Molecular characterization of Blastocystis spp. in Hotan Black chickens in southern Xinjiang.

To determine the infection status and assess the zoonotic potential of Blastocystis spp. in Hotan Black chickens in southern Xinjiang, China, fecal samples were collected from 617 chickens on 18 large-scale farms. The presence of Blastocystis spp. was determined using polymerase chain reaction based on the small subunit rRNA (SSU rRNA) locus. The results revealed an overall infection rate of 26.3% (162/617). Samples from Farm 1 in Luopu County showed the highest infection rate (76.3%, 29/38). The highest and lowest infection rates were detected in the <30-day (34.4%, 43/125) and > 90-day age groups (12.4%, 11/89), respectively. The infection rate decreased with increasing age. Statistical analysis showed significant differences in the infection rates of Blastocystis spp. among the different sampling sites (p < 0.05) and age groups (p < 0.05). Four Blastocystis spp. subtypes (ST6, ST7, ST10, and ST23) were identified. The infection rates of the zoonotic subtypes, ST6 and ST7, were 3.2% (20/617) and 22.2% (137/617), respectively. The presence of Blastocystis spp. and zoonotic subtypes provided evidence for the potential transmission of this pathogen between Hotan Black chickens and humans, especially in animal handlers in this area.

Obscured Contribution of Oxygenated Intermediate-Volatility Organic Compounds to Secondary Organic Aerosol Formation from Gasoline Vehicle Emissions.

Secondary organic aerosol (SOA) formation from gasoline vehicles spanning a wide range of emission types was investigated using an oxidation flow reactor (OFR) by conducting chassis dynamometer tests. Aided by advanced mass spectrometric techniques, SOA precursors, including volatile organic compounds (VOCs) and intermediate/semivolatile organic compounds (I/SVOCs), were comprehensively characterized. The reconstructed SOA produced from the speciated VOCs and I/SVOCs can explain 69% of the SOA measured downstream of an OFR upon 0.5-3 days' OH exposure. While VOCs can only explain 10% of total SOA production, the contribution from I/SVOCs is 59%, with oxygenated I/SVOCs (O-I/SVOCs) taking up 20% of that contribution. O-I/SVOCs (e.g., benzylic or aliphatic aldehydes and ketones), as an obscured source, account for 16% of total nonmethane organic gas (NMOG) emission. More importantly, with the improvement in emission standards, the NMOG is effectively mitigated by 35% from China 4 to China 6, which is predominantly attributed to the decrease of VOCs. Real-time measurements of different NMOG components as well as SOA production further reveal that the current emission control measures, such as advances in engine and three-way catalytic converter (TWC) techniques, are effective in reducing the "light" SOA precursors (i.e., single-ring aromatics) but not for the I/SVOC emissions. Our results also highlight greater effects of O-I/SVOCs to SOA formation than previously observed and the urgent need for further investigation into their origins, i.e., incomplete combustion, lubricating oil, etc., which requires improvements in real-time molecular-level characterization of I/SVOC molecules and in turn will benefit the future design of control measures.

Systemic meta-analysis: apigenin's effects on lung inflammation and oxidative stress.

OBJECTIVE: This study aimed to investigate the potential anti-inflammatory and antioxidant effects of apigenin in rats with acute lung injury (ALI). We also examined changes in levels of inflammatory and antioxidant factors after apigenin treatment in a rat model of ALI.Methods: We searched several databases, including PubMed, Scopus, EMBASE, Web of Science, ProQuest, and GoogleScholar, to retrieve relevant articles for our systematic review and meta-analysis.Five studies with 226 rat models of ALI were included in this study. We investigated inflammatory factors and oxidative stress with the corresponding 95% confidence interval in three groups: 1. Group1 (control vs. ALI), 2. Group2 (ALI vs. apigenin10), and 3. Group3 (ALI vs. apigenin20). RESULTS: Estimating the correlation and 95% confidence intervals for the inflammatory agents and oxidative stress in the intervention group (ALI), compared with that in the control group, respectively (correlation: 0.194; 95% confidence intervals, 0.101-0.282, p value = .001, z-value= 4.08) and (correlation: 0.099; 95% confidence intervals, 0.016-0.182, p value = .020, z value= 2.325). Estimating the correlation and 95% confidence intervals for the inflammatory agents and oxidative stress in the intervention group (apigenin 10 mg/kg), compared with that in the control group (ALI), respectively (correlation: 0.476; 95% confidence intervals, 0.391-0.553, p value = .001, z-value= 9.678) and (correlation: 0.415; 95% confidence intervals, 0.313-0.508, p value= .001, z-value= 7.349). CONCLUSION: Apigenin may have potential anti-inflammatory and antioxidant effects in rat models of ALI. However, the efficacy of apigenin as a therapeutic strategy requires further investigation through prospective controlled randomized trials.

Reduced Expression of CLEC4G in Neurons Is Associated with Alzheimer's Disease.

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aß generation, yet its brain localization and functions in Alzheimer's disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management.

Associations between postoperative cognitive dysfunction, serum interleukin-6 and postoperative delirium among patients after coronary artery bypass grafting: A mediation analysis.

BACKGROUND: POCD is a common complication among patients who underwent coronary artery bypass graft (CABG), it is linked to loss of independence and reduced quality of life. AIM: To examine the association between postoperative cognitive dysfunction (POCD), postoperative delirium (POD) and interleukin-6 (IL-6). DESIGN: A prospective cohort study. METHODS: Patients who underwent elective isolated CABG were enrolled. POCD was assessed by a set of cognitive function tools. Delirium was assessed using the CAM-ICU. The logistic regression analyses were used to identify the predictive value of POD or IL-6 on POCD. The path analysis was used to analyse the relationship among POD, IL-6 and POCD. RESULTS: A total of 212 patients were enrolled, with 25.0% of patients developing POD and 32.5% developing POCD. The multiple logistic regression analysis revealed that patients with POD had a four-fold increased hazard of POCD (OR = 3.655), and patients with IL-6 ≥ 830.50 pg/mL at the 6th hours after surgery had a 5-fold increased risk of experiencing POCD (OR = 5.042). However, the mediation effect of POD between IL-6 and POCD was not statistically significant (ß = 0.059, p = .392). CONCLUSIONS: POD and IL-6 at the 6th hour after surgery (≥830.50 pg/mL) are two potent predictors for POCD, while POD did not play a mediation effect between IL-6 and POCD. RELEVANCE TO CLINICAL PRACTICE: Early identification of risk factors (e.g., delirium assessment and testing for serum IL-6 levels) by clinical nurses for POCD may contribute to the clinical practice for the targeted prevention nursing strategies.

Clinical characteristics of venous thromboembolism onset from severe high altitude pulmonary edema in plateau regions.

BACKGROUND: To investigate venous thromboembolism (VTE) in hospitalized patients with severe high altitude pulmonary edema (HAPE), we performed a single center retrospective study to evaluate its clinical characteristics, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center in plateau regions. METHODS: We studied a total of 18 patients with severe HAPE from January 1, 2012 to December 31, 2021. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities and cardiac ultrasound, and computed tomographic pulmonary angiography (CTPA) variables were obtained, and comparisons were made between groups with and without VTE. RESULTS: Of the 18 patients hospitalized with severe HAPE (age 43 (range, 34-54) years, 14 [77.8%] men), 7 patients developed VTE (38.9%), including 5 with deep vein thrombosis (DVT) and pulmonary embolism (PE), 2 of whom had DVT only. Eighteen patients are all firstly rapid ascent to high altitudes which the mean altitude was 3700 m (3656-4050 m). Compared with patients who did not have VTE, patients with VTE had a longer time in hospital (13 [11, 19] versus 9 [7, 12]; P = 0.027), respiratory failure (6 [85.7%] versus 2 [18.2%]; P = 0.013), the shortened APTT (21.50 [19.00, 27.50] versus 26.30 [24.80, 30.10]; P = 0.044) and the higher level of D-dimer (7.81 [4.62, 9.60] versus 2.90 [1.75, 3.37]; P = 0.003). The proportion of thromboprophylaxis is too low in our cohort which 2 of 18 (11.1%) patients were given VTE prophylaxis. There was no statistically significant difference between the VTE and non-VTE groups (0 [0.0%] versus 2 [18.2%]; P = 0.497). CONCLUSIONS: The prevalence of VTE is high in hospitalized patients with severe high altitude pulmonary edema (HAPE). Prophylaxis for venous thromboembolism may be protective in severe HAPE patients after admission. Our data seem to suggest that VTE is probably an additional prognostic factors in patients with severe HAPE.

Dominant infection of Cryptosporidium baileyi in broiler chickens in Zhejiang Province, China.

Cryptosporidium is a common enteric parasite in chickens. A total of 812 fecal specimens were collected from 11 broiler farms in Zhejiang Province, China, and analyzed by nested PCR amplification based on the small subunit ribosomal RNA (SSU rRNA) gene. The overall infection rate of Cryptosporidium was 6.3% (51/812), and five of 11 farms were Cryptosporidium positive. Broilers aged > 90 days accounted for the highest infection rate of 16.1% (6/56), followed by those aged 30-60 days (10.6%, 38/358) and 60-90 days (4/378, 1.1%). Two Cryptosporidium species were identified by sequence analysis, with the predominant species being C. baileyi (96.1%, 49/51) and the minor infection being C. meleagridis (3.9%, 2/51). Based on the 60-kDa glycoprotein (gp60) gene, two C. meleagridis-positive isolates were identified as one known subtype, IIIbA24G1R1. This study indicated the common occurrence of C. baileyi in broiler chickens in this region and low zoonotic transmission potential of Cryptosporidium to humans.

A Prediction Rule Including Interleukin-6 in Pericardial Drainage Improves Prediction of New-Onset Atrial Fibrillation After Coronary Artery Bypass Grafting.

OBJECTIVE: To test the hypothesis that a prediction rule including levels of interleukin-6 in pericardial drainage (pdIL-6) would improve the discrimination in classifying patients undergoing coronary artery bypass grafting (CABG) into different postoperative atrial fibrillation (POAF) risk levels. DESIGN: Prospective cohort study. SETTING: A university-affiliated tertiary hospital. PARTICIPANTS: Patients undergoing CABG. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We prospectively recruited patients who underwent CABG into derivation and validation cohorts. The independent predictors were identified in the derivation cohort using multiple logistic regression and tested in the validation cohort. The performance of the predictive model was tested using area under the receiver operating characteristic curve (AUC) in both cohorts. A prediction rule was created by assigning points to each predictor. Patients were classified in various risk levels according to their total risk scores. We enrolled 302 and 207 patients in the derivation and validation cohorts, respectively. Multiple logistic regression analysis identified six predictors: age ≥61 y, left atrial diameter ≥49 mm, right atrial diameter ≥45 mm, number of grafts ≥3, and serum uric acid ≥226 µmol/L and pdIL-6 levels ≥166 ng/mL at postoperative 12 h. The AUC of the model was 0.78 and 0.77 for the derivation and validation cohort, respectively, which was greatly increased by adding pdIL-6. Patients were stratified into low-risk, moderate-risk and high-risk groups. CONCLUSIONS: A POAF prediction rule including pdIL-6 had good performance for stratifying CABG patients into various risk groups for POAF. The inclusion of pdIL-6 resulted in clinically meaningful improvement in risk prediction.

Longitudinal surveillance of Cryptosporidium spp. in broiler chickens in Xinjiang, northwest China: genetic diversity of Cryptosporidium meleagridis subtypes.

Cryptosporidium spp. are common enteric parasites in humans and animals. Herein, 175 faecal specimens were collected from a broiler farm in Xinjiang, China, including seven repeated samplings at 10-day intervals of broilers aged 10 to 70 days. Cryptosporidium was detected and identified by PCR-RFLP analysis. The overall infection rate of Cryptosporidium in broilers was 23.4% (41/175), with the highest infection rate of 48.0% (12/25) at 40 days of age, and no infection was detected at 10 days of age. Two Cryptosporidium species were confirmed, namely, C. baileyi (3.4%, 6/175) and C. meleagridis (20%, 35/175). In total, 21 of 35 C. meleagridis isolates were successfully subtyped based on the gp60 gene, and one known subtype, IIIgA22G3R1 (n = 1), and three novel subtypes, IIIbA25G1R1 (n = 10), IIIgA24G3R1 (n = 9) and IIIgA25G2R1 (n = 1), were identified. Our findings highlight the genetic diversity of C. meleagridis in Xinjiang and the potential endemic characteristics of the subtypes.

Higher IGFBP-1 to IGF-1 serum ratio predicts unfavourable survival in patients with nasopharyngeal carcinoma.

BACKGROUND: The insulin-like growth factor (IGF) system plays an important role in the development and progression of cancer. However, little is known about the expression of the IGF system components and their clinicopathological significance and prognostic value in nasopharyngeal carcinoma (NPC). METHODS: IGF system components (IGF-1, IGF-2, IGF-1SR, IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4 and IGFBP-6) were quantified from the plasma of NPC patients and healthy individuals using the RayBio Human Cytokine Antibody Array. IGFBP-1 and IGF-1 mRNA levels were quantified by real-time qPCR, and protein expression was detected by western blot in nine NPC cell lines and four immortalized nasopharyngeal epithelial (NPE) cell lines. Tissue-specific expression of IGFBP-1 and IGF-1 was detected by immunohistochemistry in paraffin-embedded NPC tissues. ELISA analysis was used to measure the serum levels of IGFBP-1 and IGF-1 in 142 NPC patients and 128 healthy controls and determine potential correlation with clinicopathological parameters. RESULTS: Significantly higher levels of circulating IGFBP-1 and lower levels of IGF-1 and IGF-2 were detected in NPC patients compared to healthy controls by Cytokine Antibody Array analyses (P = 0.034, 0.012, 0.046, respectively). IGFBP-1 expression was detected in the majority of NPC cell lines, but not in NPE cell lines, and was shown to localize to the nucleus of tumour cells, in contrast to the cytoplasmic staining observed in normal cells. Importantly, IGFBP-1 expression was stronger in NPC tumour tissues compared to peritumoural tissues. In contrast, IGF-1 expression was weak or absent in NPC and NPE cell lines, with the exception of the EBV-infected C666 cell line, and was found to be expressed at lower levels in tumour tissues compared to tumour-adjacent normal tissue. Levels of serum IGFBP-1 were shown to be significantly higher in patients with NPCs compared to healthy control individuals (55.23 ± 41.25 µg/L vs. 32.08 ± 29.73 µg/L, P < 0.001), whereas serum levels of IGF-1 were significantly lower in NPC patients compared to healthy controls (98.14 ± 71.48 µg/L vs. 164.01 ± 92.08 µg/L, P = 0.001). Consistently, the IGFBP-1/IGF-1 serum ratio was shown to be significantly higher in NPC patients compared to healthy control individuals (P = 0.002). Serum levels of IGFBP-1 and the IGFBP-1/IGF-1 ratio significantly correlated with age (P = 0.020; P = 0.016), WHO histological classification (P = 0.044; P = 0.048), titre of EA (EB Virus Capsid Antigen-IgA) and NPC (P = 0.015; P = 0.016). In contrast, higher IGFBP-1 serum levels and IGFBP-1/IGF-1 ratio significantly correlated with poor RFS (P = 0.046; P = 0.037) and OS (P = 0.038; P = 0.009). Multivariate analysis revealed that the IGFBP-1/IGF-1 ratio, but not serum IGFBP-1 level, represents an independent risk factor for poor RFS (P = 0.044) and OS (P = 0.035). CONCLUSIONS: A higher IGFBP-1/IGF-1 serum ratio is significantly associated with poor prognosis in NPC patients.

The quality of life of patients developed delirium after coronary artery bypass grafting is determined by cognitive function after discharge: A cross-sectional study.

AIMS: Postoperative delirium (POD) and declined cognitive function were common in patients (especially elderly patients) who underwent coronary artery bypass grafting (CABG), which may affect quality of life (QoL). The aim of this study was to determine the relationships among age, POD, declined cognitive function, and QoL in patients who underwent CABG. METHODS: Consecutive patients who underwent first time elective CABG and assessed for POD using Confusion Assessment Method for intensive care unit for 5 postoperative days from November 2013 to March 2015 were recruited. A cross-sectional study was conducted during April 2015 to assess their cognitive function and QoL, using the Telephone Interview for Cognitive Status Scale and Medical Outcomes Study 36-Item Short Form Health Survey. The relationships among age, POD, declined cognitive function, and QoL were tested using path analysis. RESULTS: Declined cognitive function was associated with poorer QoL. POD was associated with declined cognitive function but was not associated with poorer QoL. Ageing was not associated with QoL but was associated with POD and declined cognitive function. CONCLUSION: The QoL of patients developed delirium after CABG is determined by cognitive function after discharge. Necessary strategies should be implemented to prevent POD and declined cognitive function, especially in elderly patients.

Higher heat shock factor 1 expression in tumor stroma predicts poor prognosis in esophageal squamous cell carcinoma patients.

BACKGROUND: Heat shock factor 1 (HSF1) is a powerful, multifaceted modifier of carcinogenesis. However, the clinical significance and biologic function of HSF1 in esophageal squamous cell carcinoma (ESCC) remain unknown. METHODS: HSF1 was detected in ESCC cell lines, fibroblast cell lines and ESCC xenograft tumors and human ESCC tissues by real-time RT-PCR and western blotting. HSF1 protein expression was analyzed by immunochemistry in 134 ESCC patients followed by correlation with clinicopathological parameters. RESULTS: HSF1 expression is weak in fibroblast cell 3T3 and moderate in ESCC cell Eca109, but increasing expression of HSF1 was observed in both of 3T3 and Eca109 cells when they interplayed with each other. In Eca109 xenograft tumors, both tumor cells and stromal fibroblasts showed stronger expression of HSF1. In ESCC patients, the HSF1 expression in tumor or in stromal cells was significantly associated with tumor stage, lymph node metastasis and clinical stage. Multivariate analysis demonstrated a significant negative correlation between disease-free survival (DFS), overall survival (OS) and the HSF1 expression in stromal cells (P < 0.05) but not in tumor cells. Additionally, the expression of HSF1 in tumor cells or stromal cells was an independent factor for DFS (P = 0.032 or P = 0.012) and OS (P = 0.017 or P = 0.013) in metastatic ESCC patients but not for locoregional ESCC. ESCC patients with low HSF1 in both tumor cells and stromal cells had the longest survivals (P < 0.001). CONCLUSIONS: The interaction of tumor cells and stromal fibroblasts increases the expression of HSF1 reciprocally in tumor microenvironment. The HSF1 expression in stromal cells was significantly associated with poor prognosis of ESCC.

Efficacy of oral treprostinil for treating pulmonary arterial hypertension: a systematic review and meta-analysis.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive condition characterized by elevated blood pressure in the pulmonary arteries, leading to significant morbidity and mortality. Treprostinil, a synthetic analogue of prostacyclin, has emerged as a potential treatment option. Aim: The efficacy and safety of oral treprostinil in PAH patients remain subjects of ongoing research. Methods: Comprehensive literature searches were performed across multiple databases for studies assessing the efficacy and/or safety of treprostinil in PAH patients. Quality assessment and statistical analysis were performed using the Cochrane Collaboration's tool and Comprehensive Meta-Analysis software, respectively. Results: From 680 records identified, four studies met the inclusion criteria. These studies demonstrated that oral treprostinil significantly improved exercise capacity as measured by the 6-minute walk distance (6MWD), with a mean difference of 13.13 m in favor of treprostinil, despite high heterogeneity. The analysis also showed an increased risk of adverse events leading to discontinuation in the treprostinil group (OR = 4.39) but a protective effect against clinical worsening (OR = 0.554). No significant impact on mortality was observed. Conclusions: Oral treprostinil offers a significant benefit in improving exercise capacity in PAH patients, with a potential role in delaying clinical worsening. However, the increased risk of adverse events necessitates careful patient management. These findings support the inclusion of oral treprostinil in the treatment strategy for PAH, underscoring the need for further research to optimize its use and understand its long-term impact on patient outcomes.Level of evidence: I.

Transcriptomic analysis of the hypoxia-inducible factor 1α impact on the gene expression profile of chicken fibroblasts under hypoxia.

Hypoxia-inducible factor 1 (HIF-1) is a transcriptional regulator that mediates cellular adaptive responses to hypoxia. Hypoxia-inducible factor 1α (HIF-1α) is involved in the development of ascites syndrome (AS) in broiler chickens. Therefore, studying the effect of HIF-1α on the cellular transcriptome under hypoxic conditions will help to better understand the mechanism of HIF-1α in the development of AS in broilers. In this study, we analyzed the gene expression profile of the chicken fibroblast cell line (DF-1) under hypoxic conditions by RNA-seq. Additionally, we constructed the HIF-1α knockdown DF-1 cell line by using the RNAi method and analyzed the gene expression profile under hypoxic conditions. The results showed that exposure to hypoxia for 48 h had a significant impact on the expression of genes in the DF-1 cell line, which related to cell proliferation, stress response, and apoptosis. In addition, after HIF-1α knockdown more differential expression genes appeared than in wild-type cells, and the expression of most hypoxia-related genes was either down-regulated or remained unchanged. Pathway analysis results showed that differentially expressed genes were mainly enriched in pathways related to cell proliferation, apoptosis, and oxidative phosphorylation. Our study obtained transcriptomic data from chicken fibroblasts at different hypoxic times and identified the potential regulatory network associated with HIF-1α. This data provides valuable support for understanding the transcriptional regulatory mechanism of HIF-1α in the development of AS in broilers.

Expression and localization of Cyclin D1/Nanog and NF-κB/Bax protein in dysplastic testicles of mice.

Testicular dysplasia significantly impairs male reproductive capacity. This study investigated the expression of Cyclin D1/Nanog and NF-κB/Bax in dysplastic testes of mice using histological staining, Western blotting, and immunohistochemistry. The results showed that Nanog and Bax expression were significantly higher in dysplastic testicular tissue than in normal tissue (P < 0.01). Cyclin D1 protein expression was higher in normal testis tissue than in dysplastic testis (P < 0.01). NF-κB was highly expressed in cryptorchid and normal testis with no significant difference (P > 0.05). Immunolocalization revealed that Nanog, NF-κB, and Bax were expressed in the cytoplasm of Leydig and spermatogenic cells. Cyclin D1 primarily expressed in the nucleus of Sertoli cells. These findings suggest that altered expression of Nanog, Cyclin D1, and Bax may contribute to testicular dysplasia. This study provides a scientific foundation for detecting testicular dysplasia and selecting appropriate animal models, ultimately informing strategies to improve male reproductive health.

Oligodendrocyte progenitor cell-specific delivery of lipid nanoparticles loaded with Olig2 synthetically modified messenger RNA for ischemic stroke therapy.

The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is needed for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, achieving Olig2 overexpression in vivo remains a formidable technological challenge. To address this challenge, we employed lipid nanoparticle (LNP)-mediated delivery of Olig2 synthetically modified messenger RNA (mRNA) as a viable method for in vivo Olih2 protein overexpression. Specifically, we developed CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) to achieve targeted Olig2 protein expression within PDGFRα+ OPCs, with the goal of promoting remyelination for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα+ OPCs derived from mouse neural stem cells into mature oligodendrocytes in vitro, suggesting that mRNA-mediated Olig2 overexpression is a rational approach to promote oligodendrocyte differentiation and remyelination. Furthermore, when C-Olig2 was administered to a murine model of ischemic stroke, it led to improvements in blood‒brain barrier (BBB) integrity, enhanced remyelination, and rescued learning and cognitive deficits. Our comprehensive analysis, which included bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq), revealed upregulated biological processes related to learning and memory in the brains of mice treated with C-Olig2 compared to those receiving empty LNPs (Mock). Collectively, our findings highlight the therapeutic potential of multifunctional nanomedicine targeting mRNA expression for ischemic stroke and suggest that this approach holds promise for addressing various brain diseases. STATEMENT OF SIGNIFICANCE: While Olig2 overexpression in OPCs represents a promising therapeutic avenue for enhancing remyelination in ischemic stroke, in vivo strategies for achieving Olig2 expression pose considerable technological challenges. The delivery of mRNA via lipid nanoparticles is considered aa viable approach for in vivo protein expression. In this study, we engineered CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) with the aim of achieving specific Olig2 overexpression in mouse OPCs. Our findings demonstrate that C-Olig2 promotes the differentiation of OPCs into oligodendrocytes in vitro, providing evidence that mRNA-mediated Olig2 overexpression is a rational strategy to foster remyelination. Furthermore, the intravenous administration of C-Olig2 into a murine model of ischemic stroke not only improved blood-brain barrier integrity but also enhanced remyelination and mitigated learning and cognitive deficits. These results underscore the promising therapeutic potential of multifunctional nanomedicine targeting mRNA expression in the context of ischemic stroke.

Myeloperoxidase in the pericardial fluid improves the performance of prediction rules for postoperative atrial fibrillation.

OBJECTIVES: After surgery, inflammation is a prominent factor influencing postoperative atrial fibrillation. Myeloperoxidase is a major contributor to inflammatory responses after surgical tissue damage. We evaluated whether myeloperoxidase is associated with postoperative atrial fibrillation clinically and in an animal model. METHODS: This prospective cohort study included patients undergoing isolated coronary artery bypass grafting. Myeloperoxidase concentrations in blood and pericardial fluid were determined at baseline and 6, 12, and 18 hours after coronary artery bypass grafting. Myeloperoxidase activity in blood, pericardial fluid, and atrium were also evaluated in a canine coronary artery bypass grafting model. Electrophysiologic, histologic, and immunohistochemistry analyses were performed to explore underlying mechanisms. RESULTS: Postoperative atrial fibrillation occurred in 45 of 137 patients (32.8%). Patients with postoperative atrial fibrillation had significantly higher serum and pericardial myeloperoxidase levels. Individual clinical and surgical factors had moderate predictive value (area under the curve, 0.760) for postoperative atrial fibrillation. Discrimination improved remarkably when myeloperoxidase was combined with other parameters (area under the curve, 0.901). Pericardial myeloperoxidase at 6 hours postoperatively was the strongest independent predictor of postoperative atrial fibrillation (odds ratio, 19.215). The rate of postoperative atrial fibrillation increased exponentially across pericardial myeloperoxidase grades. Compared with controls, coronary artery bypass grafting-treated dogs showed higher atrial fibrillation vulnerability and maintenance, shorter atrial effective refractory period, attenuated connexin 43 expression, and increased myocardial and pericardial myeloperoxidase activity. Connexin 43 expression and atrial effective refractory period were strongly negatively correlated with myocardial and pericardial myeloperoxidase activity. CONCLUSIONS: Myeloperoxidase is linked to postoperative atrial fibrillation, and the ability to predict postoperative atrial fibrillation was remarkably improved by adding pericardial myeloperoxidase. Myeloperoxidase-related atrial structural and electrical remodeling is a physiologic substrate for this arrhythmia.

GABAergic signaling abnormalities in a novel CLU mutation Alzheimer's disease mouse model.

The CLU rs11136000C mutation (CLUC) is the third most common risk factor for Alzheimer's disease (AD). However, the mechanism by which CLUC leads to abnormal GABAergic signaling in AD is unclear. To address this question, this study establishes the first chimeric mouse model of CLUC AD. Examination of grafted CLUC medial ganglionic eminence progenitors (CLUC hiMGEs) revealed increased GAD65/67 and a high frequency of spontaneous releasing events. CLUC hiMGEs also impaired cognition in chimeric mice and caused AD-related pathologies. The expression of GABA A receptor, subunit alpha 2 (Gabrα2) was higher in chimeric mice. Interestingly, cognitive impairment in chimeric mice was reversed by treatment with pentylenetetrazole, which is a GABA A receptor inhibitor. Taken together, these findings shed light on the pathogenesis of CLUC AD using a novel humanized animal model and suggest sphingolipid signaling over-activation as a potential mechanism of GABAergic signaling disorder.

ScRNA-seq revealed an immunosuppression state and tumor microenvironment heterogeneity related to lymph node metastasis in prostate cancer.

BACKGROUND: Metastasis is a crucial aspect of disease progression leading to death in patients with prostate cancer (PCa). However, its mechanism remains unclear. We aimed to explore the mechanism of lymph node metastasis (LNM) by analyzing the heterogeneity of tumor microenvironment (TME) in PCa using scRNA-seq. METHODS: A total of 32,766 cells were obtained from four PCa tissue samples for scRNA-seq, annotated, and grouped. InferCNV, GSVA, DEG functional enrichment analysis, trajectory analysis, intercellular network evaluation, and transcription factor analysis were carried out for each cell subgroup. Furthermore, validation experiments targeting luminal cell subgroups and CXCR4 + fibroblast subgroup were performed. RESULTS: The results showed that only EEF2 + and FOLH1 + luminal subgroups were present in LNM, and they appeared at the initial stage of luminal cell differentiation, which were comfirmed by verification experiments. The MYC pathway was enriched in the EEF2 + and FOLH1 + luminal subgroups, and MYC was associated with PCa LNM. Moreover, MYC did not only promote the progression of PCa, but also led to immunosuppression in TME by regulating PDL1 and CD47. The proportion of CD8 + T cells in TME and among NK cells and monocytes was lower in LNM than in the primary lesion, while the opposite was true for Th and Treg cells. Furthermore, these immune cells in TME underwent transcriptional reprogramming, including CD8 + T subgroups of CCR7 + and IL7R+, as well as M2-like monocyte subgroups expressing tumor-associated signature genes, like CCR7, SGKI, and RPL31. Furthermore, STEAP4+, ADGRF5 + and CXCR4+, and SRGNC + fibroblast subgroups were closely related to tumor progression, tumor metabolism, and immunosuppression, indicating their contributions in PCa metastasis. Meanwhile, The presence of CXCR4 + Fibroblasts in PCa was confirmed by polychromatic immunofluorescence. CONCLUSIONS: The significant heterogeneity of luminal, immune, and interstitial cells in PCa LNM may not only directly contribute to tumor progression, but also indirectly result in TME immunosuppression, which may be the cause of metastasis in PCa and in which MYC played an role.

Expression profile analysis of sheep ovary after superovulation and estrus synchronisation treatment.

Superovulation is a widely used reproductive technique in livestock production, but the mechanism of sheep's superovulation is not yet clear. Here, a method of superovulation and estrus synchronisation was used to treat female Duolang sheep. After treatment, there were significant differences in serum FSH and LH levels and the number of dominant follicles between the two groups of sheep. We identified a total of 5021 differentially expressed genes (11, 13 and 15 days after treatment) and performed RT-qPCR analysis to identify several mRNA expression levels. GO and KEGG enrichment analysis revealed that differentially expressed genes were involved in the regulation of signalling pathways of follicular development, cell cycle, material synthesis, energy metabolism, such as COL3A1, RPS8, ACTA2, RPL7 RPS6 and TNFAIP6 may play a key role in regulating the development of follicles. Our results show a comprehensive expression profile after superovulation and estrus synchronisation treatment. We provide the basis for further research on breeding techniques to improve the ovulation rate and birth rate of livestock.