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Aflatoxin B1 (AFB1) is a potent carcinogen, and is among the most hazardous mycotoxins in agricultural products. Therefore, the development of sensitive and convenient detection methods for AFB1 is significant for food safety against mycotoxins. Herein, a bioluminescent enzyme immunoassay (BLEIA) was developed for ultrasensitive detection of AFB1, based on the novel Fc-specific antibody-nanoluciferase (Ab-Nluc) conjugates which were fabricated using an IgG-binding protein-assisted photo-conjugation strategy. In indirect competitive immunoassay format, the proposed BLEIA exhibited the detection limit of 0.0232 ng mL-1, which was 37.4-fold lower than that obtained using the classical enzyme-linked immunosorbent assay (ELISA) based on Ab-horseradish peroxidase (Ab-HRP) chemical conjugates (0.868 ng mL-1). Meanwhile, the BLEIA exhibited high accuracy and precision. Thus, the proposed Fc-specific Ab-Nluc conjugates-based BLEIA provides an ultrasensitive and reliable method for detecting toxins and has potential for use in food safety monitoring.

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BACKGROUND: Direct cardiac surgery often necessitates intensive post-operative care, and the intensive care unit (ICU) activity scale represents a crucial metric in assessing and guiding early rehabilitation efforts to enhance patient recovery. AIM: To clarify the clinical application value of the ICU activity scale in the early recovery of patients after cardiac surgery. METHODS: One hundred and twenty patients who underwent cardiac surgery between September 2020 and October 2021 were selected and divided into two groups using the random number table method. The observation group was rated using the ICU activity scale and the corresponding graded rehabilitation interventions were conducted based on the ICU activity scale. The control group was assessed in accordance with the routine rehabilitation activities, and the postoperative rehabilitation indexes of the patients in both groups were compared (time of tracheal intubation, time of ICU admission, occurrence of complications, and activity scores before ICU transfer). The two groups were compared according to postoperative rehabilitation indicators (time of tracheal intubation, length of ICU stay, and occurrence of complications) and activity scores before ICU transfer. RESULTS: In the observation group, tracheal intubation time lasted for 18.30 ± 3.28 h and ICU admission time was 4.04 ± 0.83 d, which were significantly shorter than the control group (t-values: 2.97 and 2.038, respectively, P < 0.05). The observation group also had a significantly lower number of complications and adverse events compared to the control group (P < 0.05). Before ICU transfer, the observation group (6.7%) had few complications and adverse events than the control group (30.0 %), and this difference was statistically significant (P < 0.05). Additionally, the activity score was significantly higher in the observation (26.89 ± 0.97) compared to the control groups (22.63 ± 1.12 points) (t-value; -17.83, P < 0.05). CONCLUSION: Implementation of early goal-directed activities in patients who underwent cardiac surgery using the ICU activity scale can promote the recovery of cardiac function.

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Wet Age-related Macular Degeneration (wet AMD) is a common ophthalmic disease that significantly impacts patients' vision. Optical coherence tomography (OCT) examination has been widely utilized for diagnosing, treating, and monitoring wet AMD due to its cost-effectiveness, non-invasiveness, and repeatability, positioning it as the most valuable tool for diagnosis and tracking. OCT can provide clear visualization of retinal layers and precise segmentation of lesion areas, facilitating the identification and quantitative analysis of abnormalities. However, the lack of high-quality datasets for assessing wet AMD has impeded the advancement of related algorithms. To address this issue, we have curated a comprehensive wet AMD OCT Segmentation Dataset (AMD-SD), comprising 3049 B-scan images from 138 patients, each annotated with five segmentation labels: subretinal fluid, intraretinal fluid, ellipsoid zone continuity, subretinal hyperreflective material, and pigment epithelial detachment. This dataset presents a valuable opportunity to investigate the accuracy and reliability of various segmentation algorithms for wet AMD, offering essential data support for developing AI-assisted clinical applications targeting wet AMD.

Asunto(s)

Algoritmos , Tomografía de Coherencia Óptica , Degeneración Macular Húmeda , Humanos , Degeneración Macular Húmeda/diagnóstico por imagen , Retina/diagnóstico por imagen , Retina/patología

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This was a retrospective study. This study investigated the occurrence of a composite endpoints (cardiovascular and cerebrovascular events, end-stage renal disease, and death) in 153 patients (aged ≥ 18 years) with a diagnosis of in chronic kidney disease (CKD). Based on morning blood pressure surge (MBPS) defined as ≥35 mm Hg, patients were divided into two groups: with MBPS (n = 50) and without MBPS (n = 103). All patients were followed up for at least 1 year. Baseline demographic, laboratory and follow-up data were collected. The clinical characteristics of the two groups were compared. The relationships between MBPS and endpoint events were analyzed using the Kaplan-Meier method and Cox regression model. In total, 153 patients (mean age 41.8 years; 56.86% males) were included in this study. During the follow-up period (mean 4.3 years), 34 endpoint events occurred. After adjustment for the covariates, the risk of cardiovascular and cerebrovascular events, end-stage renal disease and death remained significantly higher in patients with MBPS (hazard ratio [HR] and 95% confidence interval [CI] 3.124 [1.096-9.130]]) Among the other variables, systolic blood pressure, and night-time and daytime pulse pressures remained significantly associated with outcome in patients of CKD (1.789 [1.205-2.654], 1.710 [1.200-2.437], and 1.318 [1.096-1.586], respectively]. In conclusions, MBPS was identified as an independent prognostic factor for composite endpoint events (cardiovascular and cerebrovascular events, end-stage renal disease and death) patients with chronic kidney disease patients.

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Rheumatoid arthritis (RA) is a systemic autoimmune disorder that severely compromises joint health. The primary therapeutic strategy for advanced RA aims to inhibit joint inflammation. However, the nonspecific distribution of pharmacological agents has limited therapeutic efficacy and heightens the risks associated with RA treatment. To address this issue, we developed mesenchymal stem cell (MSC)-based biomimetic liposomes, termed MSCsome, which were composed of a fusion between MSC membranes and liposomes. MSC some with relatively simple preparation method effectively enhanced the targeting efficiency of drug to diseased joints. Interaction between lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 enhanced the affinity of the MSCsome for polarized macrophages, thereby improving its targeting capability to affected joints. The effective targeted delivery facilitated drug accumulation in joints, resulting in the significant inhibition of the inflammation, as well as protection and repair of the cartilage. In conclusion, this study introduced MSCsome as a promising approach for the effective treatment of advanced RA, providing a novel perspective on targeted drug delivery therapy for inflammatory diseases.

Asunto(s)

Artritis Reumatoide , Liposomas , Células Madre Mesenquimatosas , Liposomas/química , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/terapia , Artritis Reumatoide/patología , Animales , Ratones , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Humanos , Sistemas de Liberación de Medicamentos , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo

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Geometric isomers tend to have similar polarities and differ only in molecular shape. Vigorously developing new stationary phases to meet the requirements for the separation of isomers that have similar physicochemical properties is still an urgent topic in separation science. Poly (arylene ether)-based dendrimers are known for their multifunctional branched peripheral structures and high self-assembly properties. In this paper, two amphiphilic dendritic organic small molecule gelling agents based on poly (aryl ether), PAE-ANT and PAE-PA, were prepared and conjugated to the silica surface. SiO2@PAE-ANT and SiO2@PAE-PA were used as HPLC stationary phases for the separation of non-polar shape-restricted isomers. Both stationary phases have very high molecular shape selectivity for isomers such as polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), tocopherols and carotenoids. Separation of cis-trans geometric isomers such as diethylstilbestrol and polar compounds such as monosubstituted benzenes and anilines can also be achieved. These two columns offer more flexible selectivity and higher separation performance than commercial C18 and phenyl columns. There is a difference in molecular shape selectivity between the two stationary phases for the same analyte test probes. SiO2@PAE-ANT showed slightly better linear selectivity for non-polar shape-restricted isomers compared to SiO2@PAE-PA with Janus-type PAE-PA bonding phase. This separation behavior may be attributed to the ordered spatial structure formed by the gel factor on the surface of the stationary phase and the combined effect of multiple weak interaction centers (hydrophobic, hydrophilic, hydrogen bonding and π-π interactions). It was also possible to separate nucleoside and nucleobase strongly polar compounds well in the HILIC mode, suggesting that hydrophilic groups in PAE-ANT and PAE-PA are involved in the interactions, reflecting their amphiphilic nature. The results show that the ordered gelation of dendritic organic small molecule gelators on the SiO2 surface, along with multiple carbonyl-π, π-π and other interactions, play a crucial role in the separating shape-restricted isomers. The integrated and ordered functional groups serve as the primary driving force behind the exceptionally high molecular shape selectivity of SiO2@PAE-ANT and SiO2@PAE-PA phases. Alterations in the structure of dendritic organic small molecule gelators can impact both molecular orientation and recognition ability, while changes in the type of functional groups influences the separation mechanism of shape-restricted isomers.

Asunto(s)

Dendrímeros , Dióxido de Silicio , Dióxido de Silicio/química , Cromatografía Líquida de Alta Presión/métodos , Isomerismo , Dendrímeros/química , Hidrocarburos Policíclicos Aromáticos/química , Hidrocarburos Policíclicos Aromáticos/análisis , Hidrocarburos Policíclicos Aromáticos/aislamiento & purificación , Bifenilos Policlorados/química , Bifenilos Policlorados/análisis , Bifenilos Policlorados/aislamiento & purificación , Carotenoides/química , Carotenoides/análisis , Carotenoides/aislamiento & purificación , Tensoactivos/química

RESUMEN

Our goal was to assess the impact of childhood/adolescent cancer history on overall survival (OS) and disease-specific survival (DSS) in patients with parotid mucoepidermoid carcinoma (MEC). Patients who underwent surgical treatment for primary parotid MEC and those with a second malignancy of parotid MEC were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. The primary outcome variables were OS and DSS. The hazard ratios (HRs) of these survival rates associated with cancer history were analysed using Cox regression models. In total, 2681 patients were included, 263 of whom had a second malignancy. The 10-year OS rates in the primary (72%) and second malignancy groups (59%) were significantly different. Cox regression confirmed that a history of cancer tended to decrease OS (p = 0.062, HR: 1.28, 95% confidence interval: 0.99 to 1.64). Subgroup analyses showed that a history of solid tumour as opposed to haematological cancer predicted worse OS, with central nervous system tumours exhibiting a more significant influence than others (p = 0.030 vs p = 0.088). Cancer history was not related to DSS. A history of childhood/adolescent cancer negatively influenced the prognosis of patients with parotid MEC, and this effect was primarily driven by a history of solid malignancy.

Asunto(s)

Carcinoma Mucoepidermoide , Neoplasias de la Parótida , Humanos , Carcinoma Mucoepidermoide/cirugía , Carcinoma Mucoepidermoide/patología , Neoplasias de la Parótida/cirugía , Masculino , Femenino , Pronóstico , Adolescente , Estudios Retrospectivos , Niño , Adulto , Persona de Mediana Edad , Tasa de Supervivencia , Programa de VERF , Neoplasias Primarias Secundarias , Anciano , Preescolar , Adulto Joven

RESUMEN

Biosynthesis of the phytoalexins scopoletin and scopolin in Nicotiana species is regulated by upstream signals including jasmonate (JA), ethylene (ET) and NaWRKY3 in response to the necrotrophic fungus Alternaria alternata, which causes brown spot disease. However, how these signals are coordinated to regulate these phytoalexins remains unknown. By analyzing RNA sequencing data and RNA interference, we identified NaERF1B-like (NaERF1B-L) as a key player in Nicotiana attenuata during A. alternata infection by regulating the transcripts of Feruloyl-CoA 6'-hydroxylase 1 (NaF6'H1), encoding a key enzyme for scopoletin biosynthesis, and NaVS1-like (NaVS1-L), a putative biosynthetic gene of the phytoalexin solavetivone. We further demonstrated that the synergistic induction of these two genes by JA and ET signaling is mediated by NaERF1B-L. Additionally, we found that the two closely related proteins NaWRKY6 and NaWRKY3 physically interact to enhance NaERF1B-L expression by directly binding and activating the NaERF1B-L promoter. Collectively, our current results demonstrate that NaERF1B-L plays a positive role in resistance to A. alternata by modulating phytoalexins biosynthesis through the integration of JA/ET and NaWRKY6/3 signaling. Our findings reveal a fine-tuned transcriptional regulatory hierarchy mediated by NaERF1B-L for brown spot disease resistance in wild tobacco.

RESUMEN

Lycium ruthenicum Murray (LR), known as "black goji berry" or "black wolfberry", is widely utilized in chinese herbal medicine. LR fruit showed its antioxidant and/or anti-inflammation activity in treating cardiac injury, experimental colitis, nonalcoholic fatty liver disease, fatigue, and aging. Glaucoma is the leading cause of irreversible blindness. Besides elevated intraocular pressure (IOP), oxidative stress and neuroinflammation were recognized to contribute to the pathogenesis of glaucoma. This study investigated the treatment effects of LR water extract (LRE) on retinal ganglion cells (RGCs) threatened by sustained IOP elevation in a laser-induced chronic ocular hypertension (COH) mouse model and the DBA/2J mouse strain. The antioxidation and anti-inflammation effects of LRE were further tested in the H2O2-challenged immortalized microglial (IMG) cell line in vitro. LRE oral feeding (2 g/kg) preserved the function of RGCs and promoted their survival in both models mimicking glaucoma. LRE decreased 8-hydroxyguanosine (oxidative stress marker) expression in the retina. LRE reduced the number of Iba-1+ microglia in the retina of COH mice, but not in the DBA/2J mice. At the mRNA level, LRE reversed the COH induced HO-1 and SOD-2 overexpressions in the retina of COH mice. Further in vitro study demonstrated that LRE pretreatment to IMG cells could significantly reduce H2O2 induced oxidative stress through upregulation of GPX-4, Prdx-5, HO-1, and SOD-2. Our work demonstrated that daily oral intake of LRE can be used as a preventative/treatment agent to protect RGCs under high IOP stress probably through reducing oxidative stress and inhibiting microglial activation in the retina.

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INTRODUCTION: Patients with clinically significant portal hypertension (CSPH) are recommended to be treated with non-selective beta-blockers (ie, carvedilol) to prevent the first hepatic decompensation event by the renewing Baveno VII consensus. CSPH is defined by hepatic venous pressure gradient (HVPG)≥10 mm Hg; however, the HVPG measurement is not widely adopted due to its invasiveness. Liver stiffness (LS)≥25 kPa can be used as a surrogate of HVPG≥10 mm Hg to rule in CSPH with 90% of the positive predicting value in majority aetiologies of patients. A compelling argument is existing for using LS≥25 kPa to diagnose CSPH and then to initiate carvedilol in patients with compensated cirrhosis, and about 5%-6% of patients under this diagnosis criteria may not be benefited from carvedilol and are at risk of lower heart rate and mean arterial pressure. Randomised controlled trial on the use of carvedilol to prevent liver decompensation in CSPH diagnosed by LS remains to elucidate. Therefore, we aimed to investigate if compensated cirrhosis patients with LS≥25 kPa may benefit from carvedilol therapy. METHODS AND ANALYSIS: This study is a randomised, double-blind, placebo-controlled, multicentre trial. We will randomly assign 446 adult compensated cirrhosis patients with LS≥25 kPa and without any previous decompensated event and without high-risk gastro-oesophageal varices. Patients are randomly divided into two groups, with 223 subjects in group A and 223 subjects in group B. Group A is a carvedilol intervention group, while group B is a placebo group. All patients in both groups will receive aetiology therapies and are followed up at an interval of 6 months. The 3-year incidences of decompensated events of cirrhosis-related and liver-related death are the primary outcome. The secondary outcomes include development of each complication of portal hypertension individually (ascites, variceal bleeding or overt hepatic encephalopathy), development of spontaneous bacterial peritonitis and other bacterial infections, development of new varices, growth of small varices to large varices, delta changes in LS and spleen stiffness, change in hepatic dysfunction assessed by Child-Pugh and model for end-stage liver disease score, change in platelet count, development of hepatocellular carcinoma, development of portal vein thrombosis and adverse events with a 3-year follow-up. A predefined interim analysis will be performed to ensure that the calculation is reasonable. ETHICS AND DISSEMINATION: The study protocol has been approved by the ethics committees of the Sixth People's Hospital of Shenyang (2023-05-003-01) and independent ethics committee for clinical research of Zhongda Hospital, affiliated to Southeast University (2023ZDSYLL433-P01). The results from this trial will be submitted for publication in peer-reviewed journals and will be presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073864.

Asunto(s)

Carvedilol , Hipertensión Portal , Cirrosis Hepática , Carvedilol/uso terapéutico , Carvedilol/farmacología , Humanos , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/etiología , Cirrosis Hepática/complicaciones , Método Doble Ciego , China/epidemiología , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Antagonistas Adrenérgicos beta/uso terapéutico , Femenino , Hígado/efectos de los fármacos , Hígado/fisiopatología , Presión Portal/efectos de los fármacos , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/prevención & control , Diagnóstico por Imagen de Elasticidad , Adulto , Masculino

RESUMEN

Purpose: This study investigated whether RNA-Seq-based endometrial receptivity test (rsERT)-which provides precision for the optimal hour of the window of implantation (WOI)-can improve clinical outcomes of frozen embryo transfer (FET) cycles in patients with a history of repeated implantation failure (RIF). Methods: Patients with a history of RIF who received at least one autologous high-quality blastocyst during the subsequent FET cycle were retrospectively enrolled and divided into two groups: rsERT and FET, comprising patients who underwent rsERT-guided pET (n=115) and standard FET without rsERT (n=272), respectively. Results: In the rsERT group, 39.1% (45/115) of patients were receptive. rsERT patients showed a higher probability of achieving both positive human chorionic gonadotropin (63.5% vs. 51.5%, P=0.03) and clinical pregnancy (54.8% vs. 38.6%, P=0.003) rates. In subgroup analysis, rsERT patients with non-receptive results had higher clinical pregnancy rates than patients undergoing FET (58.6% vs. 38.6%, P=0.003). rsERT patients with receptive results guided by rsERT with a precise WOI time had higher, although non-significant, clinical pregnancy rates (48.9% vs. 38.6%, P=0.192) than patients who underwent standard-time FET. Conclusion: Hourly precise rsERT can significantly improve the probability of achieving clinical pregnancy in patients with RIF, especially in those with non-receptive rsERT results.

Asunto(s)

Implantación del Embrión , Transferencia de Embrión , Índice de Embarazo , Humanos , Femenino , Transferencia de Embrión/métodos , Embarazo , Adulto , Estudios Retrospectivos , Fertilización In Vitro/métodos , Endometrio , Resultado del Tratamiento

RESUMEN

BACKGROUND: Hypoxic Pulmonary Hypertension (HPH), a prevalent disease in highland areas, is a crucial factor in various complex highland diseases with high mortality rates. Zhishi-Xiebai-Guizhi Decoction (ZXGD), traditional Chinese medicine with a long history of use in treating heart and lung diseases, lacks a clear understanding of its pharmacological mechanism. OBJECTIVE: This study aimed to investigate the pharmacological effects and mechanisms of ZXGD on HPH. METHODS: We conducted a network pharmacological prediction analysis and molecular docking to predict the effects, which were verified through in vivo experiments. RESULTS: Network pharmacological analysis revealed 51 active compounds of ZXGD and 701 corresponding target genes. Additionally, there are 2,116 target genes for HPH, 311 drug-disease co-target genes, and 17 core target genes. GO functional annotation analysis revealed that the core target genes primarily participate in biological processes such as apoptosis and cellular response to hypoxia. Furthermore, KEGG pathway enrichment analysis demonstrated that the core targets are involved in several pathways, including the phosphatidylinositol- 3 kinase/protein kinase B (PI3K/Akt) signaling pathway and Hypoxia Inducible Factor 1 (HIF1) signaling pathway. In vivo experiments, the continuous administration of ZXGD demonstrated a significant improvement in pulmonary artery pressure, right heart function, pulmonary vascular remodeling, and pulmonary vascular fibrosis in HPH rats. Furthermore, ZXGD was found to inhibit the expression of PI3K, Akt, and HIF1α proteins in rat lung tissue. CONCLUSION: In summary, this study confirmed the beneficial effects and mechanism of ZXGD on HPH through a combination of network pharmacology and in vivo experiments. These findings provided a new insight for further research on HPH in the field of traditional Chinese medicine.

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BACKGROUND AND AIMS: Isogarcinol, a natural compound extracted from the fruits of Garcinia oblongifolia, has potential chemopreventive activity. This study aimed to elucidate the anti-tumor effects and mechanism of action of isogarcinol on nasopharyngeal carcinoma (NPC). METHODS: Isogarcinol was isolated from Garcinia oblongifolia by using chromatographic separation. The anti-tumor effects of isogarcinol in NPC cells were tested by MTT assay, flow cytometry, wound healing assay, western blotting, transwell assay, colony formation assay, immunofluorescence, and transmission electron microscopy (TEM). The anti-tumor efficacy in vivo was evaluated in NPC cells xenograft models. RESULTS: Functional studies revealed that isogarcinol inhibited the proliferation, colony formation, migration and invasion abilities of NPC cells in vitro. Isogarcinol caused mitochondrial damage to overproduce reactive oxygen species through reducing the mitochondrial membrane potential and ΔΨm. Isogarcinol also substantially inhibited NPC cells growth in a xenograft tumor model without any obvious toxicity when compared with paclitaxel (PTX). Mechanistic studies have illustrated that isogarcinol increased the Bax/Bcl-2 ratio, cleaved caspase-3, and cytoplasmic cytochrome C levels to induce mitochondrial apoptosis. The ROS overproduction by isogarcinol could suppress EMT pathway via decreasing the levels of p-Akt and Snail. Furthermore, isogarcinol promoted the conversion of LC3-Ⅰ to LC3-Ⅱ, but increased p62 level to block autophagic flux, resulting in the accumulation of damaged mitochondria to promote autophagic cell death in NPC cells. CONCLUSION: This study provides a new theoretical foundation for the anti-tumor application of Garcinia oblongifolia and confirms that isogarcinol could be developed as a candidate drug for NPC treatment with low toxicity.

Asunto(s)

Antineoplásicos Fitogénicos , Garcinia , Ratones Desnudos , Mitocondrias , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Garcinia/química , Animales , Mitocondrias/efectos de los fármacos , Línea Celular Tumoral , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Antineoplásicos Fitogénicos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Muerte Celular Autofágica/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Frutas/química

RESUMEN

AIMS: Activation of central respiratory chemoreceptors provides excitatory drive to both respiratory and sympathetic outputs. The enhanced respiratory-sympathetic coupling contributes to the onset and development of hypertension. However, the specific central targets and molecular mechanisms involved in this process remain elusive. This study aimed to investigate the role of acid-sensing ion channel 1 (ASIC1) in nucleus tractus solitarii (NTS) neurons in CO2-stimulated cardiorespiratory effects in spontaneously hypertensive rats (SHRs). MAIN METHODS: Respiration and blood pressure of conscious rats were recorded by whole-body plethysmography and telemetry, respectively. Western blot was used to detect the expression difference of ASIC1 protein in NTS region between Wistar-Kyoto (WKY) rats and SHRs. Excitability of NTS neurons were assessed by extracellular recordings. KEY FINDINGS: Compared to WKY rats, the enhanced CO2-stimulated cardiopulmonary effect and up-regulation of ASIC1 in the NTS were already observed in 4-week-old prehypertensive SHRs. Furthermore, specific blockade of ASIC1 effectively attenuated the CO2-stimulated increase in firing rate of NTS neurons in anesthetized adult SHRs. Intracerebroventricular injections of the ASIC1a blocker PcTx1 or knockdown Asic1 in NTS neurons significantly reduced the heightened CO2-stimulated ventilatory response, and diminished the CO2-stimulated increase in arterial pressure and heart rate in adult SHRs. SIGNIFICANCE: These findings showed that dysregulated ASIC1 signaling in the NTS contribute to the exaggerated CO2-stimulated cardiorespiratory effects observed in SHRs.

Asunto(s)

Canales Iónicos Sensibles al Ácido , Presión Sanguínea , Dióxido de Carbono , Hipertensión , Neuronas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Núcleo Solitario , Animales , Canales Iónicos Sensibles al Ácido/metabolismo , Núcleo Solitario/metabolismo , Ratas , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Masculino , Dióxido de Carbono/metabolismo , Hipertensión/metabolismo , Hipertensión/fisiopatología , Presión Sanguínea/efectos de los fármacos , Respiración/efectos de los fármacos , Péptidos , Venenos de Araña

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The detection of monoamine neurotransmitters is of paramount importance as the neurotransmitters are the chemical messengers regulating the gut-brain axis (GBA). It requires real-time, ultrasensitive, and selective sensing of the neurotransmitters in the gastric/intestinal fluid. However, multi-components present in the gastric/intestinal fluid make sensing challenging to achieve in terms of ultra-high sensitivity and selectivity. Herein, an approach is introduced to utilize vanadium single atom catalytic (SAC) centers in van der Waals MoS2 (V-MoS2) to selectively detect real-time serotonin (5-HT) in artificial gastric/intestinal fluid. The synergetic effect of V-SACs and the surface S-bonds on the MoS2 surface, enables an extremely wide range of 5-HT detection (from 1 pM to 100 µM), with optimum selectivity and interference resistance. By combining density functional theory calculations and scanning transmission electron microscopy, it is concluded that the V-SACs embedded in the MoS2 network create active sites that greatly facilitate the charge exchange between the material and the 5-HT molecules. This result allows the 5-HT detection in GBA studies to be more reliable, and the material tunability provides a general platform to achieve real-time and multi-component detection of other monoamine neurotransmitters in GBA such as dopamine and norepinephrine.

RESUMEN

The COVID-19 pandemic has made assessing vaccine efficacy more challenging. Besides neutralizing antibody assays, systems vaccinology studies use omics technology to reveal immune response mechanisms and identify gene signatures in human peripheral blood mononuclear cells (PBMCs). However, due to their low proportion in PBMCs, profiling the immune response signatures of dendritic cells (DCs) is difficult. Here, we develop a predictive model for evaluating early immune responses in dendritic cells. We establish a THP-1-derived dendritic cell (TDDC) model and stimulate their maturation in vitro with an optimal dose of attenuated yellow fever 17D (YF-17D). Transcriptomic analysis reveals that type I interferon (IFN-I)-induced immunity plays a key role in dendritic cells. IFN-I regulatory biomarkers (IRF7, SIGLEC1) and IFN-I-inducible biomarkers (IFI27, IFI44, IFIT1, IFIT3, ISG15, MX1, OAS2, OAS3) are identified and validated in vitro and in vivo. Furthermore, we apply this TDDC approach to various types of vaccines, providing novel insights into their early immune response signatures and their heterogeneity in vaccine recipients. Our findings suggest that a standardizable TDDC model is a promising predictive approach to assessing early immunity in DCs. Further research into vaccine efficacy assessment approaches on various types of immune cells could lead to a systemic regimen for vaccine development in the future.

Asunto(s)

Células Dendríticas , Vacunación , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Vacunación/métodos , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Células THP-1 , COVID-19/inmunología , COVID-19/prevención & control , Animales , SARS-CoV-2/inmunología , Biomarcadores , Vacunas contra la COVID-19/inmunología , Perfilación de la Expresión Génica , Ratones , Transcriptoma , Vacuna contra la Fiebre Amarilla/inmunología

RESUMEN

The tigecycline resistance gene tet(X4) has been widely reported in animals and animal products in some Asian countries including China in recent years but only sporadically detected in human. In this study, we investigated the prevalence and genetic features of tet(X4)-positive clinical E. coli strains. A total of 462 fecal samples were collected from patients in four hospitals located in four provinces in China in 2023. Nine tet(X4)-positive E. coli strains were isolated and subjected to characterization of their genetic and phenotypic features by performing antimicrobial susceptibility test, whole-genome sequencing, bioinformatic and phylogenetic analysis. The majority of the test strains were found to exhibit resistance to multiple antimicrobial agents including tigecycline but remained susceptible to colistin and meropenem. A total of seven different sequence types (STs) and an unknown ST type were identified among the nine tet(X4)-positive strains. Notably, the tet(X4) gene in six out of these nine tet(X4)-positive E. coli strains was located in a IncFIA-HI1A-HI1B hybrid plasmid, which was an tet(X4)-bearing epidemic plasmid responsible for dissemination of the tet(X4) gene in China. Furthermore, the tet(X4) gene in four out of nine tet(X4)-positive E. coli isolates could be successfully transferred to E. coli EC600 through conjugation. In conclusion, this study characterized the epidemic tet(X4)-bearing plasmids and tet(X4)-associated genetic environment in clinical E. coli strains, suggested the importance of continuous surveillance of such tet(X4)-bearing plasmids to control the increasingly widespread dissemination of tigecycline-resistant pathogens in clinical settings in China.

Asunto(s)

Antibacterianos , Infecciones por Escherichia coli , Escherichia coli , Heces , Pruebas de Sensibilidad Microbiana , Filogenia , Plásmidos , Tigeciclina , China/epidemiología , Escherichia coli/genética , Escherichia coli/efectos de los fármacos , Escherichia coli/aislamiento & purificación , Plásmidos/genética , Humanos , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/epidemiología , Antibacterianos/farmacología , Tigeciclina/farmacología , Heces/microbiología , Prevalencia , Secuenciación Completa del Genoma , Proteínas de Escherichia coli/genética , Genoma Bacteriano , Farmacorresistencia Bacteriana Múltiple/genética , Genómica

RESUMEN

Acute myeloid leukemia (AML) is frequently linked to genetic abnormalities, with the t (8; 21) translocation, resulting in the production of a fusion oncoprotein AML1-ETO (AE), being a prevalent occurrence. This protein plays a pivotal role in t (8; 21) AML's onset, advancement, and recurrence, making it a therapeutic target. However, the development of drug molecules targeting AML1-ETO are markedly insufficient, especially used in clinical treatment. In this study, it was uncovered that Neratinib could significantly downregulate AML1-ETO protein level, subsequently promoting differentiation of t (8; 21) AML cells. Based on "differentiated active" probes, Neratinib was identified as a functional inhibitor against HNRNPA3 through covalent binding. The further studies demonstrated that HNRNPA3 function as a putative m6A reader responsible for recognizing and regulating the alternative splicing of AML-ETO pre-mRNA. These findings not only contribute to a novel insight to the mechanism governing post-transcriptional modification of AML1-ETO transcript, but also suggest that Neratinib would be promising therapeutic potential for t (8; 21) AML treatment.

Asunto(s)

Diferenciación Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Quinolinas , Proteína 1 Compañera de Translocación de RUNX1 , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patología , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Quinolinas/farmacología , Diferenciación Celular/efectos de los fármacos , Proteína 1 Compañera de Translocación de RUNX1/genética , Proteína 1 Compañera de Translocación de RUNX1/metabolismo , Precursores del ARN/metabolismo , Precursores del ARN/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Translocación Genética/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/farmacología , Empalme Alternativo/efectos de los fármacos , Línea Celular Tumoral , Animales , Ratones

RESUMEN

Pandemics caused by respiratory viruses, such as the SARS-CoV-1/2, influenza virus, and respiratory syncytial virus, have resulted in serious consequences to humans and a large number of deaths. The detection of such respiratory viruses in the early stages of infection can help control diseases by preventing the spread of viruses. However, the diversity of respiratory virus species and subtypes, their rapid antigenic mutations, and the limited viral release during the early stages of infection pose challenges to their detection. This work reports a multiplexed microfluidic immunoassay chip for simultaneous detection of eight respiratory viruses with noticeable infection population, namely, influenza A virus, influenza B virus, respiratory syncytial virus, SARS-CoV-2, human bocavirus, human metapneumovirus, adenovirus, and human parainfluenza viruses. The nanomaterial of the nanozyme (Au@Pt nanoparticles) was optimized to improve labeling efficiency and enhance the detection sensitivity significantly. Nanozyme-binding antibodies were used to detect viral proteins with a limit of detection of 0.1 pg/mL with the naked eye and a microplate reader within 40 min. Furthermore, specific antibodies were screened against the conserved proteins of each virus in the immunoassay, and the clinical sample detection showed high specificity without cross reactivity among the eight pathogens. In addition, the microfluidic chip immunoassay showed high accuracy, as compared with the RT-PCR assay for clinical sample detection, with 97.2%/94.3% positive/negative coincidence rates. This proposed approach thus provides a convenient, rapid, and sensitive method for simultaneous detection of eight respiratory viruses, which is meaningful for the early diagnosis of viral infections. Significantly, it can be widely used to detect pathogens and biomarkers by replacing only the antigen-specific antibodies.

RESUMEN

Rheumatoid arthritis (RA) is a systemic immune disease with severe implications for joint health. The issue of non-specific drug distribution potentially limits the therapeutic efficacy and increases the risk associated with RA treatment. Researchers employed cytomembrane-coated biomimetic nanoparticles (NPs) to enhance the targeting delivery efficacy to meet the demand for drug accumulation within the affected joints. Furthermore, distinct cytomembranes offer unique functionalities, such as immune cell activation and augmented NP biocompatibility. In this review, the current strategies of RA treatments were summarized in detail, and then an overview of RA's pathogenesis and the methodologies for producing cytomembrane-coated biomimetic NPs was provided. The application of cytomembrane biomimetic NPs derived from various cell sources in RA therapy is explored, highlighting the distinctive attributes of individual cytomembranes as well as hybrid membrane configurations. Through this comprehensive assessment of cytomembrane biomimetic NPs, we elucidate the prospective applications and challenges in the realm of RA therapy, and the strategy of combined therapy is proposed. In the future, cytomembrane biomimetic NPs have a broad therapeutic prospect for RA.