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Abstract The growth of newly formed particles through new particle formation (NPF) contributes a significant fraction to the cloud condensation nuclei, yet the driving mechanisms remain unclear, especially for polluted environments. To investigate the potential species contributing for nanoparticle growth in environments with significant anthropogenic influences, we measured the hygroscopicity of newly formed particles at 20–40 nm at a rural observational site in the North China Plain during winter 2018. Our results demonstrate that these particles were not very hygroscopic, with the mean hygroscopicity parameter κ of 0.13 ± 0.09. Clear differences in the inferred κ of the growing material responsible for the growth were observed among different events, indicating that even at the same region, the compounds driving particle growth may not be identical. This may be synergistically influenced by the NPF precursors, oxidants and meteorological conditions, suggesting complex mechanisms might co‐exist behind nanoparticle growth in polluted environments.

Abstract Background Eustachian tube dysfunction (ETD) is the predominant cause of otitis media with effusion in children and adults. Balloon dilatation of the Eustachian tube (BDET) provides a new method for restoring the ventilatory function of Eustachian tube (ET). However, the differences in age‐related morphological changes in the dimensions and positions of ET in children and adults are unclear. Purpose This study aimed to examine age‐related morphological changes in bony and cartilage segments of the ET in a three‐dimensional space in normal population. Methods A total of 71 randomly selected computed tomography (CT) images of the temporal bones of 46 people were retrospectively studied in four age groups: A (0–3 years old); B (4–8 years old), C (9–18 years old), and D (19–65 years old). Space analytic geometry was assessed to calculate the dimensions and positions of ET. Results The bony segment of ET lengthened from infancy to adulthood with age in groups A, B and C (r = 0.562**/0.000). The cartilage segment of ET mostly extended with age from infancy to 8 years old in children (r = 0.633**/0.000), but with bending close to the sagittal plane and away from the horizontal plane with age in groups A, B and C (P .05). Conclusion The bony and cartilaginous segments of ET exhibit distinct morphological changes in space with age. The bony segment of ET extends in a constant position from infancy to adulthood. In contrast, the cartilaginous segment of the ET indicates multidimensional positional changes until adulthood, in addition to the elongation from infancy to children. This may provide an accurate morphological basis for comparing the differences in ETD pathogenesis and surgical treatment between children and adults.

Here, we compared the concentrations of cloud condensation nuclei (CCN) and particle number size distributions (PNSDs) measured during the transient period from the winter to the summer East Asian monsoon in 2021 with those in 2014 to explore possible responses to how CCN responds to upwind continental air pollutant mitigation and marine traffic fuel sulfur content (FSC) regulation over the northwest Pacific Ocean (NWPO). We also employed the Positive Matrix Factorization (PMF) analysis to apportion concentrations of CCN (Nccn) to different sources in order to quantify its source-specified responses to mitigation of air pollution during the transient period. Our results showed that (1) upwind continental mitigation likely reduced Nccn by approximately 200 cm−3 and 400 cm−3 at 0.2% and 0.4% supersaturation (SS), respectively, in the marine background atmosphere over the NWPO; (2) FSC regulation resulted in a decrease in Nccn at 0.4% SS by about 50 cm−3 and was nearly negligible at 0.2% SS over the NWPO. Additionally, a PMF-resolved factor, characterized by a dominant nucleation mode, was present only in 2014 and disappeared in 2021, likely due to the reduction. This estimation, however, suffered from uncertainties since seasonal changes were hard to be deducted accurately. PMF-resolved factors accurately represented Nccn in 80–90% of cases, but this accuracy was not observed in the remaining cases. Finally, an integrated analysis of satellite-derived cloud parameters and ship-based measurements indicated that the reduced Nccn over the NWPO might be co-limited with meteorological factors in forming cloud droplets during the transient period.

An important challenge in industrial laser ablation is laser-induced damage. In this study, reduced damage was achieved through the transition of the laser distribution from a Gaussian beam to a top-hat beam using diffractive optical elements (DOE), which overcome inhomogeneous irradiation. The higher peak fluence of a Gaussian beam far exceeded the ablation threshold and led to severely melted silicon at a higher depth covering the polished texture. The top-hat beam, with uniform irradiation, had a superior ablation characteristic and created a uniform square opening with the shallow melted silicon in the lift-off process. Thus, its effective minor carrier lifetime was 15.35% less at an ablated area fraction of 2% after re-passivation because of the decreased damage. After optimizing the ablation pattern with a top-hat beam, the local contacts improved the average open-circuit voltage (Voc) and short-circuit current (Isc) values of the cells due to the decreased damage and the uniform openings, but the damage induced by a Gaussian beam was too deep and can be partly restored under back surface field (BSF) formation. The overall increment in Isc and Voc enhanced the average efficiency by 0.05% of the absolute value for the PERC cells and 0.03% of the absolute value for bi-facial PERC cells.

To investigate the early hydration and consolidation mechanism of superfine metal tailings powder in the CaO–CaSO4–H2O system, a clinker-free consolidation material based on iron tailings powder was prepared by superfine grinding lime, gypsum, and iron tailings. From 3 min to 24 h, the liquid phase of the hydrated slurry was extracted by centrifugation and high-pressure extraction. The changes in ion concentration and conductivity were tested, and the relationship between them was analyzed. The relationship between the formation mechanism of early hydration products of a consolidated body and the change of liquid phase characteristics is studied combined with the hydration exothermic rate curve, field emission scanning electron microscope (SEM), X-ray diffraction analysis (XRD), thermogravimetry-differential thermal analysis (TG–DSC), and other test methods. The results show that lime, gypsum, and amorphous components, which are on the surface of iron tailings powder, dissolve rapidly within a few minutes after solid-liquid mixing. The concentration of each ion in the liquid phase rises sharply, reaching the peak or saturated state successively in 10–30 min, and then decreases rapidly. After 180 min, the decline rate slows down but continues to decline. The liquid conductivity has a very high positive correlation with the total concentration of Ca2+, OH–， and SO42– ions; The first hydration exothermic peak of the consolidated material is concentrated within 0–15 min, which is mainly caused by the wetting and dissolution of soluble components in the consolidated material and the exothermic behavior of lime hydration; The starting and ending time of the second hydration exothermic behavior is 20–180 min, which is mainly caused by the phase change heat generated by the formation of hydration products. Increasing the grinding time significantly prolongs the termination time of the second exothermic behavior and increases its peak value; The phase analysis of hydration products showed that AFt characteristic peak and C–S–H endothermic peak could be seen in the slurry after hydration for 90 min. Research has proved that the amorphous SiO2 and Al2O3 on the surface of superfine iron tailings powder have the characteristics of rapid dissolution in alkaline solutions, and a hydration reaction can occur when lime and gypsum components are encountered. When the solubility product of hydration products is reached, hydration products AFt and C–S–H will be generated. The two hydration products are interspersed and cemented with each other, and the unhydrated iron tailings particles will be consolidated to form a hardened body. Prolonging the grinding time can effectively increase the system’s amorphous SiO2 and Al2O3 content and the proportion of superfine particles in iron tailings, thus improving the slurry hydration rate. While increasing the amount of the hydration product, the filling effect of the micro powder part is further increased, and the strength of the consolidated body is correspondingly improved.

AimsTo verify whether the oral insulin N11005 is administered as a prandial insulin by assessing the pharmacokinetics (PK), pharmacodynamics (PD), and safety profiles of N11005 with a short-acting biosynthetic human insulin (Novolin R) as reference.MethodsThis was a randomized, open-label, single-dose, crossover hyperinsulinemic-euglycemic clamp study in healthy Chinese male subjects. A total of 12 subjects were enrolled in the test (T) group (N11005, 300 IU, p.o.) and the reference (R) group (Novolin R, 0.1 IU/Kg, i.h.) with a washout period of 14 days. All subjects were administered on the same day of the clamp study. Glucose Infusion Rates (GIR), serum insulin, and C-peptide concentration were determined during every 8-hour clamp cycle. Trial registration: Clinicaltrials.gov identifier NCT04975022.ResultsAfter administration, the ratios of mean serum C-peptide concentration to baseline concentration in both T and R groups were lower than 50%, which confirmed the stability of the clamp platform. T group (N11005) showed a more rapid onset of action (tGIR10%max≈11 min) and a comparable duration of action to the R group, which was basically in line with the characteristics of prandial insulins. No adverse events (AEs) occurred throughout the study, which demonstrated that N11005 and Novolin R are safe and well-tolerated.ConclusionsThe PD profiles of the single-dose N11005 in the human body are similar to those of prandial insulins, with an excellent safety profile.Clinical trial registrationClinicaltrials.gov, identifier NCT04975022.

Abstract Background Esophageal carcinoma (ESCA) is a common malignancy with a poor prognosis. Previous research has suggested that necroptosis is involved in anti-tumor immunity and promotes oncogenesis and cancer metastasis, which in turn affects tumor prognosis. However, the role of necroptosis in ESCA is unclear. This study aimed to investigate the relationships between necroptosis-related genes (NRGs) and ESCA. Methods and results The clinical data and gene expression profiles of ESCA patients were extracted from The Cancer Genome Atlas (TCGA), and 159 NRGs were screened from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We then identified 52 differentially expressed NRGs associated with ESCA and used them for further analysis. Gene ontology (GO) and KEGG functional enrichment analyses showed that these NRGs were mostly associated with the regulation of necroptosis, Influenza A, apoptosis, NOD-like receptor, and NF-Kappa B signaling pathway. Next, univariate and multivariate Cox regression and LASSO analysis were used to identify the correlation between NRGs and the prognosis of ESCA. We constructed a prognostic model to predict the prognosis of ESCA based on SLC25A5, PPIA, and TNFRSF10B; the model classified patients into high- and low-risk subgroups based on the patient’s risk score. Furthermore, the receiver operating characteristic (ROC) curve was plotted, and the model was affirmed to perform moderately well for prognostic predictions. In addition, Gene Expression Omnibus (GEO) datasets were selected to validate the applicability and prognostic value of our predictive model. Based on different clinical variables, we compared the risk scores between the subgroups of different clinical features. We also analyzed the predictive value of this model for drug sensitivity. Moreover, Immunohistochemical (IHC) validation experiments explored that these three NRGs were expressed significantly higher in ESCA tissues than in adjacent non-tumor tissues. In addition, a significant correlation was observed between the three NRGs and immune-cell infiltration and immune checkpoints in ESCA. Conclusions In summary, we successfully constructed and validated a novel necroptosis-related signature containing three genes (SLC25A5, PPIA, and TNFRSF10B) for predicting prognosis in patients with ESCA; these three genes might also play a crucial role in the progression and immune microenvironment of ESCA.

Exhausted shallow resources have turned mining into deep mining, with the mining depth of most mines under construction being more than 1000 m. With the continuous increase of the mining depth of mineral resources, the thickness and strength grade of the shaft lining concrete increases, resulting in higher hydration heat. The freezing method is usually used in deep well construction, resulting in a high temperature on one side and a low temperature on the other side of the shaft wall concrete. The influence law of this environment on concrete needs to be studied. It is of great theoretical significance for deep well construction and service safety to find out the change law of the shaft wall concrete performance under a freezing construction environment. The temperature difference between −5/60 ℃ and −5/70 ℃ was applied to simulate the state of the mass concrete in the freezing method construction environment. The ultrasonic parameters, compressive strength, splitting tensile strength, chloride diffusion coefficient, and bursting liability of concrete under the simulated environment were studied, and the scanning electron microscope of the concrete was analyzed. Results show that the freezing construction environment will cause certain damage to the interior of the concrete, and the damage parallel to the heating direction is greater than that in the vertical direction. The damage of the C50 concrete is greater than that of the C70 concrete, and the temperature gradient will aggravate the internal damage of the concrete. The simulated freezing environment will have adverse effects on the compressive strength, splitting tensile strength, chloride ion permeability, and bursting liability of the concrete. The temperature difference has a positive correlation with the performance reduction rate, which becomes more significant for low-strength concrete. The internal microstructure of the concrete block is uneven due to the simulated freezing environment, the concrete structure at the low-temperature end is loose, and the structure at the high-temperature end is dense, resulting in the decrease of the concrete’s performance.

Type 2 diabetes is associated with insulin resistance, impaired insulin secretion and liver steatosis. Here the authors report a proof-of-concept study for small molecule SWELL1 modulators as a therapeutic approach to treat diabetes and associated liver steatosis by enhancing systemic insulin-sensitivity and insulin secretion in mice.

IntroductionThe major challenge for universal chimeric antigen receptor T cell (UCAR-T) therapy is the inability to persist for a long time in patients leading to inferior efficacy clinically. The objective of this study was to design a novel UCAR-T cell that could avoid the occurrence of allo-rejection and provide effective resistance to allogeneic Natural Killer (NK) cell rejection, together with the validation of its safety and efficacy ex vivo and in vivo.MethodsWe prepared T-cell receptor (TCR), Human leukocyte antigen (HLA)-I/II triple-edited (TUCAR-T) cells and evaluated the anti-tumor efficacy ex vivo and in vivo. We measured the resistance of exogenous HLA-E expressing TUCAR-T (ETUCAR-T) to NK rejection by using an enhanced NK. Furthermore, we established the safety and efficacy of this regimen by treating Nalm6 tumor-bearing mice with a repeated high-dose infusion of ETUCAR-T. Moreover, we analyzed the effects of individual gene deficiency CAR-T on treated mice and the changes in the transcriptional profiles of different gene-edited T cells via RNA-Seq.ResultsData showed that HLA-II editing didn’t impair the anti-tumor efficacy of TUCAR-T ex vivo and in vivo and we found for the first time that HLA-II deficiency could facilitate the persistence of CAR-T. Contrastively, as the most commonly eliminated target in UCAR-T, TCR deficiency was found to be a key disadvantageous factor for the shorter-term anti-tumor efficacy in vivo. Our study demonstrated ETUCAR-T could effectively resist allogeneic NK rejection ex vivo and in vivo.DiscussionOur research provided a potential and effective strategy for promoting the persistence of UCAR-T cells in clinical application. And it reveals the potential key factors of the poor persistence of UCAR-T along with new insights for future development.

Persistent human papillomavirus (HPV) infection is recognized as the main cause of cervical cancer and other malignant cancers. Although early detection and treatment can be achieved by effective HPV screening methods and surgical procedures, the disease load has not been adequately mitigated yet, especially in the underdeveloped areas. Vaccine, being regarded as a more effective solution, is expected to prevent virus infection and the consequent diseases in the phases of both prevention and treatment. Currently, there are three licensed prophylactic vaccines for L1-VLPs, namely bivalent, quadrivalent and nonavalent vaccine. About 90% of HPV infections have been effectively prevented with the implementation of vaccines worldwide. However, no significant therapeutic effect has been observed on the already existed infections and lesions. Therapeutic vaccine designed for oncoprotein E6/E7 activates cellular immunity rather than focuses on neutralizing antibodies, which is considered as an ideal immune method to eliminate infection. In this review, we elaborate on the classification, mechanism, and clinical effects of HPV vaccines for disease prevention and treatment, in order to make improvements to the current situation of HPV vaccines by provoking new ideas.

Abstract. Background:. Histone deacetylase 4 (HDAC4) regulates chondrocyte hypertrophy and bone formation. The aim of the present study was to explore the effects of HDAC4 on Interleukin 1 beta (IL-1β)-induced chondrocyte extracellular matrix degradation and whether it is regulated through the WNT family member 3A (WNT3A)/β-catenin signaling pathway. Methods:. Primary chondrocytes (CC) and human chondrosarcoma cells (SW1353 cells) were treated with IL-1β and the level of HDAC4 was assayed using Western blotting. Then, HDAC4 expression in the SW1353 cells was silenced using small interfering RNA to detect the effect of HDAC4 knockdown on the levels of matrix metalloproteinase 3 (MMP3) and MMP13 induced by IL-1β. After transfection with HDAC4 plasmids, the overexpression efficiency was examined using Real-time quantitative polymerase chain reaction (qRT-PCR) and the levels of MMP3 and MMP13 were assayed using Western blotting. After incubation with IL-1β, the translocation of β-catenin into the nucleus was observed using immunofluorescence staining in SW1353 cells to investigate the activation of the WNT3A/β-catenin signaling pathway. Finally, treatment with WNT3A and transfection with glycogen synthase kinase 3 beta (GSK3β) plasmids were assessed for their effects on HDAC4 levels using Western blotting. Results:. IL-1β downregulated HDAC4 levels in chondrocytes and SW1353 cells. Furthermore, HDAC4 knockdown increased the levels of MMP3 and MMP13, which contributed to the degradation of the extracellular matrix. Overexpression of HDAC4 inhibited IL-1β-induced increases in MMP3 and MMP13. IL-1β upregulated the levels of WNT3A, and WNT3A reduced HDAC4 levels in SW1353 cells. GSK-3β rescued IL-1β-induced downregulation of HDAC4 in SW1353 cells. Conclusion:. HDAC4 exerted an inhibitory effect on IL-1β-induced extracellular matrix degradation and was regulated partially by the WNT3A/β-catenin signaling pathway.

Red mud is a solid waste produced in the process of bauxite refining alumina, with high alkali content, and its treatment methods are mainly stacking and ocean dumping, which not only occupy a large amount of cultivated land and pollute land and water sources, but also have high safety risk. The preparation of red mud-based filling materials to fill the underground goaf can improve the utilization rate of mineral resources and reduce the harm of red mud to the environment, which has the effect of killing two birds with one stone. In view of the problems of low utilization rate of bayer red mud in mine filling system, low strength, bleeding and shrinkage in filling materials slurry with low concentration, the effects of the addition ratio of fly ash, desulfurization gypsum, lime and initiator on the early strength and volume stability were studied in this paper. Scanning electron microscope- energy dispersive spectroscope (SEM-EDS) and X-ray diffraction (XRD) were used to analyze the hydration mechanism of the filling materials. The results show that when the ratio of red mud to fly ash is 4∶6, the mechanical properties of the filling material are the best. Desulfurized gypsum promotes the formation of ettringite. Lime promotes the pozzolanic effect of fly ash. The composite activator can accelerate the hydration process of red mud and fly ash. All of this enhance the red mud backfill strength. The filling materials 28 d compressive strength is 3.35 MPa, and the initial and 60 min fluidity are above 200 mm. Microscopic test results show that the hydration products of hardened paste are ettringite, lawsonite, silica aluminate gel, which fill the pores and improve the strength of slurry. Through adding activator, activating red mud activity and designing low concentration filling material, it is the direction of mass and green utilization of red mud, desulfurization gypsum and other solid wastes. The utilization ratio of solid waste of red mud filling materials reaches 92%, no bleeding, no shrinkage, and has high economic value and environmental value.

Abstract Background Ovarian cancer is one of the most common malignant tumors in the female reproductive system with the highest mortality rate. Cul4B participates in the oncogenesis and progression of several malignant tumors. However, the role of Cul4B in ovarian cancer has not been studied. Results High expression of intratumor Cul4B was associated with poor patient survival. Cul4B expression was associated with FIGO stage and Cul4B was independent risk factor of ovarian cancer disease-free survival and overall survival. In vitro studies revealed that overexpression of Cul4B promoted tumor proliferation while knockdown of Cul4B significantly inhibited the proliferation capacity of ovarian cancer cells. Mechanistically, Cul4B was found to promotes cell entering S phase from G0/G1 phase by regulating the expression of CDK2 and CyclinD1. Cul4B regulates the expression of CDK2 and CyclinD1 by repressing miR-372. Conclusions The results revealed that high expression of Cul4B is associated with poor ovarian cancer prognosis and Cul4B may serve as a potential treating target for an adjuvant therapy.

The mine tailings generated from metallic ore not only occupies a large area of surface resources but also easily causes mud-rock flow and tailings dam failure. Moreover, the existence of a large number of underground voids threatens the safety of underground mining operations and can induce mines earthquake and surface subsidence. The paste filling technology involves thickening the mine tailings into paste and placing the paste in underground voids. The technology has been widely accepted and applied around the world for its advantages in safety, environmental protection, economy, and high efficiency. The dewatering of mine tailings is a prerequisite for the paste filling process. In the paste backfill, after tailings thickening, the concentration increase is limited, the yield stress is increased, and fluidity is reduced with flocculant dosage. The flocculant dosage and thickening synergist work together to further increase unclassified tailings paste concentration and reduce slurry yield stress. The mechanism of the thickening synergist was researched from a microscopic point of view. The results show that the best addition method is to add thickening synergist after tailings settlement with flocculant dosage by settlement and rheological test. The solid mass fraction can be increased by 8.57%‒10.13%, and the yield stress can be reduced by 6.68‒12.85 Pa. The multi-component thickening synergist can not only reduce unit consumption and cost but also improve the compressive strength of the paste backfill material. The compressive strength of paste backfill material with thickening synergist and cement-tailings mass ratio of 1∶12 is 2.5 MPa at the age of 28 d. The difference is less than 20% compared with the compressive strength of the material with cement-tailings mass ratio of 1∶6 and without thickening synergist. By total organic carbon adsorption test and Zeta potential test, the synergist is found to have functions of adsorption and dispersion. It can destroy the flocculation structure and release the contained water, thereby increasing the tailings concentration and improving the fluidity of tailings particles.

The understanding of the electrophysiological mechanisms that underlie mechanosensitivity of the sinoatrial node (SAN), the primary pacemaker of the heart, has been evolving over the past century. The heart is constantly exposed to a dynamic mechanical environment; as such, the SAN has numerous canonical and emerging mechanosensitive ion channels and signaling pathways that govern its ability to respond to both fast (within second or on beat-to-beat manner) and slow (minutes) timescales. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechanoactivated channels (Piezo, TREK, and BK) and slow mechanoresponsive ion channels [including volume-regulated chloride channels and transient receptor potential (TRP)], as well as the components of mechanochemical signal transduction, which may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechanochemical signal transduction and discuss the role of specialized membrane nanodomains, namely, caveolae, in mechanical regulation of both membrane and calcium clock components of the so-called coupled-clock pacemaker system responsible for SAN automaticity. Finally, we emphasize how these mechanically activated changes contribute to the pathophysiology of SAN dysfunction and discuss controversial areas necessitating future investigations. Though the exact mechanisms of SAN mechanosensitivity are currently unknown, identification of such components, their impact into SAN pacemaking, and pathological remodeling may provide new therapeutic targets for the treatment of SAN dysfunction and associated rhythm abnormalities.

Lettuce (Lactuca sativa L.), a popular edible vegetable, is highly responsive to mineral fertilizers. A two-year field trial was carried out to determine how nitrogen (N), phosphorous (P), and potassium (K) application ratios affected lettuce growth, yield, and quality. Within a certain range of nutrient application rate, the plant height, stem diameter, yield, and the concentrations of vitamin C and soluble sugar were higher than those without fertilization. Compared with no fertilization condition, the yield increased approximately 13.56–22.03%, 15.15–42.42% and 7.14–10.32% under increased N, P, and K application conditions, respectively. Furthermore, substantial quadratic parabola relationships were observed between lettuce yield and fertilizer application amounts as well as most quality traits. The nitrate concentration was proportional to the N fertilization rate, while the concentrations of soluble sugar and vitamin C positively correlated with N and P application ratios, respectively. The lettuce leaves had the largest N (60.59%) and K (52.25%) accumulations, whereas the lettuce stem had the highest P (46.33%) accumulation. Above all, the optimal N, P, and K application amounts for lettuce were 315 kg N ha−1, 210 kg P2O5 ha−1, and 285 kg K2O ha−1, respectively.

Condensation of organic vapors is a main factor controlling the growth of atmospheric particles. Here the authors identify a distribution of organic vapors in a forested environment able to explain nanoparticle growth at the same location, contributing to understanding aerosol climate effects.

Abstract Background Ceftiofur Sodium is widely used in China. Our aim was to determine Ceftiofur Sodium activity and optimize dosing regimens against the pathogen Haemophilus parasuis using an in vitro and ex vivo pharmacokinetics/pharmacodynamics modeling approach. By adopting these strategies, we wanted to extend the effective life of Ceftiofur Sodium in reduce drug-resistance in pigs. Results We established an H. parasuis infection model in pigs, and assessed the pharmacokinetics of Ceftiofur Sodium in both healthy and infected animals. After Ceftiofur Sodium (10 mg/kg, i.m.) administration to healthy and H. parasuis-infected pigs, plasma based desfuroylceftiofur (a metabolite of Ceftiofur Sodium) was measured by High Performance Liquid Chromatography. The pharmacokinetics of Ceftiofur Sodium (desfuroylceftiofur) was consistent with a two-compartment open model, with first-order absorption. We observed no significant differences (P > 0.05) in pharmacokinetic parameters between healthy and infected pigs. Pharmacodynamics data showed that Ceftiofur Sodium was highly inhibitory against H. parasuis, with MIC, MBC, and MPC values of 0.003125, 0.0125 and 0.032 μg/mL, respectively. Desfuroylceftiofur in plasma also had strong bactericidal activity. Almost all H. parasuis cultured in plasma medium of Ceftiofur Sodium-inoculated healthy pigs, at each time point, were killed within 24 h. A weaker antibacterial activity was measured in infected-pig plasma medium at 18, 24, 36, and 48 h, after Ceftiofur Sodium inoculation. Pharmacokinetic parameters were combined with ex vivo pharmacodynamic parameters, and the bacteriostatic effect (36.006 h), bactericidal effect (71.637 h) and clearance (90.619 h) within 24 h, were determined using the Hill equation. Dose-calculation equations revealed the optimal dose of Ceftiofur Sodium to be 0.599–1.507 mg/kg. Conclusions There were no significant differences in Ceftiofur Sodium pharmacokinetic parameters between healthy and infected pigs, although pharmacokinetics/pharmacodynamics fitting curves showed obviously differences. The optimal dose of Ceftiofur Sodium was lower than recommended (3 mg/kg), which may provide improved treatments for Glässers disease, with lower drug-resistance possibility.

In view of the disadvantages of various types of industrial close-boiling liquid mixtures and azeotropic as well as high energy consumption and easy pollution caused by traditional separation methods, the integrated distillation-membrane separation process has obvious economic advantages of energy saving and consumption reduction. The systematic and economic research is helpful to realize the win-win of environment and economy. In this paper, a comprehensive solution strategy for the integrated distillation-membrane separation process based on intelligent genetic programming (GP) is proposed. According to the characteristics of the material system and separation requirements, the most suitable membrane type and material can be matched, and then the most economical and environmentally friendly new distillation-membrane separation process can be calculated quickly. On this basis, the hot issues related to chemical industry are further discussed, including energy saving and consumption reduction, carbon or other pollutant discharge control, etc. At the same time, the improvement of the separation model and the cost model are predicted for different membrane types. The significant influence of the above key factors on the system and economy of the integration process is discussed. The modification measures of membrane materials are proposed to predict whether they have industrialization potential and finally promote the common development of membrane and integration technology effectively.

The quorum sensing (QS) system controls bacterial biofilm formation, which is highly related to the virulence and resistance of pathogens. In the present study, the effect of two traditional Chinese medicine (TCM) monomers, berberine and matrine, on biofilm formation and QS-related gene expression of antimicrobial-resistant (AMR) Escherichia coli strains was investigated by laser scanning confocal microscopy (LSCM) observation and real-time PCR. The results indicated a roughly positive relationship between biofilm formation ability and antimicrobial resistance. LSCM observation showed that berberine and matrine inhibited biofilm formation of AMR E. coli strains at 1/2 minimal inhibitory concentration (MIC) (1/2 MIC berberine at OD630: 0.1020; 1/2 MIC matrine: OD630: 0.1045); furthermore, abnormal cell morphology such as rounded and elongated cells was also observed. This finding was consistent with the downregulation of QS-related genes: luxS, pfS, sdiA, hflX, motA, and fliA. At 1/2 MIC and 1/4 MIC concentrations of berberine, a significant downregulation of luxS, pfS, hflX, ftsQ, and ftsE was observed. The results indicate that berberine and matrine can inhibit biofilm formation by inhibiting the QS system and that berberine is more effective than matrine.

Background/Aims: Endothelial cell dysfunction is the principal pathological process underlying atherosclerotic cardiovascular disease. G protein-coupled receptor 124 (GPR124), an orphan receptor in the adhesion GPCR subfamily, promotes angiogenesis in the brain. In the present study, we explored the role of endothelial GPR124 in the development and progression of atherosclerosis in adult mice. Methods: Using tetracycline-inducible transgenic systems, we generated mice expressing GPR124 specifically under control of the Tie-2 promoter. The animal model of atherosclerosis was constructed by intravenously injecting AAV-PCSK9DY into tetracycline-regulated mice and feeding the mice a high-fat diet for 16 consecutive weeks. Biochemical analysis and immunohistochemistry methods were used to address the role and mechanism of GPR124 in the pathological process of atherosclerosis. Results: Higher TC (total cholesterol) and LDL-C (low density lipoprotein cholesterol) levels in serum and greater lipid deposition in the aortic sinus were found in atherosclerotic mice with GPR124 overexpression, coincident with the elevated proliferation of smooth muscle cells. We observed an elevation of ONOO- in the aortic sinus in this model by using immunofluorescence, and the experiments showed that the specific overexpression of GPR124 in the endothelium induced the up-regulation of CD68, NLRP3 and caspase-1 levels in the aortic sinus. Conclusion: The above results indicate that manipulating GPR124 in the endothelium may contribute to delayed pathological progression of atherosclerosis.

Nitrogen (N) is an essential macronutrient for plants. However, little is known about the molecular regulation of N assimilation in Brassica napus, one of the most important oil crops worldwide. Here, we carried out a comprehensive genome-wide analysis of the N assimilation related genes (NAGs) in B. napus. A total of 67 NAGs were identified encoding major enzymes involved in N assimilation, including asparagine synthetase (AS), glutamate dehydrogenase (GDH), glutamine oxoglutarate aminotransferase (GOGAT), glutamine synthetase (GS), nitrite reductase (NiR), nitrate reductase (NR). The syntenic analysis revealed that segmental duplication and whole-genome duplication were the main expansion pattern during gene evolution. Each NAG family showed different degrees of differentiation in characterization, gene structure, conserved motifs and cis-elements. Furthermore, diverse responses of NAG to multiple nutrient stresses were observed. Among them, more NAGs were regulated by N deficiency and ammonium toxicity than by phosphorus and potassium deprivations. Moreover, 12 hub genes responding to N starvation were identified, which may play vital roles in N utilization. Taken together, our results provide a basis for further functional research of NAGs in rapeseed N assimilation and also put forward new points in their responses to contrasting nutrient stresses.

Nuclear Factor-Y (NF-Y) transcription factors play vital roles in plant abiotic stress response. Here, the NF-Y family in Brassica napus, which is hyper-sensitive to nitrogen (N) deprivation, was comprehensively identified and systematically characterized. A total of 108 NF-Y family members were identified in B. napus and categorized into three subfamilies (38 NF-YA, 46 NF-YB and 24 NF-YC; part of the Arabidopsis NF-YC homologous genes had been lost during B. napus evolution). In addition, the expansion of the NF-Y family in B. napus was driven by whole-genome duplication and segmental duplication. Differed expression patterns of BnaNF-Ys were observed in response to multiple nutrient starvations. Thirty-four genes were regulated only in one nutrient deficient condition. Moreover, more BnaNF-YA genes were differentially expressed under nutrient limited environments compared to the BnaNF-YB and BnaNF-YC subfamilies. Sixteen hub genes responded diversely to N deprivation in five rapeseed tissues. In summary, our results laid a theoretical foundation for the follow-up functional study of the key NF-Y genes in B. napus in regulating nutrient homeostasis, especially N.