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Human tripartite motif protein 5α (TRIM5α) is a well-characterized restriction factor for some RNA viruses, including HIV1-5; however, reports are limited for DNA viruses6,7. Here we demonstrate that TRIM5α also restricts orthopoxviruses and, via its SPRY domain, binds to the orthopoxvirus capsid protein L3 to diminish virus replication and activate innate immunity. In response, several orthopoxviruses, including vaccinia, rabbitpox, cowpox, monkeypox, camelpox and variola viruses, deploy countermeasures. First, the protein C6 binds to TRIM5 via the RING domain to induce its proteasome-dependent degradation. Second, cyclophilin A (CypA) is recruited via interaction with the capsid protein L3 to virus factories and virions to antagonize TRIM5α; this interaction is prevented by cyclosporine A (CsA) and the non-immunosuppressive derivatives alisporivir and NIM811. Both the proviral effect of CypA and the antiviral effect of CsA are dependent on TRIM5α. CsA, alisporivir and NIM811 have antiviral activity against orthopoxviruses, and because these drugs target a cellular protein, CypA, the emergence of viral drug resistance is difficult. These results warrant testing of CsA derivatives against orthopoxviruses, including monkeypox and variola.
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Factores de Restricción Antivirales , Ciclofilina A , Poxviridae , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Proteínas Virales , Humanos , Antivirales/metabolismo , Factores de Restricción Antivirales/metabolismo , Proteínas de la Cápside/metabolismo , Línea Celular , Ciclofilina A/metabolismo , Poxviridae/metabolismo , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Virales/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
PURPOSE: This is a retrospective comparative study. We aimed to analyze the results of karyotype and chromosomal microarray analysis (CMA) of amniotic fluid across different gestational weeks and evaluate the clinical value in prenatal diagnosis, particularly in the late pregnancies. METHODS: Samples from 580 pregnant women of 18-23 weeks of gestation (mid-gestation group) and 196 pregnant women of 24-32 weeks of gestation (late group) were performed both standard G-band karyotype analysis and CMA. RESULTS: Among the 580 pregnant women in the routine group, the most common indications were positive Down's screening (213/580, 36.7%), followed by advanced maternal age (196/580, 33.8%); while fetal structural anomalies on ultrasonography were the top reason for amniocentesis in the late group (56/196, 28.6%). In the routine group, the total detection rate was 12.1% (70/580), of which 4.1% (24/580) were identified by karyotype analysis and 11.2% (65/580) by CMA. The total detection rate was 15.3% (30/196) in the late group, of which 5.1% (10/196) were detected by karyotype analysis, and 14.3% (28/196) by CMA. CONCLUSION: Karyotype analysis and CMA are complementary in detecting chromosomal abnormalities. Amniotic cavity puncture in the karyotype analysis in 18-23 weeks of gestation and 24-32 weeks of gestation is safe and effective, more obvious effect on the latter.
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BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is a highly invasive and metastatic subtype of kidney malignancy and is correlated with metabolic reprogramming for adaptation to the tumor microenvironment comprising infiltrated immune cells and immunomodulatory molecules. The role of immune cells in the tumor microenvironment (TME) and their association with abnormal fatty acids metabolism in ccRCC remains poorly understood. METHOD: RNA-seq and clinical data of KIRC from The Cancer Genome Atlas (TCGA) and E-MTAB-1980 from the ArrayExpress dataset. The Nivolumab group and Everolimus group of the CheckMate 025 study, the Atezolizumab arm of IMmotion150 and the Atezolizumab plus Bevacizumab group of IMmotion151 cohort were obtained for subsequent analysis. After differential expression genes identification, the signature was constructed through univariate Cox proportional hazard regression and simultaneously the least absolute shrinkage and selection operator (Lasso) analysis and the predictive performance of our signature was assessed by using receiver operating characteristic (ROC), Kaplan-Meier (KM) survival analysis, nomogram, drug sensitivity analysis, immunotherapeutic effect analysis and enrichment analysis. Immunohistochemistry (IHC), qPCR and western blot were performed to measure related mRNA or protein expression. Biological features were evaluated by wound healing, cell migration and invasion assays and colony formation test and analyzed using coculture assay and flow cytometry. RESULTS: Twenty fatty acids metabolism-related mRNA signatures were constructed in TCGA and possessed a strong predictive performance demonstrated through time-dependent ROC and KM survival analysis. Notably, the high-risk group exhibited an impaired response to anti-PD-1/PD-L1 (Programmed death-1 receptor/Programmed death-1 receptor-ligand) therapy compared to the low-risk group. The overall levels of the immune score were higher in the high-risk group. Additionally, drug sensitivity analysis observed that the model could effectively predict efficacy and sensitivity to chemotherapy. Enrichment analysis revealed that the IL6-JAK-STAT3 signaling pathway was a major pathway. IL4I1 could promote ccRCC cells' malignant features through JAK1/STAT3 signaling pathway and M2-like macrophage polarization. CONCLUSION: The study elucidates that targeting fatty acids metabolism can affect the therapeutic effect of PD-1/PD-L1 in TME and related signal pathways. The model can effectively predict the response to several treatment options, underscoring its potential clinical utility.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Antígeno B7-H1 , Microambiente Tumoral , Ácidos Grasos , L-Aminoácido OxidasaRESUMEN
In this paper, we aim to show the process of simulating survival data when the distribution of the overall population and one subgroup (called "positive subgroup") as well as the proportion of the subgroup is known, while the distribution of the other subgroup (called "negative subgroup") is unknown. We propose a combination method which generates survival data of the positive subgroup and negative subgroup, respectively, and survival data of the overall population are the combination of the two subgroups. The parameters of the overall population and the positive subgroup need to satisfy certain constraints, otherwise the parameters may lead to contradictions. From simulation, we show that our proposed combination method can reflect the correlation between the test statistics of overall population and positive subgroup, which makes the simulated data more realistic and the results of simulation more reliable. Moreover, for a multiplicity control in trial design, the combination method can help to determine the α splitting strategy between primary endpoints, and is helpful in designs of clinical trials as shown in three applications.
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PURPOSE OF REVIEW: The article aims to investigate the complex relationship between cancer and cardiovascular disease (CVD), with a focus on the effects of cancer treatment on cardiac health. RECENT FINDINGS: Advances in cancer treatment have improved long-term survival rates, but CVD has emerged as a leading cause of morbidity and mortality in cancer patients. The interplay between cancer itself, treatment methods, homeostatic changes, and lifestyle modifications contributes to this comorbidity. Recent research in the field of cardio-oncology has revealed common genetic mutations, risk factors, and metabolic features associated with the co-occurrence of cancer and CVD. This article provides a comprehensive review of the latest research in cardio-oncology, including common genetic mutations, risk factors, and metabolic features, and explores the interactions between cancer treatment and CVD drugs, proposing novel approaches for the management of cancer and CVD.
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Antineoplásicos , Enfermedades Cardiovasculares , Neoplasias , Humanos , Cardiotoxicidad/etiología , Cardiotoxicidad/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/complicaciones , Oncología Médica , Enfermedades Cardiovasculares/etiología , Antineoplásicos/efectos adversosRESUMEN
Stanniocalcin 2 (STC2) is identified as a glycosylated peptide hormone and estrogen-responsive gene in cancer cells. STC2 participates in angiogenesis, cell development, cytoprotection, and calcium and phosphate regulation during the development of cancer. The role of STC2 in endometrial cancer (EC) remains unclear. The data from the bioinformatic and immunohistochemical analysis showed that STC2 was upregulated in the EC tissues. The EC cells were treated with 17ß-estradiol (E2), and 0.1 µmol/L E2 increased the expression of STC2 in the EC cells. E2 also increased cell viability, promoted proliferation, and inhibited apoptosis of EC. However, the knockdown of STC2 decreased cell viability, reduced proliferation, and promoted apoptosis of E2-stimulated EC. Moreover, silencing of STC2 attenuated E2-induced downregulation of phosphorylated-AMP-activated protein kinase (AMPK) in the EC cells. The loss of STC2 reduced E2-stimulated tumor growth EC in vivo. In conclusion, STC2 deficiency suppressed E2-stimulated proliferation and tumor growth of EC through the activation of AMPK signaling.
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Neoplasias Endometriales , Glicoproteínas , Péptidos y Proteínas de Señalización Intercelular , Hormonas Peptídicas , Femenino , Humanos , Proteínas Quinasas Activadas por AMP , Línea Celular Tumoral , Neoplasias Endometriales/metabolismo , Estrógenos/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Glicoproteínas/metabolismoRESUMEN
BACKGROUND: Thyroid function is widely considered a lipid metabolism regulator. However, studies on lipid metabolism in pregnant women with low free thyroxine (FT4) levels are limited and inconclusive. Furthermore, the association between maternal FT4 deficiency and adverse lipid metabolic parameters is unknown. Therefore, we aimed to investigate this association and the effects of levothyroxine (L-T4) treatment on these metabolic indicators. METHODS: This retrospective study included 164 patients with isolated hypothyroidism (IH) (FT4 levels below the 5th percentile with normal thyroid stimulating hormone levels according to the gestational-specific reference range) and 407 euthyroidism patients (control group who had regular antenatal examinations at Zhejiang Provincial People's Hospital, Hangzhou, China) between January 1, 2019, and December 31, 2020. Patients with IH were divided into levothyroxine (L-treatment group, n = 77) and dietary iodine supplement treatment groups (dietary treatment group, n=87) according to the hospital's treatment policy and clinical experience. The intervention lasted for at least 8 weeks. Metabolic indicators, including thyroid function and lipid parameters, were collected at least twice before and after the intervention. Other data collected included maternal age, history of abortion, prepregnancy BMI, and gestational weight gain (Fig. 1). RESULTS: Compared with the control group, Patients with IH had a higher degree of dyslipidemia, reflected in elevated total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (Apo B) levels. In IH patients, an inverse correlation was found between FT4 and TG levels, which remained after adjusting for prepregnancy BMI. The L-treatment group demonstrated a significantly slower rate of hypercholesterolemia progression during pregnancy than the dietary treatment group. In addition, there was a relationship between the therapeutic effect and the degree of disease, with the main factors being FT4, TSH and TG levels prior to starting treatment. CONCLUSIONS: Low FT4 levels were associated with elevated blood lipid levels. Serum FT4 and lipid levels in patients could be improved by medical intervention.
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Hipotiroidismo , Tiroxina , Humanos , Femenino , Embarazo , Tiroxina/uso terapéutico , Estudios Retrospectivos , Tirotropina/uso terapéutico , Hormonas Tiroideas , Hipotiroidismo/tratamiento farmacológico , Lípidos , LDL-ColesterolRESUMEN
In this study, low-cost and easily obtained biochar was chosen to prepare nickel-modified biochar materials (Ni/BC) through a one-step activation pyrolysis method. Characterization with X-ray diffraction, X-ray photoelectron spectroscopy and high-resolution transmission electron microscopy proved the existence of Ni0 and NiO nanocrystals in Ni/BC catalyst. The optimal Ni0.5/BC exhibited excellent peroxymonosulfate (PMS) and peroxydisulfate (PDS) activation efficiency toward bisphenol A (BPA) degradation. The Ni0.5/BC (0.03 g) reacted with 1.0 g L-1 PMS or PDS could completely remove 20 mg L-1 BPA in 10 min with the first-order kinetic constants (k1) of 0.322 min-1 (PMS) and 0.336 min-1 (PDS). More importantly, the composite has better structural and functional attributes for the BPA degradation with universal applicability at wide pH and temperature range, proving as a better degradation mediator with high adaptation for numerous organic pollutants. Catalytic activity decreased slightly even after 4 cycles. Based on the quenching experiment and electron paramagnetic resonance, it was found that SO4â¢-, â¢OH and 1O2 were the dominant active species in BPA degradation process. Therefore, this work not only supplies a promising catalyst for the removal of organic contaminants, but also is beneficial for the further development of alternative catalysts for sulfate radical based advanced oxidation processes.
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Carbón Orgánico , Níquel , Carbón Orgánico/química , Compuestos de BencidriloRESUMEN
The CTNNB1 gene encode the ß-catenin protein which is a core unit of the cadherin/catenin multiprotein complex. The loss-of-function mutation of the CTNNB1 gene recently has been confirmed as a cause of intellectual disability. Previous studies have found that patients with CTNNB1 gene mutation may have other clinical manifestation such as microcephaly, abnormal facial features, motor and language delays, and mild visual defects. Here, we reported a 27-year-old Chinese pregnant woman with a severe intellectual disability and serious visual defects who was detected with a novel splice mutation (c.734+1G>A) in CTNNB1 gene by whole-exome sequencing and confirmed by Sanger sequencing. Further investigation showed that the variant was inherited from her mother with similar phenotypes. This report not only helps to expand the mutant spectrum of the CTNNB1 gene but also prompts a new insight into genetic diagnosis in patients with both serious intellectual disability and visual defects.
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Discapacidad Intelectual/genética , Trastornos de la Visión/genética , beta Catenina/genética , Adulto , Femenino , Humanos , Linaje , Mutación Puntual , EmbarazoRESUMEN
Lung cancer is a leading cause of cancer-related death, and the most common type of lung cancer is non-small cell lung cancer, which accounts for approximately 85 % of lung cancer diagnoses. Recent studies have revealed that ubiquitination acts as a crucial part of the development and progression of lung cancer. The E1-E2-E3 three-enzyme cascade has a core function in ubiquitination, so targeted adjustments of E3 ligases could be used in lung cancer treatment. Hence, we elucidate research advances in lung cancer-related E3 ligases by briefly describing the structure and categorization of E3 ligases. Here, we provide a detailed review of the mechanisms by which lung cancer-related E3 ligases modify substrate proteins and regulate signaling pathways to facilitate or suppress cancer progression. We hope to show a new perspective on targeted precision therapy for lung cancer.
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Cardiovascular disease is a significant cause of death in humans. Various models are necessary for the study of cardiovascular diseases, but once cellular and animal models have some defects, such as insufficient fidelity. As a new technology, organoid has certain advantages and has been used in many applications in the study of cardiovascular diseases. This article aims to summarize the application of organoid platforms in cardiovascular diseases, including organoid construction schemes, modeling, and application of cardiovascular organoids. Advances in cardiovascular organoid research have provided many models for different cardiovascular diseases in a variety of areas, including myocardium, blood vessels, and valves. Physiological and pathological models of different diseases, drug research models, and methods for evaluating and promoting the maturation of different kinds of organ tissues are provided for various cardiovascular diseases, including cardiomyopathy, myocardial infarction, and atherosclerosis. This article provides a comprehensive overview of the latest research progress in cardiovascular organ tissues, including construction protocols for cardiovascular organoid tissues and their evaluation system, different types of disease models, and applications of cardiovascular organoid models in various studies. The problems and possible solutions in organoid development are summarized.
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Tumor necrosis factor alpha (TNFα) is involved in the occurrence of negative pregnancy outcomes. The study aimed to evaluate the safety and efficacy of the immunosuppressive TNFα inhibitors (TNFαi) in the treatment of patients with a history of recurrent reproductive failure in the context of COVID-19 pandemics. We reviewed 85 patients who received TNFαi (certolizumab pegol) during Mainland China's first wave of COVID-19 pandemic, from 21st Nov 2022-11â¯th Jan 2023. We also collected corresponding data from 130 pregnant patients who never used TNFαi for comparison. There were no significant differences in the history of previous pregnancy loss, miscarriage, embryo implantation failure, comorbidities and doses of COVID-19 vaccination. 82.2% and 87.7% pregnant patients contracted primary COVID-19 with symptoms in TNFαi group and no-TNFαi group. Duration of symptoms was significantly longer in TNFαi group and the incidences of cough and lethargy was significantly higher in TNFαi group. Both groups reported similar severity to same-aged close contacts, similar rates of other symptoms and hospitalization. No deaths were reported. In the in vitro fertilization (IVF) subgroup, we achieved a biochemical pregnancy loss rate of 17.4%, miscarriage rate of 21.7%, ongoing pregnancy rate and live birth rate of 34.2%. COVID-19 did not influence the live birth rate. We concluded that TNFαi administration in pregnancy was not associated with increased susceptivity to and severity of COVID-19. However, TNFαi users showed more prominent symptoms and longer recovery time. The pregnancy outcomes with TNFαi in such high-risk group for pregnancy loss was satisfactory.
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COVID-19 , Complicaciones Infecciosas del Embarazo , SARS-CoV-2 , Factor de Necrosis Tumoral alfa , Humanos , Embarazo , Femenino , COVID-19/epidemiología , COVID-19/inmunología , SARS-CoV-2/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/virología , Adulto , Resultado del Embarazo , China/epidemiología , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Inhibidores del Factor de Necrosis Tumoral/efectos adversos , Estudios RetrospectivosRESUMEN
Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function.
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Orthopoxvirus , Virus de la Viruela , Monkeypox virus/metabolismo , Virus de la Viruela/metabolismo , Orthopoxvirus/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Virus Vaccinia/fisiología , Histona Desacetilasas/metabolismoRESUMEN
Aqueous aluminum ion batteries (AAIBs) hold significant potential for grid-scale energy storage owing to their intrinsic safety, high theoretical capacity, and abundance of aluminum. However, the strong electrostatic interactions and delayed charge compensation between high-charge-density aluminum ions and the fixed lattice in conventional cathodes impede the development of high-performance AAIBs. To address this issue, this work introduces, for the first time, high-entropy Prussian blue analogs (HEPBAs) as cathodes in AAIBs with unique lattice tolerance and efficient multipath electron transfer. Benefiting from the intrinsic long-range disorder and robust lattice strain field, HEPBAs enable the manifestation of the lattice respiration effect and minimize lattice volume changes, thereby achieving one of the best long-term stabilities (91.2% capacity retention after 10 000 cycles at 5.0 A g-1) in AAIBs. Additionally, the interaction between the diverse metal atoms generates a broadened d-band and reduced degeneracy compared with conventional Prussian blue and its analogs (PBAs), which enhances the electron transfer efficiency with one of the best rate performance (79.2 mAh g-1 at 5.0 A g-1) in AAIBs. Furthermore, exceptional element selectivity in HEPBAs with unique cocktail effect can facile tune electrochemical behavior. Overall, the newly developed HEPBAs with a high-entropy effect exhibit promising solutions for advancing AAIBs and multivalent-ion batteries.
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OBJECTIVE: Left ventricular septal myotomy provides a favorable prognosis for children with hypertrophic obstructive cardiomyopathy (HOCM). However, some children still suffer from recurrent left ventricular outflow tract obstruction (LVOTO) after surgery. Poor prognosis exists for HOCM caused by PTPN11 mutation. Therefore, the aim of this study was to determine the clinical features of recurrent obstruction in children with HOCM caused by pathogenic mutations in the PTPN11 gene. METHODS: Fifty-six children who were diagnosed with HOCM underwent septal myectomies. Whole-exome sequencing of 49 pediatric cardiomyopathy-associated genes (including PTPN11) was performed. We performed hematoxylin-eosin, Masson, and wheat germ agglutinin staining of those tissues positive and negative for PTPN11. RESULTS: Whole-exome sequencing results showed 11 children with the PTPN11 mutation (19.6%). In long-term follow-up (median 37 months, maximum 9 years), children with the PTPN11 mutation had 6 (54.5%) recurrent LVOTOs compared with other groups (P = .015) but similar survival rates (P = .514). The mean postoperative time to recurrent obstruction was 22 ± 7 months. Children with PTPN11 mutation were 9-fold more likely to experience the risk associated with recurrent obstruction (95% confidence interval, 1.77-45.81, P < .001). Hematoxylin-eosin, Masson, and wheat germ agglutinin staining also revealed more cardiomyocyte hypertrophy in tissues with the PTPN11 mutation. CONCLUSIONS: Children with PTPN11 mutation-associated hypertrophic cardiomyopathy have a greater risk of recurrent LVOTO.
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OBJECTIVE: The modified Morrow operation for hypertrophic obstructive cardiomyopathy (HOCM) in children has a favorable outcome, but some children still have a poor prognosis after the procedure. In this study, we aimed to investigate the application of cardiac computed tomography (CCT) to construct a three-dimensional(3D) model of the left ventricle (LV) and analyze the association between hypertrophy in different parts of the LV and poor prognosis. METHODS: We retrospectively analyzed 57 children with HOCM from April 2015 to October 2022, among whom 16 underwent preoperative CCT examination. All children underwent the modified Morrow surgery in our center. We defined heart failure (HF), malignant ventricular arrhythmia, and recurrent left ventricular outflow tract obstruction (LVOTO) as adverse events. We performed a retrospective Cox analysis and conducted genetic testing. A 3D model of the LV was built through the standard 17-segment method and analyzing the high-risk factors. RESULTS: 17 (29.8%) had adverse events during follow-up. Multivariate Cox analysis revealed that genetic mutation (HR:5.634, 95%CI:1.663-19.086, P=0.005), Noonan syndrome (HR:3.770, 95%CI:1.245-11.419, P=0.019), preoperational systolic anterior motion (SAM)(HR:4.596, 95%CI:1.532-13.792, P=0.007)and mid-ventricular obstruction (HR:4.763, 95%CI:1.538-14.754, P=0.007) were high-risk factors, suggesting that the degree of hypertrophy in the left ventricle is associated with poor prognosis. By analyzing the CCT with 3D model, children with poor prognosis have more hypertrophy in basal-inferior (P=0.014), mid-inferoseptal(P=0.044), mid-inferior(P=0.017). It suggests that a more hypertrophied posterior left ventricular wall portends a worse prognosis. CONCLUSION: Even after modified Morrow surgery, the prognostic impact of genetic mutation remains significant. Moreover, the degree of hypertrophy of the posterior wall in the LV was also related to the postoperative prognosis through CCT combined with 3D technology. It provides surgeons guiding to evaluate the overall prognosis and the treatment plan before surgery.
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BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although hypothermia therapy offers some neuroprotection, the recovery of neurological function is limited. Therefore, new synergistic therapies are necessary to improve the prognosis. Mesenchymal stem cell-based therapy is emerging as a promising treatment option for HIE. In this study, we studied the therapeutic efficacy of human placenta-derived mesenchymal stem cells (PD-MSCs) in the HIE rat model and analyzed the underlying therapeutic mechanisms. METHODS: Rats were divided into 6 groups (n = 9 for each) as follows: control, HIE model, HIE + normal saline, and HIE + PD-MSC transplantation at days 7, 14 and 28 postpartum. Following PD-MSC transplantation, neurological behavior was evaluated using rotarod tests, traction tests, and the Morris water maze test. The degree of brain tissue damage was assessed by histological examination and Nissl staining. Expression levels of apoptosis-related proteins and inflammatory factors were quantified by Western blotting and enzyme-linked immunosorbent assays. Immunofluorescence was used to investigate the ability of PD-MSCs to repair the morphology and function of hippocampal neurons with hypoxic-ischaemic (HI) injury. RESULTS: PD-MSC transplantation enhanced motor coordination and muscle strength in HIE rats. This treatment also improved spatial memory ability by repairing pathological damage and preventing the loss of neurons in the cerebral cortex. The most effective treatment was observed in the HIE + PD-MSC transplantation at day 7 group. Expression levels of microtubule-associated protein-2 (MAP-2), B-cell lymphoma-2 (BCL-2), interleukin (IL)-10, and transforming growth factor (TGF -ß1) were significantly higher in the HIE + PD-MSC treatment groups compared to the HIE group, whereas the levels of BCL-2-associated X protein (BAX), BCL-2-associated agonist of cell death (BAD), IL-1ß and tumour necrosis factor α (TNF-α) were significantly lower. CONCLUSIONS: We demonstrated that intravenous injection of PD-MSC at 7, 14 and 28 days after intrauterine HI damage in a rat model could improve learning, memory, and motor function, possibly by inhibiting apoptosis and inflammatory damage. These findings indicate that autologous PD-MSC therapy could have potential application for the treatment of HIE.
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Apoptosis , Hipoxia-Isquemia Encefálica , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Placenta , Ratas Sprague-Dawley , Animales , Femenino , Trasplante de Células Madre Mesenquimatosas/métodos , Embarazo , Hipoxia-Isquemia Encefálica/terapia , Humanos , Placenta/citología , Células Madre Mesenquimatosas/citología , Ratas , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Inflamación/terapia , Neuronas/metabolismo , MasculinoRESUMEN
The Orthopoxvirus (OPXV) genus of the Poxviridae includes human pathogens variola virus (VARV), monkeypox virus (MPXV), vaccinia virus (VACV), and a number of zoonotic viruses. A number of Bcl-2-like proteins of VACV are involved in escaping the host innate immunity. However, little work has been devoted to the evolution and function of their orthologues in other OPXVs. Here, we found that MPXV protein P2, encoded by the P2L gene, and P2 orthologues from other OPXVs, such as VACV protein N2, localize to the nucleus and antagonize interferon (IFN) production. Exceptions to this were the truncated P2 orthologues in camelpox virus (CMLV) and taterapox virus (TATV) that lacked the nuclear localization signal (NLS). Mechanistically, the NLS of MPXV P2 interacted with karyopherin α-2 (KPNA2) to facilitate P2 nuclear translocation, and competitively inhibited KPNA2-mediated IRF3 nuclear translocation and downstream IFN production. Deletion of the NLS in P2 or orthologues significantly enhanced IRF3 nuclear translocation and innate immune responses, thereby reducing viral replication. Moreover, deletion of NLS from N2 in VACV attenuated viral replication and virulence in mice. These data demonstrate that the NLS-mediated translocation of P2 is critical for P2-induced inhibition of innate immunity. Our findings contribute to an in-depth understanding of the mechanisms of OPXV P2 orthologue in innate immune evasion.
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Inmunidad Innata , Factor 3 Regulador del Interferón , Monkeypox virus , Señales de Localización Nuclear , Proteínas Virales , Animales , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Ratones , Humanos , Proteínas Virales/genética , Proteínas Virales/metabolismo , Proteínas Virales/inmunología , Señales de Localización Nuclear/genética , Monkeypox virus/genética , Monkeypox virus/inmunología , Células HEK293 , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Evasión Inmune , Núcleo Celular/metabolismo , Interferones/genética , Interferones/inmunología , Interferones/metabolismo , Infecciones por Poxviridae/inmunología , Infecciones por Poxviridae/virología , Infecciones por Poxviridae/veterinaria , Ratones Endogámicos C57BLRESUMEN
In this paper, a 1:21 model experiment was conducted to discuss the dust diffusion efficiency and liner trolley obstruction effect inside the tunnel at - 9% to 9%, the effect of different initial dust concentrations on dust diffusion and liner trolley obstruction effect at 6% slope, and the effect of different return air velocity on dust diffusion at 6% slope, the reliability of the results is verified by computational fluid dynamics simulations. The results show that as the slope of the tunnel changes from 0 to - 9%, the average dust diffusion time decreases by 3.7% at the working face and the dust concentration difference between the front and rear of the trolley is improved by 2.7%. When the slope of the tunnel changes from 0 to - 9%, the average dust diffusion time increases by 7.2% at the working face and the dust concentration difference between the front and rear of the trolley is improved by 17.9%. With each 100 mg/m3 increase in the initial dust concentration, the dust diffusion time at the working face and the tunnel exit increases by 9.15% and 8.17% on average, and the lining trolley obstruction time increases by 23.33 s on average. The dust diffusion times take an average reduction rate of 15.7%, with the increase of return air velocity. The recommended return air velocity is greater than 1 m/s for large slope tunnels. When the slope changes from 0° to 9°, the hindrance rate of slope on dust diffusion is 2.88462%, 8.65385%, and 16.34615% respectively. Dust diffusion efficiency will be reduced as the tunnel slope changes from 0° to 9°, The growth rate of slope on dust diffusion is - 0.96154%, - 2.88462%, and - 6.73077% respectively.
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Most existing studies characterizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of angiotensin-converting enzyme (ACE)-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, the rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations.