Regulation of mouse hepatic genes in response to diet induced obesity, insulin resistance and fasting induced weight reduction

BACKGROUND: Obesity is associated with insulin resistance that can often be improved by caloric restriction and weight reduction. Although many physiological changes accompanying insulin resistance and its treatment have been characterized, the genetic mechanisms linking obesity to insulin resistance are largely unknown. We used DNA microarrys and RT-PCR to investigate significant changes in hepatic gene transcription in insulin resistant, diet-induced obese (DIO)-C57/BL/6J mice and DIO-C57/BL/6J mice fasted for 48 hours, whose weights returned to baseline levels during these conditions. RESULTS: Transcriptional profiling of hepatic mRNA revealed over 1900 genes that were significantly perturbed between control, DIO, and fasting/weight reduced DIO mice. From this set, our bioinformatics analysis identified 41 genes that rigorously discriminate these groups of mice. These genes are associated with molecular pathways involved in signal transduction, and protein metabolism and secretion. Of particular interest are genes that participate in pathways responsible for modulating insulin sensitivity. DIO altered expression of genes in directions that would be anticipated to antagonize insulin sensitivity, while fasting/ weight reduction partially or completely normalized their levels. Among these discriminatory genes, Sh3kbp1 and RGS3, may have special significance. Sh3kbp1, an endogenous inhibitor of PI-3-kinase, was upregulated by high-fat feeding, but normalized to control levels by fasting/weight reduction. Because insulin signaling occurs partially through PI-3-kinase, increased expression of Sh3kbp1 by DIO mice may contribute to hepatic insulin resistance via inhibition of PI-3-kinase. RGS3, a suppressor of G-protein coupled receptor generation of cAMP, was repressed by high-fat feeding, but partially normalized by fasting/weight reduction. Decreased expression of RGS3 may augment levels of cAMP and thereby contribute to increased, cAMP-induced, hepatic glucose output via phosphoenolpyruvate carboxykinase (PCK1), whose mRNA levels were also elevated. CONCLUSION: These findings demonstrate that hepatocytes respond to DIO and weight reduction by controlling gene transcription in a variety of important molecular pathways. Future studies that characterize the physiological significance of the identified genes in modulating energy homeostasis could provide a better understanding of the mechanisms linking DIO with insulin resistance

Ultrastructural defects in stereocilia and tectorial membrane in aging mouse and human cochleae

The aging cochlea is subjected to a number of pathological changes to play a role in the onset of age-related hearing loss (ARHL). Although ARHL has often been thought of as the result of the loss of hair cells, it is in fact a disorder with a complex etiology, arising from the changes to both the organ of Corti and its supporting structures. In this study, we examine two aging pathologies that have not been studied in detail despite their apparent prevalence; the fusion, elongation, and engulfment of cochlear inner hair cell stereocilia, and the changes that occur to the tectorial membrane (TM), a structure overlying the organ of Corti that modulates its physical properties in response to sound. Our work demonstrates that similar pathological changes occur in these two structures in the aging cochleae of both mice and humans, examines the ultrastructural changes that underlie stereocilial fusion, and identifies the lost TM components that lead to changes in membrane structure. We place these changes into the context of the wider pathology of the aging cochlea, and identify how they may be important in particular for understanding the more subtle hearing pathologies that precede auditory threshold loss in ARHL

Neural network interpolation of the magnetic field for the LISA Pathfinder Diagnostics Subsystem

LISA Pathfinder is a science and technology demonstrator of the European Space Agency within the framework of its LISA mission, which aims to be the first space-borne gravitational wave observatory. The payload of LISA Pathfinder is the so-called LISA Technology Package, which is designed to measure relative accelerations between two test masses in nominal free fall. Its disturbances are monitored and dealt by the diagnostics subsystem. This subsystem consists of several modules, and one of these is the magnetic diagnostics system, which includes a set of four tri-axial fluxgate magnetometers, intended to measure with high precision the magnetic field at the positions of the test masses. However, since the magnetometers are located far from the positions of the test masses, the magnetic field at their positions must be interpolated. It has been recently shown that because there are not enough magnetic channels, classical interpolation methods fail to derive reliable measurements at the positions of the test masses, while neural network interpolation can provide the required measurements at the desired accuracy. In this paper we expand these studies and we assess the reliability and robustness of the neural network interpolation scheme for variations of the locations and possible offsets of the magnetometers, as well as for changes in environmental conditions. We find that neural networks are robust enough to derive accurate measurements of the magnetic field at the positions of the test masses in most circumstances

Centro cívico de Dunstable Inglaterra

This civic centre has two storeys: — The ground floor provides room for a vestibule, cloakroom, the management office, washroom for the public, the large elliptic hall and access to the stalls, dressing room for the actors, and a kitchen in communication with the restaurant situated on the higher level; — The second storey comprises a hall and bar, council room, restaurant, additional dressing rooms for actors, storage room for dresses and other performance paraphernalia, and the room for the cinematographic projectors. This civic centre has many useful functions, such as exhibitions, banquets, dress balls, theatrical performances, etc. The elliptical hall accommodates 750 seated spectators.El edificio tiene dos plantas de altura: La planta baja aloja: el vestíbulo, el guardarropas, las oficinas administrativas, los aseos para el público, el patio de butacas de la gran sala elíptica, camerinos para los artistas, una cocina en comunicación con el restaurante situado en el nivel superior, etc. La primera planta comprende: el vestíbulo con su ambigú, la sala de juntas, un restaurante, los camerinos, el almacén para attrezzo, la cabina de proyección, etc. El «Centro» se destina a usos múltiples: exposiciones, banquetes, bailes de gala, representaciones teatrales, etc. La sala elíptica tiene capacidad para 750 personas sentadas

Impact of controlled vacuum induced surface freezing on the freeze drying of human plasma

During the freezing step of a typical freeze drying process, the temperature at which nucleation is induced is generally stochastically distributed, resulting in undesired within-batch heterogeneity. Controlled nucleation techniques have been developed to address this problem; these make it possible to trigger the formation of ice crystals at the same time and temperature in all the batch. Here, the controlled nucleation technique known as vacuum induced surface freezing is compared to spontaneous freezing for the freeze drying of human plasma, a highly concentrated system commonly stored in a dried state. The potency of Factor VIII (FVIII), a sensitive, labile protein present in plasma, and the reconstitution time of the dried cakes are evaluated immediately after freeze drying, and after 1, 3, 6 or 9 months storage at different degradation temperatures. We show that the application of controlled nucleation significantly reduces the reconstitution time and in addition helps to improve FVIII stability

Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice

Hearing relies on the mechanosensory inner and outer hair cells (OHCs) of the organ of Corti, which convert mechanical deflections of their actin-rich stereociliary bundles into electrochemical signals. Several actin-associated proteins are essential for stereocilia formation and maintenance, and their absence leads to deafness. One of the most abundant actin-bundling proteins of stereocilia is plastin 1, but its function has never been directly assessed. Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies. Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length. The stereocilia of OHCs were comparatively less affected; however, they also showed signs of degeneration in ageing mice. The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents. These results show that in contrast to other actin-bundling proteins such as espin, harmonin or Eps8, plastin 1 is dispensable for the initial formation of stereocilia. However, the progressive hearing loss and morphological defects of hair cells in adult Pls1 KO mice point at a specific role for plastin 1 in the preservation of adult stereocilia and optimal hearing. Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss

Study protocol for a randomised trial of nicotine-free cigarettes as an adjunct to usual NRT-based cessation practice, in people who wish to stop smoking

This trial is funded by a programme grant from the Health Research Council of New Zealand.

UK Large-scale Wind Power Programme from 1970 to 1990: the Carmarthen Bay experiments and the Musgrove Vertical-Axis Turbines

This article describes the development of the Musgrove Vertical Axis Wind Turbine (VAWT) concept, the UK ‘Carmarthen Bay’ wind turbine test programme, and UK government’s wind power programme to 1990. One of the most significant developments in the story of British wind power occurred during the 1970s, 1980s, and 1990s, with the development of the Musgrove vertical axis wind turbine and its inclusion within the UK Government’s wind turbine test programme. Evolving from a supervisor’s idea for an undergraduate project at Reading University, the Musgrove VAWT was once seen as an able competitor to the horizontal axis wind systems that were also being encouraged at the time by both the UK government and the Central Electricity Generating Board, the then nationalised electricity utility for England and Wales. During the 1980s and 1990s the most developed Musgrove VAWT system, along with three other commercial turbine designs was tested at Carmarthen Bay, South Wales as part of a national wind power test programme. From these developmental tests, operational data was collected and lessons learnt, which were incorporated into subsequent wind power operations.http://dx.doi.org/10.1260/03095240677860621