A MnAl double adjuvant nanovaccine to induce strong humoral and cellular immune responses.

At present, the most widely used aluminum adjuvants have poor ability to induce effective Th1 type immune responses. Existing evidence suggests that manganese is a potential metal adjuvant by activating cyclic guanosine phospho-adenosine synthase (cGAS)-interferon gene stimulator protein (STING) signaling pathway to enhance humoral and cellular immune response. Hence, the effective modulation of metal components is expected to be a new strategy to improve the efficiency of vaccine immunization. Here, we constructed a manganese and aluminum dual-adjuvant antigen co-delivery system (MnO2-Al-OVA) to enhance the immune responses of subunit vaccines. Namely, the aluminum hydroxide was first fused on the surface of the pre-prepared MnO2 nanoparticles, which were synthesized by a simple redox reaction with potassium permanganate (KMnO4) and oleic acid (OA). The engineered MnO2-Al-OVA could remarkably promote cellular internalization and maturation of dendritic cells. After subcutaneous vaccination, MnO2-Al-OVA rapidly migrated into the lymph nodes (LNs) and efficiently activate the cGAS-STING pathway, greatly induced humoral and cellular immune responses. Of note, our findings underscore the importance of coordination manganese adjuvants in vaccine design by promoting the activation of the cGAS-STING-IFN-I pathway. With a good safety profile and facile preparation process, this dual-adjuvant antigen co-delivery nanovaccine has great potential for clinical translation prospects.

Kinsenoside alleviates oxidative stress-induced blood-brain barrier dysfunction via promoting Nrf2/HO-1 pathway in ischemic stroke.

An ischemic stroke usually causes blood-brain barrier (BBB) damage and excessive oxidative stress (OS) levels. Kinsenoside (KD), a major effective compound extracted in Chinese herbal medicine Anoectochilus roxburghii (Orchidaceae), has anti-OS effects. The present study focused on exploring KD's protection against OS-mediated cerebral endothelial cell damage and BBB damage within the mouse model. Intracerebroventricular administration of KD upon reperfusion after 1 h ischemia decreased infarct volumes, neurological deficit, brain edema, neuronal loss, and apoptosis 72 h post-ischemic stroke. KD improved BBB structure and function, as evidenced by a lower 18F-fluorodeoxyglucose pass rate of the BBB and upregulation of tight junction (TJ) proteins such as occludin, claudin-5, and zonula occludens-1 (ZO-1). KD protected bEnd.3 endothelial cells from oxygen and glucose deprivation/reoxygenation (OGD/R) injury in an in-vitro study. Meanwhile, OGD/R reduced transepithelial electronic resistance, whereas KD significantly increased TJ protein levels. Furthermore, based on in-vivo and in-vitro research, KD alleviated OS in endothelial cells, which is related to nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation as well as Nrf2/haem oxygenase 1 signaling protein stimulation. Our findings demonstrated that KD might serve as a potential compound for treating ischemic stroke involving antioxidant mechanisms.

Dual drugs decorated bacteria irradiate deep hypoxic tumor and arouse strong immune responses.

Intratumoral environment as a hypoxic, non-inflamed "cold" state is difficult for many agents to accumulate and activate the immune system. Intrinsically, facultative anaerobic Salmonella VNP20009 target the tumor hypoxic areas, invade into tumor cells and exhibit an immune effect. Here we engineer the bacteria by decorating their surface with newly synthesized heptamethine cyanine dyes NHS-N782 and JQ-1 derivatives to obtain the biohybrid agent N-V-J, leading to the deep tumor targeted photothermal therapy and magnified immunotherapy. Due to the mitochondrial targeting capacity of NHS-N782, N-V-J becomes susceptive to the temperature rise when reaching tumors. This synergistic strategy promotes the systemic immunity by creating an inflamed "hot" tumor state from three different dimensions, which include the inherent immunogenicity of bacteria, the near-infrared laser triggered tumor antigens and the downregulation of PD-L1 expression. All these approaches result in effective and long-lasting T cell immune responses to prevent local and distant tumors for extended time. Leveraging the attenuated bacteria to transport dual drugs to the tumor tissues for self-synthetic vaccines provides a novel paradigm to enhance the bacteria-mediated cancer immunotherapy.

Computational fluid dynamics analysis of Trichosporon fermentans flocculation in refined soybean oil wastewater and flocculation rate prediction method.

Trichosporon fermentans can be used to treat refined soybean oil wastewater (RSOW) and produce microbial lipids. Bioflocculation is an effective method to recover Trichosporon fermentans which accumulates intracellular oils from wastewater. During the flocculation, the hydrodynamic distribution and parameters in the reactor are important limiting factors of yeast flocculation performance. In a 0.25 L flocculation device, it was found that the appropriate range of turbulence kinetic energy was within 0.00065-0.00073 m2/s2, the dissipation rate was within 0.119-0.317 m2/s3, and the shear force was less than 0.433 Pa by computational fluid dynamics. In this case, the flocculation rate (Fr) of Trichosporon fermentans could reach more than 90%. The empirical formula associated Fr of Trichosporon fermentans with hydrodynamic parameters was obtained by Matlab, and improved in the enlargement of flocculation device, displaying an error of less than 3.03%. A conical draft tube airlift circulating reactor for flocculation was designed based on the empirical formula, and the Fr reached 91.3%. The study shows that it is feasible to predict Fr of Trichosporon fermentans according to hydrodynamic parameters by numerical simulation, and design the industrial reactor for flocculation harvesting yeasts. It is also helpful for large-scale treatment of RSOW in a safe environment.

Systemic In Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server.

The emergence of the new coronavirus (nCoV-19) has impacted human health on a global scale, while the interaction between the virus and the host is the foundation of the disease. The viral genome codes a cluster of proteins, each with a unique function in the event of host invasion or viral development. Under the current adverse situation, we employ virtual screening tools in searching for drugs and natural products which have been already deposited in DrugBank in an attempt to accelerate the drug discovery process. This study provides an initial evaluation of current drug candidates from various reports using our systemic in silico drug screening based on structures of viral proteins and human ACE2 receptor. Additionally, we have built an interactive online platform (https://shennongproject.ai/) for browsing these results with the visual display of a small molecule docked on its potential target protein, without installing any specialized structural software. With continuous maintenance and incorporation of data from laboratory work, it may serve not only as the assessment tool for the new drug discovery but also an educational web site for the public.

Computational fluid dynamics and factor analysis of a novel swirling demulsified airlift loop reactor for the treatment of refined soybean oil wastewater.

A swirling demulsified airlift loop reactor (SD-ALR) was developed for the treatment of oily wastewater with yeasts. Computational fluid dynamics simulations showed that the gas holdup and liquid velocity gradient in the SD-ALR were 2.9% and 0.37 m/s higher than those in the traditional airlift loop reactor. The optimization results of the swirling demulsifier showed that the optimal number and elevation angle of the blades were 8 and 45°, and the optimal installation position was 150 mm from the bottom of the draft tube. The results of treating refined soybean oil wastewater in the SD-ALR showed that the wastewater treatment time was decreased by 8 h, and the removals of chemical oxygen demand and oil content increased by 5.10% ±â€¯0.02% and 9.55% ±â€¯0.40%, respectively, compared with those in the traditional airlift loop reactor. A volumetric mass transfer coefficient model was established for SD-ALR and oily wastewater.

Trichosporon fermentans biomass flocculation from soybean oil refinery wastewater using bioflocculant produced from Paecilomyces sp. M2-1.

The soybean oil refinery (SOR) wastewater contains a high concentration of chemical oxygen demand (COD) and lipid, so the direct emissions of SOR wastewater will result in environmental pollution and waste of resources. Oleaginous yeast Trichosporon fermentans can consume organic materials in SOR wastewater to synthesize microbial oil, which achieves the purpose of SOR wastewater resource utilization. The effective harvesting technology of oleaginous yeasts can improve the utilization efficiency. In this study, Paecilomyces sp. M2-1 with high flocculating activity was isolated. The flocculants produced by M2-1 (MBF2-1) include 75% (w/w) polysaccharides, rely on cations, and display the flocculation percentage of above 77% in the range of pH 2-11. Especially under alkaline conditions, the flocculation percentage can be kept above 97%. The results of scanning electron microscope observation and zeta potential measurements suggested that the bridging, net trapping, and sweeping were the main flocculation mechanism of MBF2-1. MBF2-1 could flocculate T. fermentans that was used to reduce the organic matter in SOR wastewater and to produce microbial oil. Under the optimum conditions, the flocculation percentage of MBF2-1 against T. fermentans from SOR wastewater can reach 95%. Fatty acid content percent in microbial oil from T. fermentans was not almost affected by flocculation of MBF2-1. Moreover, MBF2-1 can further remove 55% and 53% of COD and oil content in the fermented SOR wastewater, respectively. The properties and high flocculating percentage displayed by MBF2-1 indicated its potential application prospect in oleaginous yeast harvest and food industry wastewater treatment.

Cost-effectiveness analysis of dabigatran versus rivaroxaban for stroke prevention in patients with non-valvular atrial fibrillation using real-world evidence in elderly US Medicare beneficiaries.

OBJECTIVE: Dabigatran and rivaroxaban have been approved by the US FDA to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF) patients. Newly published real-world evidence based on the US population found that elderly Medicare patients with NVAF treated with rivaroxaban experienced statistically significant increases in intracranial hemorrhage (ICH) and major extracranial bleeding, and statistically nonsignificant decreases in thromboembolic stroke and acute myocardial infarction (AMI) compared with dabigatran. This study assessed the cost-effectiveness of dabigatran vs. rivaroxaban for the treatment of US Medicare NVAF patients. METHODS: A previously published Markov model was adapted to compare dabigatran and rivaroxaban. The model considered thromboembolic stroke, bleeding events, and AMI based on the published real-world event risks. Model outputs included clinical event rates, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: Dabigatran patients experienced fewer ICH and major extracranial bleeding events than rivaroxaban patients, but more stroke and AMI events. Dabigatran was found to yield lower costs and higher QALYs than rivaroxaban, with incremental costs of -$3534 and incremental QALYs of 0.004. Results remained consistent in sensitivity analyses, with a positive net monetary benefit (willingness-to-pay thresholds of $50,000 and $100,000 per QALY) for dabigatran over rivaroxaban for all model inputs tested. CONCLUSIONS: In this study using US Medicare real-world data, dabigatran was found to dominate rivaroxaban. The analyses were limited by the short follow-up period of the real-world data and results may not be generalizable to other patient populations.

[Estimation and Visualization of Nitrogen Content in Citrus Canopy Based on Two Band Vegetation Index (TBVI)].

Nitrogen is a necessary and important element for the growth and development of fruit orchards. Timely, accurate and nondestructive monitoring of nitrogen status in fruit orchards would help maintain the fruit quality and efficient production of the orchard, and mitigate the pollution of water resources caused by excessive nitrogen fertilization. This study investigated the capability of hyperspectral imagery for estimating and visualizing the nitrogen content in citrus canopy. Hyperspectral images were obtained for leaf samples in laboratory as well as for the whole canopy in the field with ImSpector V10E (Spectral Imaging Ltd., Oulu, Finland). The spectral datas for each leaf sample were represented by the average spectral data extracted from the selected region of interest (ROI) in the hyperspectral images with the aid of ENVI software. The nitrogen content in each leaf sample was measured by the Dumas combustion method with the rapid N cube (Elementar Analytical, Germany). Simple correlation analysis and the two band vegetation index (TBVI) were then used to develop the spectra data-based nitrogen content prediction models. Results obtained through the formula calculation indicated that the model with the two band vegetation index (TBVI) based on the wavelengths 811 and 856 nm achieved the optimal estimation of nitrogen content in citrus leaves (R2 = 0.607 1). Furthermore, the canopy image for the identified TBVI was calculated, and the nitrogen content of the canopy was visualized by incorporating the model into the TBVI image. The tender leaves, middle-aged leaves and elder leaves showed distinct nitrogen status from highto low-levels in the canopy image. The results suggested the potential of hyperspectral imagery for the nondestructive detection and diagnosis of nitrogen status in citrus canopy in real time. Different from previous studies focused on nitrogen content prediction at leaf level, this study succeeded in predicting and visualizing the nutrient content of fruit trees at canopy level. This would provide valuable information for the implementation of individual tree-based fertilization schemes in precision orchard management practices.

Genomewide analysis of rat periaqueductal gray-dorsal horn reveals time-, region- and frequency-specific mRNA expression changes in response to electroacupuncture stimulation.

Electroacupuncture (EA) has been widely applied for illness prevention, treatment or rehabilitation in the clinic, especially for pain management. However, the molecular events that induce these changes remain largely uncharacterized. The periaqueductal gray (PAG) and the spinal dorsal horn (DH) have been verified as two critical regions in the response to EA stimulation in EA analgesia. In this study, a genetic screen was conducted to delineate the gene expression profile in the PAG-DH regions of rats to explore the molecular events of the analgesic effect induced by low-frequency (2-Hz) and high-frequency (100-Hz) EAs. Microarray analysis at two different time points after EA stimulation revealed time-, region- and frequency-specific gene expression changes. These expression differences suggested that modulation of neural-immune interaction in the central nervous system played an important role during EA analgesia. Furthermore, low-frequency EA could regulate gene expression to a greater degree than high-frequency EA. Altogether, the present study offers, for the first time, a characterized transcriptional response pattern in the PAG-DH regions followed by EA stimulation and, thus, provides a solid experimental framework for future in-depth analysis of the mechanisms underlying EA-induced effects.