were included in our study, divided into a training cohort (n=203, 39.9%), an internal validation cohort (n=51, 10%), and 2 external validation cohorts (n=92, 18.1%, and n=163, 32%). ML identified 8 important variables as critical for model construction: RP-ILD, erythrocyte sedimentation rate (ESR), serum albumin (ALB) level, age, C-reactive protein (CRP) level, aspartate aminotransferase (AST) level, lactate dehydrogenase (LDH) level, and the neutrophil-to-lymphocyte ratio (NLR). LR was chosen as the best algorithm for model construction, and the model demonstrated excellent performance, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.866, a sensitivity of 84.8%, and a specificity of 84.4% on the validation data set and an AUC of 0.90, a sensitivity of 85.0%, and a specificity of 83.9% on the training data set. Calibration curves and decision curve analysis (DCA) confirmed the model’s accuracy and clinical applicability. Moreover, the model showed strong predictive performance in the external validation cohorts (cohort 1: AUC=0.836, 95% CI 0.754-0.916; cohort 2: AUC=0.915, 95% CI 0.871-0.959), indicating good generalizability. This model was integrated into a web-based tool to predict the 3-month mortality for patients with anti-MDA5+DM-ILD. ConclusionsWe successfully developed a robust clinical prediction model and an accompanying web tool to estimate the 3-month mortality risk for patients with anti-MDA5+DM-ILD.

BackgroundLeft-behind children in China face challenges in sleep patterns, technology use, and mental health. This study uses an individual-centered approach to derive behavioral profiles associated with depressive symptoms.MethodsData from 131,586 left-behind children aged 8 to 18 years from the Chinese Psychological Health Guard for Children and Adolescents Project were analyzed. Participants were recruited from 569 centers across schools, community institutes, orphanages, and children’s hospitals throughout China. Latent class analysis was conducted using weekday and weekend sleep duration and smartphone use as indicators. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D).ResultsFour distinct classes emerged: Sufficient Sleep Low Users (23.6%), Moderate Sleep Medium Users (25.2%), Limited Sleep High Users (22.1%), and Healthy Sleep Low Users (29.2%). Significant differences in CES-D scores were found between classes (F(3, 131579) = 4929, p

Study region: Xiangjiang basin, a humid subtropical inland region of central-south China. Study focus: Tropical Cyclones (TCs) usually cause extreme precipitation events (EPEs) and flooding in both coastal and inland areas, resulting in severe economic losses. However, TC impacts in inland regions were seldom investigated. This study provided a climatological view of TCs, TC-induced EPEs and flooding in the Xiangjiang basin over the past nearly 70 years, and examined their relationships with ENSO using data from 127 meteorological stations, 22 hydrological stations, and TC tracks. New hydrological insights for the region: Xiangjiang basin averaged five TC visits annually, primarily between July and September, when the majority of EPEs and flooding associated with TCs occurred. Despite the relatively low frequency (less than 30 %) of TC-induced EPEs and flooding compared to coastal regions, their magnitudes were comparable to or even exceeded those in coastal regions. These influences were modulated by ENSO. In neutral years, the frequency and magnitude of TC-induced EPEs were greatest due to higher TC track density and frequency. Also, TC tracks shifted westward, increasing the likelihood of extreme TC flooding in neutral years. The southeast of the basin faced the highest risk of TC-related disasters, especially in neutral years. This paper highlights the need to strengthen monitoring and prevention for TC-induced disasters in inland regions.

Abstract Mycophenolic acid (MPA) is commonly used to treat autoimmune diseases in children, and therapeutic drug monitoring is recommended to ensure adequate drug exposure. However, multiple blood sampling is required to calculate the area under the plasma concentration‐time curve (AUC), causing patient discomfort and waste of human and financial resources. This study aims to use machine learning and deep learning algorithms to develop a prediction model of MPA exposure for pediatric autoimmune diseases with optimizing sampling frequency. Pediatric autoimmune patients' data were collected at Nanfang Hospital between June 2018 and June 2023. Univariate analysis was applied for feature selection. Ten algorithms, including Random Forest, XGBoost, LightGBM, Gradient Boosting Decision Tree, CatBoost, Artificial Neural Network, Grandient Boosting Machine, Transformer, Wide&Deep, and TabNet, were employed for modeling based on two, three, or four concentrations of MPA. A total of 614 MPA AUC0‐12h samples from 209 patients were enrolled. Among the 10 models evaluated, the Wide&Deep model exhibited the best predictive performance. The predictive performance of the Wide&Deep model using four and three blood concentration points was similar (R 2 ≈ 1 for four points; R 2 = 0.95 for three points). No significant difference in accuracy within ±30% was observed between models utilizing three and four blood concentration points (p = 0.06). This study demonstrates that in the Wide&Deep model, MPA exposure can be accurately estimated with three sampling points in children with autoimmune diseases. This model could help reduce discomfort in pediatric patients without reducing the accuracy of MPA exposure estimates in clinical practice.

Drought stress inhibits Salvia miltiorrhiza Bunge (S. miltiorrhiza) seedling growth and yield. Here, we studied the effects of drought stress on the different parts of S. miltiorrhiza seedlings through physiological, transcriptomic, and metabolomics analyses, and identified key genes and metabolites related to drought tolerance. Physiological analysis showed that drought stress increased the accumulation of hydrogen peroxide (H2O2), enhanced the activity of peroxidase (POD), decreased the activity of catalase (CAT) and the contents of chlorophyll b and total chlorophyll, reduced the degree of photosynthesis, enhanced oxidative damage in S. miltiorrhiza seedlings, and inhibited the growth of S. miltiorrhiza plants. Transcriptome analyses revealed 383 genes encoding transcription factors and 80 genes encoding plant hormones as hypothetical regulators of drought resistance in S. miltiorrhiza plants. Moreover, differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) are involved in a variety of biological processes, such as proline and glycine betaine metabolism, and biosynthesis of tanshinones and phenolic acids. Additionally, it has barely been reported that the AHL gene family may be involved in regulating the neocryptotanshinone biosynthesis. In conclusion, our results suggest that drought stress inhibits S. miltiorrhiza seedling growth by enhancing membrane lipid peroxidation, attenuating the antioxidant system, photosynthesis, and regulating proline and glycine betaine metabolism, transcription factors and plant hormones, and tanshinones and phenolic acid metabolism pathways. This study provides new insights into the complex mechanisms by which S. miltiorrhiza responds to drought stress.

Extensive use of pyrethroid insecticides poses significant risks to both ecological ecosystems and human beings. Herein, Pseudomonas aeruginosa PAO1 exhibited exceptional degradation capabilities towards a range of pyrethroid family insecticides including etofenprox, bifenthrin, tetramethrin, D-cypermethrin, allethrin, and permethrin, with a degradation efficiency reaching over 84 % within 36 h (50 mg·L-1). Strain PAO1 demonstrated effective soil bioremediation by removing etofenprox across different concentrations (25–100 mg·kg−1), with a degradation efficiency over 77 % within 15 days. Additionally, 16S rDNA high-throughput sequencing analysis revealed that introduction of strain PAO1 and etofenprox had a notable impact on the soil microbial community. Strain PAO1 displayed a synergistic effect with local degrading bacteria or flora to degrade etofenprox. UPLC-MS/MS analysis identified 2-(4-ethoxyphenyl) propan-2-ol and 3-phenoxybenzoic acid as the major metabolites of etofenprox biodegradation. A new esterase gene (estA) containing conserved motif (GDSL) and catalytic triad (Ser38, Asp310 and His313) was cloned from strain PAO1. Enzyme activity and gene knockout experiments confirmed the pivotal role of estA in pyrethroid biodegradation. The findings from this study shed a new light on elucidating the degradation mechanism of P. aeruginosa PAO1 and present a useful agent for development of effective pyrethroid bioremediation strategies.

IntroductionSynbiotics have revealed the possibility of improving constipation through gut microbiota. The synergistic efficacy of Bifidobacterium animalis subsp. lactis BL-99 (BL-99) and fructooligosaccharide (FOS) on constipation have not been investigated.MethodsLoperamide-induced constipated mice model was established to explore the effect of BL-99, FOS, and BL-99+FOS on changes of defecation-related parameters, gut microbiota and metabolites.Results and discussionThe results showed that BL-99, FOS, and BL-99+FOS each alleviated constipation, with the synbiotic showing significant efficacy in the first black stool defecation time, fecal number, fecal weight, and the gastrointestinal transit rate (P < 0.05). Additionally, significant increased in serum 5-HT and IL-10 were observed in the BL-99+FOS group, alongside an increased relative abundance of Lachnospiraceae_NK4A136_group, Blautia, and Clostridium sensu stricto 1, while significantly reducing the relative abundance of Alistipes and Bacteroides. These changes facilitated alterations in short-chain fatty acids (SCFAs) metabolism, and were closely associated with the expression of genes related to the 5-HT pathway and the modulation of serum inflammatory factors. This study provides a theoretical basis for BL-99 and FOS synbiotics to improve constipation by regulating the gut microbiota and metabolites.

AimThis study aimed to explore the association between the ratio of 4-pyridoxine (4-PA) to pyridoxal 5′-phosphate (PLP) (4-PA/PLP) and diabetic retinopathy (DR) and further assess the mediating effect of Endothelial Activation and Stress Index (EASIX) on the association between 4-PA/PLP and DR.MethodsIn this cross-sectional study, 1,698 patients with diabetes from the National Health and Nutrition Examination Survey were included. According to the median, 4-PA/PLP was categorized into a high-level group (≥0.89) and a low-level group (

Human hepatitis B virus (HBV) infection is the major cause of acute and chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma. Although the application of prophylactic vaccination programs has successfully prevented the trend of increasing HBV infection prevalence, the number of HBV-infected people remains very high. Approved therapeutic management efficiently suppresses viral replication; however, HBV infection is rarely completely resolved. The major reason for therapeutic failure is the persistence of covalently closed circular DNA (cccDNA), which forms viral minichromosomes by combining with histone and nonhistone proteins in the nucleus. Increasing evidence indicates that chromatin-modifying enzymes, viral proteins, and noncoding RNAs are essential for modulating the function of cccDNA. Therefore, a deeper understanding of the regulatory mechanism underlying cccDNA transcription will contribute to the development of a cure for chronic hepatitis B. This review summarizes the current knowledge of cccDNA biology, the regulatory mechanisms underlying cccDNA transcription, and novel anti-HBV approaches for eliminating cccDNA transcription.

Abstract Background The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. Methods Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. Results Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. Conclusions These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. Trial registration LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Abstract Nutritional intervention can greatly benefit people who suffer from side effects of medical treatments by improving intestinal post‐damage recovery. The recovery process is dependent on the regeneration of intestinal epithelial cells, which is driven by Lgr5+ intestinal stem cells (ISCs). Lactoferrin (LF) is a natural milk‐abundant protein with several gut health‐related functions such as antibacterial and immunoregulation activities, thus protecting intestine from damage. However, it is unclear whether LF also plays a role in the repair of the injured intestine, despite limited clues on its ability to modulate intestinal epithelial cell growth in vitro. Here, we show that LF accelerates intestinal epithelial recovery after both dextran sulfate sodium challenge on mice and TNF‐α treatment on intestinal organoids. Furthermore, we find LF gives rise to ISC‐mediated epithelial regeneration by directly activating the Lgr5+ stem cells. Finally, we identify Lrp5/Wnt signaling as the key pathway for LF‐enhancing ISC stemness and function. Overall, our study reveals the potential of LF as a nutrient that can be applied to promote intestinal healing.

In China, despite the continuous efforts to preserve traditional villages in recent years, a significant amount of cultural heritages continue to vanish. Commonly observed issues such as the lack of coordination between preservation and development, the imbalance in spatial environment conservation and utilization, are pervasive. Regrettably, there is a conspicuous absence of theoretical underpinning in addressing these challenges. In this study, The evaluation factor of spatial environmental protection was selected, and these factors were weighted through expert surveys and the Analytic Hierarchy Process, and applied the multi-objective linear weighting function method to obtain a comprehensive evaluation calculation formula. Subsequently, we conducted an assessment of 28 representative traditional villages in the southern Chinese regions of Guangdong, Fujian, and Jiangxi. Their current issues were systematically analyzed and cluster analysis was applied to discern 11 distinct typologies of traditional village development. Besides, the temporal evolution patterns of these villages were delved into, and their development were categorized into five stages: initiation, enhancement, prosperity, over-development, and decline. Ultimately, based on the spatial environment characteristics of each development type and evolution stage, corresponding guidelines for spatial environment conservation and utilization are proposed, which provides necessary theoretical frameworks for future work this region.

Abstract This study aimed to assess the potential of home monitoring using a monitoring application for the early prediction of acute exacerbations (AEs) in patients with fibrosing interstitial lung diseases (F-ILDs) by tracking symptoms, peripheral blood oxygen saturation (SpO2), and heart rate (HR). Data on symptoms, SpO2, and HR before and after a 1-min sit-to-stand test (1STST) were collected using an online home monitoring application. Symptoms were recorded at least 3 times a week, including cough intensity and frequency (Cough Assessment Test scale (COAT) score), breathlessness grade (modified Medical Research Council (mMRC) score), and SpO2 and HR before and after 1STST. Eighty-five patients with stable F-ILDs were enrolled. We observed a significant increase in COAT and mMRC scores, alongside a significant decrease in SpO2 before and after 1STST, 2 weeks before the first recorded AE. Furthermore, a combination of variables-an increase in COAT (≥ 4) and mMRC(≥ 1) scores, a decrease in SpO2 at rest (≥ 5%), and a decrease in SpO2 after 1STST (≥ 4%)- proved the most effective in predicting AE onset in patients with F-ILDs at 2 weeks before the first recorded AE. Home telemonitoring of symptoms, SpO2 holds potential value for early AE detection in patients with F-ILDs.

Abstract Previous findings have reported the association between frailty and chronic kidney disease. However, the causality remains ambiguous. This study aimed to determine whether frailty index is causally associated with chronic kidney disease. We obtained the frailty genome-wide association study (GWAS) data and chronic kidney disease GWAS data from the FinnGen R5 (total n = 216,743; case = 3902, control = 212,841) as the exposure and outcome, respectively. A two-sample Mendelian randomization (MR) analysis was primarily conducted using the inverse-variance weighted (IVW), weighted median and MR-Egger regression analyses. Multivariable MR analysis (MVMR) was conducted for additional adjustment. In the two-sample Mendelian randomization analyses, a total of 14 single nucleotide polymorphisms (SNPs) were recognized as effective instrumental variables. The IVW method showed evidence to support a causal association between frailty index and chronic kidney disease (beta = 1.270; 95% CI 0.608 to 1.931; P

Abstract The HBV core protein (HBc) is an important viral protein of HBV that plays an indispensable role in the lifecycle of HBV, including capsid assembly and transport, reverse transcription and virus release. In recent years, evidence has shown that HBc may be involved in the malignant progression of HCC. Thus, HBc is an attractive target for antiviral agents and provides a new strategy for the treatment of HBV-related HCC. Here, we identified a novel anti‐HBc compound—colchicine, an alkaloid compound—that promoted selective autophagic degradation of HBc through the AMPK/mTOR/ULK1 signalling pathway. We further confirmed that colchicine promoted the selective autophagy of HBc by enhancing the binding of HBc to the autophagy receptor p62. Finally, we evaluated the effects of colchicine on HBV replication and HBc-mediated HCC metastasis in vitro and in vivo. Our research indicated that the inhibitory effects of colchicine on HBV and HBV-related HCC depend on the selective autophagic degradation of HBc. Thus, colchicine is not only a promising therapeutic strategy for chronic hepatitis B but also a new treatment for HBV-related HCC.