BackgroundCeragenins, synthetic mimics of endogenous antibacterial peptides, are promising candidate antimicrobial agents. However, in some settings their strong bactericidal activity is associated with toxicity towards host cells. To modulate ceragenin CSA-13 antibacterial activity and biocompatibility, CSA-13-coated magnetic nanoparticles (MNP-CSA-13) were synthesized. Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to characterize MNP-CSA-13 physicochemical properties. Bactericidal action and ability of these new compounds to prevent Pseudomonas. aeruginosa biofilm formation were assessed using a bacteria killing assay and crystal violet staining, respectively. Release of hemoglobin from human red blood cells was measured to evaluate MNP-CSA-13 hemolytic activity. In addition, we used surface activity measurements to monitor CSA-13 release from the MNP shell. Zeta potentials of P. aeruginosa cells and MNP-CSA-13 were determined to assess the interactions between the bacteria and nanoparticles. Morphology of P. aeruginosa subjected to MNP-CSA-13 treatment was evaluated using atomic force microscopy (AFM) to determine structural changes indicative of bactericidal activity.ResultsOur studies revealed that the MNP-CSA-13 nanosystem is stable and may be used as a pH control system to release CSA-13. MNP-CSA-13 exhibits strong antibacterial activity, and the ability to prevent bacteria biofilm formation in different body fluids. Additionally, a significant decrease in CSA-13 hemolytic activity was observed when the molecule was immobilized on the nanoparticle surface.ConclusionOur results demonstrate that CSA-13 retains bactericidal activity when immobilized on a MNP while biocompatibility increases when CSA-13 is covalently attached to the nanoparticle.

Fungal infections, especially those caused by antibiotic resistant pathogens, have become a serious public health problem due to the growing number of immunocompromised patients, including those subjected to anticancer treatment or suffering from HIV infection. In this study we assessed fungicidal activity of the ceragenins CSA-13, CSA-131 and CSA-192 against four fluconazole–resistant Candida strains. We found that ceragenins activity against planktonic Candida cells was higher than activity of human LL-37 peptide and synthetic cationic peptide omiganan. Compared to LL-37 peptide, ceragenins in the presence of DNase I demonstrated an increased ability to kill DNA-induced Candida biofilm. Microscopy studies show that treatment with LL-37 or ceragenins causes Candida cells to undergo extensive surface changes indicating surface membrane damage. This conclusion was substantiated by observation of rapid incorporation of FITC-labeled CSA-13, CSA-131 or LL-37 peptide into the more lipophilic environment of the Candida membrane. In addition to activity against Candida spp., ceragenins CSA-131 and CSA-192 display strong fungicidal activity against sixteen clinical isolates including Cryptococcus neoformans and Aspergillus fumigatus. These results indicate the potential of ceragenins for future development as new fungicidal agents.

Fungal infections caused by Candida spp. represent an emerging problem during treatment of immunocompromised patients and those hospitalized with serious principal diseases. The ever-growing number of fungal strains exhibiting drug resistance necessitates the development of novel antimicrobial therapies including those based on membrane-permeabilizing agents and nanomaterials as drug carriers. In this study, the fungicidal activities of LL-37 peptide, ceragenin CSA-13 and its magnetic derivatives (MNP@LL-37, MNP@CSA-13) against laboratory and clinical strains of C. albicans, C. glabrata and C. tropicalis were evaluated. These experiments confirm the high anti-fungal activity of these well-characterized agents mediated by their interaction with the fungal membrane and demonstrate elevated activity following immobilization of LL-37 and CSA-13 on the surface of magnetic nanoparticles (MNPs). Furthermore, MNP-based nanosystems are resistant to inhibitory factors present in body fluids and effectively inhibit formation of fungal biofilm. Simultaneously, synthesized nanostructures maintain immunomodulatory properties, described previously for free LL-37 peptide and CSA-13 substrate and they do not interfere with the proliferation and viability of osteoblasts, confirming their high biocompatibility.

The objective of this study was to investigate the effects of applying different amounts of water and nitrogen on yield, fruit quality, water use efficiency (WUE), irrigation water use efficiency (IWUE) and nitrogen use efficiency (NUE) of drip-irrigated greenhouse tomatoes in northwestern China. The plants were irrigated every seven days at various proportions of 20-cm pan evaporation (E p). The experiment consisted of three irrigation levels (I1, 0.5 E p ; I2, 0.75 E p ; and I3, 1.0 E p) and three N application levels (N1, 150 kg N ha-1 ; N2, 250 kg N ha-1 ; and N3, 350 kg N ha-1). Tomato yield increased with the amount of applied irrigation water in I2 and then decreased in I3. WUE and IWUE were highest in I1. WUE was 16.5% lower in I2 than I1, but yield was 26.6% higher in I2 than I1. Tomato yield, WUE, and IWUE were significantly higher in N2 than N1 and N3. NUE decreased with increasing N levels but NUE increased with increase the amount of water applied. Increasing both water and N levels increased the foliar net photosynthetic rate. I1 and I2 treatments significantly increased the contents of total soluble solids (TSS), vitamin C (VC), lycopene, soluble sugars (SS), and organic acids (OA) and the sugar:acid ratio in the fruit and decreased the nitrate content. TSS, VC, lycopene, and SS contents were highest in N2. The harvest index was highest in I2N2. I2N2 provided the optimal combination of tomato yield, fruit quality, and WUE. The irrigation and fertilisation regime of 0.75 E p and 250 kg N ha-1 was the best strategy of water and N management for the production of drip-irrigated greenhouse tomato.

Emergency use authorization of COVID vaccines has brought hope to mitigate pandemic of coronavirus disease 2019 (COVID-19). However, there remains a need for additional effective vaccines to meet the global demand and address the potential new viral variants. mRNA technologies offer an expeditious path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on the spike (S) glycoprotein of SARS-CoV-2. Several mRNA constructs of S-protein, including wild type, a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), as well as others, were tested in animal models for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques, and for efficacy in a Syrian golden hamster model. The selected 2P/GSAS vaccine formulation, designated MRT5500, elicited potent nAbs as measured in neutralization assays in all three preclinical models and more importantly, protected against SARS-CoV-2-induced weight loss and lung pathology in hamsters. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate (NHP), thus alleviating a hypothetical concern of potential vaccine-associated enhanced respiratory diseases known associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for entering clinical development.

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Background Postpartum depression was associated with maternal suffering and diminished functioning, increased risk of marital conflict as well as adverse child outcomes. Perceived social support during pregnancy was associated with postpartum depression among women. However, its causal relationship remains unclear. Therefore, we prospectively evaluate the association between perceived social support during early pregnancy and postpartum depressive symptoms. Methods We prospectively examined whether perceived social support during early pregnancy affected depressive symptoms at 6 weeks postpartum in a cohort of 3310 women. Perceived social support and postpartum depression were assessed by ENRICHD Social Support Instrument (ESSI) and the postpartum Edinburgh Postpartum Depression Scale (EPDS), respectively. Prevalence of postpartum depressive symptoms was 11.4% (EPDS cutoff≥10). As a test of heterogeneity of association in subpopulations, logistic regression models were performed to analyze the association between social support and postpartum depressive symptoms in strata which were defined by the potential confounder candidates. After multiple imputation, multivariable logistic regression was performed to assess the effect of social support on postpartum symptoms in individual items and total score. Two models were built. Model I adjusted for the variables associated with social support or postpartum depression and changed the association estimates by ≥10%. Model II adjusted for all variables that may be related to social support or postpartum depression. Results Significant associations between low perceived social support and postpartum depressive symptoms was found(Model I odds ratio: 1.63, 95% confidence interval: 1.15, 2.30; Model II odds ratio: 1.77, 95% confidence interval: 1.24–2.52). Stratified analyses showed that there was little evidence of heterogeneity of association in subpopulations by basic characteristics of participants. Conclusions These findings suggest that early intervention may be able to help protect against depression symptoms at 6 weeks postpartum. Electronic supplementary material The online version of this article (10.1186/s12888-019-2188-2) contains supplementary material, which is available to authorized users.

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