Search Results (8)

Huntington’s disease is one of the most common dominantly inherited neurodegenerative disorders caused by an expansion of a polyglutamine (polyQ) stretch in the N-terminal region of huntingtin (Htt). Among all the molecular mechanisms, affected by the mutation, emerging evidence proposes glycosphingolipid dysfunction as one of the major determinants. High levels of sphingolipids have been found to localize in the myelin sheaths of oligodendrocytes, where they play an important role in myelination stability and functions. In this study, we investigated any potential existing link between sphingolipid modulation and myelin structure by performing both ultrastructural and biochemical analyses. Our findings demonstrated that the treatment with the glycosphingolipid modulator THI preserved myelin thickness and the overall structure and reduced both area and diameter of pathologically giant axons in the striatum of HD mice. These ultrastructural findings were associated with restoration of different myelin marker protein, such as myelin-associated glycoprotein (MAG), myelin basic protein (MBP) and 2′, 3′ Cyclic Nucleotide 3′-Phosphodiesterase (CNP). Interestingly, the compound modulated the expression of glycosphingolipid biosynthetic enzymes and increased levels of GM1, whose elevation has been extensively reported to be associated with reduced toxicity of mutant Htt in different HD pre-clinical models. Our study further supports the evidence that the metabolism of glycosphingolipids may represent an effective therapeutic target for the disease. Full article

Developing microwave absorbing composites with lightweight and wide absorption bands is an essential direction for electromagnetic wave stealth and shielding application. In this article, PAN/PMMA blend fibers and sheath-core blend fibers with PAN/PMMA as the sheath and PMMA as the core were spun by uniaxial and coaxial electrostatic spinning, respectively. Porous carbon nanofiber (PCNF) and hollow porous carbon nanofiber (HPCNF) were obtained after pre-oxidation and carbonization of the corresponding two precursor fibers. The microwave absorption composite samples with PCNF and HPCNF as absorbents and paraffin as matrix were prepared, respectively. Their electromagnetic parameters were investigated by the reflective-transmission network parameter method. The microwave absorption properties of the corresponding composites were calculated based on a model for a single-layer planewave absorber from electromagnetic parameters. The results showed diversity between the microwave absorbing performance of the composites filled with PCNF and HPCNF. HPCNF performs better than PCNF as an absorbent; that is, the lowest reflection loss of composite filled with HPCNF is −20.26 dB and the effective bandwidth (lower than −10 dB) is to 4.56 GHz, while the lowest reflection loss of a composite filled with PCNF is −13.70 dB, and the effective bandwidth (lower than −10 dB) is 2.68 GHz when the absorbent content is 7%, and the thickness is 3 mm. Much lower reflection loss and a wider absorption band could be expected from HPCNF. The presence of a hollow structure in HPCNF, which may increase the degree of polarization and provide more interfaces for the interference phase extinction of reflected electromagnetic waves, might help to improve the attenuation of electromagnetic waves and broaden the absorption band. Full article

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies. Full article

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive, genomically complex, have soft tissue sarcomas, and are derived from the Schwann cell lineage. Patients with neurofibromatosis type 1 syndrome (NF1), an autosomal dominant tumor predisposition syndrome, are at a high risk for MPNSTs, which usually develop from pre-existing benign Schwann cell tumors called plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the NF1 gene, which encode neurofibromin, a Ras GTPase activating protein (GAP) and negative regulator of RasGTP-dependent signaling. In addition to bi-allelic loss of NF1, other known tumor suppressor genes include TP53, CDKN2A, SUZ12, and EED, all of which are often inactivated in the process of MPNST growth. A sleeping beauty (SB) transposon-based genetic screen for high-grade Schwann cell tumors in mice, and comparative genomics, implicated Wnt/β-catenin, PI3K-AKT-mTOR, and other pathways in MPNST development and progression. We endeavored to more systematically test genes and pathways implicated by our SB screen in mice, i.e., in a human immortalized Schwann cell-based model and a human MPNST cell line, using CRISPR/Cas9 technology. We individually induced loss-of-function mutations in 103 tumor suppressor genes (TSG) and oncogene candidates. We assessed anchorage-independent growth, transwell migration, and for a subset of genes, tumor formation in vivo. When tested in a loss-of-function fashion, about 60% of all TSG candidates resulted in the transformation of immortalized human Schwann cells, whereas 30% of oncogene candidates resulted in growth arrest in a MPNST cell line. Individual loss-of-function mutations in the TAOK1, GDI2, NF1, and APC genes resulted in transformation of immortalized human Schwann cells and tumor formation in a xenograft model. Moreover, the loss of all four of these genes resulted in activation of Hippo/Yes Activated Protein (YAP) signaling. By combining SB transposon mutagenesis and CRISPR/Cas9 screening, we established a useful pipeline for the validation of MPNST pathways and genes. Our results suggest that the functional genetic landscape of human MPNST is complex and implicate the Hippo/YAP pathway in the transformation of neurofibromas. It is thus imperative to functionally validate individual cancer genes and pathways using human cell-based models, to determinate their role in different stages of MPNST development, growth, and/or metastasis. Full article

Animal models are crucial to understanding human disease biology and developing new therapies. By far the most common animal used to investigate prevailing questions about human disease is the mouse. Mouse models are powerful tools for research as their small size, limited lifespan, and defined genetic background allow researchers to easily manipulate their genome and maintain large numbers of animals in general laboratory spaces. However, it is precisely these attributes that make them so different from humans and explains, in part, why these models do not accurately predict drug responses in human patients. This is particularly true of the neurofibromatoses (NFs), a group of genetic diseases that predispose individuals to tumors of the nervous system, the most common of which is Neurofibromatosis type 1 (NF1). Despite years of research, there are still many unanswered questions and few effective treatments for NF1. Genetically engineered mice have drastically improved our understanding of many aspects of NF1, but they do not exemplify the overall complexity of the disease and some findings do not translate well to humans due to differences in body size and physiology. Moreover, NF1 mouse models are heavily reliant on the Cre-Lox system, which does not accurately reflect the molecular mechanism of spontaneous loss of heterozygosity that accompanies human tumor development. Spontaneous and genetically engineered large animal models may provide a valuable supplement to rodent studies for NF1. Naturally occurring comparative models of disease are an attractive prospect because they occur on heterogeneous genetic backgrounds and are due to spontaneous rather than engineered mutations. The use of animals with naturally occurring disease has been effective for studying osteosarcoma, lymphoma, and diabetes. Spontaneous NF-like symptoms including neurofibromas and malignant peripheral nerve sheath tumors (MPNST) have been documented in several large animal species and share biological and clinical similarities with human NF1. These animals could provide additional insight into the complex biology of NF1 and potentially provide a platform for pre-clinical trials. Additionally, genetically engineered porcine models of NF1 have recently been developed and display a variety of clinical features similar to those seen in NF1 patients. Their large size and relatively long lifespan allow for longitudinal imaging studies and evaluation of innovative surgical techniques using human equipment. Greater genetic, anatomic, and physiologic similarities to humans enable the engineering of precise disease alleles found in human patients and make them ideal for preclinical pharmacokinetic and pharmacodynamic studies of small molecule, cellular, and gene therapies prior to clinical trials in patients. Comparative genomic studies between humans and animals with naturally occurring disease, as well as preclinical studies in large animal disease models, may help identify new targets for therapeutic intervention and expedite the translation of new therapies. In this review, we discuss new genetically engineered large animal models of NF1 and cases of spontaneous NF-like manifestations in large animals, with a special emphasis on how these comparative models could act as a crucial translational intermediary between specialized murine models and NF1 patients. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1^G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1^G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management. Full article

The tensile force of pre-stressed concrete (PSC) girders is the most important factor for managing the stability of PSC bridges. The tensile force is induced using pre-stressing (PS) tendons of a PSC girder. Because the PS tendons are located inside of the PSC girder, the tensile force cannot be measured after construction using conventional NDT (non-destructive testing) methods. To monitor the induced tensile force of a PSC girder, an embedded EM (elasto-magnetic) sensor was proposed in this study. The PS tendons are made of carbon steel, a ferromagnetic material. The magnetic properties of the ferromagnetic specimen are changed according to the induced magnetic field, temperature, and induced stress. Thus, the tensile force of PS tendons can be estimated by measuring their magnetic properties. The EM sensor can measure the magnetic properties of ferromagnetic materials in the form of a B (magnetic density)-H (magnetic force) loop. To measure the B-H loop of a PS tendon in a PSC girder, the EM sensor should be embedded into the PSC girder. The proposed embedded EM sensor can be embedded into a PSC girder as a sheath joint by designing screw threads to connect with the sheath. To confirm the proposed embedded EM sensors, the experimental study was performed using a down-scaled PSC girder model. Two specimens were constructed with embedded EM sensors, and three sensors were installed in each specimen. The embedded EM sensor could measure the B-H loop of PS tendons even if it was located inside concrete, and the area of the B-H loop was proportionally decreased according to the increase in tensile force. According to the results, the proposed method can be used to estimate the tensile force of unrevealed PS tendons. Full article

This report presents improvements of investigations on the Tethered Satellite System (TSS)-1R electron current enhancement due to magnetic limited collections. New analytical expressions are obtained for the potential and temperature changes across the pre-sheath. The mathematical treatments in this work are more rigorous than one past approach. More experimental measurements collected in the ionosphere during the TSS-1R mission are adopted for validations. The relations developed in this work offer two bounding curves for these data points quite successfully; the average of these two curves is close to the curve-fitting results for the measurements; and an average of 2.95 times larger than the Parker-Murphy theory is revealed. The results indicate that including the pre-sheath analysis is important to compute the electron current enhancement due to magnetic limitations. Full article