37 research outputs found

    Variable Expression of Cre Recombinase Transgenes Precludes Reliable Prediction of Tissue-Specific Gene Disruption by Tail-Biopsy Genotyping

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    The Cre/loxP-system has become the system of choice for the generation of conditional so-called knockout mouse strains, i.e. the tissue-specific disruption of expression of a certain target gene. We here report the loss of expression of Cre recombinase in a transgenic mouse strain with increasing number of generations. This eventually led to the complete abrogation of gene expression of the inserted Cre cDNA while still being detectable at the genomic level. Conversely, loss of Cre expression caused an incomplete or even complete lack of disruption for the protein under investigation. As Cre expression in the tissue of interest in most cases cannot be addressed in vivo during the course of a study, our findings implicate the possibility that individual tail-biopsy genotypes may not necessarily indicate the presence or absence of gene disruption. This indicates that sustained post hoc analyses in regards to efficacy of disruption for every single study group member may be required

    Exploring the relationships between International Classification of Functioning, Disability and Health (ICF) constructs of Impairment, Activity Limitation and Participation Restriction in people with osteoarthritis prior to joint replacement

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    <p>Abstract</p> <p>Background</p> <p>The International Classification of Functioning, Disability and Health (ICF) proposes three main constructs, impairment (I), activity limitation (A) and participation restriction (P). The ICF model allows for all paths between the constructs to be explored, with significant paths likely to vary for different conditions. The relationships between I, A and P have been explored in some conditions but not previously in people with osteoarthritis prior to joint replacement. The aim of this paper is to examine these relationships using separate measures of each construct and structural equation modelling.</p> <p>Methods</p> <p>A geographical cohort of 413 patients with osteoarthritis about to undergo hip and knee joint replacement completed the Aberdeen measures of Impairment, Activity Limitation and Participation Restriction (Ab-IAP). Confirmatory factor analysis was used to test the three factor (I, A, P) measurement model. Structural equation modelling was used to explore the I, A and P pathways in the ICF model.</p> <p>Results</p> <p>There was support from confirmatory factor analysis for the three factor I, A, P measurement model. The structural equation model had good fit [S-B Chi-square = 439.45, df = 149, CFI robust = 0.91, RMSEA robust = 0.07] and indicated significant pathways between I and A (standardised coefficient = 0.76 p < 0.0001) and between A and P (standardised coefficient = 0.75 p < 0.0001). However, the path between I and P was not significant (standardised coefficient = 0.01).</p> <p>Conclusion</p> <p>The significant pathways suggest that treatments and interventions aimed at reducing impairment, such as joint replacement, may only affect P indirectly, through A, however, longitudinal data would be needed to establish this.</p

    Short Telomeres Compromise β-Cell Signaling and Survival

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    The genetic factors that underlie the increasing incidence of diabetes with age are poorly understood. We examined whether telomere length, which is inherited and known to shorten with age, plays a role in the age-dependent increased incidence of diabetes. We show that in mice with short telomeres, insulin secretion is impaired and leads to glucose intolerance despite the presence of an intact β-cell mass. In ex vivo studies, short telomeres induced cell-autonomous defects in β-cells including reduced mitochondrial membrane hyperpolarization and Ca2+ influx which limited insulin release. To examine the mechanism, we looked for evidence of apoptosis but found no baseline increase in β-cells with short telomeres. However, there was evidence of all the hallmarks of senescence including slower proliferation of β-cells and accumulation of p16INK4a. Specifically, we identified gene expression changes in pathways which are essential for Ca2+-mediated exocytosis. We also show that telomere length is additive to the damaging effect of endoplasmic reticulum stress which occurs in the late stages of type 2 diabetes. This additive effect manifests as more severe hyperglycemia in Akita mice with short telomeres which had a profound loss of β-cell mass and increased β-cell apoptosis. Our data indicate that short telomeres can affect β-cell metabolism even in the presence of intact β-cell number, thus identifying a novel mechanism of telomere-mediated disease. They implicate telomere length as a determinant of β-cell function and diabetes pathogenesis

    Photonic beam forming of mm-wave smart antennas

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    In this contribution we present experimental results of optically controlled mm-wave array antennas which may be used in broadband mobile communication systems. Two operation principles have been investigated: downlink beam forming for transmission and uplink beam steering for optimization of the reception. In both cases the field distributions of the antennas were formed by a Silica based photonic beam forming network

    Experiments on DOA-estimation and beamforming for 60 GHz smart antennas

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    In this paper we present experimental results on direction of arrival (DOA) estimation and optical beamforming. In the first part of the paper we describe the experimental setup for the antenna calibration and DOA estimation at 60 GHz. A pilot signal generator and an array receiver are implemented. The feasibility of the DOA estimation is evaluated for real conditions. The experimental results show that the array calibration works reliable and there is a good agreement between simulation and experiment in the DOA estimation. In the second part, we present the experimental results on beamforming, which is performed using optical millimeter-wave generation technique. The millimeter-wave signals are generated by heterodyning the signals of two lasers. Beamforming is accomplished by a newly developed SiO /Si beamforming network, which enables individual control of amplitudes and hases of millimeter-wave signals feeding a planar 1x4 array antenna by means of the maximum directivity beamformer algorithm. Farfield measurements show good agreement between theory and experiment

    Maximum directivity beam-former at 60 GHz with optical feeder

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    We present an optically controlled 60 GHz array antenna which may be used as a smart antenna in an envisaged broadband mobile communication system. The desired field patterns of the antenna were synthesized using the maximum directivity beam-forming algorithm which enables an optimum radio link to a selected mobile terminal to be created while the signals of other terminals are suppressed by the nulls of the antenna's field distribution. The 60 GHz signals were generated by optically heterodyning the signals of two laser diodes. The field distribution of the antenna was formed by a silica based photonic beam-forming network. The experimentally obtained data confirmed the calculated field patterns
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