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Hui Xie,* Gang Li,* Kangkang Liu, Zhun Wang, Zhiqun Shang, Zihao Liu, Zhilei Xiong, Changyi Quan, Yuanjie Niu Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin 300211, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuanjie NiuDepartment of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, No. 23, Pingjiang Road, Hexi District, Tianjin 300211, People’s Republic of ChinaTel +86 1 520 221 6807Email niuyuanjie68@163.comPurpose: In recent years, there has been an increase in the incidence of small renal masses (SRMs) and nephrectomy was the standard management of this disease in the past. Currently, the use of active surveillance has been recommended as an alternative option in the case of some patients with SRMs due to its heterogenicity. However, limited studies focused on the regarding risk stratification. Therefore, in the current study, we developed a nomogram for the purpose of predicting the presence of high-grade SRMs on the basis of the patient information provided (clinical information, hematological indicators, and CT imaging data).Patients and methods: A total of 329 patients (consisting of development and validation cohort) who had undergone nephrectomy for SRMs between January 2013 and May 2016 retrospectively were recruited for the present study. All preoperative information, including clinical predictors, hematological indicators, and CT predictors, were obtained. Lasso regression model was used for data dimension reduction and feature selection. Multivariable logistic regression analysis was applied for the establishment of the predicting model. The performance of the nomogram was assessed with respect to its calibration and discrimination properties and externally validated.Results: The predictors used in the assessment of the nomogram included tumor size, CT tumor contour, CT necrosis, CT tumor exophytic properties, and CT collecting system oppression. Based on these parameters, the nomogram was evaluated to have an effective discrimination and calibration ability, and the C-index was found to be 0.883 after internal validation and 0.887 following external validation.Conclusion: Based on the aforementioned findings, it can be concluded that CT imaging–based preoperative nomogram is an effective predictor of SRMs and hence can be used in the preoperative evaluation of SRMs, due to its calibration and discrimination abilities.Keywords: renal cell carcinoma, small renal masses, SRMs, nomogram, tumor histology, CT

Chunji Quan,1,2,* Jie Sun,1,3,* Zhenhua Lin,1,3 Tiefeng Jin,1,3 Bing Dong,1,3 Ziqi Meng,1,3 Junjie Piao1,31Department of Pathology and Cancer Research Center, Yanbian University Medical College, Yanji 133002, People’s Republic of China; 2Department of Pathology, Affiliated Hospital of Yanbian University, Yanji 133000, People’s Republic of China; 3Key Laboratory of the Science and Technology, Department of Jilin Province, Yanji 133002, People’s Republic of China*These authors contributed equally to this workBackground: Ezrin and YAP are abnormally expressed in various cancers, and play pivotal roles in cancer initiation and development. However, the mechanisms of Ezrin in pancreatic cancer have not been fully elucidated. In this study, we aimed to elucidate the functions and mechanisms of Ezrin in the pathogenesis of pancreatic cancer.Methods: Effects of Ezrin deregulation on pancreatic cancer phenotype were determined in Capan-1 and BxPC-3 cells using MTT, colony formation, transwell, wound-healing, and chick chorioallantoic membrane assays. To find out the underlying mechanism of Ezrin, multiple assays were performed to detect the effect of Ezrin on Akt pathway activation and YAP expression. Then, Ezrin and YAP expression was analyzed in pancreatic cancer and normal pancreas samples. Finally, the prognostic value of Ezrin and YAP was evaluated in pancreatic cancer patients.Results: Ezrin promoted proliferation, invasion, epithelial–mesenchymal transition (EMT) progression, and angiogenesis of pancreatic cancers. Mechanistically, Ezrin activated Akt/mTOR pathways and induced YAP phosphorylation and nucleus translocation. The PI3K/Akt pathway inhibitor, rapamycin, and LY294002 could partially attenuate the effect of Ezrin on cell proliferation, invasion, EMT progression, and YAP phosphorylation and translocation. Moreover, both Ezrin and YAP were significantly overexpressed in pancreatic cancer tissues compared with adjacent normal pancreas, and correlated with poor prognosis in pancreatic cancer patients. Multivariate survival analysis showed that Ezrin was an independent prognostic marker for pancreatic cancer. Furthermore, the expression status of Ezrin and YAP had positive correlations in pancreatic cancer tissues.Conclusion: Ezrin promoted pancreatic cancer proliferation, invasion, migration, and EMT progression, partially through activating the PI3K/Akt pathway, and also regulated YAP phosphorylation and translocation, partially through the PI3K/Akt pathway. Ezrin and YAP were significantly overexpressed in pancreatic cancers, and correlated with poor prognosis in pancreatic cancer patients.Keywords: Ezrin, YAP, PI3K/Akt pathway, pancreatic cancer, survival

Background. In rapidly developing regions of the world such as Southeast Asia, marked industrialization with insufficient regulation places children at increased risk for significant environmental exposures. Health care providers have a key role in identifying, treating and preventing environmentally-related illnesses. Objectives. The authors undertook a survey of pediatric health care providers in Vietnam in order to gain preliminary insight into environmental hazard knowledge, and attitudes and beliefs regarding the relative importance of environmental factors in child health that could guide future initiatives towards building up capacity for children’s environmental health in the region. Methods. A formal written and self-administered survey instrument was adapted from the World Health Organization’s Children’s Environmental Health Survey and translated into Vietnamese. The survey was administered via convenience sampling after formal introduction to children’s environmental health (CEH) was made through lectures or meetings with pediatric care providers affiliated with the major children’s hospitals and pediatric departments in Vietnam. Results. One hundred forty-one pediatric care providers completed the survey. Most indicated environmental factors are considered to be very important in child health (84%); 98% felt the magnitude of the problem is increasing; and air pollution is seen as the top environmental health issue facing the country. The most commonly identified problems in their clinical experience included: food poisoning due to microbiological agents (85%); pesticide poisoning (77%); tobacco smoke exposure (75%); and inadequate sanitation (60%). Although most (80%) endorsed asking about children’s environmental conditions in clinical practice, a little more than a third (39%) were confident taking an environmental exposure history. For most key topics, less than half had received specific training. A majority (63%) of survey respondents were very interested in more environmental health training. Conclusions. Pediatric health care providers in Vietnam believe that environmental hazards in child health is an important topic that is routinely encountered in their care of patients, but training, experience and self-efficacy in these topics are limited. Financial Disclosure. None reported

Abstract Background Xuefu Zhuyu decoction (XFZYD) has been extensively utilized to treat traumatic brain injury (TBI). However, the bioactive compounds and the underlying mechanisms have not yet been elucidated. Objectives This study aimed to investigate the bioactive constituents of XFYZD that are absorbed in the blood and the mechanisms in treating TBI. Methods The study presents an integrated strategy in three steps to investigate the material basis and pharmacological mechanisms of XFZYD. The first step involves: (1) performing metabolomics analysis of XFZYD to obtain the main functions and targets; (2) screening the blood-entry ingredients and targets of XFZYD from databases; (3) obtaining the potential components targeting the key functions by integrated analysis of metabolomics and network pharmacology. The second step involves screening pharmacological effects with active ingredients in vitro. In the third step, the effects of the top active compound were validated in vivo, and the mechanisms were explored by protein antagonist experiments. Results Metabolomics analysis revealed that XFZYD treated TBI mice mainly through affecting the functions of blood vessels. We screened 62 blood-entry ingredients of XFZYD by network pharmacology. Then, we focused on 39 blood-entry ingredients related to vascular genes enriched by XFZYD-responsive metabolites. Performing the natural products library, we verified that hydroxysafflor yellow A (HSYA), vanillin, ligustilide, paeoniflorin, and other substances promoted endothelial cell proliferation significantly compared to the control group. Among them, the efficacy of HSYA was superior. Further animal studies demonstrated that HSYA treatment alleviated neurological dysfunction in TBI mice by mNSS and foot fault test, and decreased neuronal damage by HE, nissl, and TUNEL staining. HSYA increased the density of cerebral microvessels, raised the expression of angiogenesis marker proteins VEGFA and CD34, and activated the PI3K/Akt/mTOR signaling pathway significantly. The angiogenic effects disappeared after the intervention of PI3K antagonist LY294002. Conclusion By applying a novel strategy of integrating network pharmacology of constituents absorbed in blood with metabolomics, the research screened HSYA as one of the top bioactive constituents of XFZYD, which stimulates angiogenesis by activating the PI3K/Akt/mTOR signaling pathway after TBI.

Abstract Psychiatric disorders are severe health challenges that exert a heavy public burden. Air pollution has been widely reported as related to psychiatric disorder risk, but their casual association and pathological mechanism remained unclear. Herein, we systematically investigated the large genome-wide association studies (6 cohorts with 1,357,645 samples), single-cell RNA (26 samples with 157,488 cells), and bulk-RNAseq (1595 samples) datasets to reveal the genetic causality and biological link between four air pollutants and nine psychiatric disorders. As a result, we identified ten positive genetic correlations between air pollution and psychiatric disorders. Besides, PM2.5 and NO2 presented significant causal effects on schizophrenia risk which was robust with adjustment of potential confounders. Besides, transcriptome-wide association studies identified the shared genes between PM2.5/NO2 and schizophrenia. We then discovered a schizophrenia-derived inhibitory neuron subtype with highly expressed shared genes and abnormal synaptic and metabolic pathways by scRNA analyses and confirmed their abnormal level and correlations with the shared genes in schizophrenia patients in a large RNA-seq cohort. Comprehensively, we discovered robust genetic causality between PM2.5, NO2, and schizophrenia and identified an abnormal inhibitory neuron subtype that links schizophrenia pathology and PM2.5/NO2 exposure. These discoveries highlight the schizophrenia risk under air pollutants exposure and provide novel mechanical insights into schizophrenia pathology, contributing to pollutant-related schizophrenia risk control and therapeutic strategies development. Graphical Abstract

Due to the transmission demand for massive demand-side data， the pressure on communication networks has doubled and redoubled， leading to communication delays， congestion， interruptions， and other problems， which impact the real-time interaction of supply and demand services and hinder further implementation of load scheduling. To address the aforementioned issues and achieve precise consumption of new energy generation under communication constraints， a refined load scheduling strategy considering communication resource optimization is proposed. Firstly， based on information physical fusion technology， a scheduling mechanism for thermostatically-controlled loads considering the influence of communication networks is established. Subsequently， by use of a communication network model and an improved thermostatically-controlled load model that takes account of communication delay， an improved particle swarm optimization （PSO） that combines adaptive weighting and reverse learning is utilized， a refined thermostatically -controlled load scheduling considering communication resource balance is achieved. Finally， numerical simulation demonstrates that the proposed method can reasonably allocate communication resources and thermostatically-controlled loads maintain good consumption capability even under significant communication link delays.

Abstract Background Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. Methods Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme‐linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos‐tag sodium dodecyl‐sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin‐like protein 4 (ANGPTL4) phosphorylation. Results We identified that an elevated intracellular lipid level represents a crucial characteristic of node‐positive (N+) GC and further demonstrated that a high‐fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity‐related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol‐requiring enzyme‐1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase‐2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. Conclusions Leptin‐induced phosphorylation of ANGPTL4 facilitates LPL‐mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.

Abstract Background The myeloblastosis (MYB) transcription factor (TF) family is one of the largest and most important TF families in plants, playing an important role in a life cycle and abiotic stress. Results In this study, 268 Avena sativa MYB (AsMYB) TFs from Avena sativa were identified and named according to their order of location on the chromosomes, respectively. Phylogenetic analysis of the AsMYB and Arabidopsis MYB proteins were performed to determine their homology, the AsMYB1R proteins were classified into 5 subgroups, and the AsMYB2R proteins were classified into 34 subgroups. The conserved domains and gene structure were highly conserved among the subgroups. Eight differentially expressed AsMYB genes were screened in the transcriptome of transcriptional data and validated through RT-qPCR. Three genes in AsMYB2R subgroup, which are related to the shortened growth period, stomatal closure, and nutrient and water transport by PEG-induced drought stress, were investigated in more details. The AsMYB1R subgroup genes LHY and REV 1, together with GST, regulate ROS homeostasis to ensure ROS signal transduction and scavenge excess ROS to avoid oxidative damage. Conclusion The results of this study confirmed that the AsMYB TFs family is involved in the homeostatic regulation of ROS under drought stress. This lays the foundation for further investigating the involvement of the AsMYB TFs family in regulating A. sativa drought response mechanisms.

Abstract Background Breast cancer has become a major public health problem in the current society, and its incidence rate ranks the first among Chinese female malignant tumors. This paper once again confirmed the efficacy of lncRNA in tumor regulation by introducing the mechanism of the diagnosis of breast cancer by the MIR497HG/miR-16-5p axis. Methods The abnormal expression of MIR497HG in breast cancer was determined by RT-qPCR method, and the correlation between MIR497HG expression and clinicopathological characteristics of breast cancer patients was analyzed via Chi-square test. To understand the diagnostic potential of MIR497HG in breast cancer by drawing the receiver operating characteristic curve (ROC). The overexpressed MIR497HG (pcDNA3.1-MIR497HG) was designed and constructed to explore the regulation of elevated MIR497HG on biological function of BT549 and Hs 578T cells through Transwell assays. Additionally, the luciferase gene reporter assay and Pearson analysis evaluated the targeting relationship of MIR497HG to miR-16-5p. Results MIR497HG was decreased in breast cancer and had high diagnostic function, while elevated MIR497HG inhibited the migration and invasion of BT549 and Hs 578T cells. In terms of functional mechanism, miR-16-5p was the target of MIR497HG, and MIR497HG reversely regulated the miR-16-5p. miR-16-5p mimic reversed the effects of upregulated MIR497HG on cell biological function. Conclusions In general, MIR497HG was decreased in breast cancer, and the MIR497HG/miR-16-5p axis regulated breast cancer tumorigenesis, providing effective insights for the diagnosis of patients.

Abstract It is widely acknowledged that aging, mitochondrial dysfunction, and cellular phenotypic abnormalities are intricately associated with the degeneration of bone and cartilage. Consequently, gaining a comprehensive understanding of the regulatory patterns governing mitochondrial function and its underlying mechanisms holds promise for mitigating the progression of osteoarthritis, intervertebral disc degeneration, and osteoporosis. Mitochondrial hormesis, referred to as mitohormesis, represents a cellular adaptive stress response mechanism wherein mitochondria restore homeostasis and augment resistance capabilities against stimuli by generating reactive oxygen species (ROS), orchestrating unfolded protein reactions (UPRmt), inducing mitochondrial-derived peptides (MDP), instigating mitochondrial dynamic changes, and activating mitophagy, all prompted by low doses of stressors. The varying nature, intensity, and duration of stimulus sources elicit divergent degrees of mitochondrial stress responses, subsequently activating one or more signaling pathways to initiate mitohormesis. This review focuses specifically on the effector molecules and regulatory networks associated with mitohormesis, while also scrutinizing extant mechanisms of mitochondrial dysfunction contributing to bone and cartilage degeneration through oxidative stress damage. Additionally, it underscores the potential of mechanical stimulation, intermittent dietary restrictions, hypoxic preconditioning, and low-dose toxic compounds to trigger mitohormesis, thereby alleviating bone and cartilage degeneration.

Abstract Background Single nuclear polymorphisms (SNPs) have been published to be correlated with multiple diseases. Transcription Factor 21 (TCF21) is a critical transcription factor involved in various types of cancers. However, the association of TCF21 genetic polymorphisms with gastric cancer (GC) susceptibility and prognosis remains unclear. Methods A case-control study comprising 890 patients diagnosed with GC and an equal number of cancer-free controls was conducted. After rigorous statistical analysis, molecular experiments were carried out to elucidate the functional significance of the SNPs in the context of GC. Results TCF21 rs2327430 (OR = 0.78, P = 0.026) provides protection against GC, while rs4896011 (OR = 1.39, P = 0.005) exhibit significant associations with GC risk. Furthermore, patients with the (TC + CC) genotype of rs2327430 demonstrate a relatively favorable prognosis (OR = 0.47, P = 0.012). Mechanistically, chromatin immunoprecipitation assay and luciferase reporter assay revealed that the C allele of rs2327430 disrupts the binding of Transcription Factor AP-2 Alpha (TFAP2A) to the promoter region of TCF21, resulting in increased expression of TCF21 and inhibition of malignant behaviors in GC cells. Conclusion Our findings highlight the significant role of TCF21 SNPs in both the risk and prognosis of GC and provide valuable insights into the underlying molecular mechanisms. Specifically, the disruptive effect of rs2327430 on TCF21 expression and its ability to modulate malignant cell behaviors suggest that rs2327430 may serve as a potential predictive marker for GC risk and prognosis.

We presented a case of a 66-year-old female whose initial symptom was headache without obvious inducement. The patient's condition progressed rapidly to a semi-coma state after symptomatic treatment. The 18F-FDG PET/CT scan revealed circular FDG hypermetabolism and central metabolic defect of the pons and left frontal lobe lesions. The combination of clinical findings, MRI, and Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid led to the diagnosis of Balamuthia mandrillaris encephalitis. The patient died 5 days after discharge.

Induced pluripotent stem cells (iPSCs) can be personalized and differentiated into neural stem cells (NSCs), thereby effectively providing a source of transplanted cells for spinal cord injury (SCI). To further improve the repair efficiency of SCI, we designed a functional neural network tissue based on TrkC-modified iPSC-derived NSCs and a CBD-NT3-modified linear-ordered collagen scaffold (LOCS). We confirmed that transplantation of this tissue regenerated neurons and synapses, improved the microenvironment of the injured area, enhanced remodeling of the extracellular matrix, and promoted functional recovery of the hind limbs in a rat SCI model with complete transection. RNA sequencing and metabolomic analyses also confirmed the repair effect of this tissue from multiple perspectives and revealed its potential mechanism for treating SCI. Together, we constructed a functional neural network tissue using human iPSCs-derived NSCs as seed cells based on the interaction of receptors and ligands for the first time. This tissue can effectively improve the therapeutic effect of SCI, thus confirming the feasibility of human iPSCs-derived NSCs and LOCS for SCI repair and providing a valuable direction for SCI research.

Background: A significant cause of advanced renal failure is diabetic nephropathy (DKD), with few treatment options available. Calcitriol shows potential in addressing fibrosis related to DKD, though its molecular mechanisms remain poorly understood. This research seeks to pinpoint the crucial genes and pathways influenced by calcitriol within the scope of DKD-related fibrosis. Methods: Single-cell gene expression profiling of calcitriol treated DKD rat kidney tissue and screening of fibrosis-associated cell subsets. Mendelian randomization and enrichment analyses (CIBERSORT, GSVA, GSEA, Motif Enrichment) were used to explore gene-immune cell interactions and signaling pathways. Key findings were validated using independent datasets and protein expression data from the Human Protein Atlas. Results: Calcitriol treatment reduced proliferative cell populations and highlighted the FoxO signaling pathway's role in DKD. SUMO3 and CD74 were identified as key markers linked to immune infiltration and renal function. These genes were significantly associated with creatinine levels and eGFR, indicating their potential role in DKD progression. Conclusion: Our results suggest that calcitriol modulates DKD fibrosis through the FoxO pathway, with SUMO3 and CD74 serving as potential biomarkers for kidney protection. These results provide fresh insights into strategies for treating DKD.

The heterogeneity of immune cells and metabolic pathways in hepatocellular carcinoma (HCC) patients has not been fully elucidated, leading to diverse clinical outcomes. Accurately distinguishing different HCC subtypes and recommending appropriate treatments is are highly important. In this study, we conducted a comprehensive analysis of 28 immune cells and 85 metabolic pathways in the TCGA-LIHC and GSE14520 datasets. Metabolism-related first principal component (MRPC1) and cytotoxic T lymphocyte (CTL) infiltration were used to assess the metabolic and immune infiltration levels of HCC patients, respectively. These two quantifiable indicators were then used to construct an immune‒metabolic classifier, which categorized HCC patients into three distinct groups. The potential biological mechanisms were explored through multiomics analysis, revealing that group S1 exhibited high metabolic activity and a high level of immune infiltration, that group S2 presented a low level of immune infiltration, and that group S3 presented low metabolic activity. This new immune‒metabolic classifier was well validated in a pancancer cohort of 9296 patients. The efficacy of multiple treatment approaches was assessed in relation to different immune‒metabolic groups, indicating that group S1 patients may benefit from immunotherapy, that group S2 patients are suitable for transcatheter arterial chemoembolization (TACE), and that group S3 patients are appropriate candidates for tyrosine kinase inhibitors. In conclusion, this immune‒metabolic classifier is anticipated to address the differences in treatment efficacy among HCC patients due to the heterogeneity of the tumor microenvironment, and to help refine the individualized treatment choices for clinical patients.

ObjectiveTo evaluate the association between musculoskeletal pain and incident sarcopenia and further explore the mediating effect of depressive symptoms among middle-aged and older Chinese adults.MethodsUsing the data from the China Health and Retirement Longitudinal Study 2011 and 2015, we included 12,788 participants in the cross-sectional analysis and 8,322 for the longitudinal analysis. Musculoskeletal pains located in the neck, back, waist, shoulder, arm, wrist, leg, knee, and ankle were self-reported at baseline and follow-up. The diagnosis criteria of sarcopenia was based on the Asian Working Group for Sarcopenia 2019. Multivariable logistic regression models were used to evaluate the association between musculoskeletal pain, and the Karlson–Holm–Breen (KHB) method was used to explore the mediating effect of depressive symptoms.ResultsOver the 4-year follow-up, 445 participants were identified with incident sarcopenia. In the longitudinal analysis, participants with baseline musculoskeletal pain (adjusted odds ratio (OR): 1.37, 95% confidence interval (CI): 1.07–1.76), persistent musculoskeletal pain (OR:1.68, 95%CI: 1.28–2.24), and persistent waist pain (OR:1.46, 95%CI: 1.04–2.03) were significantly associated with increased the risk of incident sarcopenia. Furthermore, depressive symptoms were found to partially mediate the association between musculoskeletal pain and incident sarcopenia.ConclusionPersistent musculoskeletal pain, especially in waist area, was positively associated with a higher risk of sarcopenia among the middle-aged and older Chinese. Depressive symptoms played a partial mediating role in this association.

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

Cellular senescence, a permanent halt in cell division due to stress, spurs functional and structural changes, contributing to vascular aging characterized by endothelial dysfunction and vascular remodeling. This process raises the risk of ischemic stroke (IS) in older individuals, with its mechanisms still not completely understood despite ongoing research efforts. In this review, we have analyzed the impact of vascular aging on increasing susceptibility and exacerbating the pathology of IS. We have emphasized the detrimental effects of endothelial dysfunction and vascular remodeling influenced by oxidative stress and inflammatory response on vascular aging and IS. Our goal is to aid the understanding of vascular aging and IS pathogenesis, particularly benefiting older adults with high risk of IS.

A new MRI technique is presented for three-dimensional fast simultaneous whole brain mapping of myelin water fraction (MWF), T1, proton density (PD), R2*, magnetic susceptibility (QSM), and B1 transmit field (B1+). Phantom and human (N = 9) datasets were acquired using a dual-flip-angle blipped multi-gradient-echo (DFA-mGRE) sequence with a stack-of-stars (SOS) trajectory. Images were reconstructed using a subspace-based algorithm with a locally low-rank constraint. A novel joint-sparsity-constrained multicomponent T2*-T1 spectrum estimation (JMSE) algorithm is proposed to correct for the T1 saturation effect and B1+/B1− inhomogeneities in the quantification of MWF. A tissue-prior-based B1+ estimation algorithm was adapted for B1 correction in the mapping of T1 and PD. In the phantom study, measurements obtained at an acceleration factor (R) of 12 using prospectively under-sampled SOS showed good consistency (R2 > 0.997) with Cartesian reference for R2*/T1app/M0app. In the in vivo study, results of retrospectively under-sampled SOS with R = 6, 12, 18, showed good quality (structure similarity index measure > 0.95) compared with those of fully-sampled SOS. Besides, results of prospectively under-sampled SOS with R = 12 showed good consistency (intraclass correlation coefficient > 0.91) with Cartesian reference for T1/PD/B1+/MWF/QSM/R2*, and good reproducibility (coefficient of variation < 7.0 %) in the test-retest analysis for T1/PD/B1+/MWF/R2*. This study has demonstrated the feasibility of simultaneous whole brain multiparametric mapping with a two-minute scan using the DFA-mGRE SOS sequence, which may overcome a major obstacle for neurological applications of multiparametric MRI.

Objectives: This study aimed to investigate the role of BMP2 in hepatocellular carcinoma (HCC) growth and metastasis using a dual approach combining single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq. Methods: scRNA-seq data from the GEO database and bulk RNA-seq data from the TCGA database were analyzed. Differentially expressed marker genes of endothelial cells were identified and analyzed using enrichment analysis, PPI analysis, correlation analysis, and GSEA. In vitro, experiments were conducted using the Huh-7 HCC cell line, and in vivo, models of HCC growth and metastasis were established by knocking down BMP2. Results: The scRNA-seq analysis identified BMP2 as a key marker gene in endothelial cells of HCC samples. Elevated BMP2 expression correlated with poor prognosis in HCC. In vitro experiments showed that silencing BMP2 inhibited the proliferation, migration, and invasion of liver cancer cells. In vivo studies confirmed increased BMP2 expression in HCC tissues, promoting angiogenesis and HCC growth. Conclusion: This study highlights the role of BMP2 in tumor angiogenesis and HCC progression. Targeting BMP2 could be a promising therapeutic strategy against HCC.

Abstract Background Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. Methods Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796–456,380) in 15 autoimmune diseases (N = 14,890–314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. Results In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10–4] and NOX [OR: 1.34, p = 2.86 × 10–3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10–2] and PM2.5 [OR: 2.60, p = 5.96 × 10–3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10–2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10–3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10–4] and PM2.5 [OR: 0.17, p = 3.18 × 10–3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. Conclusion This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases. Graphical abstract (Built by the Biorender)

Abstract Background In lung transplantation (LTx) surgery, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide mechanical circulatory support to patients with cardiopulmonary failure. However, the use of heparin in the administration of ECMO can increase blood loss during LTx. This study aimed to evaluate the safety of heparin-free V-A ECMO strategies. Methods From September 2019 to April 2022, patients who underwent lung transplantation at the First Affiliated Hospital of Guangzhou Medical University were retrospectively reviewed. A total of 229 patients were included, including 117 patients in the ECMO group and 112 in the non-ECMO group. Result There was no significant difference in the incidence of thrombus events and bleeding requiring reoperation between the two groups. The in-hospital survival rate after single lung transplantation (SLTx) was 81.08%in the ECMO group and 85.14% in the Non-ECMO group, (P = 0.585). The in-hospital survival rate after double lung transplantation (DLTx) was 80.00% in the ECMO group and 92.11% in the Non-ECMO groups (P = 0.095). Conclusions In conclusion, the findings of this study suggest that the heparin-free V-A ECMO strategy in lung transplantation is a safe approach that does not increase the incidence of perioperative thrombotic events or bleeding requiring reoperation.

Viruses are among the main pathogens causing diarrhoea in calves. The current study found that bovine norovirus (BNoV) is one of the principal viruses causing diarrhoea in calves in Xinjiang, China.

Abstract Cytotoxic T lymphocytes (CTLs) play critical antitumor roles, encompassing diverse subsets including CD4+, NK, and γδ T cells beyond conventional CD8+ CTLs. However, definitive CTLs biomarkers remain elusive, as cytotoxicity-molecule expression does not necessarily confer cytotoxic capacity. CTLs differentiation involves transcriptional regulation by factors such as T-bet and Blimp-1, although epigenetic regulation of CTLs is less clear. CTLs promote tumor killing through cytotoxic granules and death receptor pathways, but may also stimulate tumorigenesis in some contexts. Given that CTLs cytotoxicity varies across tumors, enhancing this function is critical. This review summarizes current knowledge on CTLs subsets, biomarkers, differentiation mechanisms, cancer-related functions, and strategies for improving cytotoxicity. Key outstanding questions include refining the CTLs definition, characterizing subtype diversity, elucidating differentiation and senescence pathways, delineating CTL-microbe relationships, and enabling multi-omics profiling. A more comprehensive understanding of CTLs biology will facilitate optimization of their immunotherapy applications. Overall, this review synthesizes the heterogeneity, regulation, functional roles, and enhancement strategies of CTLs in antitumor immunity, highlighting gaps in our knowledge of subtype diversity, definitive biomarkers, epigenetic control, microbial interactions, and multi-omics characterization. Addressing these questions will refine our understanding of CTLs immunology to better leverage cytotoxic functions against cancer.

Abstract Regulatory T cells (Tregs) expressing the transcription factor FoxP3 are essential for maintaining immunological balance and are a significant component of the immunosuppressive tumor microenvironment (TME). Single-cell RNA sequencing (ScRNA-seq) technology has shown that Tregs exhibit significant plasticity and functional diversity in various tumors within the TME. This results in Tregs playing a dual role in the TME, which is not always centered around supporting tumor progression as typically believed. Abundant data confirms the anti-tumor activities of Tregs and their correlation with enhanced patient prognosis in specific types of malignancies. In this review, we summarize the potential anti-tumor actions of Tregs, including suppressing tumor-promoting inflammatory responses and boosting anti-tumor immunity. In addition, this study outlines the spatial and temporal variations in Tregs function to emphasize that their predictive significance in malignancies may change. It is essential to comprehend the functional diversity and potential anti-tumor effects of Tregs to improve tumor therapy strategies.

Abstract Energy supply policy quality is an important factor that would impact national energy security. While existing research conducted policy evaluation from the lens of performance assessment, less study has been devoted to evaluating energy supply policy from the perspective of policy making. This study takes the energy supply policy documents issued by China's central government during the ‘13th Five‐Year Plan’ period (2016–2020) as the research sample, and pioneers the use of the extended policy modelling consistency (PMC) index model combined with the text mining methodology to construct a policy evaluation index system with the characteristics of the energy supply policy which conducts a more in‐depth quantitative evaluation of the energy supply policy documents. The results show that the average PMC index value of China's energy supply policies is 7.26, and the overall quality is high. The concerns of existing policies are mainly focused on reform and development planning, safety production management and project engineering construction, but there is still room for improvement in policy predictability, coordination of policy areas, clarity of policy basis and goals and comprehensiveness of policy tool combinations. Based on this, China should improve the comprehensiveness of its energy supply policy tool combinations in terms of policy design norm; strengthen policy predictability and coordination of policy areas in terms of policy implementation guarantee; and clarify the basis and goals of policies in terms of policy orientation enhancement, to provide a reference basis for the formulation and improvement of future energy supply policies and to realise the sustainable development of energy supply.

Abstract SULF1 has been implicated in a number of malignancies. The function of SULF1 in gastric cancer is disputed. The objective of this study was to examine the role and underlying molecular mechanisms of SULF1 in the context of gastric cancer. We found that the expression of SULF1 was increased in gastric cancer, especially in cancer-associated fibroblasts. The overexpression of SULF1 was found to be significantly correlated with unfavorable prognosis among individuals diagnosed with gastric cancer. Functionally, cancer-associated fibroblasts-derived SULF1 served as a oncogenic molecule which facilitated gastric cancer cells metastasis and CDDP resistance. Mechanistically, SULF1 regulated the communication between gastric cancer cells and cancer-associated fibroblasts in tumor microenvironment as a signaling molecule. Cancer-associated fibroblasts-secreted SULF1 interfered with the interaction between TGF-β1 and TGFBR3 by combining with TGFBR3 on gastric cancer cell membrane, subsequently activated TGF-β signaling pathway. In conclusion, our findings have presented novel approaches for potential treatment and prognosis prediction in individuals diagnosed with gastric cancer through the targeting of the CAFs-SULF1-TGFBR3-TGF-β1 signaling axis.

For the first time, a trifunctional high-temperature AlN ceramic material that combines the extreme wicking, evaporative, and cooling functionalities for enhancing the efficiency of evaporation-based technologies was created through engineering a hierarchical surface nano/microstructure. The developed interfacially-engineered structure is an array of tapered micropillars, the surface of which is textured with irregular/regular nanostructures. The created material exhibits excellent wicking, evaporative, and cooling functionalities in a temperature range of 23–230 °C, both in the absence and presence of airflow. The wicking functionality provides unprecedentedly fast capillary flow of intensively boiling water on the AlN surface, even at a temperature of 230 °C. The developed ceramic also provides a very efficient evaporative cooling performance (from 230 to 126 °C). Our important result is a high evaporation rate of the AlN material at various airflows that exceeds that of a free water surface by a factor of 2.5–7.5, depending on the airflow velocity and temperature. The excellent performance of the trifunctional AlN ceramic at low and high temperatures under various airflow conditions shows its great potential for a large variety of evaporation-based technologies, including dew-point (DP) evaporative cooling systems for increasing power generation efficiency, water purification/desalination, thermal management, waste heat recovery, and other existing and emerging evaporation-based technologies.

Abstract Background Myasthenia gravis (MG) and the experimental autoimmune MG (EAMG) animal model are characterized by T-cell-induced and B-cell-dominated autoimmune diseases that affect the neuromuscular junction. Several subtypes of CD4+ T cells, including T helper (Th) 17 cells, follicular Th cells, and regulatory T cells (Tregs), contribute to the pathogenesis of MG. However, increasing evidence suggests that CD8+ T cells also play a critical role in the pathogenesis and treatment of MG. Main body Herein, we review the literature on CD8+ T cells in MG, focusing on their potential effector and regulatory roles, as well as on relevant evidence (peripheral, in situ, cerebrospinal fluid, and under different treatments), T-cell receptor usage, cytokine and chemokine expression, cell marker expression, and Treg, Tc17, CD3+CD8+CD20+ T, and CXCR5+ CD8+ T cells. Conclusions Further studies on CD8+ T cells in MG are necessary to determine, among others, the real pattern of the Vβ gene usage of autoantigen-specific CD8+ cells in patients with MG, real images of the physiology and function of autoantigen-specific CD8+ cells from MG/EAMG, and the subset of autoantigen-specific CD8+ cells (Tc1, Tc17, and IL-17+IFN-γ+CD8+ T cells). There are many reports of CD20-expressing T (or CD20 + T) and CXCR5+ CD8 T cells on autoimmune diseases, especially on multiple sclerosis and rheumatoid arthritis. Unfortunately, up to now, there has been no report on these T cells on MG, which might be a good direction for future studies.

With the expansion and implementation of rural revitalization strategies, there is a constant need for new energy sources for the construction of new townships. Consequently, integrated energy systems with the interconnection and interaction of multiple energy sources are developing rapidly. Biomass energy, a renewable green energy source with low pollution and wide distribution, has significant application potential in integrated energy systems. Considering the application of biomass energy in townships, this study established an integrated biomass energy system and proposed a model to optimize its operation. Lowest economic cost and highest clean energy utilization rate were considered as the objective functions. In addition, a plan was suggested to adjust the heat-electricity ratio based on the characteristics of the combined heat and power of the biomass. Finally, a simulation analysis conducted for a town in China was discussed, demonstrating that the construction of a township integrated-energy system and the use of biomass can significantly reduce operating costs and improve the energy utilization rate. Moreover, by adjusting the heat-electricity ratio, the economic cost was further reduced by 6.70%, whereas the clean energy utilization rate was increased by 5.14%.

Abstract Background Colorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker‐drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter‐ or intra‐tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians. Review In this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations. Conclusion In recent years, exploration of subtypes through cell lines, animal models, patient‐derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype‐specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR‐associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

Abstract Background and main body The anti‐tumour and tumour‐promoting roles of B cells in the tumour microenvironment (TME) have gained considerable attention in recent years. As essential orchestrators of humoral immunity, B cells potentially play a crucial role in anti‐tumour therapies. Chemotherapy, a mainstay in cancer treatment, influences the proliferation and function of diverse B‐cell subsets and their crosstalk with the TME. Modulating B‐cell function by targeting B cells or their associated cells may enhance chemotherapy efficacy, presenting a promising avenue for future targeted therapy investigations. Conclusion This review explores the intricate interplay between chemotherapy and B cells, underscoring the pivotal role of B cells in chemotherapy treatment. We summarise promising B‐cell‐related therapeutic targets, illustrating the immense potential of B cells in anti‐tumour therapy. Our work lays a theoretical foundation for harnessing B cells in chemotherapy and combination strategies for cancer treatment. Key points Chemotherapy can inhibit B‐cell proliferation and alter subset distributions and functions, including factor secretion, receptor signalling, and costimulation. Chemotherapy can modulate complex B‐cell–T‐cell interactions with variable effects on anti‐tumour immunity. Targeting B‐cell surface markers or signalling improves chemotherapy responses, blocks immune evasion and inhibits tumour growth. Critical knowledge gaps remain regarding B‐cell interactions in TME, B‐cell chemoresistance mechanisms, TLS biology, heterogeneity, spatial distributions, chemotherapy drug selection and B‐cell targets that future studies should address.

ObjectiveThis study aimed to characterize multivariate trajectories of blood pressure [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] jointly and examine their impact on incident cardiovascular disease (CVD) among a Chinese elderly medical examination population.MethodsA total of 13,504 individuals without CVD during 2018–2020 were included from the Chinese geriatric physical examination cohort study. The group-based trajectory model was used to construct multi-trajectories of systolic blood pressure and diastolic blood pressure. The primary outcome was the incidence of the first CVD events, consisting of stroke and coronary heart diseases, in 2021. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between BP multi-trajectories and incident CVD events.ResultsWe identified four blood pressure (BP) subclasses, summarized by their SBP and DBP levels from low to high as class 1 (7.16%), class 2 (55.17%), class 3 (32.26%), and class 4 (5.41%). In 2021, we documented 890 incident CVD events. Compared with participants in class 1, adjusted HRs were 1.56 (95% CI: 1.12–2.19) for class 2, 1.75 (95% CI: 1.24–2.47) for class 3, and 1.88 (95% CI: 1.24–2.85) for class 4 after adjustment for demographics, health behaviors, and metabolic index. Individuals aged 65 years and above with higher levels of BP trajectories had higher risks of CVD events in China.ConclusionsIndividuals with higher levels of both SBP and DBP trajectories over time were associated with an increased risk of incident CVD in the Chinese elderly population.

IntroductionLucerne (Medicago sativa), is a cornerstone of China’s livestock industry, however, due to the backward agronomic strategies and technology, lucerne in China faces cultivation challenges that result in lower productivity and quality than global standards. Therefore, we undertook a meta-analysis to evaluate the impact of five distinct fertilization types on lucerne yield and nutritional quality in various locations in China. The fertilizer practices included manure application, combined mineral fertilizer and manure application (FM), biological fertilizer application, unbalanced application of two or more mineral fertilizer types, and balanced mineral fertilizer application. Furthermore, we investigate influential factors of yield and quality of lucerne under fertilization, including climatic variables (mean annual precipitation, mean annual temperature), initial soil properties (soil organic carbon; total nitrogen, pH), and agronomic factors (seeding rate, harvest frequency, and lucerne stand age).MethodsOur study analyzed 53 published papers to discern the most beneficial fertilizer for enhancing lucerne yield and nutritional quality.Results and discussionThe results showed that the fertilizer practices, on average, significantly improved yield by 31.72% and crude protein content by 11.29%, with FM emerging as the most effective, this is because mineral fertilizers provide available nutrients for lucerne, manure provides essential organic matter for microorganisms and improve soil properties. In addition, the fertilizer practices significantly reduced neutral and acid detergent fiber contents by 6.28% and 8.50%, respectively, while increasing ash content and relative feeding value. Furthermore, climatic variables, soil properties, and planting system factors such as sowing date and harvest frequency significantly affected yield and nutritional quality. The practical implications of our results emphasize the need for balanced and strategic fertilizer application to optimize lucerne production and highlight the potential to adjust cultivation practices according to environmental conditions. Balanced and strategic fertilizer application can simultaneously improve soil properties, enhance soil carbon sequestration, and reduce the emission of greenhouse gases from the soil, which is a vital measure for realizing sustainable agricultural development.

ObjectivesTo identify clinical characteristics and risk factors for pulmonary involvements in asymptomatic and mildly symptomatic patients infected with SARS-CoV-2 Omicron variant by chest imaging analysis.MethodsDetailed data and chest computed tomography (CT) imaging features were retrospectively analyzed from asymptomatic and mildly symptomatic patients infected with Omicron between 24 April and 10 May 2022. We scored chest CT imaging features and categorized the patients into obvious pulmonary involvements (OPI) (score > 2) and not obvious pulmonary involvements (NOPI) (score ≤ 2) groups based on the median score. The risk factors for OPI were identified with analysis results visualized by nomogram.ResultsIn total, 339 patients were included (145 were male and 194 were female), and the most frequent clinical symptoms were cough (75.5%); chest CT imaging features were mostly linear opacities (42.8%). Pulmonary involvements were more likely to be found in the left lower lung lobe, with a significant difference in the lung total severity score of the individual lung lobes (p < 0.001). Logistic regression analysis revealed age stratification [odds ratio (OR) = 1.92, 95% confidence interval (CI) (1.548–2.383); p 8d) [OR = 1.842, 95% CI (1.104–3.073); p = 0.019], and pulmonary diseases [OR = 4.698, 95% CI (1.159–19.048); p = 0.03] as independent OPI risk factors.ConclusionAsymptomatic and mildly symptomatic patients infected with Omicron had pulmonary involvements which were not uncommon. Potential risk factors for age stratification, prolonged NCT, and pulmonary diseases can help clinicians to identify OPI in asymptomatic and mildly symptomatic patients infected with Omicron.

Summary: Background: The FDA's alerts regarding the T-cell lymphoma risk post CAR-T therapy has garnered global attention, yet a comprehensive profile of second primary malignancies (SPMs) following CAR-T treatment is lacking. Methods: We extracted adverse event reports of hematological malignancies (HMs) patients with clearly definable SPMs from the FAERS and VigiBase databases (2017–2023). Disproportionality analysis using reporting odds ratio (ROR) and adjusted ROR was performed to assess associations between SPMs and CAR-T therapy. Time-to-onset analysis explored factors affecting SPM manifestation. Findings: SPMs post CAR T-cell therapy include HMs and solid tumors. T-cell lymphoma and myelodysplastic syndromes were consistently identified as positive signals across the overall and subgroup analyses. Hematological SPMs showed earlier onset with increasing annual incidence post CAR-T therapy, whereas solid tumors exhibit delayed manifestation. SPMs in CAR-T recipients had significantly earlier onset than non-recipients. Furthermore, age-specific characteristics reveal earlier SPM manifestations in pediatric, adolescent, and young adult populations compared to older populations post CAR-T therapy. Interpretation: The current SPM profile highlights the necessity of long-term safety monitoring for all CAR-T recipients given the observed yearly increase of SPMs. Customizing long-term SPM screening across different age groups may enhance early detection and intervention strategies, ultimately improving patient outcomes in the follow-up of CAR-T recipients. Funding: This work was supported by grants from the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020), the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750, 82172811, and 82260546), the Guangdong Basic and Applied Basic Research Foundation (Guangdong–Guangzhou Joint Funds) (2022A1515111212), and the Science and Technology Program of Guangzhou (2023A04J1257).

Abstract Currently, tumor treatment modalities such as immunotherapy and targeted therapy have more stringent requirements for obtaining tumor growth information and require more accurate and easy‐to‐operate tumor information detection methods. Compared with traditional tissue biopsy, liquid biopsy is a novel, minimally invasive, real‐time detection tool for detecting information directly or indirectly released by tumors in human body fluids, which is more suitable for the requirements of new tumor treatment modalities. Liquid biopsy has not been widely used in clinical practice, and there are fewer reviews of related clinical applications. This review summarizes the clinical applications of liquid biopsy components (e.g., circulating tumor cells, circulating tumor DNA, extracellular vesicles, etc.) in tumorigenesis and progression. This includes the development process and detection techniques of liquid biopsies, early screening of tumors, tumor growth detection, and guiding therapeutic strategies (liquid biopsy‐based personalized medicine and prediction of treatment response). Finally, the current challenges and future directions for clinical applications of liquid biopsy are proposed. In sum, this review will inspire more researchers to use liquid biopsy technology to promote the realization of individualized therapy, improve the efficacy of tumor therapy, and provide better therapeutic options for tumor patients.

Summary: Stem cell therapy for intrauterine adhesions (IUAs) has been widely used in clinical treatment. However, intravenous injection lacks sufficient targeting capabilities, while in situ injection poses challenges in ensuring the effective survival of stem cells. Furthermore, the mechanism underlying the interaction between stem cells and endometrial cells in vivo remains poorly understood, and there is a lack of suitable in vitro models for studying these problems. Here, we designed an extracellular matrix (ECM)-adhesion mimic hydrogel for intrauterine administration, which was more effective than direct injection in treating IUAs. Additionally, we analyzed the epithelial-mesenchymal transition (EMT) and confirmed that the activation of endometrial epithelial stem cells is pivotal. Our findings demonstrated that umbilical cord mesenchymal stem cells (UC-MSCs) secrete WNT7A to activate endometrial epithelial stem cells, thereby accelerating regeneration of the endometrial epithelium. Concurrently, under transforming growth factor alpha (TGFA) stimulation secreted by the EMT epithelium, UC-MSCs upregulate E-cadherin while partially implanting into the endometrial epithelium.

PurposeDepression and anxiety are prevalent mental health challenges among college students. Music therapy has shown effectiveness in addressing depressive symptoms and enhancing psychosomatic functioning. This study aimed to evaluate the effectiveness of a 4-step structured music therapy program in improving mood and reducing symptoms of depression and anxiety among medical school students.Materials and methodsThe self-controlled study involved 45 medical school students (21 men and 24 women) aged 18–24 years to examine the prevalence of depression and anxiety, common mental health issues among medical school students. Participants underwent psychological assessment using the Symptom Checklist-90 (SCL-90), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS). An 8-week music therapy intervention, comprising four steps—sociality, interaction, music lessons, and creative expression—was administered.ResultsBefore-intervention, 55.6% and 15.6% students were identified as suffering from depression and anxiety respectively. Post-intervention, significant reductions in psychological distress, particularly in the Global Severity Index (GSI) and Positive Symptom Total (PST) on the SCL-90 scale, were observed (P < 0.05). Male students exhibited notable improvements in various psychological symptoms compared to females. Junior grade students demonstrated greater improvements, and clinical medicine students exhibited significant enhancements in specific areas post-intervention.ConclusionThe structured music therapy program showed promising results in improving mood and regulating emotions among medical school students. Music therapy holds potential as a holistic approach to address mental health challenges in this demographic.

The activation levels of biologically significant gene sets are emerging tumor molecular markers and play an irreplaceable role in the tumor research field; however, web-based tools for prognostic analyses using it as a tumor molecular marker remain scarce. We developed a web-based tool PESSA for survival analysis using gene set activation levels. All data analyses were implemented via R. Activation levels of The Molecular Signatures Database (MSigDB) gene sets were assessed using the single sample gene set enrichment analysis (ssGSEA) method based on data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), The European Genome-phenome Archive (EGA) and supplementary tables of articles. PESSA was used to perform median and optimal cut-off dichotomous grouping of ssGSEA scores for each dataset, relying on the survival and survminer packages for survival analysis and visualisation. PESSA is an open-access web tool for visualizing the results of tumor prognostic analyses using gene set activation levels. A total of 238 datasets from the GEO, TCGA, EGA, and supplementary tables of articles; covering 51 cancer types and 13 survival outcome types; and 13,434 tumor-related gene sets are obtained from MSigDB for pre-grouping. Users can obtain the results, including Kaplan-Meier analyses based on the median and optimal cut-off values and accompanying visualization plots and the Cox regression analyses of dichotomous and continuous variables, by selecting the gene set markers of interest. PESSA (https://smuonco.shinyapps.io/PESSA/ OR http://robinl-lab.com/PESSA) is a large-scale web-based tumor survival analysis tool covering a large amount of data that creatively uses predefined gene set activation levels as molecular markers of tumors.

Abstract Well‐defined nanostructures are crucial for precisely understanding nano‐bio interactions. However, nanoparticles (NPs) fabricated through conventional synthesis approaches often lack poor controllability and reproducibility. Herein, a synthetic biology‐based strategy is introduced to fabricate uniformly reproducible protein‐based NPs, achieving precise control over heterogeneous components of the NPs. Specifically, a ferritin assembly toolbox system is developed that enables intracellular assembly of ferritin subunits/variants in Escherichia coli. Using this strategy, a proof‐of‐concept study is provided to explore the interplay between ligand density of NPs and their tumor targets/penetration. Various ferritin hybrid nanocages (FHn) containing human ferritin heavy chains (FH) and light chains are accurately assembled, leveraging their intrinsic binding with tumor cells and prolonged circulation time in blood, respectively. Further studies reveal that tumor cell uptake is FH density‐dependent through active binding with transferrin receptor 1, whereas in vivo tumor accumulation and tissue penetration are found to be correlated to heterogeneous assembly of FHn and vascular permeability of tumors. Densities of 3.7 FH/100 nm2 on the nanoparticle surface exhibit the highest degree of tumor accumulation and penetration, particularly in tumors with high permeability compared to those with low permeability. This study underscores the significance of nanoparticle heterogeneity in determining particle fate in biological systems.

Line commutated converter based high-voltage direct-current (LCC-HVDC) transmissions are prone to harmonic oscillation under weak grids. Impedance modeling is an effective method for assessing interaction stability. Firstly, this paper proposes an improved calculation method for the DC voltage and AC currents of commutation stations to address the complex linearization of the commutation process and constructs an overall harmonic state-space (HSS) model of an LCC-HVDC. Based on the HSS model, the closed-loop AC impedances on the LCC-HVDC sending and receiving ends are then derived and verified. The impedance characteristics of the LCC-HVDC are then analyzed to provide a physical explanation for the harmonic oscillation of the system. The effects of the grid strength and control parameters on system stability are also analyzed. To improve the impedance characteristics and operating stability of the LCC-HVDC system, a virtual impedance based stability enhancement control is proposed, and a parameter design method is considered to ensure satisfactory phase margins at both the sending and receiving ends. Finally, simulation results are presented to verify the validity of the impedance model and virtual impedance based stability enhancement control.

Pore structure is an important parameter for the gas-bearing evaluation of lacustrine shale. However, the characteristics and influencing factors of pore structure and the shale reservoir capacity remain unclear due to the heterogeneity and complexity of shale reservoirs. This study focused on Da’anzhai shale to research the pore structure characteristics using a combination of field emission scanning electron microscopy, low pressure gas adsorption, and mercury intrusion porosimetry. The effects of different matrix components on multi-scale pore structure and the reservoir capacity are discussed. The results show that the total organic carbon (TOC) and vitrinite reflectance (Ro) are 0.7%–1.68% (average of 0.98%) and 1.42%, respectively. The organic macerals are vitrinite, inertinite, and solid bitumen, with the vitrinite predominating. The main minerals are clay minerals, quartz, and calcite. Matrix pores, including mineral-associated pores and organic matter pores, and microfractures jointly constitute the pore system of the Da’anzhai shale. Clay-mineral pores dominate, followed by organic matter pores. Pore sizes mainly range from 0.3 nm to 20 nm, reaching up to 10μm. Mesopore volumes are dominant, followed by micropores and macropores. The pore specific surface areas are 12.76–21.24 m2/g (average of 17.43 m2/g), of which micropores and mesopores account for 48.7% and 51.3%, respectively. TOC, organic macerals, and clay minerals are the controlling factors of the pore structure. In contrast, the impacts of Ro and the framework mineral content on shale pore structure are relatively weak. Da’anzhai shale has sufficient pore volume and specific surface area but the shale is dominated by clay mineral-associated large-size pores and microfractures with few organic micropores, resulting in limited adsorption capacity for the shale. A greater understanding of the pore formation mechanism of shale reservoirs is obtained through this study, which is of great significance for gas-bearing evaluations.

Abstract Data mining from RNA-seq or microarray data has become an essential part of cancer biomarker exploration. Certain existing web servers are valuable and broadly utilized, but the meta-analysis of multiple datasets is absent. Most web servers only contain tumor samples from the TCGA database with only one cohort for each cancer type, which also means that the analysis results mainly derived from a single cohort are thin and unstable. Indeed, consistent performance across multiple independent cohorts is the foundation for an excellent biomarker. Moreover, the deeper exploration of specific biomarkers on underlying mechanisms, tumor microenvironment, and drug indications are missing in existing tools. Thus, we introduce BEST (Biomarker Exploration for Solid Tumors), a web application for comprehensive biomarker exploration on large-scale data in solid tumors. To ensure the comparability of genes between different sequencing technologies and the legibility of clinical traits, we re-annotated transcriptome data and unified the nomenclature of clinical traits. BEST delivers fast and customizable functions, including clinical association, survival analysis, enrichment analysis, cell infiltration, immunomodulator, immunotherapy, candidate agents, and genomic alteration. Together, our web server provides multiple cleaned-up independent datasets and diverse analysis functionalities, helping unleash the value of current data resources. It is freely available at https://rookieutopia.com/ .

Abstract Though TDP-43 protein can be translocated into mitochondria and causes mitochondrial damage in TDP-43 proteinopathy, little is known about how TDP-43 is imported into mitochondria. In addition, whether mitochondrial damage is caused by mitochondrial mislocalization of TDP-43 or a side effect of mitochondria-mediated TDP-43 degradation remains to be investigated. Here, our bioinformatical analyses reveal that mitophagy receptor gene FUNDC1 is co-expressed with TDP-43, and both TDP-43 and FUNDC1 expression is correlated with genes associated with mitochondrial protein import pathway in brain samples of patients diagnosed with TDP-43 proteinopathy. FUNDC1 promotes mitochondrial translocation of TDP-43 possibly by promoting TDP-43-TOM70 and DNAJA2-TOM70 interactions, which is independent of the LC3 interacting region of FUNDC1 in cellular experiments. In the transgenic fly model of TDP-43 proteinopathy, overexpressing FUNDC1 enhances TDP-43 induced mitochondrial damage, whereas down-regulating FUNDC1 reverses TDP-43 induced mitochondrial damage. FUNDC1 regulates mitochondria-mediated TDP-43 degradation not only by regulating mitochondrial TDP-43 import, but also by increasing LONP1 level and by activating mitophagy, which plays important roles in cytosolic TDP-43 clearance. Together, this study not only uncovers the mechanism of mitochondrial TDP-43 import, but also unravels the active role played by mitochondria in regulating TDP-43 homeostasis.

Low-temperature stress during the germination stage is an important abiotic stress that affects the growth and development of northern spring maize and seriously restricts maize yield and quality. Although some quantitative trait locis (QTLs) related to low-temperature tolerance in maize have been detected, only a few can be commonly detected, and the QTL intervals are large, indicating that low-temperature tolerance is a complex trait that requires more in-depth research. In this study, 296 excellent inbred lines from domestic and foreign origins (America and Europe) were used as the study materials, and a low-coverage resequencing method was employed for genome sequencing. Five phenotypic traits related to low-temperature tolerance were used to assess the genetic diversity of maize through a genome-wide association study (GWAS). A total of 14 SNPs significantly associated with low-temperature tolerance were detected (−log10(P) > 4), and an SNP consistently linked to low-temperature tolerance in the field and indoors during germination was utilized as a marker. This SNP, 14,070, was located on chromosome 5 at position 2,205,723, which explained 4.84–9.68% of the phenotypic variation. The aim of this study was to enrich the genetic theory of low-temperature tolerance in maize and provide support for the innovation of low-temperature tolerance resources and the breeding of new varieties.

AbstractPseudofabraea citricarpa (Dermateaceae: Helotiales) is known as a significant pathogen causing Citrus target spot disease and results in profound yield loss. In the present study, the complete mitochondrial genome (mitogenome) determined based on next-generation sequencing technology. The circular mitogenome (56,935 bp) comprised 14 conserved protein-coding genes (PCGs), 16 ORFs, two ribosomal RNA genes (rns and rnl), one non-coding RNA gene (rnpB), one ribosomal protein S3 (rps3) and 28 transfer RNA (tRNA) genes. The overall base composition is as follows: 36.08% A, 35.25% T, 13.04% C, and 15.63% G, with a GC content of 28.70%. The phylogenetic analysis shows that P. citricarpa, belonging to Dermateaceae, forms a separate clade and is sister to Sclerotiniaceae. The mitogenome of P. citricarpa reported in this study provides more molecular data for further research on the evolutionary relationships of Helotiales.

Callose, found in the cell walls of higher plants such as β-1,3-glucan with β-1,6 branches, is pivotal for both plant development and responses to biotic and abiotic stressors. Plasmodesmata (PD), membranous channels linking the cytoplasm, plasma membrane, and endoplasmic reticulum of adjacent cells, facilitate molecular transport, crucial for developmental and physiological processes. The regulation of both the structural and transport functions of PD is intricate. The accumulation of callose in the PD neck is particularly significant for the regulation of PD permeability. This callose deposition, occurring at a specific site of pathogenic incursion, decelerates the invasion and proliferation of pathogens by reducing the PD pore size. Scholarly investigations over the past two decades have illuminated pathogen-induced callose deposition and the ensuing PD regulation. This gradual understanding reveals the complex regulatory interactions governing defense-related callose accumulation and protein-mediated PD regulation, underscoring its role in plant defense. This review systematically outlines callose accumulation mechanisms and enzymatic regulation in plant defense and discusses PD’s varied participation against viral, fungal, and bacterial infestations. It scrutinizes callose-induced structural changes in PD, highlighting their implications for plant immunity. This review emphasizes dynamic callose calibration in PD constrictions and elucidates the implications and potential challenges of this intricate defense mechanism, integral to the plant’s immune system.