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Lipid droplets (LDs) form inter-organelle contacts with the endoplasmic reticulum (ER) that promote their biogenesis, while LD contacts with mitochondria enhance ß-oxidation of contained fatty acids. Viruses have been shown to take advantage of lipid droplets to promote viral production, but it remains unclear whether they also modulate the interactions between LDs and other organelles. Here, we showed that coronavirus ORF6 protein targets LDs and is localized to the mitochondria-LD and ER-LD contact sites, where it regulates LD biogenesis and lipolysis. At the molecular level, we find that ORF6 inserts into the LD lipid monolayer via its two amphipathic helices. ORF6 further interacts with ER membrane proteins BAP31 and USE1 to mediate ER-LDs contact formation. Additionally, ORF6 interacts with the SAM complex in the mitochondrial outer membrane to link mitochondria to LDs. In doing so, ORF6 promotes cellular lipolysis and LD biogenesis to reprogram host cell lipid flux and facilitate viral production.
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Coronavirus , Coronavirus/metabolismo , Retículo Endoplásmico/metabolismo , Gotas Lipídicas/metabolismo , Lipólisis , Ácidos Grasos/metabolismoRESUMEN
BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a significant global health issue in recent years. Numerous studies indicate that COVID-19 during pregnancy is associated with an increased likelihood of pregnancy complications. Additionally, pregnancy itself is known to elevate the risk of severe SARS-CoV-2 infection. To explore the potential impact of SARS-CoV-2 infection on the probability of Down syndrome in fetuses, we conducted serological testing of Down syndrome markers in pregnant women who had contracted the virus. METHODS: Serological experiments were conducted utilizing a particle chemiluminescence test. The cohort of pregnant women was categorized into three groups: a control group with no infection, a group infected with SARS-CoV-2 Omicron within the first six weeks of gestation, and a group infected beyond the sixth week of gestation. RESULTS: In the group of individuals infected within 6 gestational weeks, the infection resulted in a decrease in alpha-fetoprotein (AFP) levels and a higher positive rate of Down syndrome screening tests (p Ë 0.05). However, in this study, SARS-CoV-2 infection did not lead to an increase in the occurrence of Down syndrome in the fetus. The positive rate of women infected beyond 6 gestational weeks was slightly higher than the non-infected group (6.2% vs. 5.7%), but these differences were not statistically significant (p > 0.05). Within the group infected beyond 6 gestational weeks, there was, compared to the control group, a decrease in free beta human chorionic gonadotropin (ß-hCG) levels (p < 0.05). CONCLUSIONS: This study presents a novel investigation into the impact of SARS-CoV-2 infection on AFP and ß-hCG levels. It has been observed that pregnant women who contract SARS-CoV-2 may exhibit an increased likelihood of positive results in serum tests conducted for Down syndrome screening. However, it is important to note that the occurrence of Down syndrome in the developing fetus does not appear to be elevated. To validate these findings, additional research involving larger and diverse cohorts is necessary.
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COVID-19 , Síndrome de Down , Complicaciones Infecciosas del Embarazo , SARS-CoV-2 , alfa-Fetoproteínas , Humanos , Síndrome de Down/diagnóstico , Síndrome de Down/sangre , alfa-Fetoproteínas/análisis , Femenino , Embarazo , COVID-19/diagnóstico , COVID-19/sangre , COVID-19/epidemiología , Complicaciones Infecciosas del Embarazo/sangre , Complicaciones Infecciosas del Embarazo/diagnóstico , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/virología , Adulto , Diagnóstico Prenatal/métodos , Biomarcadores/sangreRESUMEN
BACKGROUND: Toll-like receptor 2 (TLR2) is a crucial factor in the development of tuberculosis. However, no studies have explored the association between TLR2 polymorphisms and tuberculosis susceptibility. OBJECTIVES: This study aimed to explore the correlation between tuberculosis susceptibility and TLR2 polymorphisms (rs3804099, rs3804100, rs1898830, rs5743708, rs121917864, and (-196-174) del). METHODS: All relevant online databases including PubMed, CNKI, WANFANG DATA, and METSTR-FMRS were systematically searched. STATA17.0 (Stata Corp LP, College Station, Texas, USA) was used. RESULTS: A total of 37 studies, covering six polymorphisms and comprising 9,474 cases and 10,295 controls, were included in this analysis. rs3804099(C vs T: OR = 1.00, 95 % CI: 0.93-1.08, CC + TC vs TT: OR = 1.04, 95 % CI: 0.98-1.10), rs3804100 (C vs T: OR = 1.19, 95 % CI: 0.93-1.07, CC + TC vs TT: OR = 0.97, 95 % CI: 0.89-1.06), rs1898830(G vs A: OR = 0.90, 95 % CI: 0.81-1.00, GG + AG vs AA: OR = 0.87, 95 % CI: 0.67-1.12), (-196 â¼174) del polymorphism (Del vs Ins: OR = 0.93,95 % CI: 0.76-1.14, DD + DI vs II: OR = 0.92,95 % CI: 0.72-1.17). CONCLUSIONS: This study indicated that only the TLR2 rs5743708 polymorphism exhibited a significant association with a higher tuberculosis risk, while TLR2 rs3804099, rs3804100, rs1898830, rs121917864, and (-196-174) del polymorphisms were not associated with tuberculosis susceptibility.
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Receptor Toll-Like 2 , Tuberculosis , Humanos , Receptor Toll-Like 2/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético/genética , Tuberculosis/genética , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
OBJECTIVE: To assess the effectiveness of e-cigarettes in smoking cessation in the USA from 2017 to 2019, given the 2017 increase in high nicotine e-cigarette sales. METHODS: In 2017, the PATH Cohort Study included data on 3578 previous year smokers with a recent quit attempt and 1323 recent former smokers. Respondents reported e-cigarettes or other products used to quit cigarettes and many covariates associated with e-cigarette use. Study outcomes were 12+ months of cigarette abstinence and tobacco abstinence in 2019. We report weighted unadjusted estimates and use propensity score matched analyses with 1500 bootstrap samples to estimate adjusted risk differences (aRD). RESULTS: In 2017, 12.6% (95% CI 11.3% to 13.9%) of recent quit attempters used e-cigarettes to help with their quit attempt, a decline from previous years. Cigarette abstinence for e-cigarette users (9.9%, 95% CI 6.6% to 13.2%) was lower than for no product use (18.6%, 95% CI 16.0% to 21.2%), and the aRD for e-cigarettes versus pharmaceutical aids was -7.3% (95% CI -14.4 to -0.4) and for e-cigarettes versus any other method was -7.7% (95% CI -12.2 to -3.2). Only 2.2% (95% CI 0.0% to 4.4%) of recent former smokers switched to a high nicotine e-cigarette. Subjects who switched to e-cigarettes appeared to have a higher relapse rate than those who did not switch to e-cigarettes or other tobacco, although the difference was not statistically significant. CONCLUSIONS: Sales increases in high nicotine e-cigarettes in 2017 did not translate to more smokers using these e-cigarettes to quit smoking. On average, using e-cigarettes for cessation in 2017 did not improve successful quitting or prevent relapse.
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Sistemas Electrónicos de Liberación de Nicotina , Cese del Hábito de Fumar , Humanos , Cese del Hábito de Fumar/métodos , Estudios de Cohortes , Nicotina , Dispositivos para Dejar de Fumar TabacoRESUMEN
The genus Bandavirus, belonging to family Phenuiviridae, order Bunyavirales, consists of eight tick-borne bunyaviruses. The Dabie bandavirus, formerly known as severe fever with thrombocytopenia virus (SFTSV), belongs to the genus Bandavirus. This emerging pathogen was first identified in central China in 2009. In recent years, the disease has been reported to cause several outbreaks in eastern Asia areas, including China, Japan, Korea, and Vietnam. Tick-to-human transmission is the main route of infection in humans, and transmission via the contact of body fluids from person-to-person was also reported. Despite its high fatality rate, there is currently no vaccine or antiviral therapy available. The therapeutic efficacies of several antiviral agents against Dabie bandavirus are still being evaluated. However, the virus is a potent pathogen with high biosafety experimental conditions. Therefore, replication-incompetent pseudotyped viruses play an important role. In this chapter, we succinctly summarize the basic features concerning Dabie bandavirus, including virion structure, genome characteristics, especially the characteristics of glycoprotein, and probable pathogenic mechanism. And, we put an important part in expounding the construction of pseudoviruses and its application.
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Phlebovirus , Virus ARN , Humanos , Phlebovirus/química , Phlebovirus/genética , Pseudotipado Viral , Glicoproteínas/química , AntiviralesRESUMEN
Water must be separated from water-in-oil (W/O) emulsion because of the corrosion it brings to the relative equipment in the process of transportation and storage. It is an effective method to apply external electric field to achieve high performance of separating small, dispersed water droplets from W/O emulsion; however, the coalescing micromechanism of such small salty droplets under AC electric field is unclear. In this paper, molecular dynamics simulation was adopted to investigate the coalescence and separation process of two NaCl-aqueous droplets under AC electric field and discuss the effect of AC electric field frequency, as well as the time required for contacting, the critical electric field strength, the dynamic coalescence process and the stability of the final merged droplet. The results show that the critical electric field strength of the droplet coalescence increases with the increase of frequency, while the time required for droplet contacting becomes shorter. The shrinkage function curve was applied to characterize the droplet coalescence effect and it was found that the droplets coalescence and form a nearly spherical droplet under the AC electric field with a frequency of 1.25 GHz and strength of 0.5 V/nm. When the electric field frequency is 10 GHZ, the merged droplet presents a periodic fluctuation with the same period as the AC electric field, which mainly depends on the periodic movement of cations and anions under the AC electric field. The results can provide theoretical basis for the practical application of electrostatic demulsification technology in the petroleum or chemical industry from the microscopic perspective.
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BACKGROUND: Immune checkpoint blockade (ICB) has transformed cancer therapy, with long-term responses and a favorable safety profile; however, only a minority of patients respond. Response to ICB is influenced by immune-related genetic factors such as HLA haplotype, potentially including patient blood type and associated differences in diversity of the T-cell repertoire. A minority of patients experience immune-related adverse events (irAEs), with unclear relation to response or resistance. MATERIALS AND METHODS: In this single institution study, we aimed to investigate the relationship of time to treatment failure (TTF) with patient blood type and with occurrence of irAEs, among patients with metastatic cancer receiving ICB. RESULTS: We found a strong association of improved TTF with presence of irAEs, and also among patients with type O blood, compared with type A/B/AB blood. Among patients with type O blood, TTF was substantially longer among those experiencing an irAE (n = 44; adjusted HR 0.41, 95% CI 0.18,0.96). For patients with type A/B/AB blood, no significant association was present (n = 63; adjusted HR 0.69, 95% CI 0.39,1.21). For type O patients, median TTF of ICB was 13.4 months (95% CI: 3.79 months, NA) vs 2.55 months (95% CI: 1.95 months, 4.95 months) for other patients. CONCLUSION: This retrospective study of a cohort of patients receiving ICB suggests a preferential benefit among patients with type O blood and, in particular, among patients with type O blood who developed irAEs. Validation in future independent cohorts and investigation of a potential biologic basis for this finding is warranted.
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Neoplasias Primarias Secundarias , Neoplasias , Estudios de Cohortes , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias Primarias Secundarias/complicaciones , Estudios RetrospectivosRESUMEN
BACKGROUND: Pembrolizumab (PD-1 inhibitor) and cetuximab (EGFR inhibitor) are active as single agents and in combination with cytotoxic chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Given each drug's single agent activity and unique mechanism of action, we aimed to evaluate the anti-tumour activity of PD-1 blockade with EGFR inhibition in recurrent or metastatic HNSCC. METHODS: This study is an open-label, non-randomised, multi-arm, phase 2 trial done at four academic centres in the USA. Participants were required to have platinum-resistant or platinum-ineligible, recurrent or metastatic HNSCC, be at least 18 years old, have an Eastern Cooperative Oncology Group performance status 0-1, have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and to have received no previous immunotherapy or EGFR inhibition. All participants received pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m2 intravenously followed by 250 mg/m2 intravenously weekly (21 day cycle). The primary endpoint was overall response rate defined as the proportion of participants with a partial or complete responses (per RECIST version 1.1) by 6 months in the intention-to-treat population. The safety population included all participants who received at least one dose of pembrolizumab. Herein, the final analysis of cohort 1 (no previous PD-1, PD-L1, or EGFR inhibition for recurrent or metastatic HNSCC) is reported. Three additional cohorts (two for participants with a previous response to immunotherapy followed by relapse or progression, with or without previous cetuximab exposure, and one for cutaneous HNSCC) will be reported separately once fully accrued. This study is registered with ClinicalTrials.gov, NCT03082534, and remains open as the three additional cohorts are actively accruing participants. FINDINGS: Between March 22, 2017, and July 16, 2019, 33 participants were enrolled to cohort 1. All 33 participants received at least one dose of pembrolizumab. Median follow-up duration was 7·3 months (IQR 3·9-10·9). By 6 months, the overall response rate was 45% (95% CI 28-62), with 15 of 33 participants achieving a partial response. The most common grade 3-4 treatment-related adverse event was oral mucositis (three [9%] of 33 participants), and serious treatment-related adverse events occurred in five (15%) participants. No treatment-related deaths occurred. INTERPRETATION: Pembrolizumab combined with cetuximab shows promising clinical activity for recurrent or metastatic HNSCC, and merits further investigation. FUNDING: Merck Sharp & Dohme.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cetuximab/administración & dosificación , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/genética , Cetuximab/efectos adversos , Receptores ErbB/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
Pearl millet (Pennisetum americanum (L.) K. Schum) has been proven as a potential remediation plant of the pollution caused by atrazine. Plants used in remediation can release root exudates to communicate with rhizosphere microorganisms and accelerate the removal of pollutants in soil. However, the response of pearl millet root exudates under atrazine stress has remained unclear. In this study, hydroponic experiments were conducted at Northeast Agricultural University, Harbin, China, to investigate the oxidative stress response and the changes in composition of root exudates in pearl millet plants that were exposed to 19.4 mgL-1 of atrazine, compared to the untreated control. The experiment was established as six treatments with exposure to no atrazine for 2, 4 and 6 days (CK-2, CK-4, CK-6) and 19.4 mgL-1 atrazine for 2, 4 and 6 days (AT-2, AT-4, AT-6), respectively. The results suggest that the growth of the seedlings changed slightly when exposed to atrazine for 2 days. The content of thiobarbituric acid reactive substances exposed to atrazine for 6 days increased 26% compared with the treatment that was exposed for 2 days. Moreover, the reactive oxygen species in test plant obviously increased when exposed to atrazine for 6 days. In addition, the activity of superoxide dismutase increased from 30.82 ug-1 to 37.33 ug-1 fresh weight after 6 days of exposure to atrazine. The results of a nontargeted metabolomic analysis suggest that carbohydrate metabolism, fatty acid metabolism and amino acid metabolism in pearl millet were obviously affected by the oxidative stress caused by atrazine. The contents of sphinganine and methylimidazole acetaldehyde in CK-6 increased by 5.14 times and 2.05 times, respectively, compared with those of CK-2. Furthermore, the contents of (S)-methylmalonic acid semialdehyde and 1-pyrroline-2-carboxylic acid decreased by 0.56 times and 0.5 times, respectively, compared with the AT-6. These results strongly suggest that the changes observed in the composition of root exudates in pearl millet seedlings can be attributed to the oxidative stress caused by atrazine.
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Atrazina/toxicidad , Herbicidas/toxicidad , Estrés Oxidativo/fisiología , Pennisetum/efectos de los fármacos , Exudados de Plantas/metabolismo , Atrazina/metabolismo , China , Herbicidas/metabolismo , Oxidación-Reducción , Pennisetum/metabolismo , Pennisetum/fisiología , Rizosfera , Plantones/metabolismo , Suelo/química , Superóxido Dismutasa/metabolismoRESUMEN
Electronic cigarettes (e-cigarettes) are the preferred smoking-cessation aid in the United States; however, there is little evidence regarding long-term effectiveness among those who use them. We used the Population Assessment of Tobacco and Health Study to compare long-term abstinence between matched US smokers who tried to quit with and without use of e-cigarettes as a cessation aid. We identified a nationally representative cohort of 2,535 adult US smokers in 2014-2015 (baseline assessment), who, in 2015-2016 (exposure assessment), reported a past-year attempt to quit and the cessation aids used, and reported smoking status in 2016-2017 (outcome assessment; self-reported ≥12 months continuous abstinence). We used propensity-score methods to match each e-cigarette user with similar nonusers. Among US smokers who used e-cigarettes to help quit, 12.9% (95% confidence interval (CI): 9.1%, 16.7%) successfully attained long-term abstinence. However, there was no difference compared with matched non-e-cigarette users (cigarette abstinence difference: 2%; 95% CI: -3%, 7%). Furthermore, fewer e-cigarette users were abstinent from nicotine products in the long term (nicotine abstinence difference: -4%; 95% CI: -7%, -1%); approximately two-thirds of e-cigarette users who successfully quit smoking continued to use e-cigarettes. These results suggest e-cigarettes may not be an effective cessation aid for adult smokers and, instead, may contribute to continuing nicotine dependence.
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Sistemas Electrónicos de Liberación de Nicotina/estadística & datos numéricos , Cese del Hábito de Fumar/estadística & datos numéricos , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Estados Unidos , Adulto JovenRESUMEN
Rabies is a fatal zoonosis which could affect all mammals. Glycoprotein (G protein) from the rabies virus plays an important role in the binding of virus to target cells. However, expression of the G protein with native conformation has been a great challenge for many years. In this study, we solved this problem by replacing the original signal peptide of rabies virus G protein with the one from the heavy chain of human IgG. The expression levels of recombinant G protein dramatically increased from a few µg/L to 50 mg/L in the culture supernatants. The identity of the recombinant G protein was confirmed by western blotting using both 6XHis mAb 6E2 and rabies G protein mAb 7G3. The correct conformation of the recombinant G protein was shown by using rabies virus neutralizing antibodies. In addition, the recombinant G protein had immune-reactivities with mice sera raised against rabies vaccines and vice versa. Taken together, our data suggested that by replacing the signal peptide, the expression level of the G protein with native conformation could be significantly improved. This would help the development of a rabies subunit vaccine, structural studies of rabies G protein, elucidation of the signal pathway of RABV infection.
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Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Antígenos Virales/administración & dosificación , Cadenas Pesadas de Inmunoglobulina/genética , Virus de la Rabia/inmunología , Rabia/prevención & control , Proteínas Recombinantes de Fusión/genética , Proteínas del Envoltorio Viral/administración & dosificación , Animales , Antígenos Virales/genética , Antígenos Virales/inmunología , Clonación Molecular , Protección Cruzada , Escherichia coli/genética , Escherichia coli/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Humanos , Sueros Inmunes/química , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Cadenas Pesadas de Inmunoglobulina/metabolismo , Ratones , Ingeniería de Proteínas/métodos , Señales de Clasificación de Proteína/genética , Rabia/virología , Vacunas Antirrábicas/administración & dosificación , Vacunas Antirrábicas/biosíntesis , Vacunas Antirrábicas/genética , Virus de la Rabia/genética , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunologíaRESUMEN
The development of therapies for human smallpox is needed due to the increasing concern over the potential use of smallpox virus as a biological weapon. Here, we report a high-throughput screening for anti-smallpox virus drugs from a 767-small-molecule library, employing two vaccinia virus (VACV) strains containing firefly luciferase (VTT-Fluc and VG9-Fluc) as surrogate viruses. Using an eight-point dose response format assay, 26 compounds of different pharmacological classes were identified with in vitro anti-VACV activities. Mycophenolate mofetil (MMF) and tranilast (TRA) were detected to possess the highest anti-VACV potency (selectivity index values of >334 and >74, respectively); they could inhibit VTT-Fluc replication in nude mice at 5 days post-infection by 99% (10 mg/kg, P < .01) and 59% (45 mg/kg, P = .01), respectively, as indicated by bioluminescent intensity. In conclusion, MMF and TRA are promising anti-smallpox virus candidates for further optimization and repurposing for use in clinical practice.
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Antivirales/farmacología , Reposicionamiento de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Bibliotecas de Moléculas Pequeñas/farmacología , Virus Vaccinia/efectos de los fármacos , Animales , Línea Celular , Chlorocebus aethiops , Aprobación de Drogas , Descubrimiento de Drogas , Femenino , Ratones , Ratones Desnudos , Viruela/tratamiento farmacológico , Vaccinia/tratamiento farmacológico , Células VeroRESUMEN
Optimization of compatible solutes (ectoine) extraction and purification from Halomonas elongata cell fermentation had been investigated in the laboratory tests of a large scale commercial production project. After culturing H. elongata cells in developed medium at 28 °C for 23-30 h, we obtained an average yield and biomass of ectoine for 15.9 g/L and 92.9 (OD600), respectively. Cell lysis was performed with acid treatment at moderate high temperature (60-70 °C). The downstream processing operations were designed to be as follows: filtration, desalination, cation exchange, extraction of crude product and three times of refining. Among which the cation exchange and extraction of crude product acquired a high average recovery rate of 95 and 96%; whereas a great loss rate of 19 and 15% was observed during the filtration and desalination, respectively. Combined with the recovering of ectoine from the mother liquor of the three times refining, the average of overall yield (referring to the amount of ectoine synthesized in cells) and purity of final product obtained were 43% and over 98%, respectively. However, key factors that affected the production efficiency were not yields but the time used in the extraction of crude product, involving the crystallization step from water, which spended 24-72 h according to the production scale. Although regarding to the productivity and simplicity on laboratory scale, the method described here can not compete with other investigations, in this study we acquired higher purity of ectoine and provided downstream processes that are capable of operating on industrial scale.
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Aminoácidos Diaminos/química , Aminoácidos Diaminos/aislamiento & purificación , Halomonas/química , Halomonas/metabolismo , Microbiología Industrial/métodos , Técnicas de Cultivo Celular por Lotes , Biomasa , Reactores Biológicos/microbiología , Técnicas de Química Analítica/métodos , Medios de Cultivo , Fermentación , Halomonas/crecimiento & desarrollo , Concentración de Iones de Hidrógeno , TemperaturaRESUMEN
Recently, the use of photon counting detectors in computed tomography (PCCT) has attracted extensive attention. It is highly desired to improve the quality of material basis image and the quantitative accuracy of elemental composition, particularly when PCCT data is acquired at lower radiation dose levels. In this work, we develop a physics-constrained and noise-controlled diffusion model, PRECISION in short, to address the degraded quality of material basis images and inaccurate quantification of elemental composition mainly caused by imperfect noise model and/or hand-crafted regularization of material basis images, such as local smoothness and/or sparsity, leveraged in the existing direct material basis image reconstruction approaches. In stark contrast, PRECISION learns distribution-level regularization to describe the feature of ideal material basis images via training a noise-controlled spatial-spectral diffusion model. The optimal material basis images of each individual subject are sampled from this learned distribution under the constraint of the physical model of a given PCCT and the measured data obtained from the subject. PRECISION exhibits the potential to improve the quality of material basis images and the quantitative accuracy of elemental composition for PCCT.
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Toll-like receptor 2 (TLR2) is a pattern recognition receptor expressed on the surface of leukocytes. Various ligands can activate or inhibit TLR2, therefore regulating the inflammation and apoptosis of immune cells. Mycobacterium tuberculosis (MTB) typically parasitizes macrophages. Further, after infecting the body, MTB can interact with TLR2 on the surface of various immune cells, including macrophages, leading to the release of cytokines that can affect the state and proliferation of MTB in the body. Additional research is needed to understand the polymorphism of TLR2 at the molecular level. Current studies indicate that the majority of TLR2 polymorphisms are not associated with susceptibility to MTB infection. This review provides an overview of the researches related to TLR2 and its ligands, the immune regulation activities of TLR2 following MTB infection, and the association of TLR2 polymorphism with susceptibility to MTB.
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Mycobacterium tuberculosis , Receptor Toll-Like 2 , Tuberculosis , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 2/inmunología , Humanos , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/fisiología , Polimorfismo Genético , Animales , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Reducing current clinical symptoms and the risks of future exacerbations is the main goal of stable COPD management. Traditional Chinese medicine has unique advantages in chronic disease management. YuPingFeng (YPF), as a classical prescription, has been proven to reduce the risk of exacerbations, but there is a lack of high-quality evidence for the assessment of clinical symptoms and quality of life, particularly for the assessment of treatment response of microecology and immunity. METHODS/DESIGN: This is a prospective, multicentre, randomized, double-blind, placebo-controlled clinical trial. A total of 316 eligible subjects with moderate to severe COPD will be randomized 1:1 to receive YPF or placebo. Participants will receive either YPF or a placebo at 5 g three times daily for 52 weeks. The primary outcome will be the change in the COPD Assessment Test (CAT) score after 52 weeks of treatment. Secondary outcomes will include changes in the St George's Respiratory Questionnaire (SGRQ) score and clinical symptom score, among others. Outcomes will be measured at each visit. The study will continue for 52 weeks and will include six visits to each subject (at day 0 and weeks 4,12,24,36 and 52). In the event of exacerbations, subjects will be required to go back to the hospital once on the first day of exacerbation or when their condition permits. DISCUSSION: This trial will provide research methods to evaluate the clinical efficacy, safety, and the possible mechanism of YPF in the treatment of stable moderate-to-severe COPD patients. In addition, we hope to provide more possibilities for TCM to participate in the management of stable COPD. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trials Registry on 3 June 2022 (ChiCTR2200060476; date recorded: 3/6/2022, https://www.chictr.org.cn/ ).
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Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Humanos , Estudios Prospectivos , Método Doble Ciego , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfeng powder (YPF) is a classic traditional Chinese medicine prescription with a long history of clinical application. However, there is a consensus on the clinical efficacy of YPF in the prevention and treatment of influenza, the underlying pharmacological mechanisms and functional substances have not been thoroughly investigated. AIM OF THE STUDY: This study aimed to elucidate the functional substances and potential mechanisms of YPF against influenza infections by integrating network analysis, metabolomics, computational system pharmacology, and in vitro experiments. MATERIALS AND METHODS: In this study, the active ingredients, related targets, and potential mechanisms of YPF against influenza were identified through network pharmacology and GEO database mining. Combined with metabolomics to corroborate the results of network pharmacology analysis and construct C-T-P-D-M network. Based on this, the key network motifs (KNM) with significance were predicted by system pharmacology algorithm. Finally, the key components as functional substances in the KNM were validated by the coverage of influenza-causing genes and functional pathways, and in vitro experiments. RESULTS: A total of 238 active components and 158 potential target genes intersecting with influenza infection differential genes were screened from YPF. KEGG enrichment analysis indicated that metabolism participated in YPF-provided prevention and treatment on influenza, and metabolomic results further corroborated the significance of the metabolic pathways intervened by YPF included pyruvate metabolism, Valine, leucine and isoleucine degradation, etc. The KNM prediction strategy was computed to include wogonin and isoimperaporin, a group of 48 potential functional components. This functional component group maintained a high degree of consistency with the corresponding C-T network in terms of the coverage of influenza pathogenic genes, and the coverage of functional pathways. Meanwhile, the in vitro results showed that wogonin and isoimperaporin had significant inhibitory effects on inflammation induced by influenza infection, confirming the reliability and accuracy of the KNM prediction strategy. CONCLUSION: YPF against influenza has multi-target and multi-pathway effects, and the underlying mechanisms may be related to metabolism. The pharmacodynamic effects of core components such as wogonin and isoimperaporin on influenza prevention and treatment were confirmed, which represent promising functional candidates for subsequent influenza prevention and treatment, and provide references for the pharmacological and mechanistic analyses of subsequent formulas.
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Lipid droplets (LDs) are dynamic lipid storage organelles that can be degraded by autophagy machinery to release neutral lipids, a process called lipophagy. However, specific receptors and regulation mechanisms for lipophagy remain largely unknown. Here, we identify that ATG14, the core unit of the PI3KC3-C1 complex, also targets LD and acts as an autophagic receptor that facilitates LD degradation. A negative regulator, Syntaxin18 (STX18) binds ATG14, disrupting the ATG14-ATG8 family members interactions and subverting the PI3KC3-C1 complex formation. Knockdown of STX18 activates lipophagy dependent on ATG14 not only as the core unit of PI3KC3-C1 complex but also as the autophagic receptor, resulting in the degradation of LD-associated anti-viral protein Viperin. Furthermore, coronavirus M protein binds STX18 and subverts the STX18-ATG14 interaction to induce lipophagy and degrade Viperin, facilitating virus production. Altogether, our data provide a previously undescribed mechanism for additional roles of ATG14 in lipid metabolism and virus production.
Asunto(s)
Gotas Lipídicas , Metabolismo de los Lípidos , Gotas Lipídicas/metabolismo , Metabolismo de los Lípidos/fisiología , Proteínas/metabolismo , Autofagia/fisiologíaRESUMEN
BACKGROUND: The motion relationship and time intervals of the pulsed-wave Doppler (PWD) spectrum are essential for diagnosing fetal arrhythmia. However, few technologies currently are available to automatically calculate fetal cardiac time intervals (CTIs). OBJECTIVE: The purpose of this study was to develop a fetal heart rhythm intelligent quantification system (HR-IQS) for the automatic extraction of CTIs and establish the normal reference range for fetal CTIs. METHODS: A total of 6498 PWD spectrums of 2630 fetuses over the junction between the left ventricular inflow and outflow tracts were recorded across 14 centers. E, A, and V waves were manually labeled by 3 experienced fetal cardiologists, with 17 CTIs extracted. Five-fold cross-validation was performed for training and testing of the deep learning model. Agreement between the manual and HR-IQS-based values was evaluated using the intraclass correlation coefficient and Spearman's rank correlation coefficient. The Jarque-Bera test was applied to evaluate the normality of CTIs' distributions, and the normal reference range of 17 CTIs was established with quantile regression. Arrhythmia subset was compared with the non-arrhythmia subset using the Mann-Whitney U test. RESULTS: Significant positive correlation (P <.001) and moderate-to-excellent consistency (P <.001) between the manual and HR-IQS automated measurements of CTIs was found. The distribution of CTIs was non-normal (P <.001). The normal range (2.5th to 97.5th percentiles) was successfully established for the 17 CTIs. CONCLUSIONS: Using our HR-IQS is feasible for the automated calculation of CTIs in practice and thus could provide a promising tool for the assessment of fetal rhythm and function.