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Miller et al. (2010) previously suggested that borderline pathology, vulnerable narcissism, and Factor 2 psychopathy share a common "Vulnerable Dark Triad" (VDT) core. The present study (N = 1,023 community participants) aims to test that hypothesis using exploratory and confirmatory bifactor analyses. We found support for a bifactor model that obtained satisfactory fits and other adequate validity indices, which included a general VDT factor and three group factors (Reckless, Entitled, Hiding). The general VDT factor was mostly saturated with borderline symptoms items reflecting self‐hatred and worthlessness, which did not form a group factor; these results add to previous research suggesting that features of borderline pathology may represent the core of personality pathology. The three group factors had distinctive relationships with Dark Triad traits, pathological trait domains, and aggression. In contrast with the three group factors, the general VDT factor more strongly incremented the prediction of negative affectivity and hostility; the group factors more strongly incremented the prediction of grandiosity, egocentrism, callousness, Machiavellianism, and direct (physical/verbal) aggression. Alignment of the retained bifactor model with influent models of personality pathology and conceptual/methodological implications of the present results for research on the hypothesized VDT are discussed, as well as some clinical implications of the findings. [ABSTRACT FROM AUTHOR]

Neuron‐derived orphan receptor 1, NR4A3 (Nor1)/NR4A3 is an orphan nuclear receptor involved in the transcriptional control of developmental and neurological functions. Oxidative stress‐induced conditions are primarily associated with neurological defects in humans, yet the impact on Nor1‐mediated transcription of neuronal genes remains with unknown mechanism. Here, we demonstrate that Nor1 is a non‐conventional target of SUMO2/3 conjugation at Lys‐137 contained in an atypic ψKxSP motif referred to as the pSuM. Nor1 pSuM SUMOylation differs from the canonical process with the obligate phosphorylation of Ser‐139 by Ras signaling to create the required negatively charged interface for SUMOylation. Additional phosphorylation at sites flanking the pSuM is also mediated by the coordinated action of protein kinase casein kinase 2 to function as a small ubiquitin‐like modifier enhancer, regulating Nor1‐mediated transcription and proteasomal degradation. Nor1 responsive genes involved in cell proliferation and metabolism, such as activating transcription factor 3, cyclin D1, CASP8 and FADD‐like apoptosis regulator, and enolase 3 were upregulated in response to pSuM disruption in mouse HT‐22 hippocampal neuronal cells and human neuroblastoma SH‐SY5Y cells. We also identified critical antioxidant genes, such as catalase, superoxide dismutase 1, and microsomal glutathione S‐transferase 2, as responsive targets of Nor1 under pSuM regulation. Nor1 SUMOylation impaired gene transcription through less effective Nor1 chromatin binding and reduced enrichment of histone H3K27ac marks to gene promoters. These effects resulted in decreased neuronal cell growth, increased apoptosis, and reduced survival to oxidative stress damage, underlying the role of pSuM‐modified Nor1 in redox homeostasis. Our findings uncover a hierarchical post‐translational mechanism that dictates Nor1 non‐canonical SUMOylation, disrupting Nor1 transcriptional competence, and neuroprotective redox sensitivity. [ABSTRACT FROM AUTHOR]

ABSTRACT Retinoic acid (RA) signaling plays a key role in the development and function of several systems in mammals. We previously discovered that the de novo mutations c.1159C>T (p.Arg387Cys) and c.1159C>A (p.Arg387Ser) in the RA Receptor Beta ( RARB) gene cause microphthalmia and diaphragmatic hernia. However, the natural history of affected subjects beyond the prenatal or neonatal period was unknown. Here, we describe nine additional subjects with microphthalmia who have de novo mutations in RARB, including the previously described p.Arg387Cys as well as the novel c.887G>C (p.Gly296Ala) and c.638T>C (p.Leu213Pro). Moreover, we review the information on four previously reported cases. All subjects who survived the neonatal period ( n = 10) displayed severe global developmental delay with progressive motor impairment due to spasticity and/or dystonia (with or without chorea). The majority of subjects also showed Chiari type I malformation and severe feeding difficulties. We previously found that p.Arg387Cys and p.Arg387Ser induce a gain-of-function. We show here that the p.Gly296Ala and p.Leu213Pro RARB mutations further promote the RA ligand-induced transcriptional activity by twofold to threefold over the wild-type receptor, also indicating a gain-of-function mechanism. These observations suggest that precise regulation of RA signaling is required for brain development and/or function in humans. [ABSTRACT FROM AUTHOR]

The scavenger receptor CD36 plays a central role in lipid metabolism by promoting macrophage cholesterol efflux with the potential to reduce atherosclerotic lesions. However, the effect of CD36 on de novo cholesterol synthesis is not known. Here, we describe the cellular mechanism by which CD36 activation induces cholesterol depletion in HepG2 cells. Using the CD36 ligand hexarelin, we found a rapid phosphorylation of HMG-CoA reductase Ser-872 in treated cells, resulting in inactivation of the rate-limiting enzyme in sterol synthesis. Degradation of HMGCoA reductase by the ubiquitin-proteasome pathway was also enhanced by hexarelin, through an increased recruitment of the anchor proteins insulin-induced gene (Insig)-l and Insig-2. Genes encoding key enzymes involved in cholesterol synthesis and under the control of transcription factor sterol regulatory element-binding protein (SREBP)-2 remained unresponsive to sterol depletion, due to retention of the SREBP-2 escort protein Scap by Insig-1/2. Insigl and Insig2 gene expression was also increased through activation of nuclear receptor peroxisome-proliferator activating receptor y (PPARγ) by CD36, which lifted the inhibitory effect of PPARγ1 Ser-84 phosphorylation. Recruitment of coactivator peroxisome proliferator-activated receptor-γ coactivator l a (PGClα) to activated AMPKα was also promoted, resulting in PGC-1α transcriptional activation through Sirtl-mediated deacetylation, increased recruitment of PPARγ, and up-regulation of Insig-1/2, revealing a regulatory role of CD36 on PGC-lα signaling. Our data identify CD36 as a novel regulator of HMG-CoA reductase function and Insig-1/2 expression, 2 critical steps regulating cholesterol synthesis in hepatocytes.--Rodrigue-Way, A., Caron, V., Bilodeau, S., Keil, S., Hassan, M., Lévy, E., Mitchell, G. A., Tremblay, A. Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARγ/PGC-lα pathway and Insig1/2 expression in hepatocytes. [ABSTRACT FROM AUTHOR]