OBJECTIVES: To evaluate the therapeutic effect of gastrodin against hypoxic-ischemic brain damage (HIBD) in neonatal mice and explore the role of GPX4/SLC7A11/FTH1 signaling in mediating its effect. METHODS: Twenty-four 9- to 11-day-old C57BL/6J mice were randomized equally into 4 groups for sham operation, HIBD modeling by right common carotid artery ligation and subsequent exposure to hypoxia for 1 h, or gastrodin treatment at 100 or 200 mg/kg before and at 1 and 2 days after modeling. The mice then underwent neurological assessment (Zea-Longa scores), and the cerebral cortical penumbra tissue were collected for HE and Nissl staining, detection of ferroptosis biomarkers and protein expressions of GPX4, SLC7A11, and FTH1 with Western blotting and immunofluorescence co-localization, and observation of mitochondrial ultrastructure with electron microscopy. In cultured HT22 neuronal cells with oxygen-glucose deprivation (OGD) for 2 h, the effects of pretreatments with 0.5 mmol/L gastrodin, 10 μmol/L RSL3 (a GPX4 inhibitor), alone or in combination, were analyzed on expressions of ferroptosis-related proteins, cellular Fe²⁺, ROS, lipid peroxidation, MDA, and GSH levels, mitochondrial membrane potential (JC-1), and cell viability. RESULTS: Gastrodin treatment at the two doses both significantly ameliorated HIBD and neurological deficits of the mice, reduced mitochondrial damage and Fe²⁺, MDA and ROS levels, increased GSH level, and upregulated GPX4, SLC7A11, and FTH1 protein expressions. In HT22 cells, gastrodin pretreatment obviously attenuated OGD-induced ferroptosis and improved cell viability and mitochondrial function. Co-treatment with RSL3 potently abrogated the inhibitory effects of gastrodin on Fe²⁺, ROS, BODIPY-C11, and MDA levels and attenuated its protective effects on GSH level, cell viability, and mitochondrial membrane potential. CONCLUSIONS Gastrodin provides neuroprotective effects in neonatal mice with HIBD by suppressing neuronal ferroptosis via upregulating the GPX4/SLC7A11/FTH1 signaling pathway.
Animals ; Ferroptosis/drug effects* ; Hypoxia-Ischemia, Brain/drug therapy* ; Mice ; Mice, Inbred C57BL ; Signal Transduction/drug effects* ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Glucosides/pharmacology* ; Animals, Newborn ; Benzyl Alcohols/pharmacology* ; Amino Acid Transport System y+/metabolism*

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Nipah virus (NiV) and related viruses form a distinct henipavirus genus within the Paramyxoviridae family. NiV continues to spillover into the humans causing deadly outbreaks with increasing human-bat interaction. NiV encodes the large protein (L) and phosphoprotein (P) to form the viral RNA polymerase machinery. Their sequences show limited homologies to those of non-henipavirus paramyxoviruses. We report two cryo-electron microscopy (cryo-EM) structures of the Nipah virus (NiV) polymerase L-P complex, expressed and purified in either its full-length or truncated form. The structures resolve the RNA-dependent RNA polymerase (RdRp) and polyribonucleotidyl transferase (PRNTase) domains of the L protein, as well as a tetrameric P protein bundle bound to the L-RdRp domain. L-protein C-terminal regions are unresolved, indicating flexibility. Two PRNTase domain zinc-binding sites, conserved in most Mononegavirales, are confirmed essential for NiV polymerase activity. The structures further reveal anchoring of the P protein bundle and P protein X domain (XD) linkers on L, via an interaction pattern distinct among Paramyxoviridae. These interactions facilitate binding of a P protein XD linker in the nucleotide entry channel and distinct positioning of other XD linkers. We show that the disruption of the L-P interactions reduces NiV polymerase activity. The reported structures should facilitate rational antiviral-drug discovery and provide a guide for the functional study of NiV polymerase.
Nipah Virus/chemistry* ; Cryoelectron Microscopy ; Viral Proteins/genetics* ; RNA-Dependent RNA Polymerase/genetics* ; Phosphoproteins/genetics* ; Humans ; Models, Molecular ; Protein Binding

OBJECTIVES: To investigate the clinical characteristics and drug resistance profile of invasive non-typhoidal Salmonella (NTS) enteritis in children in Chengdu, China, providing a reference for rational drug use and empirical treatment in clinical practice. METHODS: A retrospective analysis was conducted on the clinical data of 130 children with invasive bacterial enteritis due to NTS identified by fecal bacterial culture and the results of drug sensitivity tests for NTS in Chengdu from January 2022 to December 2023. RESULTS: NTS infections were mainly observed from April to September (113 cases, 86.9%), with a peak in August (36 cases, 27.7%). Children aged <36 months accounted for 86.2% (112/130) of all cases, and the main symptoms were diarrhea (130 cases, 100%), fever (123 cases, 94.6%), and hematochezia (112 cases, 86.2%). The 130 NTS isolates exhibited a sensitivity rate of 64.6% to ceftriaxone and 63.8% to cefotaxime, and a sensitivity rate of >90.0% to piperacillin-tazobactam and nitrofurantoin (nitrofurans). The detection rate of multidrug-resistant strains was 48.5% (63/130), and the clinical efficacy of third-generation cephalosporins used in 38 patients (29.2%) was inconsistent with the results of drug sensitivity tests. CONCLUSIONS The peak of invasive NTS enteritis in children aged 0-6 years occurs in August in the Chengdu area, with a relatively high incidence rate in children aged <36 months. The situation of drug resistance is severe for NTS, and piperacillin-tazobactam may be an effective option for treating multidrug-resistant NTS infections in children, while nitrofuran antibiotics might be used to treat such infections.
Humans ; Infant ; Child, Preschool ; Enteritis/microbiology* ; Retrospective Studies ; Male ; Salmonella Infections/microbiology* ; Female ; Child ; Salmonella/drug effects* ; Infant, Newborn ; Microbial Sensitivity Tests ; Anti-Bacterial Agents/therapeutic use*

OBJECTIVE: To investigate the spatiotemporal patterns and socioeconomic factors influencing the incidence of tuberculosis (TB) in the Guangdong Province between 2010 and 2019. METHOD: Spatial and temporal variations in TB incidence were mapped using heat maps and hierarchical clustering. Socioenvironmental influencing factors were evaluated using a Bayesian spatiotemporal conditional autoregressive (ST-CAR) model. RESULTS: Annual incidence of TB in Guangdong decreased from 91.85/100,000 in 2010 to 53.06/100,000 in 2019. Spatial hotspots were found in northeastern Guangdong, particularly in Heyuan, Shanwei, and Shantou, while Shenzhen, Dongguan, and Foshan had the lowest rates in the Pearl River Delta. The ST-CAR model showed that the TB risk was lower with higher per capita Gross Domestic Product (GDP) [Relative Risk ( RR), 0.91; 95% Confidence Interval ( CI): 0.86-0.98], more the ratio of licensed physicians and physician ( RR, 0.94; 95% CI: 0.90-0.98), and higher per capita public expenditure ( RR, 0.94; 95% CI: 0.90-0.97), with a marginal effect of population density ( RR, 0.86; 95% CI: 0.86-1.00). CONCLUSION The incidence of TB in Guangdong varies spatially and temporally. Areas with poor economic conditions and insufficient healthcare resources are at an increased risk of TB infection. Strategies focusing on equitable health resource distribution and economic development are the key to TB control.
Humans ; China/epidemiology* ; Incidence ; Bayes Theorem ; Spatio-Temporal Analysis ; Tuberculosis/epidemiology* ; Socioeconomic Factors

Objective To explore the application effect of the"safe harbor"humanistic care program in mechanically ventilated patients.Methods A quasi experimental study design method was used to select 106 mechanically ventilated patients admitted to the department of intensive care unit(ICU)of the First Affiliated Hospital of Nanchang University from December 2024 to February 2025 as the study subjects.They were randomly divided into a control group and an experimental group,with 53 patients in each group.The control group adopted a conventional nursing mode(pain relief and sedation management,daily awakening,active and passive limb activities,respiratory function exercise,nutritional and psychological support,etc.),while the experimental group implemented a"safe harbor"humanistic care mode plan based on conventional nursing(structured visit management,therapeutic environment creation,professional nursing process optimization,and multidimensional safety guarantee system,including 6 dimensions and 16 measures,mainly including:family support system reconstruction,progressive activity training,structured visit management,therapeutic environment creation,professional nursing process optimization,and multidimensional safety guarantee system).The difference in the incidence of anxiety and depression,ICU-acquired weakness(ICU-AW),ICU delirium and mechanical ventilation time,ICU hospitalization time,Barthel index scores were compared between the two groups.Results Ultimately,97 patients completed the study,with 52 in the control group and 45 in the experimental group.The incidence of anxiety and depression,ICU-AW,delirium in the experimental group was significantly reduced compared to the control group[anxiety and depression incidence:26.67%(12/45)vs.46.15%(24/52),ICU-AW incidence:13.33%(6/45)vs.40.38%(21/52),delirium incidence:17.78%(8/45)vs.42.31%(22/52),all P<0.05],the ICU hospitalization time and mechanical ventilation time in the experimental group were significantly shortened compared to the control group[ICU hospitalization time(days):9(8,10)vs.10(9,11),mechanical ventilation time(hours):67.0(60.5,78.5)vs.85.0(63.0,75.0),both P<0.05].The Barthel index score significantly increased[66.0(56.0,75.5)vs.58.0(48.5,69.5),P<0.05].Conclusion The"safe harbor"humanistic care model can improve the physical and mental outcomes of mechanically ventilated patients and has clinical promotion value.

Carbon ion radiotherapy(CIRT)is an advanced radiotherapy method with unique physical and biological properties.It increases the dose to the tumor target area while providing better protection to normal tissues.CIRT can be used for hypoxic tumors resistant to photon radiotherapy.It also has the potential superiority of inducing immune responses and can produce the"abscopal effect"when com-bined with different immunotherapies.Radioimmunotherapy can not only ablate tumors at the irradiated site but also partially control dis-tant metastases at the unirradiated site.However,the underlying mechanism has not been fully elucidated.Due to the protection of the tu-mor microenvironment,tumors can sometimes be difficult to completely clear through CIRT-mediated anti-tumor immunity;this can also in-dicate functional limitations of some immune organs after CIRT.Therefore,this study reviewed the impact of CIRT on both innate and adapt-ive immune responses.It also examined the relationship between different radiation doses/fractions and immune protein expression,as well as compared the differences in imaging techniques between carbon ion radiotherapy and traditional radiotherapy.We have also proposed future directions to enhance the superiority of CIRT.This study aimed to provide a strong theoretical basis for improving the efficacy of CIRT and its combination therapy,ultimately benefiting more patients with cancer.

In China, the number of chronic pain patients has exceeded 300 million, making chronic pain the third major health problem after tumors and cardiovascular diseases. Particularly concerning is the gradual emergence of hypertension and chronic low back pain as public health problems that threaten public health and increase the global economic burden. Modern research shows that the incidence of coexisting hypertension is higher among patients with chronic low back pain. Additionally, evidence indicates that the use of NSAIDs for pain relief can have adverse effects on blood pressure, and some antihypertensive medications may trigger symptoms of low back pain. Thus, addressing chronic pain in hypertensive patients while stabilizing blood pressure is one of the important research questions in the modern treatment of hypertension among middle-aged and elderly individuals. From ancient to modern traditional Chinese medicine(TCM) theory, kidney deficiency has been regarded as the core pathogenesis of low back pain. Recent clinical practices and literature indicate that kidney deficiency plays a crucial role in the modern pathogenesis of hypertension. Both hypertension and chronic low back pain are closely associated with kidney deficiency in TCM theory, revealing a potential mechanism linking the two conditions. Combining the theories of " kidney-essence-marrow" and " nourishing water to moisten wood", a therapeutic strategy centered on tobifying kidney was proposed, including selecting single drugs with kidney-tonifying effects as well as compound formulations and elaborating modern research evidence. The aim is to achieve stable blood pressure control in hypertension patients with chronic low back pain while providing a new treatment perspective for chronic low back pain. This article systematically elaborates on the understanding of hypertension combined with chronic low back pain from both TCM and modern medicine, as well as the therapeutic strategy involving kidney-tonifying drugs, to offer useful references for clinical practice.
Humans ; Hypertension/complications* ; Low Back Pain/complications* ; Drugs, Chinese Herbal/therapeutic use* ; Kidney/drug effects* ; Medicine, Chinese Traditional ; Chronic Pain/drug therapy*

ObjectiveTo deeply understand the lived experience and needs of patients with end-stage heart failure， and to provide references for better implementing hospice care for patients with heart failure. MethodsA qualitative phenomenological research method was adopted to conduct in-depth interviews with 15 patients with end-stage heart failure. The Colaizzi 7-step analysis method was used to code， analyze， and extract themes from the interview data. ResultsFour themes and 10 sub-themes were identified： first， experiencing physical and psychological distress （a desire for relief from physical pain and a need for psychological counseling）； second， ambivalence towards family support （yearning for care but feeling guilty）； third， actively seeking social support （expecting to be understood and valued， facilitating access to support from the medical system， and differing perceptions of doctor-patient shared decision-making）； fourth， complex psychological experience regarding prognosis （experiencing fear and worry， feeling disappointed， living in the moment， and accepting death）. ConclusionMedical staff， family caregivers， and society should jointly pay attention to the physical and mental feelings and needs of patients with end-stage heart failure and provide targeted care. It is recommended to implement multidisciplinary team management， promote doctor-patient shared decision-making， meet individualized needs， and provide appropriate education on life and death concepts， thereby establishing a palliative and hospice care service model for end-stage heart failure with characteristics.

Purpose To explore the value of 5.0T MRI arterial spin labeling and morphological indexes for staging chronic kidney disease(CKD).Materials and Methods Ninety-five patients with CKD in Chongqing University Three Gorges Hospital from January to August 2024 were collected prospectively,all of whom underwent 5.0T MRI routine and arterial spin labeling examination with calculation of renal blood flow(RBF)and morphological evaluation.According to the estimated glomerular filtration rate(eGFR),the patients were categorized into early CKD group[eGFR 60-89 ml/(min?1.73 m2)]and intermediate-late CKD group[eGFR<59 ml/(min?1.73 m2)]and were further divided into stage 1-5.The differences in RBF between early and intermediate-late CKD patients were compared,and the differences in morphological indexes among different stages of CKD were also analyzed.Binary Logistic regression analysis was used to screen for independent influences on early or intermediate-late CKD staging.Receiver operating characteristic curve was used to evaluate the diagnostic efficacy of RBF values and morphological indexes for early CKD.RBF in CKD stages 1-5 were compared,with Bonferroni pairwise comparisons.The correlation between RBF values and both clinical and morphological indexes were also assessed.Results Whether in CKD stage 2 or 5,morphological factors affecting CKD staging were renal parenchymal signal,renal corticomedullary demarcation,renal volume and renal envelope(χ2=53.715,73.368,36.488,56.688,35.630,39.499,28.520,32.632,all P<0.001).In CKD stage 2,the independent influences screened by multivariate binary Logistic regression analysis were renal parenchymal signal(P<0.001)and renal corticomedullary demarcation(P=0.021).Both renal RBF values in early CKD were significantly higher than that in intermediate-late CKD(Z=-5.975,-5.885,both P<0.001).The areas under the curve for diagnosing early CKD using mean RBF of both kidneys,morphological indexes,and the combination of mean RBF with renal morphological indexes were 0.854,0.932 and 0.951,respectively.RBF values for both kidneys showed statistically significant differences among the five CKD stages(left:H=48.738;right:H=48.102,both P<0.001)and between non-adjacent stages(all P<0.05).Both kidneys RBF values showed a positive correlation with renal parenchymal signal and renal corticomedullary demarcation(left:r=0.600,0.503;right:r=0.550,0.504,both P<0.001).Conclusion The integration of arterial spin labeling and morphological assessment on 5.0T MRI enables a noninvasive and precise functional and morphological evaluation of early renal damage in CKD patients,providing a foundation for subsequent clinical CKD staging.