PagJAZ5 regulates cambium activity through coordinately modulating cytokinin concentration and signaling in poplar.

Wood is resulted from the radial growth paced by the division and differentiation of vascular cambium cells in woody plants, and phytohormones play important roles in cambium activity. Here, we identified that PagJAZ5, a key negative regulator of jasmonate (JA) signaling, plays important roles in enhancing cambium cell division and differentiation by mediating cytokinin signaling in poplar 84K (Populus alba × Populus glandulosa). PagJAZ5 is preferentially expressed in developing phloem and cambium, weakly in developing xylem cells. Overexpression (OE) of PagJAZ5m (insensitive to JA) increased cambium activity and xylem differentiation, while jaz mutants showed opposite results. Transcriptome analyses revealed that cytokinin oxidase/dehydrogenase (CKXs) and type-A response regulators (RRs) were downregulated in PagJAZ5m OE plants. The bioactive cytokinins were significantly increased in PagJAZ5m overexpressing plants and decreased in jaz5 mutants, compared with that in 84K plants. The PagJAZ5 directly interact with PagMYC2a/b and PagWOX4b. Further, we found that the PagRR5 is regulated by PagMYC2a and PagWOX4b and involved in the regulation of xylem development. Our results showed that PagJAZ5 can increase cambium activity and promote xylem differentiation through modulating cytokinin level and type-A RR during wood formation in poplar.

Non-invasive neurostimulation to improve sleep quality and depressive symptoms in patients with major depressive disorder: A meta-analysis of randomized controlled trials.

BACKGROUND: Non-invasive neurostimulation, including bright light therapy (BLT), repetitive transcranial magnetic (rTMS) and transcranial direct current stimulation (tDCS), has been shown to alleviate depressive symptoms in major depressive disorder (MDD). However, the efficacy of these interventions in addressing sleep disturbances in MDD patients remains a subject of debate. OBJECTIVE: We aimed to conduct a meta-analysis of available randomized controlled trials (RCTs) to assess the effectiveness of non-invasive neurostimulation in improving sleep disturbances and depressive symptoms in MDD patients. METHODS: Systematic searches for relevant RCTs were conducted in the databases PubMed, Cochrane Library, Web of Science, EMBASE, Wanfang and China National Knowledge Infrastructure up to January 2024. Data on outcomes comparable across the studies were meta-analyzed using Review Manager 5.3 and Stata 14. The pooled results were reported as standardized mean differences (SMD) with their respective 95% confidence intervals (CI). RESULTS: Our analysis encompassed 15 RCTs involving 1348 patients. Compared to sham or no stimulation, non-invasive neurostimulation significantly improved sleep quality (SMD -0.74, 95%CI -1.15 to -0.33, p = 0.0004) and sleep efficiency (SMD 0.35, 95%CI 0.10 to 0.60, p = 0.006). It also significantly reduced severity of depressive symptoms (SMD -0.62, 95%CI -0.90 to -0.35, p < 0.00001). Subgroup analysis further demonstrated that patients experiencing sleep improvements due to neurostimulation showed a marked decrease in depressive symptoms compared to the control group (SMD = -0.90, 95% CI [-1.26, -0.54], p < 0.0001). CONCLUSION: Current evidence from RCTs suggests that neurostimulation can enhance sleep quality and efficiency in individuals with MDD, which in turn may be associated with mitigation of depressive symptoms. PROSPERO REGISTRATION: CRD42023423844.

Neurotrophic keratitis caused by lightning injury: a case report.

BACKGROUND: This study aimed to report a case of neurotrophic keratitis caused by lightning. CASE PRESENTATION: A 38-year-old man was hit by lightning and suffered eye injury. He eventually developed neurotrophic keratitis. RESULTS: The patient's injury history and burn site were analyzed, and it was judged that lightning directly damaged his cornea, eventually resulting in neurotrophic keratitis. Fortunately, the patient's vision improved after treatment. CONCLUSION: Lightning can cause eye damage, and the clinical manifestations are diverse. Lightning currents cause corneal nerve loss, resulting in neurotrophic keratitis. To maintain corneal integrity and prevent disease progression, early assessment and appropriate treatment are necessary.

PAS-7 is Superior to APAIS for Assessing Preoperative Anxiety in the Chinese Population.

PURPOSE: The purpose of this study was to analyze the reliability and validity of the Perioperative Anxiety Scale-7 (PAS-7), which was created by Chinese medical professionals, by using the State-Trait Anxiety Scale (STAI-S) as the standard for the diagnosis of preoperative anxiety, and to compare whether there is a difference between the PAS-7 and the Amsterdam Preoperative Anxiety and Information Scale (APAIS) in the diagnosis of preoperative anxiety in the Chinese population. DESIGN: This study was an observational study. METHODS: The PAS-7, APAIS, and STAI-S were all completed the day before surgery. The internal consistency test was used to evaluate the scale's reliability, and exploratory factor analysis and confirmatory factor analysis were used to assess the scale's construct validity. Pearson correlation was used to analyze the correlation between PAS-7 and STAI-S, and APAIS. The area under the receiver operating characteristic (ROC) curve was used to compare the diagnostic value of PAS-7 and APAIS. FINDINGS: The PAS-7 Cronbach's α coefficient was 0.804. The indicators of the overall fitting coefficient were within the acceptable range. PAS-7 scores correlated well with STAI-S and APAIS scores (P < .01). The area under the ROC curve of PAS-7 was 0.808 (0.752-0.856), and the area under the ROC curve of APAIS was 0.674 (0.611-0.733). The difference between areas was 0.133 (0.0612-0.206), P < .001, and the diagnostic value of PAS-7 was higher than that of APAIS. CONCLUSIONS: The PAS-7 scale has high reliability and validity and can be used to assess preoperative anxiety in patients undergoing elective surgery. PAS-7 is superior to APAIS for assessing preoperative anxiety in the Chinese population.

KDM4C represses liver fibrosis by regulating H3K9me3 methylation of ALKBH5 and m6A methylation of snail1 mRNA.

OBJECTIVE: We aimed to disclose the molecular mechanism of snail1 in liver fibrosis. METHODS: Carbon tetrachloride (CCl4) was used to induce a liver fibrosis model in mice whereby serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated, and liver pathological alternations were assessed. Rat hepatic stellate cells (HSC-T6) were irritated with transforming growth factor (TGF)-ß1, followed by assessment of cell viability and migration. The levels of snail1, ALKBH5, and lysine specific demethylase 4C (KDM4C) were quantified by immunohistochemistry, western blot, or reverse transcription-quantitative polymerase chain reaction, in addition to α-smooth muscle actin (SMA), anti-collagen type I α1 (COL1A1), vimentin, and E-cadherin. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation and RNA stability were evaluated to determine the relationship between ALKBH5 and snail1. Changes in KDM4C-bound ALKBH5 promoter and enrichment of histone H3 lysine 9 trimethylation (H3K9me3) at the ALKBH5 promoter were determined using chromatin immunoprecipitation. RESULTS: In fibrosis mice, snail1 was upregulated while ALKBH5 and KDM4C were downregulated. KDM4C overexpression reduced serum ALT and AST levels, liver injury, and α-SMA, COL1A1 and VIMENTIN expressions but increased E-cadherin expression. However, the aforementioned trends were reversed by concurrent overexpression of snail1. In HSC-T6 cells exposed to TGF-ß1, ALKBH5 overexpression weakened cell viability and migration, downregulated α-SMA, COL1A1 and VIMENTIN, upregulated E-CADHERIN, and decreased m6A modification of snail1 and its mRNA stability. KDM4C increased ALKBH5 expression by lowering H3K9me3 level, but inhibited HSC-T6 cell activation by regulating the ALKBH5/snail1 axis. CONCLUSION: KDM4C decreases H3K9me3 methylation to upregulate ALKBH5 and subsequently inhibits snail1, ultimately impeding liver fibrosis.

Thymol Induces Fenton-Reaction-Dependent Ferroptosis in Vibrio parahemolyticus.

Thymol has efficient bactericidal activity against a variety of pathogenic bacteria, but the bactericidal mechanism against Vibrio parahemolyticus (V. parahemolyticus) has rarely been reported. In the current study, we investigated the bactericidal mechanism of thymol against V. parahemolyticus. The Results revealed that 150 µg/mL of thymol had 99.9% bactericidal activity on V. parahemolyticus. Intracellular bursts of reactive oxygen species (ROS), Fe2+accumulation, lipid peroxidation, and DNA breakage were checked by cell staining. The exogenous addition of H2O2 and catalase promoted and alleviated thymol-induced cell death to a certain extent, respectively, and the addition of the ferroptosis inhibitor Liproxstatin-1 also alleviated thymol-induced cell death, confirming that thymol induced Fenton-reaction-dependent ferroptosis in V. parahemolyticus. Proteomic analysis revealed that relevant proteins involved in ROS production, lipid peroxidation accumulation, and DNA repair were significantly upregulated after thymol treatment. Molecular docking revealed two potential binding sites (amino acids 46H and 42F) between thymol and ferritin, and thymol could promote the release of Fe2+ from ferritin proteins through in vitro interactions analyzed. Therefore, we hypothesized that ferritin as a potential target may mediate thymol-induced ferroptosis in V. parahemolyticus. This study provides new ideas for the development of natural inhibitors for controlling V. parahemolyticus in aquatic products.

Bi-regional dynamic contrast-enhanced MRI for prediction of microvascular invasion in solitary BCLC stage A hepatocellular carcinoma.

OBJECTIVES: To construct a combined model based on bi-regional quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), as well as clinical-radiological (CR) features for predicting microvascular invasion (MVI) in solitary Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC), and to assess its ability for stratifying the risk of recurrence after hepatectomy. METHODS: Patients with solitary BCLC stage A HCC were prospective collected and randomly divided into training and validation sets. DCE perfusion parameters were obtained both in intra-tumoral region (ITR) and peritumoral region (PTR). Combined DCE perfusion parameters (CDCE) were constructed to predict MVI. The combined model incorporating CDCE and CR features was developed and evaluated. Kaplan-Meier method was used to investigate the prognostic significance of the model and the survival benefits of different hepatectomy approaches. RESULTS: A total of 133 patients were included. Total blood flow in ITR and arterial fraction in PTR exhibited the best predictive performance for MVI with areas under the curve (AUCs) of 0.790 and 0.792, respectively. CDCE achieved AUCs of 0.868 (training set) and 0.857 (validation set). A combined model integrated with the α-fetoprotein, corona enhancement, two-trait predictor of venous invasion, and CDCE could improve the discrimination ability to AUCs of 0.966 (training set) and 0.937 (validation set). The combined model could stratify the prognosis of HCC patients. Anatomical resection was associated with a better prognosis in the high-risk group (p < 0.05). CONCLUSION: The combined model integrating DCE perfusion parameters and CR features could be used for MVI prediction in HCC patients and assist clinical decision-making. CRITICAL RELEVANCE STATEMENT: The combined model incorporating bi-regional DCE-MRI perfusion parameters and CR features predicted MVI preoperatively, which could stratify the risk of recurrence and aid in optimizing treatment strategies. KEY POINTS: Microvascular invasion (MVI) is a significant predictor of prognosis for hepatocellular carcinoma (HCC). Quantitative DCE-MRI could predict MVI in solitary BCLC stage A HCC; the combined model improved performance. The combined model could help stratify the risk of recurrence and aid treatment planning.

Biomechanical comparison of the therapeutic effect of a novel proximal femoral bionic intramedullary nail and traditional inverted triangle hollow screw on femoral neck fracture.

OBJECTIVE: A novel Proximal Femoral Bionic Nail (PFBN) has been developed by a research team for the treatment of femoral neck fractures. This study aims to compare the biomechanical properties of the innovative PFBN with those of the conventional Inverted Triangular Cannulated Screw (ITCS) fixation method through biomechanical testing. METHODS: Sixteen male femoral specimens preserved in formalin were selected, with the donors' age at death averaging 56.1 ± 6.3 years (range 47-64 years), and a mean age of 51.4 years. The femurs showed no visible damage and were examined by X-rays to exclude diseases affecting bone quality such as tumors, severe osteoporosis, and deformities. The 16 femoral specimens were randomly divided into an experimental group (n = 8) and a control group (n = 8). All femurs were prepared with Pauwels type III femoral neck fractures, fixed with PFBN in the experimental group and ITCS in the control group. Displacement and stress limits of each specimen were measured through cyclic compression tests and failure experiments, and vertical displacement and strain values under a 600 N vertical load were measured in all specimens through vertical compression tests. RESULTS: In the vertical compression test, the average displacement at the anterior head region of the femur was 0.362 mm for the PFBN group, significantly less than the 0.480 mm for the ITCS group (p < 0.001). At the fracture line area, the average displacement for the PFBN group was also lower than that of the ITCS group (0.196 mm vs. 0.324 mm, p < 0.001). The difference in displacement in the shaft area was smaller, but the average displacement for the PFBN group (0.049 mm) was still significantly less than that for the ITCS group (0.062 mm, p = 0.016). The situation was similar on the posterior side of the femur. The average displacements in the head area, fracture line area, and shaft area for the PFBN group were 0.300 mm, 0.168 mm, and 0.081 mm, respectively, while those for the ITCS group were 0.558 mm, 0.274 mm, and 0.041 mm, with significant differences in all areas (p < 0.001). The average strain in the anterior head area for the PFBN group was 4947 µm/m, significantly less than the 1540 µm/m for the ITCS group (p < 0.001). Likewise, in the fracture line and shaft areas, the average strains for the PFBN group were significantly less than those for the ITCS group (p < 0.05). In the posterior head area, the average strain for the PFBN group was 4861 µm/m, significantly less than the 1442 µm/m for the ITCS group (p < 0.001). The strain conditions in the fracture line and shaft areas also showed the PFBN group was superior to the ITCS group (p < 0.001). In cyclic loading experiments, the PFBN fixation showed smaller maximum displacement (1.269 mm vs. 1.808 mm, p < 0.001), indicating better stability. In the failure experiments, the maximum failure load that the PFBN-fixated fracture block could withstand was significantly higher than that for the ITCS fixation (1817 N vs. 1116 N, p < 0.001). CONCLUSION: The PFBN can meet the biomechanical requirements for internal fixation of femoral neck fractures. PFBN is superior in biomechanical stability compared to ITCS, particularly showing less displacement and higher failure resistance in cyclic load and failure experiments. While there are differences in strain performance in different regions between the two fixation methods, overall, PFBN provides superior stability.

Kinetics of hydrogen absorption/desorption in the Zr-2.5Nb alloy.

The Zr-2.5Nb alloy is a typical pressure tube material in heavy water nuclear reactors, and an increase of hydrogen isotope content in the alloy during service can pose major safety risks; hot vacuum extraction-mass spectrometry is an efficient method for evaluating hydrogen isotope concentrations in the Zr-2.5Nb alloy. This work investigates the kinetics and thermodynamic properties of deuterium (D) absorption and desorption of the Zr-2.5Nb alloy using the constant volume adsorption method and the hot vacuum extraction method. In addition to the previously reported volume contraction model, it was observed that at 600 °C and above, the reaction between D2 and Zr-2.5Nb is dominated by diffusion, while the reaction is predominantly influenced by surface adsorption and dissociation below 600 °C. Phase transition sequence of Zr-2.5Nb deuterides during non-isothermal desorption was established using quantitatively calibrated thermal desorption spectra combined with the phase transition process of deuteride decomposition. These results can provide important references for optimizing the process parameters of the hot vacuum extraction-mass spectrometry method.

Metabolomics-based study on the significance of differential metabolite binding IgG isoforms in Hemolytic disease of newborn.

BACKGROUND: Hemolytic disease of the newborn (HDN) is a common condition that can have a severe impact on the health of newborns due to the hemolytic reactions it triggers. Although numerous studies have focused on understanding the pathogenesis of HDN, there are still many unanswered questions. METHODS: In this retrospective study, serum samples were collected from 15 healthy newborns and 8 infants diagnosed with hemolytic disease. The relationship between different metabolites and various IgG subtypes in Healthy, HDN and BLI groups was studied by biochemical technique and enzyme-linked immunosorbent assay (ELISA). Metabolomics analysis was conducted to identify the differential metabolites associated with HDN. Subsequently, Pearson's correlation analysis was used to determine the relation of these differential metabolites with IgG isoforms. The relationship between the metabolites and IgG subtypes was observed after treatment. RESULTS: The study results revealed that infants with hemolytic disease exhibited abnormal elevations in TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4 levels when compared to healthy newborns. Additionally, differences in metabolite contents were also observed. N, N-DIMETHYLARGININE showed negative correlations with TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4, while 2-HYDROXYBUTYRATE, AMINOISOBUTANOATE, Inosine, and ALLYL ISOTHIOCYANATE exhibited positive correlations with TBA, IgG1, IgG2a, IgG2b, IgG3, and IgG4. Through metabolomics-based research, we have discovered associations between differential metabolites and different IgG isoforms during the onset of HDN. CONCLUSION: These findings suggest that changes in metabolite and IgG isoform levels are linked to HDN. Understanding the involvement of IgG isoforms and metabolites can provide valuable guidance for the diagnosis and treatment of HDN.

Dual cross-linked self-healing hydrogel enhanced by dopamine nanoparticles and raffinose for wound healing.

A series of intricate and dynamic physiological healing processes are involved in the healing of skin wounds. Herein, a multifunctional hydrogel is firstly designed and constructed by L-arginine-grafted O-carboxymethyl chitosan (CMCA), catechol-modified oxidized hyaluronic acid (DOHA), and dopamine nanoparticles (pDA-NPs). pDA-NPs were loaded in hydrogel for inherently powerful antimicrobial properties and could be as a cross-linking agent to construct hydrogels. Raffinose (Raf) was further incorporated to obtain CMCA-DOHA-pDA2@Raf hydrogel for its function of modulating epidermal differentiation. The hydrogel has good physicochemical properties and could promote cell proliferation and migration, which shows superior hemostatic capabilities in animal models of hemorrhage. The hydrogel significantly promoted wound healing on rat skin defect models by upregulating VEGF and CD31 and decreasing IL-6 and TNF-α, stimulating neovascularization and collagen deposition in epithelial structures. This multifunctional hydrogel implies the potential to be a dynamic wound dressing.

Information infrastructure and corporate green innovation quality incentive.

We use a sample of Chinese firms from 2006 to 2020 to investigate the effect of information infrastructure on the quality of green innovation. Findings show that information infrastructure significantly improves corporate green innovation quality, and information infrastructure improves the pricing efficiency, improves valuation levels, accelerates the flow of innovation resources, and induces the growth effect of corporate innovation resources. Furthermore, we find that executive salary incentives, internal control quality, and market-oriented environmental regulation have adaptive incentives for information infrastructure to improve the quality of green innovation. Our findings provide justification to promote the construction of an information infrastructure and adopt market-oriented environmental regulations to improve corporate green innovation quality.

A miRNA-7704/IL2RB/AKT feedback loop regulates tumorigenesis and chemoresistance in ovarian cancer.

Ovarian cancer is one of the most common gynecological tumors worldwide. Despite the availability of multiple treatments for ovarian cancer, its resistance to chemotherapy remains a significant challenge. miRNAs play crucial roles in the initiation and progression of cancer by affecting processes such as differentiation, proliferation, and chemoresistance. According to microarray and qPCR analyses, miR-7704 is significantly downregulated in cisplatin-resistant cells compared to parental cells. In this study, we found that miR-7704 inhibited the proliferation and promoted cisplatin sensitivity of ovarian cancer cells in vitro and in vivo. Moreover, ectopic expression of miR-7704 had the same effect as IL2RB knockdown. Further mechanistic studies revealed that miR-7704 played an inhibitory role by regulating IL2RB expression to inactivate the AKT signaling pathway. Furthermore, IL2RB reversed the miR-7704 mediated resistance to cisplatin in ovarian cancer. Based on these findings, miR-7704 and IL2RB show the potential as novel therapeutic targets for ovarian cancer.

Identification of clinically relevant subsets CD39+PD-1+CD8+ T cells and CD39+ regulatory T cells in intrahepatic cholangiocarcinoma using single-cell CyTOF.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive liver malignancy with limited treatment options and a dismal prognosis. The tumor immune microenvironment (TIME) is crucial for iCCA progression, yet its comprehensive characterization remains incomplete. This study utilized mass cytometry by time of flight (CyTOF) to comprehensively analyze immune cell populations in fresh iCCA tumor samples and adjacent peritumor liver tissues. Notably, NK cell percentages significantly decreased in iCCA lesions compared to peritumor liver tissues. Conversely, an enrichment of immunosuppressive CD39+Foxp3+CD4+ regulatory T cells (CD39+T-regs) and exhausted-like CD8+T cells (with pronounced CD39 and PD-1 expression) within TIME was identified and confirmed by multiplex immunofluorescence staining in an independent patient cohort (n = 140). Crucially, tumor-infiltrating CD39+T-regs and CD39+PD-1+CD8+T cells emerged as independent prognostic indicators associated with an unfavorable prognosis in iCCA. These findings unveil the intricate immune landscape within iCCA, offering valuable insights for disease management and novel cancer immunotherapies.

Cardiovascular mortality risk in patients with ovarian cancer: a population-based study.

OBJECTIVES: Ovarian cancer (OC) can occur at different ages and is affected by a variety of factors. In order to evaluate the risk of cardiovascular mortality in patients with ovarian cancer, we included influencing factors including age, histological type, surgical method, chemotherapy, whether distant metastasis, race and developed a nomogram to evaluate the ability to predict occurrence. At present, we have not found any correlation studies on cardiovascular death events in patients with ovarian cancer. This study was designed to provide targeted measures for effective prevention of cardiovascular death in patients with ovarian cancer. METHODS: Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of cardiovascular diseases on overall survival (OS) and ovarian cancer-specific survival (OCSS). We compared multiple groups including clinical, demographic, therapeutic characteristics and histological types. Cox risk regression analysis, Kaplan-Meier survival curves, and propensity score matching were employed for analyzing the data. RESULTS: A total of 88,653 ovarian cancer patients were collected, of which 2,282 (2.57%) patients died due to cardiovascular-related diseases. Age, chemotherapy and whether satisfactory cytoreduction surgery is still the most important factors affecting the prognosis of ovarian cancer patients, while different histological types, diagnosis time, and race also have a certain impact on the prognosis. The newly developed nomogram model showed excellent predictive performance, with a C-index of 0.759 (95%CI: 0.757-0.761) for the group. Elderly patients with ovarian cancer are still a high-risk group for cardiovascular death [HR: 21.07 (95%CI: 5.21-85.30), p < 0.001]. The calibration curve showed good agreement from predicted survival probabilities to actual observations. CONCLUSION: This study found that age, histology, surgery, race, chemotherapy, and tumor metastasis are independent prognostic factors for cardiovascular death in patients with ovarian cancer. The nomogram-based model can accurately predict the OS of ovarian cancer patients. It is expected to inform clinical decision-making and help develop targeted treatment strategies for this population.

Remodeling of the Intra-Conduit Inflammatory Microenvironment to Improve Peripheral Nerve Regeneration with a Neuromechanical Matching Protein-Based Conduit.

Peripheral nerve injury (PNI) remains a challenging area in regenerative medicine. Nerve guide conduit (NGC) transplantation is a common treatment for PNI, but the prognosis of NGC treatment is unsatisfactory due to 1) neuromechanical unmatching and 2) the intra-conduit inflammatory microenvironment (IME) resulting from Schwann cell pyroptosis and inflammatory-polarized macrophages. A neuromechanically matched NGC composed of regenerated silk fibroin (RSF) loaded with poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (P:P) and dimethyl fumarate (DMF) are designed, which exhibits a matched elastic modulus (25.1 ± 3.5 MPa) for the peripheral nerve and the highest 80% elongation at break, better than most protein-based conduits. Moreover, the NGC can gradually regulate the intra-conduit IME by releasing DMF and monitoring sciatic nerve movements via piezoresistive sensing. The combination of NGC and electrical stimulation modulates the IME to support PNI regeneration by synergistically inhibiting Schwann cell pyroptosis and reducing inflammatory factor release, shifting macrophage polarization from the inflammatory M1 phenotype to the tissue regenerative M2 phenotype and resulting in functional recovery of neurons. In a rat sciatic nerve crush model, NGC promoted remyelination and functional and structural regeneration. Generally, the DMF/RSF/P:P conduit provides a new potential therapeutic approach to promote nerve repair in future clinical treatments.

Nano-energy interference: A novel strategy for blunting tumor adaptation and metastasis.

Blunting the tumor's stress-sensing ability is an effective strategy for controlling tumor adaptive survival and metastasis. Here, we have designed a cyclically amplified nano-energy interference device based on lipid nanoparticles (LNP), focused on altering cellular energy metabolism. This innovative nano device efficiently targets and monitors the tumor's status while simultaneously inhibiting mitochondrial respiration, biogenesis and ribosome production. To this end, we first identified azelaic acid (AA), a binary acid capable of disrupting the mitochondrial respiratory chain. Upon encapsulation in LNP and linkage to mitochondrial-targeting molecules, this disruptive effect is further augmented. Consequently, tumors exhibit a substantial upregulation of the glycolytic pathway, intensifying their glucose demand and worsening the tumor's energy-deprived microenvironment. Then, the glucose analog, 2-Deoxy-D-glucose (2-DG), linked to the LNP, efficiently targets tumors and competitively inhibits the tumor's normal glucose uptake. The synergetic results of combining AA with 2-DG induce comprehensive energy deficiency within tumors, blocking the generation of energy-sensitive ribosomes. Ultimately, the disruption of both mitochondria and ribosomes depletes energy supply and new protein-generating capacity, weakening tumor's ability to adapt to environmental stress and thereby inhibiting growth and metastasis. Comprehensively, this nano-energy interference device, by controlling the tumor's stress-sensing ability, provides a novel therapeutic strategy for refractory tumors.

Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has been proven to be an ideal choice for treating unresectable hepatocellular carcinoma (uHCC). HAIC-based treatment showed great potential for treating uHCC. However, large-scale studies on HAIC-based treatments and meta-analyses of first-line treatments for uHCC are lacking. AIM: To investigate better first-line treatment options for uHCC and to assess the safety and efficacy of HAIC combined with angiogenesis inhibitors, programmed cell death of protein 1 (PD-1) and its ligand (PD-L1) blockers (triple therapy) under real-world conditions. METHODS: Several electronic databases were searched to identify eligible randomized controlled trials for this meta-analysis. Study-level pooled analyses of hazard ratios (HRs) and odds ratios (ORs) were performed. This was a retrospective single-center study involving 442 patients with uHCC who received triple therapy or angiogenesis inhibitors plus PD-1/PD-L1 blockades (AIPB) at Sun Yat-sen University Cancer Center from January 2018 to April 2023. Propensity score matching (PSM) was performed to balance the bias between the groups. The Kaplan-Meier method and cox regression were used to analyse the survival data, and the log-rank test was used to compare the suvival time between the groups. RESULTS: A total of 13 randomized controlled trials were included. HAIC alone and in combination with sorafenib were found to be effective treatments (P values for ORs: HAIC, 0.95; for HRs: HAIC + sorafenib, 0.04). After PSM, 176 HCC patients were included in the analysis. The triple therapy group (n = 88) had a longer median overall survival than the AIPB group (n = 88) (31.6 months vs 14.6 months, P < 0.001) and a greater incidence of adverse events (94.3% vs 75.4%, P < 0.001). CONCLUSION: This meta-analysis suggests that HAIC-based treatments are likely to be the best choice for uHCC. Our findings confirm that triple therapy is more effective for uHCC patients than AIPB.

The association of exposure to polychlorinated biphenyls with lipid profile and liver enzymes in umbilical cord blood samples.

Evidence on prenatal exposure to polychlorinated biphenyls (PCBs) and its effects on newborns and potential biological mechanisms is not well defined yet. Therefore, this study aimed to examine whether PCBs are associated with lipid profile and non-invasive markers of hepatocyte injuries in samples of blood obtained from the umbilical cord. This study included 450 mothers-newborn pairs. Umbilical levels of PCBs were measured using Gas Chromatography/Mass Spectrophotometry (GC/MS). Lipid profile including low-density lipoprotein (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein (HDL-C), as well as liver enzymes i.e., alanine amino transferase (ALT), aspartate amino transferase (AST), γ-glutamyl-transferase (GGT) and alkaline phosphatase (ALP) were determined from umbilical cord blood samples. Quantile g-computation analysis was applied to evaluate the collective influence of PCBs on both lipid profiles and liver enzymes, along with the impact of lipid profiles on liver enzymes. Exposure to the mixture of PCBs was significantly associated with increases in ALP, AST, ALT, and GGT levels in cord blood samples, with increments of 90.38 U/L (95%CI: 65.08, 115.70, p < 0.01), 11.88 U/L (95%CI: 9.03, 14.74, p < 0.01), 2.19 U/L (95%CI:1.43, 2.94, p < 0.01), and 50.67 U/L (95%CI: 36.32, 65.03, p < 0.01), respectively. Additionally, combined PCBs exposure was correlated with significant increases in umbilical TG, TC, and LDL-C levels, with values of 3.97 mg/dL (95%CI: 0.86, 7.09, p = 0.01), 6.30 mg/dL (95%CI: 2.98, 9.61, p < 0.01), and 4.63 mg/dL (95%CI: 2.04, 7.23, p < 0.01) respectively. Exposure to the mixture of lipids was linked to elevated levels of AST and GGT in umbilical cord blood samples. Furthermore, a noteworthy mediating role of TC and LDL-C was observed in the association between total PCBs exposure and umbilical cord blood liver enzyme levels. Overall our findings suggested that higher levels of umbilical cord blood PCBs and lipid profile could affect liver function in newborns.

Gut commensal Christensenella minuta modulates host metabolism via acylated secondary bile acids.

A strong correlation between gut microbes and host health has been observed in numerous gut metagenomic cohort studies. However, the underlying mechanisms governing host-microbe interactions in the gut remain largely unknown. Here we report that the gut commensal Christensenella minuta modulates host metabolism by generating a previously undescribed class of secondary bile acids with 3-O-acylation substitution that inhibit the intestinal farnesoid X receptor. Administration of C. minuta alleviated features of metabolic disease in high fat diet-induced obese mice associated with a significant increase in these acylated bile acids, which we refer to as 3-O-acyl-cholic acids. Specific knockout of intestinal farnesoid X receptor in mice counteracted the beneficial effects observed in their wild-type counterparts. Finally, we showed that 3-O-acyl-CAs were prevalent in healthy humans but significantly depleted in patients with type 2 diabetes. Our findings indicate a role for C. minuta and acylated bile acids in metabolic diseases.