Discovery of membrane-targeting amphiphilic honokiol derivatives containing an oxazolethione moiety to combat methicillin-resistant Staphylococcus aureus (MRSA) infections.

Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major pathogen causing infections in hospitals and the community, and there is an urgent need for the development of novel antibacterials to combat MRSA infections. Herein, a series of amphiphilic honokiol derivatives containing an oxazolethione moiety were prepared and evaluated for their in vitro antibacterial and hemolytic activities. The screened optimal derivative, I3, exhibited potent in vitro antibacterial activity against S. aureus and clinical MRSA isolates with MIC values of 2-4 µg/mL, which was superior to vancomycin in terms of its rapid bactericidal properties and was less susceptible to the development of resistance. The SARs analysis indicated that amphiphilic honokiol derivatives with fluorine substituents had better antibacterial activity than those with chlorine and bromine substituents. In vitro and in vivo toxicity studies revealed that I3 has relatively low toxicity. In a MRSA-infected mouse skin abscess model, I3 (5 mg/kg) effectively killed MRSA at the infected site and attenuated the inflammation effects, comparable to vancomycin. In a MRSA-infected mouse sepsis model, I3 (12 mg/kg) was found to significantly reduce the bacterial load in infected mice and increase survival of infected mice. Mechanistic studies indicated that I3 has membrane targeting properties and can interact with phosphatidylglycerol (PG) and cardiolipin (CL) of MRSA cell membranes, thereby disrupting MRSA cell membranes, further inducing the increase of reactive oxygen species (ROS), protein and DNA leakage to achieve rapid bactericidal effects. Finally, we hope that I3 is a potential candidate molecule for the development of antibiotics to conquer superbacteria-related infections.

Mycoplasma genitalium membrane lipoprotein induces GAPDH malonylation in urethral epithelial cells to regulate cytokine response.

Membrane lipoproteins serve as primary pro-inflammatory virulence factors in Mycoplasma genitalium. Membrane lipoproteins primarily induce inflammatory responses by activating Toll-like Receptor 2 (TLR2); however, the role of the metabolic status of urethral epithelial cells in inflammatory response remains unclear. In this study, we found that treatment of uroepithelial cell lines with M. genitalium membrane lipoprotein induced metabolic reprogramming, characterized by increased aerobic glycolysis, decreased oxidative phosphorylation, and increased production of the metabolic intermediates acetyl-CoA and malonyl-CoA. The metabolic shift induced by membrane lipoproteins is reversible upon blocking MyD88 and TRAM. Malonyl-CoA induces malonylation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and malonylated GAPDH could dissociate from the 3' untranslated region of TNF-α and IFN-γ mRNA. This dissociation greatly reduces the inhibitory effect on the translation of TNF-α and IFN-γ mRNA, thus achieving fine-tuning control over cytokine secretion. These findings suggest that GAPDH malonylation following M. genitalium infection is an important inflammatory signal that plays a crucial role in urogenital inflammatory diseases.

Beyond Loading: Functions of Plant ARGONAUTE Proteins.

ARGONAUTE (AGO) proteins are key components of the RNA-induced silencing complex (RISC) that mediates gene silencing in eukaryotes. Small-RNA (sRNA) cargoes are selectively loaded into different members of the AGO protein family and then target complementary sequences to in-duce transcriptional repression, mRNA cleavage, or translation inhibition. Previous reviews have mainly focused on the traditional roles of AGOs in specific biological processes or on the molecular mechanisms of sRNA sorting. In this review, we summarize the biological significance of canonical sRNA loading, including the balance among distinct sRNA pathways, cross-regulation of different RISC activities during plant development and defense, and, especially, the emerging roles of AGOs in sRNA movement. We also discuss recent advances in novel non-canonical functions of plant AGOs. Perspectives for future functional studies of this evolutionarily conserved eukaryotic protein family will facilitate a more comprehensive understanding of the multi-faceted AGO proteins.

The fertility willingness and acceptability of preimplantation genetic testing in Chinese patients with autosomal dominant polycystic kidney disease.

BACKGROUND: With the development and progression of genetic technology, preimplantation genetic testing (PGT) has made it possible to block the inheritance of autosomal dominant polycystic kidney disease (ADPKD) as early as possible. However, we need to know the patients' fertility intentions and their acceptance of PGT. METHODS: A questionnaire survey was conducted to collect data on the basic demographic data, quality of life, social support, fertility willingness, and level of understanding of genetic testing for blocking the inheritance of ADPKD among patients aged 18-45 years in seven hospitals from January 2018 to December 2018. After verification, statistics were calculated. RESULTS: A total of 260 patients with ADPKD were interviewed, including 137males (52.7%) and 123 females (47.3%). The overall fertility willingness rate was low (n = 117, 45.0%). The proportion of married patients aged 25-34 years that were at the optimal reproductive age but did not yet have children was relatively high (n = 77, 67.0%). The fertility intentions of ADPKD patients were significantly influenced by age (OR: 0.101, 95% CI 0.045-0.225, P < 0.001) and education level (OR: 2.134, 95% CI 1.162-3.917, P = 0.014). Among patients who are willing to have children, 207 (79.6%) of them would choose PGT technology. Among those who were not sure whether they would choose PGT technology, the first major concern was technical safety (49.2%). CONCLUSIONS: The reproductive desire of childbearing ADPKD patients in China was low. Strengthening the health education of ADPKD genetic knowledge and reducing the cost of related technologies may improve the fertility intentions and reduce the barriers to acceptance of PGT.

CO2 methanation on the catalyst of Ni/MCM-41 promoted with CeO2.

CO2 as a raw feed combined with renewable hydrogen for the production of useful chemicals and alternative energy products is one of the solutions to environmental and energy problems. In this study, a series of Ni-xCeO2/MCM-41 catalysts with a nickel content of 20wt% were prepared through deposition precipitation method for CO2 methanation. Different characterization methods, including BET, XRD, TEM, SEM, H2-TPR and H2-TPD were applied to help explore the influence mechanism of CeO2 on Ni/MCM-41 in CO2 methanation. It was found that all CeO2-promoted catalysts exhibited enhanced catalytic activity when compared to Ni/MCM-41. The catalyst modified with 20wt% CeO2 showed the best catalytic performance, with CO2 conversion and CH4 selectivity of 85.6% and 99.8%, respectively, at the temperature of 380°C under atmospheric pressure. The synergetic effects among Ni0 active sites, the promoter and the support, including nickel dispersion improvement and increased CO2 adsorption sites due to the addition of CeO2, were considered as important factors for high reactivity of the promoted catalysts. The stability test showed that the promoted catalyst maintained its high reactivity after 30h.

Effects of torrefaction on hemicellulose structural characteristics and pyrolysis behaviors.

The effects of torrefaction on hemicellulose characteristics and its pyrolysis behaviors were studied in detail. The oxygen content decreased significantly after torrefaction, leading to the increase of high heating value. Two-dimensional perturbation correlation analysis based on diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) was performed to characterize the structural evolutions. It was found the dehydration of hydroxyls and the dissociation of branches were the main reactions at low torrefaction temperature. When the temperature further increased, the depolymerization of hemicellulose and the fragmentation of monosaccharide residues occurred. The distributed activation energy model with double Gaussian functions based on reaction-order model was used to investigate the pyrolysis kinetics. The results showed that torrefaction enhanced the activation energy for degradation reactions while lowered that for condensation reactions, and increased the devolatilization contribution of condensation reactions. Besides, torrefaction decreased the yields of typical pyrolytic products, such as acids, furans, alicyclic ketones and so on.

[Study of the neuropsychology and aural event related evoked potential on patients with the infarction in basal ganglia region].

AIM: To learn the condition of the memory and the visual space of the patient who has suffered from the infarction in basal ganglia region, and to analyze its impact on and the characteristics of the patients' cognition. METHODS: By testing respectively on 21 subjects who were initially infarcted in basal ganglia with single focus on one side, and 21 healthy volunteers with corresponding age, gender and educational background with Rey-Osterrieth Complex Figure Scale (Rey), Clinical Memory Scale (CMS), Hospital Anxiety-Depression Scale (HAD), National Institute of Health Stroke Scale (NIHSS), Oxford Handicap Scale (OHS), Barthel Index (BI), and Aural Event Related Evoked Potential (AERP) as well. RESULTS: Compared with the control group, the patient group got higher scores of anxiety and depression in HAD), which showed absolutely statistical significance; they demonstrated longer reaction time in AERP, which also showed statistical significance; and in CMS. they displayed inferior performance in the free picture recall and the memory quotient (MQ), which again had statistical significance. However, compared with the control group, the patient group got scores with no significance in copy, immediate recall and delayed recall in Rey. CONCLUSION: The infarction in basal ganglia region with single focus on one side may impact on the patient's executive function, memory function and emotion. But no impact is showed on patient's visual space function.