Restoring lipid droplet (LD) content has been reported to reverse hepatic stellate cell (HSC) activation during liver fibrosis. Although the mitochondrial citrate carrier SLC25A1 is known to drive metabolic reprogramming in cancer and steatohepatitis, its specific role in regulating LDs remains unclear. This study aimed to elucidate the role of SLC25A1 in controlling LD homeostasis during HSC activation and to determine whether therapeutic inhibition of SLC25A1 could ameliorate liver fibrosis by restoring peroxisome proliferator–activated receptor-γ (PPARγ)-dependent lipid storage. Knockdown of Slc25a1 was achieved using either an adeno‑associated viral vector expressing Slc25a1 short hairpin RNA or hyaluronic acid–modified, HSC membrane–biomimetic nanovesicles containing Slc25a1 small interfering RNA (HA@JMNVs/siSlc25a1). Both approaches effectively attenuated HSC activation in three distinct mouse models, induced by carbon tetrachloride, methionine- and choline-deficient diet, and bile duct ligation, respectively. Mechanistically, SLC25A1 deficiency reduced cytosolic acetyl-coenzyme A levels in activated the human immortalized hepatic stellate cell line LX-2, resulting in reduced overall acetylation of neural precursor cell expressed, developmentally downregulated 4 (NEDD4). This reduction subsequently suppressed the NEDD4-mediated ubiquitination and degradation of PPARγ at lysine 197 (K197). The metabolic–post-translational signaling cascade increased perilipin-2 (PLIN2) transcription, inhibited lipophagy, and ultimately restored LD accumulation, thereby reversing HSC activation. Collectively, these findings establish the SLC25A1-regulated metabolic axis as a promising therapeutic target and offer a robust preclinical proof-of-concept for targeted gene therapies against liver fibrosis.

Zhejiang Province, China, has implemented a free influenza vaccination program for the elderly population for five consecutive years. However, data on real-world vaccine effectiveness against influenza among the local elderly population during the 2024–2025 influenza season are still lacking. A multicenter, retrospective test-negative design (TND) was adopted in this study. Sentinel surveillance networks were established across designated sentinel hospitals in six cities of Zhejiang Province, covering the period from October 2024 to July 2025. On a weekly basis, all or a systematic sample of patients aged ≥ 60 years presenting with influenza-like illness (ILI) were enrolled in the study. Epidemiological data were collected, respiratory specimens were obtained, and laboratory assays were conducted to detect influenza virus types and subtypes. Of the 4694 enrolled elderly patients with ILI, 1587 (33.81

OBJECTIVE:To investigate the characteristics of gut microbiota changes in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy and to explore the relationship between infectious complications and gut microbiota. METHODS:Fecal samples were collected from 37 newly diagnosed AML patients at four time points: before induction chemotherapy, during chemotherapy, during the neutropenic phase, and during the recovery phase. Metagenomic sequencing was used to analyze the dynamic changes in gut microbiota. Correlation analyses were conducted to assess the relationship between changes in gut microbiota and the occurrence of infectious complications. RESULTS:During chemotherapy, the gut microbiota α-diversity (Shannon index) of AML patients exhibited significant fluctuations. Specifically, the diversity decreased significantly during induction chemotherapy, further declined during the neutropenic phase (P < 0.05, compared to baseline), and gradually recovered during the recovery phase, though not fully returning to baseline levels.The abundances of beneficial bacteria, such as Firmicutes and Bacteroidetes, gradually decreased during chemotherapy, whereas the abundances of opportunistic pathogens, including Enterococcus, Klebsiella, and Escherichia coli, progressively increased.Analysis of the dynamic changes in gut microbiota of seven patients with bloodstream infections revealed that the bloodstream infection pathogens could be detected in the gut microbiota of the corresponding patients, with their abundance gradually increasing during the course of infection. This finding suggests that bloodstream infections may be associated with opportunistic pathogens originating from the gut microbiota.Compared to non-infected patients, the baseline samples of infected patients showed a significantly lower relative abundance of Bacteroidetes (P < 0.05). Regression analysis indicated that Bacteroidetes abundance is an independent predictive factor for infectious complications (P < 0.05, OR =13.143). CONCLUSION:During induction chemotherapy in AML patients, gut microbiota α-diversity fluctuates significantly, and the abundance of opportunistic pathogens increase, which may be associated with bloodstream infections. Patients with lower baseline Bacteroidetes abundance are more prone to infections, and its abundance can serve as an independent predictor of infectious complications.

The tumor microenvironment (TME) plays a critical role in the development and treatment of liver cancer, which ranks sixth in incidence and third in mortality worldwide, according to the "Global Cancer Statistics 2022". Hepatocellular carcinoma (HCC), the most common form of liver cancer, is heavily influenced by the TME, which affects tumor growth, invasion, metastasis, and the response to various treatments. Despite advancements in surgery, liver transplantation, targeted therapies, and immunotherapy, the complexity of the TME often limits treatment efficacy, especially in advanced-stage HCC cases. The TME consists of a dynamic interaction between tumor cells, immune cells, fibroblasts, blood vessels, and signaling molecules, all of which contribute to cancer progression and therapy resistance. Assessing the HCC TME is essential for designing effective, personalized treatments and improving patient outcomes. Recent research highlights the value of imaging technologies as non-invasive tools to evaluate the TME, offering new possibilities for more targeted therapies and better prognosis monitoring in HCC patients.

Caspase recruitment domain protein 9 (CARD9) is an important signaling protein involved in the fungal immune process. In terms of treatment, adequate fungicide is often given in clinical practice, but the problems of drug resistance and hepatorenal toxicity of traditional fungicides make it an inevitable trend to seek new treatment methods. Photodynamic therapy (PDT) has the advantages of less trauma, faster healing, and better cosmetic effects. 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is effective in the treatment of fungal skin infections and skin ulcers. We report a rare patient with a CARD9 gene defect who received two ALA-PDT treatments and nursing care for a facial Trichophyton rubrum ulcer. After two times of (ALA-PDT), the ulcer area was reduced. The ulcer healed up completely after a month and no recurrence was found in one year follow-up. The results showed that ALA-PDT had a significant therapeutic effect on fungal ulcers caused by gene defects.

Purpose:Relapse remains the leading cause of treatment failure in high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome-IB (MDS-IB) patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ruxolitinib has demonstrated antileukemic activity in vitro, and decitabine has been found to be tolerable when combined with modified busulfan-cyclophosphamide (mBu/Cy) conditioning regimen. Here, we investigated the efficacy of ruxolitinib and decitabine plus a mBu/Cy conditioning regimen (Rux-Dec-mBu/Cy) in reducing relapse in high-risk AML/MDS patients (ClinicalTrials.gov identifier: NCT04582604). Patients and methods:This prospective investigational study enrolled 58 patients between May 2020 and July 2023. These patients had either a relapsed/refractory status, remission status with adverse genetic abnormalities or positive measurable residual disease (MRD+) prior to conditioning. Ruxolitinib (days -15 to -1) and decitabine (days -15 to -10) were administered, followed by mBu/Cy conditioning. The outcomes of a historical cohort of 58 patients (matched 1:1) who received mBu/Cy are described for reference. Results:All 58 patients achieved engraftment. With a median follow-up of 967 (464-1597) days, the 2-year cumulative incidence of relapse was 19.0%. The probabilities of 2-year overall survival (OS), disease-free survival (DFS) and graft-versus-host disease-free, relapse-free survival (GRFS) were 70.3%, 70.6% and 65.2%, respectively. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 44.1%. The most common grade ≥3 adverse event was oropharyngeal mucositis (8.6%, n=5). Within 6 months post-transplantation, the cumulative incidence of cytomegalovirus (CMV) reactivation was 34.5%, and that of Epstein-Barr virus (EBV) reactivation was 62.1%. Conclusions:This investigational study revealed that the Rux-Dec-mBu/Cy conditioning was tolerable and reduced relapse in high-risk AML/MDS patients.

Background:Ruxolitinib (RUX) suppresses antiviral immunity in patients with hematologic diseases. For steroid-refractory acute graft-versus-host disease (aGVHD), studies have yielded conflicting results regarding whether RUX treatment increases the risk of Epstein-Barr virus (EBV) infection. However, in newly diagnosed aGVHD, the use of RUX raises concerns about the potential risk of EBV infection. This study aimed to evaluate the incidence of EBV reactivation and EBV-related posttransplant lymphoproliferative disease (EBV-PTLD) in patients receiving a regimen of 5 mg/day RUX combined with 1 mg·kg-1·d-1 methylprednisolone as first-line therapy for aGVHD. Method:In this retrospective cohort study, allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients were consecutively screened at the Chinese PLA General Hospital. Patients who developed grade II-IV aGVHD were retrospectively categorized on the basis of first-line treatment. The RUX plus steroid (RUX-steroid) group (5 mg/day RUX + 1 mg·kg-1·d-1 methylprednisolone) included patients who received this dose in a phase 2 dose-escalation study of RUX, the intervention arm of a phase 3 trial evaluating this regimen as first-line therapy for aGVHD, and patients who were deemed unsuitable for high-dose steroids owing to active infections. The steroid regimen group (2 mg·kg-1·d-1 methylprednisolone) included patients treated in routine clinical practice and those in the control arm of the same phase 3 trial. EBV reactivation, EBV-PTLD incidence, and other transplantation outcomes were assessed. T-cell reconstitution was also analyzed at day 100 post-transplant. Results:A total of 487 patients treated between January 2018 and December 2023 were included in this study, with a median follow-up of 26.6 months (range, 2.8-69.9). Among these patients, 105 received RUX (5 mg/day) plus methylprednisolone (1 mg·kg-1·d-1) as a first-line treatment for grade II-IV aGVHD and were categorized into the RUX-steroid group. Moreover, 115 patients who received methylprednisolone alone (2 mg·kg-1·d-1) formed the steroid group. The median duration of RUX exposure was 177 days (range, 17-447 days). The cumulative incidence of EBV reactivation within 180 days was significantly greater in the RUX-steroid group (82.9%) than that in the steroid group (70.2%) (hazard ratio [HR]: 1.43, 95% CI: 1.03-1.97; p = 0.03). The cumulative incidence of PTLD was comparable between the RUX-steroid group (5.0%) and the steroid group (4.5%) (HR: 1.12, 95% CI: 0.33-3.83; p = 0.86). Multivariate analysis revealed that the use of a matched-sibling donor (MSD) was significantly associated with a decreased risk of both EBV reactivation (p < 0.001) and EBV-PTLD (p = 0.034). The 2-year nonrelapse mortality (NRM) was 14.9% in the RUX-steroid group, comparable to 13.7% in the steroid group (HR: 1.01, 95% CI: 0.50-2.03; p = 0.98). Conclusion:RUX was associated with an increased risk of EBV reactivation in patients after allo-HSCT but not with PTLD. Regular monitoring of the EBV viral load to enable timely intervention remains essential in these patients.

BACKGROUND:Esophageal cancer (ESCA) poses a significant challenge in oncology because of the limited treatment options and poor prognosis. Therefore, enhancing the therapeutic effects of radiotherapy for ESCA and identifying relevant therapeutic targets are crucial for improving both the survival rate and quality of life of patients. AIM:To define the role of the transcription factor Snail family transcriptional repressor 1 (SNAI1) in ESCA, particularly its regulation of radiosensitivity. METHODS:A comprehensive analysis of TCGA data assessed SNAI1 expression in ESCA. Survival curves correlated SNAI1 levels with radiotherapy outcomes. Colony formation assays, flow cytometry, and a xenograft model were used to evaluate tumor radiosensitivity and apoptosis. Western blot validated protein expression, while Chromatin immunoprecipitation assays examined SNAI1's role in regulating epithelial-mesenchymal transition (EMT). RESULTS:SNAI1 expression in ESCA cell lines and clinical specimens emphasizes its central role in this disease. Elevated SNAI1 expression is correlated with unfavorable outcomes in radiotherapy. Downregulation of SNAI1 enhances the sensitivity of ESCA cells to ionizing radiation (IR), resulting in remarkable tumor regression upon IR treatment in vivo. This study underscores the direct involvement of SNAI1 in the regulation of EMT, particularly under IR-induced conditions. Furthermore, inhibiting deacetylation effectively suppresses EMT, suggesting a potential avenue to enhance the response to radiotherapy in ESCA. CONCLUSION:This study highlights SNAI1's role in ESCA radiosensitivity, offering prognostic insights and therapeutic strategies to enhance radiotherapy by targeting SNAI1 and modulating EMT processes.

Stress urinary incontinence (SUI), characterized by involuntary urine leakage during increased abdominal pressure, remains poorly understood regarding its pathophysiology and treatment. In this study, we utilized single-cell sequencing to analyze the transcriptomic profiles of different cell types in anterior vaginal wall of SUI patients, aiming to explore the heterogeneity of the extracellular matrix (ECM) and immune microenvironment in SUI pathogenesis. Our results identified eleven cell types, including connective tissue cells, immune cells, and glial cells. Specifically, fibroblasts, smooth muscle cells, epithelial cells and T cells displayed transcriptional characteristics highly relevant to SUI pathogenesis. We observed that most cell types participate in ECM metabolism and immune-inflammatory responses, indicating a synergistic role of multiple vaginal cell types in SUI. Furthermore, altered intercellular communication, particularly between fibroblasts and T cells, was noted in SUI. This study provides novel single-cell insights into SUI and identifies potential biomarkers and therapeutic targets for future research.

Insects and their natural microbial pathogens are intertwined in constant arms races, with pathogens continually seeking entry into susceptible hosts through distinct routes. Entomopathogenic fungi are primarily believed to infect host insects through external cuticle penetration. Here, we report a new variety, Beauveria bassiana var. majus (Bbm), that can infect insects through the previously unrecognized foregut. Dual routes of infection significantly accelerate insect mortality. The pH-responsive transcription factor PacC in Bbm exhibits rapid upregulation and efficient proteolytic processing via PalC for alkaline adaptation in the foregut. Expression of PalC is regulated by the adjacent downstream gene Aia. Compared to non-enteropathogenic strains such as ARSEF252, Aia in Bbm lacks a 249-bp fragment, resulting in its enhanced alkaline-induced expression. This induction promotes PalC upregulation and facilitates PacC activation. Expressing the active form of BbmPacC in ARSEF252 enables intestinal infection. This study uncovers the pH-responsive Aia-PalC-PacC cascade enhancing fungal alkaline tolerance for intestinal infection, laying the foundation for developing a new generation of fungal insecticides to control destructive insect pests.

OBJECTIVE:To investigate the relationship between IGF2BP3 gene expression and prognosis in patients with acute myeloid leukemia (AML).METHODS:High throughput transcriptome sequencing was performed on bone marrow primary leukemia cells from 27 patients with AML in our center, the relationship between IGF2BP3 expression levels and clinical characteristics were analyzed and verify the samples from patients with newly treated AML and refractory AML. The expression level of IGF2BP3 gene were analyzed in 20 healthy subjects and 26 patients with AML. The expression of IGF2BP3 in two anthracycline-resistant cell lines (HL60/ADR, K562/ADR) was detected by RT-qPCR and Western blot, and the expression difference of IGF2BP3 was compared with that in sensitive cells (HL60, K562). The relationship between the expression level of IGF2BP3 in patients with AML and prognostic were analyzed through data analysis of 746 patients with AML, and the prognostic value of IGF2BP3 in AML was analyzed by multivariate Cox regression analysis.RESULTS:In the bone marrow primary leukemia cells of 27 AML patients in our center, the expression level of IGF2BP3 in patients with refractory AML was significantly higher than that in chemotherapy sensitive patients (P =0.0343). The expression of IGF2BP3 in leukemia patients with extramedullary infiltration (EMI) was significantly higher than that in AML patients without extramedullary infiltration (P =0.0049). Compared with healthy subjects (n=20), IGF2BP3 expression in AML patients (n=26) was higher (P =0.0009). The expression of IGF2BP3 mRNA in the anthracycline resistant cell lines (HL60/ADR, K562/ADR) was significantly higher than that in the sensitive cell lines (K562/ADR vs K562,P =0.0430; HL60/ADR vs HL60, P =0.7369). Western blot results showed that the expression of IGF2BP3 protein in mycin resistant cells was significantly higher than that in sensitive cells (P < 0.001). qPCR results showed that the expression level of IGF2BP3 mRNA in refractory AML patients was significantly higher than that in patients with chemotherapy sensitive (P =0.002). High expression of IGF2BP3 was associated with poor prognosis in AML (P < 0.05) in 3 large sample cohorts of AML patients. Univariate and multivariate prognostic analyses demonstrated that high expression of IGF2BP3 was significantly associated with shorter event-free survival (EFS, HR=1.887, P =0.024) and overall survival (OS, HR=1.619, P =0.016).CONCLUSION:The high expression of IGF2BP3 gene may be an important factor in the poor prognosis of AML, suggesting that IGF2BP3 gene may be a new molecular marker for the clinical prognosis evaluation and treatment strategy of AML.

Liver is a key metabolic organ, and its dysfunction has been found to facilitate the progression of various liver diseases. Radiation-induced liver damage (RILD) is a specific form of liver disease caused by radiotherapy or accidental exposure to ionizing radiation (IR). Nevertheless, it remains unclear whether and how dysregulated metabolic mechanisms are involved. In this study, the disturbance of lipid metabolism induced by IR was identified by using 10×Genomics single-cell transcription technology, which was then verified by morphological, pathological and biochemical analysis, both in vivo and in vitro. Furthermore, it was determined that PPARα/FABP1/SCD1 signaling may act as a potential regulatory mechanism of RILD, affecting both lipid metabolism and the process of ferroptosis. Moreover, it has been demonstrated that the PPARα agonist WY14643 effectively suppresses ferroptosis, which is involved in RILD. In conclusion, the present study indicates that lipid metabolism-related PPARα via FABP1/SCD1 ferroptosis pathway might play a crucial role in the development of RILD, which might be a novel target for the prevention and treatment of this disease.

Supplementary Tables contain Supplementary Tables S1-17

Entomopathogenic fungi infect insects by penetrating through the cuticle into the host body. To breach the host cuticle, some fungal pathogens produce specialized infection cells called appressoria, which develop enormous turgor pressure to allow cuticle penetration. However, regulatory mechanisms underlying appressorium turgor generation are poorly understood. Here, we show that the histone lysine methyltransferase ASH1 in the insecticidal fungus Metarhizium robertsii, which is strongly induced during infection of the mosquito cuticle, regulates appressorium turgor generation and cuticle penetration by activating the peroxin gene Mrpex16 via H3K36 dimethylation. MrPEX16 is required for the biogenesis of peroxisomes that participate in lipid catabolism and further promotes the hydrolysis of triacylglycerols stored in lipid droplets to produce glycerol for turgor generation, facilitating appressorium-mediated insect infection. Together, the ASH1-PEX16 pathway plays a pivotal role in regulating peroxisome biogenesis to promote lipolysis for appressorium turgor generation, providing insights into the molecular mechanisms underlying fungal pathogenesis.

List of DMRs and specifications between normal B cells and CLL as returned from the DMR caller

Introduction: Accurate prediction of individual response to anti-hypertensive treatment is crucial in enhancing the safety and efficiency of offering appropriate regimens to attain desired blood pressure (BP) goals. Hypothesis: Machine learning (ML) based models could accurately predict the BP reduction of different antihypertensive regimens. Methods: We utilized data from the LIGHT study, a pragmatic, cluster-randomized trial conducted in 94 primary care institutions in China, involving 13146 visits of 5192 patients who were required to attend the clinic for hypertension management every 3 months during an overall study period of 1 year. Clinical and laboratory variables, baseline BP, and anti-hypertensive therapies at baseline and at follow-up were used to develop models for predicting post-treatment individual BP response. Five ML algorithms were applied as candidate models, and mean squared error (MSE) was used to evaluate the model performance ( panel A ). Results: The mean (standard deviation) age of the study population at baseline was 64.2 (14.0) years, and 2207 (42.5%) were female. 29 features selected by the least absolute shrinkage and selection operator method and purposeful selection were used to build the model, including age, sex, weight, waist circumference, BMI, baseline systolic and diastolic BP, smoking status, visit interval, history of coronary heart disease, diabetes, and dyslipidemia, and baseline and prescript antihypertensive drugs. Among all candidate models, the Catboost model had the best performance with a training MSE of 149.6 and a validation MSE of 135.2 ( panel B ). The most important features include baseline BP, age, weight, and BMI ( panel C and D ). Conclusions: We developed an ML-based model for predicting the response to antihypertensive regimens for assisting clinicians to achieve individualized antihypertensive treatment effectively and safely.

Methylation dynamics across CLL progression

Methylation landscape of CD5 positive and negative naïve and memory B cells is highly similar