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Brain lipoprotein receptors have been shown to regulate the metabolism of ApoE and β-amyloid (Aβ) and are potential therapeutic targets for Alzheimer’s disease (AD). Previously, we identified E3 ubiquitin ligase IDOL as a negative regulator of brain lipoprotein receptors. Genetic ablation of Idol increases low-density lipoprotein receptor protein levels, which facilitates Aβ uptake and clearance by microglia. In this study, we utilized an antisense oligonucleotide (ASO) to reduce IDOL expression therapeutically in the brains of APP/PS1 male mice. ASO treatment led to decreased Aβ pathology and improved spatial learning and memory. Single-cell transcriptomic analysis of hippocampus revealed that IDOL inhibition upregulated lysosomal/phagocytic genes in microglia. Furthermore, clustering of microglia revealed that IDOL-ASO treatment shifted the composition of the microglia population by increasing the prevalence of disease-associated microglia. Our results suggest that reducing IDOL expression in the adult brain promotes the phagocytic clearance of Aβ and ameliorates Aβ-dependent pathology. Pharmacological inhibition of IDOL activity in the brain may represent a therapeutic strategy for the treatment of AD.

Background Pharmacologic inhibition of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppressed pathology and cognitive deficits in Alzheimer's disease (AD) mouse models. To validate that the effect of the antagonist was specifically via C5aR1 inhibition, mice lacking C5aR1 were generated and compared in behavior and pathology. In addition, since C5aR1 is primarily expressed on cells of the myeloid lineage, and only to a lesser extent on endothelial cells and neurons in brain, gene expression in microglia isolated from adult brain at multiple ages was compared across all genotypes. Methods C5aR1 knock out mice were crossed to the Arctic AD mouse model, and characterized for pathology and for behavior performance in a hippocampal dependent memory task. CX3CR1GFP and CCR2RFP reporter mice were bred to C5aR1 sufficient and knockout wild type and Arctic mice to enable sorting of microglia (GFP-positive, RFP-negative) isolated from adult brain at 2, 5, 7 and 10 months of age followed by RNA-seq analysis. Results A lack of C5aR1 prevented behavior deficits at 10 months, although amyloid plaque load was not altered. Immunohistochemical analysis showed no CCR2+ monocytes/macrophages near the plaques in the Arctic brain with or without C5aR1. Microglia were sorted from infiltrating monocytes (GFP and RFP-positive) for transcriptome analysis. RNA-seq analysis identified inflammation related genes as differentially expressed, with increased expression in the Arctic mice relative to wild type and decreased expression in the Arctic/C5aR1KO relative to Arctic. In addition, phagosomal-lysosomal gene expression was increased in the Arctic mice relative to wild type but further increased in the Arctic/C5aR1KO mice. A decrease in neuronal complexity was seen in hippocampus of 10 month old Arctic mice at the time that correlates with the behavior deficit, both of which were rescued in the Arctic/C5aR1KO. Conclusions These data are consistent with microglial polarization in the absence of C5aR1 signaling reflecting decreased induction of inflammatory genes and enhancement of degradation/clearance pathways, which is accompanied by preservation of CA1 neuronal complexity and hippocampal dependent cognitive function. These results provide links between microglial responses and loss of cognitive performance and, combined with the previous pharmacological approach to inhibit C5aR1 signaling, support the potential of this receptor as a novel therapeutic target for AD in humans. Electronic supplementary material The online version of this article (10.1186/s13024-017-0210-z) contains supplementary material, which is available to authorized users.

Liver X receptors limit cellular lipid uptake by stimulating the transcription of Inducible Degrader of the LDL Receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of diet-induced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose, endothelium, intestine, skeletal muscle), but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to control of metabolism. Finally, we identify VLDLR rather than LDLR as the primary mediator of IDOL effects on energy balance. These studies identify a role for the neuronal IDOL-VLDLR pathway in metabolic homeostasis and diet-induced obesity.

The kinetics of base hydrolysis of the low-spin iron(II)-diimine complex [Fe(fertri)3]2+, where fertri=3-(2-pyridyl)-5,6-bis(2-furyl)-1,2,4-triazine, as a function of hydroxide concentration, solvent composition (water; aqueous MeOH), and pressure are reported. Rate constants are also reported for dissociation of the [Fe(fertri)3]2+ cation in 50–64% MeOH, determined from replacement of the fertri ligands by 1,10-phenanthroline. The reactivity of this fertri complex is compared with reactivities of a selection of other iron(II)-diimine complexes and, where possible, their ligand-sulfonated derivatives. The activation volume for base hydrolysis of [Fe(fertri)3]2+ is +10.7 cm3 mol−1, in 40% MeOH.

What are the most efficient and effective methods in measuring outcomes for assurance of learning in higher education? This study examines the merits of outsourcing part of the assessment workload by comparing ratings completed by trained student interns to ratings completed by faculty. Faculty evaluation of students’ written work samples provides the most detailed, actionable data useful for improving the curriculum. While this approach may be efficacious, it is also labor-intensive. Both the faculty and student interns were trained to use a scoring rubric developed for this assessment to rate undergraduate student essay responses to an ethical reasoning scenario. The convergent validity, discriminant validity, and source bias showed no significant difference between the values for the student raters versus those for the faculty raters. These findings support the hypothesis that trained student interns can do as well as faculty at evaluating undergraduate student work samples.

Imazethapyr was applied at 0.14 kg ae/ha to soybean, peanut, sicklepod. Florida beggarweed, and redroot pigweed as either a soil, foliar, or soil plus foliar application. Soybean and peanut were the most tolerant species; redroot pigweed was the most sensitive, with sicklepod and Florida beggarweed being intermediate. Foliar or foliar plus soil applications were more effective in reducing sicklepod and Florida beggarweed fresh weights than soil application alone. Foliar absorption of14C-imazethapyr 72 h after treatment was greater than 90% for soybean, peanut, sicklepod, and redroot pigweed, but only 77% in Florida beggarweed. For the species evaluated, the amount translocated from the treated leaf ranged from 5 to 16% after 72 h. Within this same time period, an average of 90% of the root-absorbed imazethapyr had been translocated to the shoot in all species except peanut. The half-life of imazethapyr was 6.6, 6.5, 14.4, 24.0, and 32.1 days in soybean, peanut, Florida beggarweed, sicklepod, and redroot pigweed, respectively. Tolerance was most closely associated with imazethapyr half-life within these species.

Absorption of foliar-applied14C-imazaquin {2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3-quinolinecarboxylic acid} 72 h after treatment was higher than 90% for soybean [Glycine max(L.) Merr. ‘Braxton’], peanut (Arachis hypogaeaL. ‘Florunner’), common cocklebur (Xanthium strumariumL. # XANST), sicklepod (Cassia obtusifoliaL. # CASOB), and Florida beggarweed [Desmodium tortuosum(SW.) # DEDTO]. Both symplasmic and apoplasmic translocation of the herbicide were evident. Imazaquin half-life was 4.4 days in soybean, 5.3 days in peanut, 9.6 days in Florida beggarweed, 12.7 days in sicklepod, and 39.8 days in cocklebur. Tolerance of these species to foliar-applied imazaquin as determined in greenhouse studies with 21-day-old seedlings was as follows: soybean = peanut > Florida beggarweed > sicklepod > cocklebur. Tolerance was directly correlated to imazaquin halflife within the tissue of the respective species.

Tolerance of species to foliar applications of the ethyl ester of chlorimuron as determined in greenhouse studies with 21-day-old seedlings was: soybean = peanut > prickly sida > sicklepod > Florida beggarweed > common cocklebur. Absorption of foliar-applied14C-chlorimuron 72 h after application was similar in soybean, peanut, sicklepod, common cocklebur, and prickly sida, but much less in Florida beggarweed. Slight symplasmic and apoplasmic translocation of the herbicide was evident in all species. Metabolism of chlorimuron 72 h after application was greatest in soybean and least in common cocklebur. Species tolerance to chlorimuron was directly correlated (r2= 0.93) to the amount of unmetabolized chlorimuron (dpm/g dry wt) in the plant. Peanut exhibited increased tolerance to chlorimuron with age; this result was attributed to reduced absorption and translocation and more extensive metabolism of the absorbed herbicide by older plants.

Postemergence treatments utilizing various combinations of fluazifop-P, paraquat, and 2,4-DB were compared to a preplant-incorporated (PPI) application of benefin followed by a ground-cracking application of alachlor and dinoseb plus naptalam and a postemergence application of 2,4-DB for weed control, peanut yield, and net economic return to land, overhead, and management. The greatest peanut yields (3-yr average of 4510 kg/ha) and net returns (3-yr average of $521/ha) were provided by a postemergence system that utilized one ground-cracking and one postemergence application of paraquat and one postemergence application of fluazifop-P and 2,4-DB. Seven postemergence systems provided equivalent or greater yield and net returns than the PPI and dinoseb plus naptalam system. Fresh weight reductions of Texas panicum, sicklepod, Florida beggarweed, and pitted morningglory from postemergence weed control systems were equivalent to reductions obtained from the PPI and dinoseb plus naptalam system. The addition of paraquat and 2,4-DB to the PPI and dinoseb plus naptalam system improved the 3-yr average peanut yield and net economic return by 510 kg/ha and $136/ha, respectively, compared to the same system without paraquat and 2,4-DB.

This study was conducted to provide standardization data and information on the reliability and factorial validity of the recently developed Adolescent Activities Checklist (AAC). A total of 563 adolescents in grades 7 through 12 served as subjects. Significant main effects for gender, race, and grade were obtained in a multivariate analysis of variance. On the basis of this information, standardization data were established for these three variables. Further investigation indicated that the internal consistency of the AAC was high. In addition, results of a principal components analysis conducted on the frequencies of the Unpleasant and Pleasant Activities subscales revealed four and three factors, respectively. For unpleasant activities, the major dimensions were found to occur in three situations--namely, social interactions, family situations, and school situations. Stressful events also occurred as one of the four unpleasant activities dimensions. For pleasant activities, three dimensions appeared: heterosocial behavior, reinforcing interpersonal situations, and social reinforcement.