Early Neurodegeneration Progresses Independently of Microglial Activation by Heparan Sulfate in the Brain of Mucopolysaccharidosis IIIB Mice

BACKGROUND: In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease. METHODOLOGY/PRINCIPAL FINDINGS: In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency. CONCLUSIONS/SIGNIFICANCE: These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease

Heterodyne receiver for Origins

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FABRICATION AND CHARACTERIZATION OF SUBMICRON FABRICATION AND CHARACTERIZATION OF SUBMICRON AlGaN/GaN HEMTS

ABSTRACT Using our in-house 0.3 µm mushroom gate process, AlGaN/GaN high electron mobility transistors (HEMTs) with total gate periphery up to 0.6 mm were fabricated and characterized. The transistors were processed on an AlGaN/GaN heterostructure grown by MBE on sapphire. Output current densities up to 1 A/mm and extrinsic DC-transconductances (g m ) of 240 mS/mm were measured. Extrinsic cut-off frequencies (f t ) of 35 GHz, maximum frequencies of oscillation (f max ) of 75 GHz, were calculated from S-parameters measurements. On wafer Load-Pull measurements were performed without any active cooling on HEMTs of different sizes. Continuous wave (CW) output power densities up to 3.2 W/mm at 6 dB compression and 1.9 W/mm at 3 dB compression at 6 GHz were achieved

Reversal of pathology in the entire brain of mucopolysaccharidosis type VII mice after lentivirus-mediated gene transfer

Gene transfer vectors derived from human immunodeficiency virus (HIV-1) efficiently transduce nondividing cells and remain stably integrated in their genome. Long-term expression of reporter genes has been documented after intracerebral injection of these vectors. Using a HIV-based vector, we looked for a reversal of brain damage in the beta-glucuronidase-deficient mucopolysaccharidosis type VII mouse, an animal model of human lysosomal storage diseases. The vector suspension was injected stereotactically in the brain of 10-week-old animals, an age at which storage lesions are patent in glia, perivascular cells, and neurons. Either a single intrastriatal injection or multiple injections in both cerebral hemispheres and in the cerebellum were performed. Local tolerance, enzyme delivery, and correction of storage lesions were investigated by comprehensive analysis of serial sections of the entire brain of mice killed 6 or 16 weeks postinjection. Histochemical staining detected enzyme activity in widely distributed areas, the size of which increased with time. Clearance of lysosomal storage extended far beyond enzyme-positive areas. In mice receiving multiple injections of the vector, complete correction or significant reduction of the pathology was observed in every section, suggesting disease regression in the entire brain. These results may have implications for the treatment of neurological symptoms in lysosomal storage diseases

On the large-signal modelling of AlGaN/GaN HEMTs and SiC MESFETs

A general purpose LS model for GaN and SiC FET devices was developed and evaluated with DC, S, and Large Signal measurements (LS). The FET model is generalized and extended with new feature in order to improve the management of harmonics, provide a more physical treatment of the dispersion as well as delay and model other specific effects in these devices. The model was implemented in a commercial CAD tool and exhibit good overall accuracy

Comparison of the DC and microwave performance of AlGaN/GaN HEMTs grown on SiC by MOCVD with Fe-doped or unintentionally doped GaN buffer layers

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Improved bandwidth of a 2THz hot-electron bolometer heterodyne mixer fabricated on sapphire with a GaN buffer layer

We report on the signal-to-noise and gain bandwidth of a niobium nitride (NbN) hot-electron bolometer (HEB) mixer at 2 THz fabricated on a sapphire substrate with a GaN buffer layer. Two mixers with different DC properties and geometrical dimensions were studied and they demonstrated very close bandwidth performance. The signal-to-noise bandwidth is increased to 8 GHz in comparison to the previous results, obtained without a buffer-layer. The data were taken in a quasi-optical system with the use of the signal-to-noise method, which is close to the signal levels used in actual astrophysical observations. We find an increase of the gain bandwidth to 5 GHz. The results indicate that prior results obtained on a substrate of crystalline GaN can also be obtained on a conventional sapphire substrate with a few micron MOCVD-deposited GaN buffer-layer