The E3 ubiquitin ligase IDOL regulates synaptic ApoER2 levels and is important for plasticity and learning.

Neuronal ApoE receptors are linked to learning and memory, but the pathways governing their abundance, and the mechanisms by which they affect the function of neural circuits are incompletely understood. Here we demonstrate that the E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. IDOL-dependent changes in ApoER2 abundance modulate dendritic filopodia initiation and synapse maturation. Loss of IDOL in neurons results in constitutive overexpression of ApoER2 and is associated with impaired activity-dependent structural remodeling of spines and defective LTP in primary neuron cultures and hippocampal slices. IDOL-deficient mice show profound impairment in experience-dependent reorganization of synaptic circuits in the barrel cortex, as well as diminished spatial and associative learning. These results identify control of lipoprotein receptor abundance by IDOL as a post-transcriptional mechanism underlying the structural and functional plasticity of synapses and neural circuits

Patient-Specific Orthotopic Glioblastoma Xenograft Models Recapitulate the Histopathology and Biology of Human Glioblastomas In Situ

SummaryFrequent discrepancies between preclinical and clinical results of anticancer agents demand a reliable translational platform that can precisely recapitulate the biology of human cancers. Another critical unmet need is the ability to predict therapeutic responses for individual patients. Toward this goal, we have established a library of orthotopic glioblastoma (GBM) xenograft models using surgical samples of GBM patients. These patient-specific GBM xenograft tumors recapitulate histopathological properties and maintain genomic characteristics of parental GBMs in situ. Furthermore, in vivo irradiation, chemotherapy, and targeted therapy of these xenograft tumors mimic the treatment response of parental GBMs. We also found that establishment of orthotopic xenograft models portends poor prognosis of GBM patients and identified the gene signatures and pathways signatures associated with the clinical aggressiveness of GBMs. Together, the patient-specific orthotopic GBM xenograft library represent the preclinically and clinically valuable “patient tumor’s phenocopy” that represents molecular and functional heterogeneity of GBMs

TERT Promotes Epithelial Proliferation through Transcriptional Control of a Myc- and Wnt-Related Developmental Program

Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERTci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERTci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways

A Comparative Analysis of Chemical, Plasma and In Situ Modification of Graphene Nanoplateletes for Improved Performance of Fused Filament Fabricated Thermoplastic Polyurethane Composites Parts

The limited number of materials and mechanical weakness of fused deposition modeling (FDM) parts are deficiencies of FDM technology. The preparation of polymer composites parts with suitable filler is a promising method to improve the properties of the 3D printed parts. However, the agglomerate of filler makes its difficult disperse in the matrix. In this work, graphene nanoplatelets (GnPs) were surface modified with chemical, low-temperature plasma and in situ methods, in order to apply them as fillers for thermoplastic polyurethane (TPU). Following its modification, the surface chemical composition of GnPs was analyzed. Three wt% of surface-modified GnPs were incorporated into TPU to produce FDM filaments using a melting compounding process. Their effects on rheology properties and electrical conductivity on TPU/GnPs composites, as well as the dimensional accuracy and mechanical properties of FDM parts, are compared. The images of sample facture surfaces were examined by scanning electron microscope (SEM) to determine the dispersion of GnPs. Results indicate that chemical treatment of GnPs with zwitterionic surfactant is a good candidate to significantly enhance TPU filaments, when considering the FDM parts demonstrated the highest mechanical properties and lowest dimensional accuracy

The E3 ubiquitin ligase Idol controls brain LDL receptor expression, ApoE clearance, and Aβ amyloidosis

Apolipoprotein E (ApoE) is an important modifier of Alzheimer's disease (AD) pathogenesis, and its abundance has been linked to the clearance of β-amyloid (Aβ) in the brain. The pathways that control the clearance of ApoE in the brain are incompletely understood. We report that Idol, an E3 ubiquitin ligase that targets the low-density lipoprotein receptor (LDLR) for degradation, is a critical determinant of brain ApoE metabolism and Aβ plaque biogenesis. Previous work has shown that Idol contributes minimally to the regulation of hepatic LDLR expression in mice. By contrast, we demonstrate that Idol is a primary physiological regulator of LDLR protein in the brain, controlling the clearance of both ApoE-containing high-density lipoprotein (HDL) particles and Aβ. We studied the consequences of loss of Idol expression in a transgenic mouse model of Aβ amyloidosis. Idol deficiency increased brain LDLR, decreased ApoE, decreased soluble and insoluble Aβ, reduced amyloid plaque burden, and ameliorated neuroinflammation. These findings identify Idol as a gatekeeper of LDLR-dependent ApoE and Aβ clearance in the brain and a potential enzyme target for therapeutic intervention in AD

Fully Biobased Shape Memory Thermoplastic Vulcanizates from Poly(Lactic Acid) and Modified Natural Eucommia Ulmoides Gum with Co-Continuous Structure and Super Toughness

Novel, fully biobased shape memory thermoplastic vulcanizates (TPVs) were prepared using two sustainable biopolymers, poly(lactic acid) (PLA), and modified natural Eucommia ulmoides gum (EUG-g-GMA), via a dynamic vulcanization technique. Simultaneously, in situ compatibilization was achieved in the TPVs to improve interfacial adhesion and the crosslinked modified Eucommia ulmoides gum (EUG) was in “netlike” continuous state in the PLA matrix to form “sea-sea” phase structure. The promoted interface and co-continuous structure played critical roles in enhancing shape memory capacity and toughness of the TPVs. The TPV with 40 wt % modified EUG displayed the highest toughness with an impact strength of 54.8 kJ/m2 and the most excellent shape memory performances with a shape fixity ratio (Rf) of 99.83% and a shape recovery ratio (Rr) of 93.74%. The prepared shape memory TPVs would open up great potential applications in biobased shape memory materials for smart medical devices

<i>NTRK1</i> Fusion in Glioblastoma Multiforme

<div><p>Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor, yet with no targeted therapy with substantial survival benefit. Recent studies on solid tumors showed that fusion genes often play driver roles and are promising targets for pharmaceutical intervention. To survey potential fusion genes in GBMs, we analysed RNA-Seq data from 162 GBM patients available through The Cancer Genome Atlas (TCGA), and found that 3′ exons of neurotrophic tyrosine kinase receptor type 1 (<i>NTRK1</i>, encoding TrkA) are fused to 5′ exons of the genes that are highly expressed in neuronal tissues, neurofascin (<i>NFASC</i>) and brevican (<i>BCAN</i>). The fusions preserved both the transmembrane and kinase domains of <i>NTRK1</i> in frame. <i>NTRK1</i> is a mediator of the pro-survival signaling of nerve growth factor (NGF) and is a known oncogene, found commonly altered in human cancer. While GBMs largely lacked <i>NTRK1</i> expression, the fusion-positive GBMs expressed fusion transcripts in high abundance, and showed elevated <i>NTRK1</i>-pathway activity. Lentiviral transduction of the <i>NFASC-NTRK1</i> fusion gene in NIH 3T3 cells increased proliferation <i>in vitro</i>, colony formation in soft agar, and tumor formation in mice, suggesting the possibility that the fusion contributed to the initiation or maintenance of the fusion-positive GBMs, and therefore may be a rational drug target.</p></div