Infection with COVID-19 Complicated by Sinus Arrest.

As a respiratory tract-transmitted disease, coronavirus disease 2019 (COVID-19) exerts a profound immune injury effect, leading not only to pulmonary impairment but also to cardiac complications. We present a case of a 79-year-old woman, who had previously contracted COVID-19 and subsequently developed sinus arrest (SA) following her second infection. The longest asystole time detected by Holter monitoring was 7.2 seconds. Although the patient met criteria for permanent pacemaker implantation, her family declined this intervention and conservative management was pursued instead. However, after a period of observation, the patient's SA resolved. The present case study describes a patient who experienced SA upon reinfection with COVID-19, which was not present during the initial infection. It emphasizes the impact of COVID-19 on cardiac health, particularly its potential to induce arrhythmias. In addition, it is worth noting that the arrhythmia induced by a COVID-19 infection may show reversibility, suggesting that a permanent pacemaker might not be the priority option if further pacing therapy is being considered.

The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism.

Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.

Efficacy and Safety of Interleukin-1 Inhibitors in the Management of Patients with Recurrent Pericarditis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: The efficacy and safety of interleukin-1 (IL-1) inhibitors in patients with recurrent pericarditis (RP) remain to be determined. OBJECTIVE: We aimed to conduct a meta-analysis to investigate the impact of IL-1 inhibitors on patients suffering from RP. METHODS: The Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov, and Web of Science databases were systematically searched to identify articles investigating the effects of IL-1 inhibitors in patients with RP up until January 2024. Relevant data on study characteristics and results were selected based on predefined criteria. The results were combined using a random effects model. RESULTS: The study included a total of 102 patients from three open-label randomized controlled trials. Overall, the use of IL-1 inhibitors, in comparison to placebo, demonstrated a significant reduction in the risk of pericarditis recurrence [risk ratio (RR) 0.13; 95% confident interval (CI) 0.05-0.30; p < 0.05; I2 = 0%]. However, the administration of IL-1 inhibitors may lead to certain adverse events (AEs), including infections and injection-site reactions. The risk of AEs is significantly higher with IL-1 inhibitors compared with placebo (RR 1.88; 95% CI 1.30-2.72; p < 0.05; I2 = 0%). Nevertheless, the occurrence of serious AEs among patients was relatively rare, and no fatalities were reported. CONCLUSION: This meta-analysis showed that IL-1 inhibitors can effectively reduce the risk of recurrence in patients with RP and are relatively safe. REGISTRATION: PROSPERO identifier number CRD42023492904.

The Role of Angiotensin II Receptor Blockers in the Management of Hypertrophic Cardiomyopathy: An Updated Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: The use of angiotensin II receptor blockers (ARBs) in the treatment of hypertrophic cardiomyopathy (HCM) remains a subject of controversy. METHODS: We conducted a comprehensive search of the Cochrane Library, PubMed, EMBASE, ClinicalTrials.gov, and Web of Science databases until October 2023 to identify articles investigating the effects of ARBs in patients diagnosed with HCM. Predefined criteria were utilized for selecting data on study characteristics and results. RESULTS: The study included a total of 387 patients from 6 randomized controlled trials, which were reported in 7 articles. The results of the meta-analysis revealed that the utilization of ARBs did not yield a reduction in left ventricular (LV) mass (p = 0.07) and maximum LV wall thickness (p = 0.25), nor did it demonstrate any improvement in LV fibrosis (p = 0.39). Furthermore, there was no significant impact observed on early diastolic mitral annular velocity (p = 0.19) and LV ejection fraction (p = 0.44). CONCLUSIONS: The administration of ARBs does not appear to yield improvements in cardiac structure, function, and myocardial fibrosis in patients with HCM.

Cellulose-based materials in environmental protection: A scientometric and visual analysis review.

As sustainable materials, cellulose-based materials have attracted significant attention in the field of environmental protection, resulting in the publication of numerous academic papers. However, there is a scarcity of literature that involving scientometric analysis within this specific domain. This review aims to address this gap and highlight recent research in this field by utilizing scientometric analysis and a historical review. As a result, 21 highly cited articles and 10 mostly productive journals were selected out. The scientometric analysis reveals that recent studies were objectively clustered into five interconnected main themes: extraction of cellulose from raw materials and its degradation, adsorption of pollutants using cellulose-based materials, cellulose-acetate-based membrane materials, nanocellulose-based materials, and other cellulose-based materials such as carboxymethyl cellulose and bacterial cellulose for environmental protection. Analyzing the distribution of author keywords and thoroughly examining relevant literature, the research focuses within these five themes were summarized. In the future, the development of eco-friendly and cost-effective methods for extracting and preparing cellulose and its derivatives, particularly nanocellulose-based materials, remains an enduring pursuit. Additionally, machine learning techniques holds promise for the advancement and application of cellulose-based materials. Furthermore, there is potential to expand the research and application scope of cellulose-based materials for environmental protection.

Therapeutic efficacy of a novel self-assembled immunostimulatory siRNA combining apoptosis promotion with RIG-I activation in gliomas.

BACKGROUND: Current cancer therapies often fall short in addressing the complexities of malignancies, underscoring the urgent need for innovative treatment strategies. RNA interference technology, which specifically suppresses gene expression, offers a promising new approach in the fight against tumors. Recent studies have identified a novel immunostimulatory small-interfering RNA (siRNA) with a unique sequence (sense strand, 5'-C; antisense strand, 3'-GGG) capable of activating the RIG-I/IRF3 signaling pathway. This activation induces the release of type I and III interferons, leading to an effective antiviral immune response. However, this class of immunostimulatory siRNA has not yet been explored in cancer therapy. METHODS: IsiBCL-2, an innovative immunostimulatory siRNA designed to suppress the levels of B-cell lymphoma 2 (BCL-2), contains a distinctive motif (sense strand, 5'-C; antisense strand, 3'-GGG). Glioblastoma cells were subjected to 100 nM isiBCL-2 treatment in vitro for 48 h. Morphological changes, cell viability (CCK-8 assay), proliferation (colony formation assay), migration/invasion (scratch test and Transwell assay), apoptosis rate, reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) were evaluated. Western blotting and immunofluorescence analyses were performed to assess RIG-I and MHC-I molecule levels, and ELISA was utilized to measure the levels of cytokines (IFN-ß and CXCL10). In vivo heterogeneous tumor models were established, and the anti-tumor effect of isiBCL-2 was confirmed through intratumoral injection. RESULTS: IsiBCL-2 exhibited significant inhibitory effects on glioblastoma cell growth and induced apoptosis. BCL-2 mRNA levels were significantly decreased by 67.52%. IsiBCL-2 treatment resulted in an apoptotic rate of approximately 51.96%, accompanied by a 71.76% reduction in MMP and a 41.87% increase in ROS accumulation. Western blotting and immunofluorescence analyses demonstrated increased levels of RIG-I, MAVS, and MHC-I following isiBCL-2 treatment. ELISA tests indicated a significant increase in IFN-ß and CXCL10 levels. In vivo studies using nude mice confirmed that isiBCL-2 effectively impeded the growth and progression of glioblastoma tumors. CONCLUSIONS: This study introduces an innovative method to induce innate signaling by incorporating an immunostimulatory sequence (sense strand, 5'-C; antisense strand, 3'-GGG) into siRNA, resulting in the formation of RNA dimers through Hoogsteen base-pairing. This activation triggers the RIG-I signaling pathway in tumor cells, causing further damage and inducing a potent immune response. This inventive design and application of immunostimulatory siRNA offer a novel perspective on tumor immunotherapy, holding significant implications for the field.

Development of Nanostructured Lanthanum Strontium Cobalt Ferrite/Gadolinian-Doped Ceria Composite Electrodes of Solid Oxide Cells Formed by In Situ Polarization.

In the development of nanoscale oxygen electrodes of high-temperature solid oxide cells (SOCs), the interface formed between the nanoelectrode particles and the electrolyte or electrolyte scaffolds is the most critical. In this work, a new synthesis technique for the fabrication of nanostructured electrodes via in situ electrochemical polarization treatment is reported. The lanthanum strontium cobalt ferrite (LSCF) precursor solution is infiltrated into a gadolinia-doped ceria (GDC) scaffold presintered on a yttria-stabilized zirconia (YSZ) electrolyte, followed by in situ polarization current treatment at SOC operation temperatures. Electrode ohmic and polarization resistances decrease with an increase in the polarization current treatment. Detailed microstructure analysis indicates the formation of a convex-shaped interface between the LSCF nanoparticles (NPs) and the GDC scaffold, very different from the flat contact between LSCF and GDC observed after heating at 800 °C with no polarization current treatment. The embedded LSCF NPs on the GDC scaffold contribute to the superior stability under both fuel cell and electrolysis operation conditions at 750 °C and a high peak power density of 1.58 W cm-2 at 750 °C. This work highlights a novel and facile route to in situ construct a stable and high-performing nanostructured electrode for SOCs.

Luminescence properties and energy transfer of broadband NIR phosphor Li2MgZrO4: 1.0%Cr3+, y%Yb3.

The discovery of high thermal stability, broad-band near-infrared (NIR) fluorescent phosphors holds significant potential in applications such as non-destructive testing, promoting plant growth, and night vision devices. In this study, a novel broad-band NIR phosphors Li2MgZrO4 (LMZ): 1.0 %Cr3+, y%Yb3+ were synthesized via a high-temperature solid-state reaction method, with the optimal doping concentration found to be y = 1.5. These phosphors exhibited broad NIR emission in the range of 700-1050 nm by effective energy transfer from Cr3+ to Yb3+. The maximum full width at half maximum (FWHM) of the Cr3+/Yb3+ co-doped LMZ phosphor is 270 nm. The thermal stability of the phosphors was improved with Yb3+ co-doping. Additionally, energy transfer from Cr3+ to Yb3+ was confirmed through luminescence spectra and lifetime analysis. Finally, NIR pc-LED devices composed of a 460 nm ultraviolet chip and LMZ: 1.0 %Cr3+, 1.5 %Yb3+ phosphors were fabricated, offering a highly promising source of invisible light. These results demonstrate the wide-ranging potential applications of this novel, high thermal stability, and ultra-broad NIR emitting fluorescent phosphor.

Comparative single-cell RNA sequencing analysis of immune response to inactivated vaccine and natural SARS-CoV-2 infection.

Uncovering the immune response to an inactivated SARS-CoV-2 vaccine (In-Vac) and natural infection is crucial for comprehending COVID-19 immunology. Here we conducted an integrated analysis of single-cell RNA sequencing (scRNA-seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In-Vac compared with those from COVID-19 patients. Our study reveals that In-Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In-Vac modestly upregulates IFN-α but downregulates NF-κB pathways, while natural infection triggers hyperactive IFN-α and NF-κB pathways. Both In-Vac and natural infection alter T/B cell receptor repertoires, but COVID-19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL-15RA/IL-15 receptor pathway after In-Vac boost, suggesting its potential role in enhancing In-Vac-induced immunity. Collectively, our study illuminates multifaceted immune responses to In-Vac and natural infection, providing insights for optimizing SARS-CoV-2 vaccine efficacy.

CircMYBL1 suppressed acquired resistance to osimertinib in non-small-cell lung cancer.

Circular RNAs (circRNAs) play an important role in the development of acquired resistance to many anticancer drugs. We developed the Non-Small-Cell Lung Cancer (NSCLC) cell lines with acquired resistance to osimertinib, a third-generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and evaluated the different expression profiles of circRNAs in osimertinib-sensitive and -resistant NSCLC cell lines using RNA sequencing (RNA-Seq). The expression of selected differentially expressed circRNAs was verified using quantitative real-time PCR (qRT-PCR) in paired osimertinib-sensitive and -resistant NSCLC cell lines, and in plasma samples of osimertinib-sensitive and -resistant NSCLC patients. We found that circMYBL1(has_circ_0136924) was downregulated after acquired resistance to osimertinib, inhibiting circMYBL1 expression facilitated the proliferation, migration, and invasion in osimertinib-sensitive NSCLC cells. CircMYBL1 may be a novel molecular biomarker and therapeutic target for osimertinib-resistant NSCLC.

Novel CAR-T cells targeting TRKB for the treatment of solid cancer.

Chimeric antigen receptor (CAR) T-cell therapy is highly effective for treating blood cancers such as B-cell malignancies, however, its effectiveness as an approach to treat solid tumors remains to be further explored. Here, we focused on the development of CAR-T cell therapies targeting tropomyosin-related kinase receptor B (TRKB), a highly expressed protein that is significantly associated with tumor progression, malignancy, and drug resistance in multiple forms of aggressive solid tumors. To achieve this, we screened brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NTF4) ligand-based CAR-T cells for their efficiency in targeting the TRKB receptor in the context of solid tumors, particularly hepatocellular carcinoma and pancreatic cancer. We demonstrated that TRKB is overexpressed not only in hepatocellular carcinoma and pancreatic carcinoma cell lines but also in cancer stem-like cells (CSCs). Notably, BDNF-CAR T and NTF4-CAR T cells could not only effectively target and kill TRKB-expressing pan-cancer cell lines in a dose-dependent manner but also effectively kill CSCs. We also performed in vivo studies to show that NTF4-CAR T cells have a better potential to inhibit the tumor growth of hepatocellular carcinoma xenografts in mice, compared with BDNF-CAR T cells. Taken together, our findings suggest that CAR-T targeting TRKB may be a promising approach for developing novel therapies to treat solid cancers.

Colorimetric and fluorescent independent dual "signal on" biosensor for accurate detection of ochratoxin A based on aptamer-triggered biocatalytic reactions.

Ochratoxin A (OTA) is a hazardous food contaminant with significant health risks. Dual-channel OTA detection is noted for its cross-reference capability and high accuracy. Still, challenges in addressing in-system corrections and "signal off" related false positives and limited signal gains remain. Herein, we developed a dual-channel "signal on" aptasensor with one recognition process and two independent signal outputs for OTA analysis. The OTA aptamer binds to magnetic beads (MBs) and partially hybridizes with a complementary-trigger (cDNA-Trigger) sequence. Adding OTA disrupts the duplex sequence, leading to G-quadruplex (G4) formation and enrichment on the MBs, which then interacts with hemin to catalyze a color signal. Concurrently, the freed cDNA-Trigger catalyzes an enzyme-free DNA circuit, producing a fluorescence signal. The magnetic enrichment and signal amplification strategies make the proposed assay demonstrate excellent sensitivity toward OTA, with limits of detection (LOD) of 0.017 pM in the fluorescence channel and 48.1 pM in the colorimetric channel. Both channels have effectively detected OTA in grape juice and baijiu, demonstrating their applicability and reliability. Moreover, given the widespread use of smartphones globally, a mini-program with a self-correction function was designed to facilitate on-site colorimetric channel monitoring, making OTA detection more accessible and user-friendly.

Macrophage membrane (MMs) camouflaged near-infrared (NIR) responsive bone defect area targeting nanocarrier delivery system (BTNDS) for rapid repair: promoting osteogenesis via phototherapy and modulating immunity.

Bone defects remain a significant challenge in clinical orthopedics, but no targeted medication can solve these problems. Inspired by inflammatory targeting properties of macrophages, inflammatory microenvironment of bone defects was exploited to develop a multifunctional nanocarrier capable of targeting bone defects and promoting bone regeneration. The avidin-modified black phosphorus nanosheets (BP-Avidin, BPAvi) were combined with biotin-modified Icaritin (ICT-Biotin, ICTBio) to synthesize Icaritin (ICT)-loaded black phosphorus nanosheets (BPICT). BPICT was then coated with macrophage membranes (MMs) to obtain MMs-camouflaged BPICT (M@BPICT). Herein, MMs allowed BPICT to target bone defects area, and BPICT accelerated the release of phosphate ions (PO43-) and ICT when exposed to NIR irradiation. PO43- recruited calcium ions (Ca2+) from the microenvironment to produce Ca3(PO4)2, and ICT increased the expression of osteogenesis-related proteins. Additionally, M@BPICT can decrease M1 polarization of macrophage and expression of pro-inflammatory factors to promote osteogenesis. According to the results, M@BPICT provided bone growth factor and bone repair material, modulated inflammatory microenvironment, and activated osteogenesis-related signaling pathways to promote bone regeneration. PTT could significantly enhance these effects. This strategy not only offers a solution to the challenging problem of drug-targeted delivery in bone defects but also expands the biomedical applications of MMs-camouflaged nanocarriers.

hsa_circ_0087100/hsa-miR-6743-5p affects Th1 cell differentiation by regulating STAT1 in diabetic retinopathy.

Objective: To elucidate the role of the competitive endogenous RNA (ceRNA) network in immune infiltration of diabetic retinopathy (DR). Methods: We obtained differentially expressed (DE) circRNAs, miRNAs and mRNAs from the Gene Expression Omnibus database. Then, we identified immune infiltration by CIBERSORT and single-sample gene set enrichment analysis and discovered co-expression genes by weighted gene co-expression network analysis. Furthermore, STAT1-mediated Th1 differentiation was determined in DR cell models, DR patients and DR mouse models. Results: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 was involved in immune infiltration of Th1 cells. Aberrant expression of the ceRNA network and STAT1-mediated Th1 differentiation was thus verified in vitro and in vivo. Conclusion: hsa_circ_0087100/hsa-miR-6743-5p/STAT1 may affect Th1 cell differentiation in DR.

Modification of Welan gum with poly(2-oxazoline) to obtain thermoviscosifying polymer for enhanced oil recovery.

Thermoviscosifying polymers refer to a category of smart materials that exhibit a responsive behavior to environmental stimuli, specifically demonstrating a natural rise in viscosity of solutions as the temperature increases. The temperature-dependent behavior exhibited by thermally viscous polymers renders them potentially advantageous in the context of Enhanced Oil Recovery (EOR). There exists a dearth of research pertaining to the application of thermoviscosifying polymer for better recovery in reservoirs characterized by high temperatures and high salt content. In order to tackle the mentioned concerns, this study examined the utilization of welan gum modified with poly(2-oxazoline) as thermally responsive chain segments to enhance viscosity. The objective was to evaluate the ability to enhance viscosity under thermal conditions and to assess their effectiveness in displacement of reservoir oil in high temperature and high salt environments. This study aimed to establish a theoretical framework for understanding the correlation between the molecular structure and performance of novel thermally viscous polymers. Additionally, it sought to offer practical insights into designing the molecular structure of thermally viscous polymers suitable for polymer flooding in high temperature and high salt environments. Furthermore, the study proposed the application of these new thermoviscosifying polymers for EOR.

Achieving Clearance of Drug-Resistant Bacterial Infection and Rapid Cutaneous Wound Regeneration Using an ROS-Balancing-Engineered Heterojunction.

Intractable infected microenvironments caused by drug-resistant bacteria stalls the normal course of wound healing. Sono-piezodynamic therapy (SPT) is harnessed to combat pathogenic bacteria, but the superabundant reactive oxygen species (ROS) generated during SPT inevitably provoke severe inflammatory response, hindering tissue regeneration. Consequently, an intelligent nanocatalytic membrane composed of poly(lactic-co-glycolic acid) (PLGA) and black phosphorus /V2C MXene bio-heterojunctions (2D2-bioHJs) is devised. Under ultrasonication, 2D2-bioHJs effectively eliminate drug-resistant bacteria by disrupting metabolism and electron transport chain (ETC). When ultrasonication ceases, they enable the elimination of SPT-generated ROS. The 2D2-bioHJs act as a "lever" that effectively achieves a balance between ROS generation and annihilation, delivering both antibacterial and anti-inflammatory properties to the engineered membrane. More importantly, in vivo assays corroborate that the nanocatalytic membranes transform the stalled chronic wound environment into a regenerative one by eradicating the bacterial population, dampening the NF-κB inflammatory pathway and promoting angiogenesis. As envisaged, this work demonstrates a novel tactic to arm membranes with programmed antibacterial and anti-inflammatory effects to remedy refractory infected wounds from drug-fast bacteria.

TET2-mediated ECM1 hypomethylation promotes the neovascularization in active proliferative diabetic retinopathy.

BACKGROUND: Studies have shown that tet methylcytosine dioxygenase 2 (TET2) is highly expressed in diabetic retinopathy (DR), which reduces the DNA methylation of downstream gene promoters and activates the transcription. Abnormally expressed TET2 and downstream genes in a high-glucose environment are associated with retinal capillary leakage and neovascularization. Here, we investigated the downstream genes of TET2 and its potential association with neovascularization in proliferative diabetic retinopathy (PDR). METHODS: GSE60436, GSE57362, and GSE158333 datasets were analyzed to identify TET2-related hypomethylated and upregulated genes in PDR. Gene expression and promoter methylation of these genes under high glucose treatment were verified. Moreover, TET2 knockdown was used to assess its impact on tube formation and migration in human retinal microvascular endothelial cells (HRMECs), as well as its influence on downstream genes. RESULTS: Our analysis identified three key genes (PARVB, PTPRE, ECM1) that were closely associated with TET2 regulation. High glucose-treated HRMECs exhibited increased expression of TET2 and ECM1 while decreasing the promoter methylation level of ECM1. Subsequently, TET2 knockdown led to decreased migration ability and tube formation function of HRMECs. We further found a decreased expression of PARVB, PTPRE, and ECM1, accompanied by an increase in the promoter methylation of ECM1. CONCLUSIONS: Our findings indicate the involvement of dysregulated TET2 expression in neovascularization by regulating the promoter methylation and transcription of downstream genes (notably ECM1), eventually leading to PDR. The TET2-induced hypomethylation of downstream gene promoters represents a potential therapeutic target and offers a novel perspective on the mechanism underlying neovascularization in PDR.

Modeling and Analysis of Bio-Inspired, Reconfigurable, Piezo-Driven Vibration Isolator for Spacecraft.

The positioning accuracy of spacecraft in orbit is easily affected by low-frequency micro-vibrations of the environment and internal disturbances caused by the payload. Inspired by the neck structure of birds, this study devised a piezo-driven active vibration isolation unit with high stiffness. First, a dynamic model and two-sensor feedback control method for the isolation unit were developed, and the isolation mechanism and anti-disturbance characteristics were analyzed. Further, the stability of the closed-loop was verified. Simulation models of serial and parallel systems based on the proposed vibration isolation unit were implemented to demonstrate its feasibility. The results indicate that the proposed isolation units can provide excellent low-frequency vibration isolation performance and inertial stability and that they can effectively resist the internal disturbance of the payload. Moreover, its performance can be further improved via serial or parallel reconfiguration that facilitates its adaptation to the varied isolation requirements of spacecraft.

Cebp1 and Cebpß transcriptional axis controls eosinophilopoiesis in zebrafish.

Eosinophils are a group of granulocytes well known for their capacity to protect the host from parasites and regulate immune function. Diverse biological roles for eosinophils have been increasingly identified, but the developmental pattern and regulation of the eosinophil lineage remain largely unknown. Herein, we utilize the zebrafish model to analyze eosinophilic cell differentiation, distribution, and regulation. By identifying eslec as an eosinophil lineage-specific marker, we establish a Tg(eslec:eGFP) reporter line, which specifically labeled cells of the eosinophil lineage from early life through adulthood. Spatial-temporal analysis of eslec+ cells demonstrates their organ distribution from larval stage to adulthood. By single-cell RNA-Seq analysis, we decipher the eosinophil lineage cells from lineage-committed progenitors to mature eosinophils. Through further genetic analysis, we demonstrate the role of Cebp1 in balancing neutrophil and eosinophil lineages, and a Cebp1-Cebpß transcriptional axis that regulates the commitment and differentiation of the eosinophil lineage. Cross-species functional comparisons reveals that zebrafish Cebp1 is the functional orthologue of human C/EBPεP27 in suppressing eosinophilopoiesis. Our study characterizes eosinophil development in multiple dimensions including spatial-temporal patterns, expression profiles, and genetic regulators, providing for a better understanding of eosinophilopoiesis.

Pharmacokinetics and tissue distribution of vigabatrin enantiomers in rats.

Purpose: To investigate the pharmacokinetics and tissue distribution of VGB racemate and its single enantiomers, and explore the potential of clinic development for single enantiomer S-VGB. Methods: In the pharmacokinetics study, male Sprague-Dawley rats were gavaged with VGB racemate or its single enantiomers dosing 50, 100 or 200 mg/kg, and the blood samples were collected during 12 h at regular intervals. In the experiment of tissue distribution, VGB and its single enantiomers were administered intravenously dosing 200 mg/kg, and the tissues including heart, liver, spleen, lung and kidney, eyes, hippocampus, and prefrontal cortex were separated at different times. The concentrations of R-VGB and S-VGB in the plasma and tissues were measured using HPLC. Results: Both S-VGB and R-VGB could be detected in the plasma of rats administered with VGB racemate, reaching Cmax at approximately 0.5 h with t1/2 2-3 h. There was no significant pharmacokinetic difference between the two enantiomers when VGB racemate was given 200 mg/kg and 100 mg/kg. However, when given at the dose of 50 mg/kg, S-VGB presented a shorter t1/2 and a higher Cl/F than R-VGB, indicating a faster metabolism of S-VGB. Furthermore, when single enantiomer was administered respectively, S-VGB presented a slower metabolism than R-VGB, as indicated by a longer t1/2 and MRT but a lower Cmax. Moreover, compared with the VGB racemate, the single enantiomers S-VGB and R-VGB had shorter t1/2 and MRT, higher Cmax and AUC/D, and lower Vz/F and Cl/F, indicating the stronger oral absorption and faster metabolism of single enantiomer. In addition, regardless of VGB racemate administration or single enantiomer administration, S-VGB and R-VGB had similar characteristics in tissue distribution, and the content of S-VGB in hippocampus, prefrontal cortex and liver was much higher than that of R-VGB. Conclusions: Although there is no transformation between S-VGB and R-VGB in vivo, those two enantiomers display certain disparities in the pharmacokinetics and tissue distribution, and interact with each other. These findings might be a possible interpretation for the pharmacological and toxic effects of VGB and a potential direction for the development and optimization of the single enantiomer S-VGB.