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Contains fulltext : 208518.pdf (publisher's version ) (Open Access), Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

Contains fulltext : 208518.pdf (publisher's version ) (Open Access), Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

Contains fulltext : 208518.pdf (publisher's version ) (Open Access), Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

Contains fulltext : 116495.pdf (publisher's version ) (Open Access), BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Contains fulltext : 116495.pdf (publisher's version ) (Open Access), BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

Contains fulltext : 116495.pdf (publisher's version ) (Open Access), BACKGROUND: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis. AIMS AND METHODS: To determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing. RESULTS AND CONCLUSIONS: We detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype-phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purposes.

In this work a simulation based comparative study of organic field effect transistors designed using standard lithographic and printing designs is presented. The device simulations were performed using two dimensional drift-diffusion equations with a Poole-Frenkel field dependent mobility model. Both photolithographic and coarse printing transistor designs employed common materials such as 150 nm thick pentacene, 150 nm thick parylene gate insulator, gold source-drain electrodes and aluminum gate electrodes. The major differences between the two fabrication specifications are the minimum source/ drain line width and the transistor channel length. The typical specifications for the minimum line width and channel length were 2m and 5m for photolithography and 25m and 20m for coarse printing techniques, respectively. The gate, source, and drain capacitances and channel on-resistances at various channel lengths and gate overlaps have been extracted and presented specifically for both process schemes. Due to increased channel length and gate-source/drain overlap of printed electrodes relative to lithographic design, the resulting on-resistance and capacitances for coarse printing are significantly higher. These results demonstrate a substantial operating frequency reduction for printing design relative to photolithographic design. For the tested materials and designs it is shown that the cut-off frequency for the photolithographic process was 400 kHz but decreased to a much lower 26 kHz for the coarse printing process. Since printing technology uses various other materials,which typically have less performance than the ones used for this simulation, the actual printed device might have even lower performance than predicted here., Published in the journal "Thin Solid Films", 2010. Prepared in cooperation with University of Texas at Tyler, and University of Texas at Dallas, Richardson.

In this paper we describe solutions to address critical challenges in direct fabrication of amorphous silicon thin film transistor (TFTs) arrays for high information content active matrix flexible displays for Army applications. For all flexible substrates a manufacturable handling protocol in automated display-scale equipment is required. For metal foil substrates the principal challenges are planarization and electrical isolation, and management of coefficient of thermal expansion induced stress (CTE mismatch) during TFT fabrication. For plastic substrates the principal challenge is dimensional instability management., See also ADM002187. Presented at the Army Science Conference (26th), held in Orlando, Florida on 1-4 December 2008. Prepared in collaboration with Army Research Laboratory (ARL), Adelphi, MD. The original document contains color images.

After a brief review of the characteristics of electrical stress degradation of flexible, amorphous silicon thin film transistors, the implications for various types of flexible circuitry including active matrix backplanes, integrated drivers and general purpose digital circuitry are examined. A circuit modeling tool that enables the prediction of complex circuit degradation is presented. Experimental results for a variety of flexible digital circuits including programmable logic arrays and memories are presented. Finally, we discuss the principal remaining challenges to building a fully flexible electronic system., See also ADM002187. Presnted at the Army Science Conference (26th) held in Orlando, Florida on 1-4 December 2008. Published in the Proceedings of the Army Science Conference (26th), December 2008. The original document contains color images.

The following paper details the development of a new phosphorescent emitting dopant molecule for organic light emitting diodes (OLEDs). A systematic series of heteroleptic tris-cyclometallated iridium compounds were fabricated. Of the molecules, the fac- Ir(dfppy)(dfppz)2 compound had the blue-est emission with the highest quantum efficiency. Phosphorescent emitting OLEDs (PhOLED) were fabricated and properties measured. The emitting dopant was integrated into a device structure and the properties measured as a function of doping concentration. The device efficiency is 20 lm/W at 100 cd/m2 and a peak emission of 498 nm. The Army's Flexible Display Center (FDC) has fabricated thin film transistors on a rigid opaque substrate that make up an active matrix (AM) backplane. ARL's OLEDs are being integrated with the AM backplanes to demonstrate high performance emissive test demonstrator displays with a 1.1" diag., See also ADM002075. Presented at the Army Science Conference (25th) held in Orlando, FL, on 27-30 Nov 2006. Prepared in cooperation with U.S. Army Natick Soldier System Center, Natick, MA. Prepared in collaboration with Arizona State University. The original document contains color images.

The infiltration by atomic layer deposition of three-dimensional opal structures has been investigated as a means of fabricating photonic crystal phosphors. ZnS:Mn infiltrated and inverse opals have been demonstrated with filling fractions >95%. Characterization of these structures by scanning electron microscopy, specular reflectance, and photoluminescence is reported. Specular reflectance measurements confirm successful infiltration, and demonstrate modification of the electromagnetic density of states consistent with calculated photonic (111) pseudo band gaps. Photoluminescence measurements reveal modification of emission by the photonic crystal consistent with angular dependent specular reflectance measurements. These results reveal a flexible and convenient route for fabricating high performance photonic crystal structures and optical microcavities., The original document contains color images. Pub. in Phys. Stat. Sol. B v241 n3 p763-766, 2004

The infiltration of three-dimensional opal structures has been investigated by atomic layer deposition. Demonstrations using ZnS:Mn show that filling fractions >95% can be achieved and that the infiltrated material is of high-quality crystalline material as assessed by photoluminescence measurements. These results demonstrate a flexible and practical pathway to attaining high-performance photonic crystal structures and optical microcavities., Published in Applied Physics Letters, v83 n13 p2566-2568, 29 Sep 2003. Prepared in cooperation with University of Colorado, Boulder, CO. Prepared in collaboration with Army Research Laboratory (ARL), Adelphi, MD. Sponsored in part by Sandia National Laboratories, contract no. 18499.