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  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Landes Bioscience. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Forskningsöversikt (refereegranskat)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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  • Yuan, J. Y., et al. (författare)
  • Population Pharmacokinetics of Lithium in Young Pediatric Patients With Intellectual Disability
  • 2021
  • Ingår i: Frontiers in Pharmacology. - 1663-9812. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Lithium is a well-established treatment for bipolar disorders and has been shown to be neuroprotective, and thus low doses might be useful for the treatment of childhood brain injury and neurological sequelae. However, pharmacokinetic (PK) data in children are limited. This study was to investigate the PKs after oral administration of low-dose lithium carbonate in young children with intellectual disability. Methods: Fifty-two children with intellectual disability aged 4-10 years old were enrolled. A series of blood samples were collected after a single-dose administration of lithium carbonate. The serum lithium concentration was measured using a validated ion chromatography assay, and the PK concentration data were modeled using a nonlinear mixed effect model in the NONMEM program. Results: The lithium concentration over time was adequately described by a two-compartment disposition, with a transient absorption and first-order elimination process. The inclusion of body weight as an allometric factor significantly improved the model fit, but age and gender were not associated with the PKs of lithium. The clearance, central volume, inter-compartmental clearance, and peripheral volume estimates from the final population PK model were 0.98 L/h, 13.1 L, 0.84 L/h, and 8.2 L for children with a body weight of 20 kg. The model evaluation suggested that there is no obvious discrepancy between the observations and predictions in the proposed model. A visual predictive check demonstrated the good predictive performance of the final model. Conclusions: The lithium PK properties in young children were similar to those in older children and adults. The proposed model can be used for further PK/PD analysis to optimize the dosage regimen of lithium in children.
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  • Liu, Dajiang J., et al. (författare)
  • Exome-wide association study of plasma lipids in > 300,000 individuals
  • 2017
  • Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 49:12, s. 1758-1766
  • Tidskriftsartikel (refereegranskat)abstract
    • We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
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