Post-treatment using a sensitive RT-qPCR test was essential to ensure that virus clearance had been achieved, since failure to clear even one cat can result in re-infection of the others. Records of virus shedding by cats before treatment provided a retrospective control significantly more cats stopped shedding virus after Mutian X than recovered from infection during the control period (p  less then  .00001). This is the first report of the successful elimination of faecal FCoV shedding in chronically infected cats. DNA sequence variants in the TBK1 gene associate with or cause sporadic or familial amyotrophic lateral sclerosis (ALS). Here we show that mice bearing human ALS-associated TBK1 missense loss-of-function mutations, or mice in which the Tbk1 gene is selectively deleted in motor neurons, do not display a neurodegenerative disease phenotype. However, loss of TBK1 function in motor neurons of the SOD1G93A mouse model of ALS impairs autophagy, increases SOD1 aggregation, and accelerates early disease onset without affecting lifespan. By contrast, point mutations that decrease TBK1 kinase activity in all cells also accelerate disease onset but extend the lifespan of SOD1 mice. This difference correlates with the failure to activate high levels of expression of interferon-inducible genes in glia. We conclude that loss of TBK1 kinase activity impacts ALS disease progression through distinct pathways in different spinal cord cell types and further implicate the importance of glia in neurodegeneration. There is a continuous need to develop new antibacterial agents with non-traditional mechanisms to combat the nonstop emerging resistance to most of the antibiotics used in clinical settings. We identified novel pyrazolidinone derivatives as antibacterial hits in an in-house library screening and synthesized several derivatives in order to improve the potency and increase the polarity of the discovered hit compounds. The oxime derivative 24 exhibited promising antibacterial activity against E. coli TolC, B. subtilis and S. aureus with MIC values of 4, 10 and 20 µg/mL, respectively. The new lead compound 24 was found to exhibit a weak dual inhibitory activity against both the E. coli MurA and MurB enzymes with IC50 values of 88.1 and 79.5 µM, respectively, which could partially explain its antibacterial effect. A comparison with the previously reported, structurally related pyrazolidinediones suggested that the oxime functionality at position 4 enhanced the activity against MurA and recovered the activity against the MurB enzyme. Compound 24 can serve as a lead for further development of novel and safe antibiotics with potential broad spectrum activity. Fungal infections have become a serious medical problem due to the high infection rate and the frequent emergence of drug resistance. Ergosterol is an important structural component of the fungal cell membrane, its synthetases (squalene epoxidase (SE) and 14α-demethylase (CYP51)) are considered as the key points to block the ergosterol synthesis. In this study, we designed a series of dual-target arylamides derivatives based on the analysis of active sites (SE, CYP51). Subsequently, these target compounds were synthesized, and their antifungal activity was evaluated. Most of compounds demonstrate the potent antifungal activity against multiple Candida spp. and A. this website fum. In particular, the antifungal activities of compounds 10b and 11c are not only superior to positive control drugs, but also have significant inhibitory effects on drug-resistant fungi (C.alb. Strain100, C.alb. Strain103). Therefore, their action mechanism was further studied. Cellular uptake and electron microscopy observation showed that target compounds were able to enter fungal cytoplasmic region through free diffusion, and destroyed cell membrane structure. At the same time, preliminary mechanisms have demonstrated that they can affect the synthesis of ergosterol by inhibiting the activity of dual targets. It is worth noting that they also can exhibit excellent antifungal activity and low toxic side effects in vivo. Their ADMET properties and binding models were established will be useful for further lead optimization. BACKGROUND AND AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and atherogenic lipoprotein abnormalities. Previous studies suggest an association of fibroblast growth factor 21 (FGF21) with NAFLD. Therefore, we assessed the association of circulating FGF21 levels with inflammatory markers, lipoprotein profile and NAFLD in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS Among 6814 participants free of apparent cardiovascular disease at baseline (2000-2002), 3634 participants had valid data on variables of interest. After excluding participants with excessive alcohol consumption, 3446 participants were included in the analysis. NAFLD was defined using non-contrast cardiac computed tomography with a liver-to-spleen ratio (LSR)  less then  1 or liver attenuation less then 40 Hounsfield units (HU). RESULTS The mean age of the participants was 63.5 years with 54% females, 36% Caucasian, 10% Chinese American, 31% African American and 23% Hispanic. 17% of the participants had NAFLD. After adjustment for demographic, socioeconomic and other confounders, a 1-SD increment in ln-transformed FGF21 level was associated with a 5.1% higher IL-6 level, a 0.31 nm larger very-low-density lipoprotein particle diameter, a 0.014 nm smaller high-density lipoprotein particle diameter, and a 5.25 nmol/L lower intermediate-density lipoprotein particle concentration (all p  less then  0.05). A 1-SD increment in ln-transformed FGF21 level was associated with LSR less then 1 and liver attenuation less then 40 HU (OR = 1.38 and 1.48; both p  less then  0.01), even after adjusting for the aforementioned inflammation and lipoprotein parameters. CONCLUSIONS This study suggests an association between FGF21 and NAFLD, independent of inflammation and atherogenic lipoprotein abnormalities. Further studies are needed to assess FGF21 as a biomarker for future NAFLD risk. Assessment methods on data quality and environmental variability are lacking for microplastics (MP). Here we assess occurrence and variability of MP number concentrations in two Dutch rivers. Strict QA/QC procedures were applied to identify MP using Fourier-transform infrared (FTIR) microscopy followed by state of the art automated image analysis. For a series of randomly selected, yet ever smaller subareas of filters, we assessed how accurately MP numbers and polymer types are represented during partial filter analysis. Levels of uncertainty were acceptable when analysing 50% of a filter during chemical mapping, and when identifying at least a subset of 50 individual particles with attenuated total reflection (ATR)-FTIR. Applying these guidelines, MP number concentrations between 67 and 11532 MP m-3 were detected in Dutch riverine surface waters. Spatial differences caused MP number concentrations to vary by two orders of magnitude. Temporal differences were lower and induced a maximum variation of one order of magnitude.