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BACKGROUND: The complex relationship between atrial fibrillation (AF) and type 2 diabetes mellitus (T2DM) suggests a potential role for epicardial adipose tissue (EAT) that requires further investigation. This study employs bioinformatics and experimental approaches to clarify EAT's role in linking T2DM and AF, aiming to unravel the biological mechanisms involved. METHOD: Bioinformatics analysis initially identified common differentially expressed genes (DEGs) in EAT from T2DM and AF datasets. Pathway enrichment and network analyses were then performed to determine the biological significance and network connections of these DEGs. Hub genes were identified through six CytoHubba algorithms and subsequently validated biologically, with further in-depth analyses confirming their roles and interactions. Experimentally, db/db mice were utilized to establish a T2DM model. AF induction was executed via programmed transesophageal electrical stimulation and burst pacing, focusing on comparing the incidence and duration of AF. Frozen sections and Hematoxylin and Eosin (H&E) staining illuminated the structures of the heart and EAT. Moreover, quantitative PCR (qPCR) measured the expression of hub genes. RESULTS: The study identified 106 DEGs in EAT from T2DM and AF datasets, underscoring significant pathways in energy metabolism and immune regulation. Three hub genes, CEBPZ, PAK1IP1, and BCCIP, emerged as pivotal in this context. In db/db mice, a marked predisposition towards AF induction and extended duration was observed, with HE staining verifying the presence of EAT. Additionally, qPCR validated significant changes in hub genes expression in db/db mice EAT. In-depth analysis identified 299 miRNAs and 33 TFs as potential regulators, notably GRHL1 and MYC. GeneMANIA analysis highlighted the hub genes' critical roles in stress responses and leukocyte differentiation, while immune profile correlations highlighted their impact on mast cells and neutrophils, emphasizing the genes' significant influence on immune regulation within the context of T2DM and AF. CONCLUSION: This investigation reveals the molecular links between T2DM and AF with a focus on EAT. Targeting these pathways, especially EAT-related ones, may enable personalized treatments and improved outcomes.
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Fibrilación Atrial , Diabetes Mellitus Tipo 2 , Tejido Adiposo Epicárdico , Perfilación de la Expresión Génica , Pericardio , Animales , Humanos , Masculino , Ratones , Fibrilación Atrial/genética , Biología Computacional/métodos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Tejido Adiposo Epicárdico/metabolismo , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Ratones Endogámicos C57BL , Pericardio/metabolismo , Pericardio/patología , TranscriptomaRESUMEN
Obiective Alzheimer’s disease (AD) is a degenerative disease of the central nervous system (CNS) caused by a variety of risk factors. There are various pathological changes, but apoptosis of the neurological meridian cells is one of the most important pathological bases. Hyperlipidemia is a high-risk factor for the development of AD, which can lead to increased levels of oxidized low-density lipoprotein (ox-LDL) in brain tissues. PCSK9 is a protease closely related to lipid metabolism, but studies have shown that it may be related to the development of AD. LRP1 is abundantly expressed in neuronal cells, and it is an important transporter for the clearance of Aβ. There is now a large amount of literature confirming that PCSK9 can induce the degradation of LRP1. PI3K/AKT is an important signaling pathway in vivo, which plays an important role in apoptosis, and there is now a large amount of literature confirming that LRP1 activates the PI3K/AKT pathway, which has an anti-apoptotic effect. So can PCSK9 affect the PI3K/AKT pathway through LRP1 and thus regulate neuronal apoptosis? This deserves further investigation.The aim of this study was to explore the role of PCSK9 in mediating ox-LDL pro-apoptotic neuronal cell death and its mechanism, and then further elaborate the mechanism of hyperlipidemia leading to neurodegenerative diseases such as AD. MethodsFirstly, PC12 cells were treated with different concentrations of ox-LDL (0, 25, 50, 75 and 100 mg/L) for 24 h. Oil red O staining was used to detect lipid accumulation in PC12 cells, Hoechst33258 staining and flow cytometry to detect apoptosis in PC12 cells, ELISA to detect the content of Aβ secreted by PC12, Western blot to detect expression of SREBP2, PCSK9 and LRP1. Then PC12 cells were treated with 75 mg/L ox-LDL for different times (0, 6, 12, 24, 48 h), and Western blot were performed to detect the expression of SREBP2, PCSK9 and LRP1. Finally, after transfecting 100 nmol/L PCSK9 siRNA into PC12 cells for 48 h, PC12 cells were treated with 75 mg/L ox-LDL for 24 h, Hoechst33258 staining and flow cytometry to detect apoptosis rate of PC12 cells, and Western blot to detect PCSK9, LRP1, PI3K, AKT, P-PI3K , P-AKT, NF-κB, Bcl-2, Bax, Caspase-9 and Caspase-3 expression, and ELISA detected Aβ content secreted by PC12 cells. Resultsox-LDL increased lipid accumulation and promoted apoptosis and Aβ secretion in PC12 cells, as well as increasing the expression of SREBP2 and PCSK9 and decreasing the expression of LRP1 in PC12 cells. pCsk9 siRNA could be inhibited through the PI3K/AKT pathway and the NF-κB-Bcl-2/Bax-Caspase-9/3 pathway to inhibit ox-LDL-induced apoptosis in PC12 cells while increasing Aβ secretion in PC12 cells. Conclusionox-LDL plays a bidirectional regulatory role in ox-LDL-induced apoptosis of PC12 cells by inducing an increase in PCSK9 expression and a decrease in LRP1 expression in PC12 cells, which in turn affects different signaling pathways downstream.
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Demoralization syndrome is prevalence among cancer patients in China. However, little research has examined how demoralization syndrome is associated with quality of life (QOL). The aims of this study were to investigate the relationship between mindfulness state, demoralization syndrome and QOL of thyroid cancer patients, and explore the mediating effect of mindfulness on demoralization syndrome and QOL. A correlational cross-sectional study was performed using an online questionnaire. The study was conducted from July to October 2022 among 310 thyroid cancer patients. General information questionnaire, the Demoralization Scale, Five Facet Mindfulness Questionnaire, short form health survey questionnaire were used for investigation. Calculations were performed using SPSS Statistics, version 25. Descriptive statistics, correlation, and process plug-in mediation effect analyses were used to analyze the data. A total of 310 valid questionnaires were finally recovered. The Five Facet Mindfulness Questionnaire score of 310 patients was (120.80 ± 16.57), Demoralization Scale score was (12.49 ± 4.73), short form health survey questionnaire score was (146.15 ± 28.46). Mindfulness played a partial mediating role between demoralization syndrome and QOL of thyroid cancer patients, and the mediating effect accounted for 68.57% of the total effect. Demoralization syndrome can influence QOL through mindfulness state. Measures are needed to increase the QOL of thyroid cancer patients by developing mindfulness programs to decrease their demoralization syndrome.
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Desmoralización , Atención Plena , Neoplasias , Neoplasias de la Tiroides , Humanos , Calidad de Vida , Estudios Transversales , Neoplasias/epidemiología , Encuestas y CuestionariosRESUMEN
Spatial transcriptomics, which combine gene expression data with spatial information, has quickly expanded in recent years. With application of this method in liver research, our knowledge about liver development, regeneration, and diseases have been greatly improved. While this field is moving forward, a variety of problems still need to be addressed, including sensitivity, limited capacity to obtain exact single-cell information, data processing methods, as well as others. Methods like single-cell RNA sequencing (scRNA-seq) are usually used together with spatial transcriptome sequencing (ST-seq) to clarify cell-specific gene expression. In this review, we explore how advances of scRNA-seq and ST-seq, especially ST-seq, will pave the way to new opportunities to investigate fundamental questions in liver research. Finally, we will discuss the strengths, limitations, and future perspectives of ST-seq in liver research.
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Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both in vitro and in vivo biophysical and biological assays. X-ray crystallographic analysis of the lead antibody C59 in complex with the human Chi3l1 protein revealed that the kappa light contributes to majority of the antibody-antigen interaction; and that C59 binds to the 4α-5ß loop and 4α-helix of Chi3l1, which is a functional epitope and hotspot for the development of Chi3l1 blocking antibodies. We humanized the C59 antibody by complementarity-determining region grafting and kappa chain framework region reverse mutations. The humanized C59 antibody exhibited similar efficacy as the parental rabbit antibody C59 in attenuating AILI in vivo. Our findings validate Chi3l1 as a potential drug target for AILI and provide proof of concept of developing Chi3l1 blocking antibody as a therapy for the treatment of AILI.
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The paper explores the evolution of "bone-approaching" acupuncture, its effect target and mechanism. The concrete operation procedure of "bone-approaching" method is recorded originally in Huangdi Neijing (Inner Canon of Yellow Emperor) as short needling and Shu needling (referring to the category of the five needling technique). The periosteum is the most effective stimulation target of "bone-approaching" acupuncture for analgesia, regaining consciousness and regulating spirit. The "bone-approaching" acupuncture is not only prominently effective on bone bi syndrome, but also has the unique effect on painful, encephalogenic and emotional diseases. The paper summarizes and improves "bone-approaching" acupuncture, i.e. "touching bone surface" with needle tip by slow insertion, "touching bone surface" without pain by swift insertion and "touching bone" with needle body by oblique insertion. It contributes to the inheritance, development and supplementation to the bone needling techniques in Huangdi Neijing and is significant for broadening the clinical application range of acupuncture.
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Humanos , Terapia por Acupuntura , Periostio , Analgesia , Manejo del Dolor , Estado de Conciencia , DolorRESUMEN
The prevalence of type 2 diabetes is associated with inflammatory bowels diseases, nonalcoholic steatohepatitis and even a spectrum of cancer such as colon cancer and liver cancer, resulting in a substantial healthcare burden on our society. Autophagy is a key regulator in metabolic homeostasis such as lipid metabolism, energy management and the balance of cellular mineral substances. Mitophagy is selective autophagy for clearing the damaged mitochondria and dysfunctional mitochondria. A myriad of evidence has demonstrated a major role of mitophagy in the regulation of type 2 diabetes and metabolic homeostasis. It is well established that defective mitophagy has been linked to the development of insulin resistance. Moreover, insulin resistance is further progressed to various diseases such as nephropathy, retinopathy and cardiovascular diseases. Concordantly, restoration of mitophagy will be a reliable and therapeutic target for type 2 diabetes. Recently, various phytochemicals have been proved to prevent dysfunctions of ß-cells by mitophagy inductions during diabetes developments. In agreement with the above phenomenon, mitophagy inducers should be warranted as potential and novel therapeutic agents for treating diabetes. This review focuses on the role of mitophagy in type 2 diabetes relevant diseases and the pharmacological basis and therapeutic potential of autophagy regulators in type 2 diabetes.
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Diabetes Mellitus Tipo 2 , Mitofagia , Autofagia/fisiología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Mitocondrias/metabolismo , Dinámicas Mitocondriales , Mitofagia/fisiologíaRESUMEN
Aim To evaluate the protective effect of Dexrazoxane(Dex)on onco-Cardiology caused by chemotherapeutic drugs other than anthracycline antitumor drugs using zebrafish embryos, including:cisplatin, paclitaxel, vincristine sulfate, 5-fluorouracil and cyclophosphamide. Methods Zebrafish embryos at 24 hpf(hours post-fertilization)were exposed to different concentrations of drugs. The survival rate and the overall animal morphology at 48 hpf, 72 hpf and 96 hpf were observed with a microscope. Heart rate, ventricular contraction fraction, ventricular volume, and cardiac output were measured and calculated by video recordings made with a VCD system. The protective effect of Dex was evaluated using the established model of onco-Cardiology induced by anti-tumor drugs other than anthracyclines. Results In terms of acute toxicity, cisplatin, vincristine sulfate, 5-fluorouracil and cyclophosphamide all significantly reduced the survival rate of zebrafish embryos. The LC50 value was 437.655, 25.538, 65.606 and 19.021 mmol·L-1, respectively. In addition to paclitaxel, the other four anti-tumor drugs all showed significant changes in overall animal morphology and cardiac function indicators. In the study of the protective effect of Dex on four kinds of tumor heart diseases except anthracyclines, only cisplatin had a significant protective effect, which could improve the cardiotoxicity caused by cisplatin. The optimal concentration of Dex was 80 μmol·L-1. Conclusions Zebrafish models of drug toxicity caused by cisplatin, vincristine sulfate, 5-fluorouracil, and cyclophosphamide is established, which proves that Dex only has a protective effect on the toxicity caused by cisplatin.
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Objective: To analyze the influencing factors of iron metabolism assessment in patients with myelodysplastic syndrome. Methods: MRI and/or DECT were used to detect liver and cardiac iron content in 181 patients with MDS, among whom, 41 received regular iron chelation therapy during two examinations. The adjusted ferritin (ASF) , erythropoietin (EPO) , cardiac function, liver transaminase, hepatitis antibody, and peripheral blood T cell polarization were detected and the results of myelofibrosis, splenomegaly, and cyclosporine were collected and comparative analyzed in patients. Results: We observed a positive correlation between liver iron concentration and ASF both in the MRI group and DECT groups (r=0.512 and 0.606, respectively, P<0.001) , only a weak correlation between the heart iron concentration and ASF in the MRI group (r=0.303, P<0.001) , and no significant correlation between cardiac iron concentration and ASF in the DECT group (r=0.231, P=0.053) . Moreover, transfusion dependence in liver and cardiac [MRI group was significantly associated with the concentration of iron in: LIC: (28.370±10.706) mg/g vs (7.593±3.508) mg/g, t=24.30, P<0.001; MIC: 1.81 vs 0.95, z=2.625, P<0.05; DECT group: liver VIC: (4.269±1.258) g/L vs (1.078±0.383) g/L, t=23.14, P<0.001: cardiac VIC: 1.69 vs 0.68, z=3.142, P<0.05]. The concentration of EPO in the severe iron overload group was significantly higher than that in the mild to moderate iron overload group and normal group (P<0.001) . Compared to the low-risk MDS group, the liver iron concentration in patients with MDS with cyclic sideroblasts (MDS-RS) was significantly elevated [DECT group: 3.80 (1.97, 5.51) g/L vs 1.66 (0.67, 2.94) g/L, P=0.004; MRI group: 13.7 (8.1,29.1) mg/g vs 11.6 (7.1,21.1) mg/g, P=0.032]. Factors including age, bone marrow fibrosis, splenomegaly, T cell polarization, use of cyclosporine A, liver aminotransferase, and hepatitis antibody positive had no obvious effect on iron metabolism. Conclusion: There was a positive correlation between liver iron concentration and ASF in patients with MDS, whereas there was no significant correlation between cardiac iron concentration and ASF. Iron metabolism was affected by transfusion dependence, EPO concentration, and RS.
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Humanos , Ferritinas , Hierro , Sobrecarga de Hierro , Hígado/metabolismo , Síndromes Mielodisplásicos/terapia , Mielofibrosis Primaria , Estudios Retrospectivos , EsplenomegaliaRESUMEN
Particulate matter (PM) can damage respiratory system, cardiovascular system, nervous system and immune system, but there are few researches on reproductive damage of particulate matter. The objectives of this study were to investigate the effect of short-term particulate matter 2.5 (PM
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Acute kidney injury (AKI) is a known complication of COVID-19 and is associated with an increased risk of in-hospital mortality. Unbiased proteomics using biological specimens can lead to improved risk stratification and discover pathophysiological mechanisms. Using measurements of [~]4000 plasma proteins in two cohorts of patients hospitalized with COVID-19, we discovered and validated markers of COVID-associated AKI (stage 2 or 3) and long-term kidney dysfunction. In the discovery cohort (N= 437), we identified 413 higher plasma abundances of protein targets and 40 lower plasma abundances of protein targets associated with COVID-AKI (adjusted p <0.05). Of these, 62 proteins were validated in an external cohort (p <0.05, N =261). We demonstrate that COVID-AKI is associated with increased markers of tubular injury (NGAL) and myocardial injury. Using estimated glomerular filtration (eGFR) measurements taken after discharge, we also find that 25 of the 62 AKI-associated proteins are significantly associated with decreased post-discharge eGFR (adjusted p <0.05). Proteins most strongly associated with decreased post-discharge eGFR included desmocollin-2, trefoil factor 3, transmembrane emp24 domain-containing protein 10, and cystatin-C indicating tubular dysfunction and injury. Using clinical and proteomic data, our results suggest that while both acute and long-term COVID-associated kidney dysfunction are associated with markers of tubular dysfunction, AKI is driven by a largely multifactorial process involving hemodynamic instability and myocardial damage.
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Objective: To compare epicardial electrograms between the left atrium (LA) and pulmonary veins (PVs) dynamically at development of persistent atrial fibrillation(AF) in goats PVs. Methods: Ten female goats were instrumented with electrodes at the LA and left side PV. Sustained AF (ï¼24 h) was induced in the goat by rapid intermittent left atrial pacing for(9.5±2.3)days at a pacing interval of 20 ms for 1 s with a maximum output of 6.0 V, followed by a 2-s period without pacing. Characteristics of PVs and LA epicardial electrograms were analyzed in the development of AF. Results: With prolonged stimulation, the duration of AF was prolonged, complex fractionated atrial electrograms(CFAEs) in LA and was increased gradually, PVs had more CFAEs than LA all the time. When induced AF lasted for more than 24 h, CFAEs in PVs became sustained approximately (2.7%±3.6% vs 92.6%±6.4%, at onset of AF vs AF lasted for more than 24 h, Pï¼0.05), and the ratio of CFAEs in PVs was more than that in LA (92.6%±6.4% vs 72.8%±5.3%, Pï¼0.05). Conclusion: The epicardial CFAEs are in specific area, which increase along with electrical remodeling. The epicardial CFAEs may play an important role in the maintenance of AF in this model.
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Fibrilación Atrial , Venas Pulmonares , Animales , Técnicas Electrofisiológicas Cardíacas , Femenino , Cabras , Atrios CardíacosRESUMEN
Background: Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. Methods: Mice were fasted overnight before intraperitoneally (i.p.) injected with APAP at a dose of 210 mg/kg for male mice and 325 mg/kg for female mice. Platelets adherent to Kupffer cells were determined in both mice and patients overdosed with APAP. The impact of α-chitinase 3-like-1 (α-Chi3l1) on alleviation of AILI was determined in a therapeutic setting, and liver injury was analyzed. Results: The present study unveiled a critical role of Chi3l1 in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chil1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of Cd44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chil1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chil1-/- mice, but not in Cd44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Conclusions: We uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI. Funding: ZS received funding from NSFC (32071129). FWL received funding from NIH (GM123261). ALFSG received funding from NIDDK (DK 058369). ZA received funding from CPRIT (RP150551 and RP190561) and the Welch Foundation (AU-0042-20030616). CJ received funding from NIH (DK122708, DK109574, DK121330, and DK122796) and support from a University of Texas System Translational STARs award. Portions of this work were supported with resources and the use of facilities of the Michael E. DeBakey VA Medical Center and funding from Department of Veterans Affairs I01 BX002551 (Equipment, Personnel, Supplies). The contents do not represent the views of the US Department of Veterans Affairs or the US Government.
Acetaminophen, also called paracetamol outside the United States, is a commonly used painkiller, with over 50 million people in the United States taking the drug weekly. While paracetamol is safe at standard doses, overdose can cause acute liver failure, which leads to 30,000 patients being admitted to emergency care in the United States each year. There is only one approved antidote to overdoses, which becomes significantly less effective if its application is delayed by more than a few hours. This has incentivized research into identify new drug targets that could lead to additional treatment options. Acetaminophen overdose triggers blood clotting and inflammation, contributing to liver injury. It also causes a decrease in cells called platelets circulating in the blood, which has been observed in both mice and humans. In mice, this occurs because platelets accumulate in the liver. Removing these excess cells appears to reduce the severity of the damage caused by acetaminophen, but it remains unclear how the drug triggers their accumulation in the liver. In 2018, researchers showed that a protein called Chi3l1 plays an important role in another form of liver damage. Shan et al. including many of the researchers involved in the 2018 study have examined whether the protein also contributes to acetaminophen damage in the liver. Shan et al. showed that mice lacking the gene that codes for Chi3l1 developed less severe liver injury and had fewer platelets in the liver following acetaminophen overdose. They also found that human patients with acute liver failure due to acetaminophen had high levels of Chi3l1 and significant accumulation of platelets in the liver. To test whether damage could be prevented, Shan et al. used antibodies to neutralize Chi3l1 in mice after giving them an acetaminophen overdose. This reduced platelet accumulation in the liver and the associated damage. These findings suggest that targeting Chi3l1 may be an effective strategy to prevent liver damage caused by acetaminophen overdose. Further research could help develop new treatments for acetaminophen-induced liver injury and perhaps other liver conditions.
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Acetaminofén/efectos adversos , Plaquetas , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Proteína 1 Similar a Quitinasa-3 , Hígado , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/patología , Proteína 1 Similar a Quitinasa-3/metabolismo , Proteína 1 Similar a Quitinasa-3/farmacología , Femenino , Hígado/citología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Assays to measure SARS-CoV-2-specific neutralizing antibodies are important to monitor seroprevalence, to study asymptomatic infections and to reveal (intermediate) hosts. A recently developed assay, the surrogate virus-neutralization test (sVNT) is a quick and commercially available alternative to the "gold standard" virus neutralization assay using authentic virus, and does not require processing at BSL-3 level. The assay relies on the inhibition of binding of the receptor binding domain (RBD) on the spike (S) protein to human angiotensin-converting enzyme 2 (hACE2) by antibodies present in sera. As the sVNT does not require species- or isotype-specific conjugates, it can be similarly used for antibody detection in human and animal sera. In this study, we used 298 sera from PCR-confirmed COVID-19 patients and 151 sera from patients confirmed with other coronavirus or other (respiratory) infections, to evaluate the performance of the sVNT. To analyze the use of the assay in a One Health setting, we studied the presence of RBD-binding antibodies in 154 sera from nine animal species (cynomolgus and rhesus macaques, ferrets, rabbits, hamsters, cats, cattle, mink and dromedary camels). The sVNT showed a moderate to high sensitivity and a high specificity using sera from confirmed COVID-19 patients (91.3% and 100%, respectively) and animal sera (93.9% and 100%), however it lacked sensitivity to detect low titers. Significant correlations were found between the sVNT outcomes and PRNT50 and the Wantai total Ig and IgM ELISAs. While species-specific validation will be essential, our results show that the sVNT holds promise in detecting RBD-binding antibodies in multiple species.
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[This corrects the article DOI: 10.1371/journal.ppat.1006773.].
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This research aimed at the key issue that chemical drugs and Chinese medicine hydrophilic small molecule anti-tumor drugs were difficult to break through the dense interstitial permeability barrier of pancreatic cancer to achieve the key problem of drug efficacy in the deep part of tumor tissue. To solve this problem, the lipophilic molecule squalene (SQ) and the hydrophilic anti-tumor drug chidamide (CHI) were linked by a trypsin responsive bond to form a prodrug (SQ-CHI) and a folic acid modified prodrug self-assembled nanoparticles (FA-SQ-CHI NPs) were further developed. The feature of prodrug molecules and nanoparticles were characterized. The in vitro release characteristics and cytotoxicity of blank vector were investigated. The efficacy and permeability of the prodrug nanoparticles in the PSN-1 monolayer cell and PSN-1/HSPC co-cultured tumor spheroids model was evaluated. The results showed that SQ-CHI prodrug molecules and FA-SQ-CHI NPs were successfully developed. The nanoparticles were regular spherical, well-dispersed, with a particle size of (173.3 ± 1.5) nm, a drug load of (59.02 ± 0.8) % and showed trypsin responsive release ability. The prodrug nanoparticles can significantly enhance the penetration and anti-proliferation effects of CHI in the PSN-1/HSPC tumor spheroids. In conclusion, the construction of folic acid-modified SQ-CHI prodrug self-assembled nanoparticles can significantly enhance the penetration of CHI in the pancreatic cancer microenvironment in vitro. This research would provide a new idea for the construction of targeted drug delivery system for chemical drugs and Chinese medicine hydrophilic small molecule drugs in the application of anti-pancreatic cancer.
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Psoriasis is an autoimmune disease presented in the context of inflammation, and it mainly results from proliferation and differentiation defects of keratinocytes and abnormal immune response. However, some cellular and molecular mechanisms remain unclear. Although a variety of drugs and physiotherapies are applicable to this disease, they can only be utilized for a short-term period considering their transient effect, high cost, and serious adverse reactions. It is difficult to achieve satisfactory long-term results in the treatment of psoriasis. With the development of network pharmacology and molecular biology and the modernization of traditional Chinese medicine (TCM), the multi-component and multi-target characteristics of TCM have become prominent, promoting the in-depth research on TCM by doctors and scholars. Nevertheless, there is no detailed summarization on the mechanisms of TCM in interfering with T helper 17 (Th17)/regulatory T (Treg) cell balance to prevent and treat psoriasis. After reviewing the recent literature data, this paper has found that Chinese herbal monomers, active ingredients, and compounds obviously regulate the Th17/Treg axis in psoriasis. Th17 cells have a pro-inflammatory effect, while Treg cells are responsible for maintaining peripheral tolerance. They function in a mutually exclusive manner, and maintaining the Th17/Treg balance helps to effectively reduce inflammatory reaction and regulate immune homeostasis. As revealed by a series of clinical and experimental studies carried out based on the Th17/Treg axis in psoriasis, reducing the percentage of Th17 cells,increasing the percentage of Treg cells,and regulating the levels of related cytokines and transcription factors are conducive to alleviating inflammation and regaining immune homeostasis,which has provided new ideas for further elucidating the pathological mechanism of psoriasis and alternative plans for developing new treatments against psoriasis.
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OBJECTIVE@#To detect the relationship between leukocytes derived microparticle (CD45@*METHODS@#The expression of CD45@*RESULTS@#The percentages of CD45@*CONCLUSION@#High level of CD45
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Humanos , Citometría de Flujo , Leucemia Mieloide Aguda , Leucocitos , Neoplasia Residual , PronósticoRESUMEN
OBJECTIVE@#To investigate the value of CD44@*METHODS@#Flow cytometry was used to detected the proportion of CD44@*RESULTS@#The percentage of CD44@*CONCLUSION@#HCD44
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Humanos , Citometría de Flujo , Receptores de Hialuranos , Quimioterapia de Inducción , Leucemia Mieloide Aguda/tratamiento farmacológico , Neoplasia Residual , Pronóstico , BazoRESUMEN
We explored rates of premature births and neonatal intensive care unit (NICU) admissions at the Mount Sinai Hospital after the implementation of COVID-19 lockdown measures (March 16, 2020) and phase one reopening (June 8, 2020), comparing them to those of the same time periods from 2012-2019. Mount Sinai Hospital is in New York City (NYC), an early epicenter of COVID-19 in the United States, which was heavily impacted by the pandemic during the study period. Among 43,963 singleton births, we observed no difference in either outcome after the implementation of lockdown measures when compared to the same trends in prior years (p=0.09-0.35). Of interest, we observed a statistically significant decrease in premature births after NYC phase one reopening compared to those of the same time period in 2012-2019 across all time windows (p=0.0028-0.049), and a statistically significant decrease in NICU admissions over the largest time window (2.75 months) compared to prior years (p=0.0011).