Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production.

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.This work was supported by Grant number 09/0003840, Diabetes UK https://www.diabetes.org.uk/ (MW); Grant number 5-2006-229, Juvenile Diabetes Research Foundation https://www.jdrf.org.uk/ (KO); Grant number BBS/E/B/0000C236 Biotechnology and Biological Sciences Research Council (KO); Grant number health-f5-2009-241883 European Research Council 7th Frame Programme http://ec.europa.eu/research/fp7/index_en.cfm (AC); and Grant number 02BX12ACYD, the Britain Israel Research and Academic Exchange Partnership (BIRAX) http://www.britishcouncil.org.il/en/programmes/science/birax.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014651

Physiologic regulation of heart rate and blood pressure involves connexin 36-containing gap junctions

Chronically elevated sympathetic nervous activity underlies many cardiovascular diseases. Elucidating the mechanisms contributing to sympathetic nervous system output may reveal new avenues of treatment. The contribution of the gap junctional protein connexin 36 (Cx36) to the regulation of sympathetic activity and thus blood pressure and heart rate was determined, using a mouse with specific genetic deletion of Cx36. Ablation of the Cx36 protein was confirmed in sympathetic preganglionic neurons of Cx36 knockout (KO) mice. Telemetric analysis from conscious Cx36 KO mice revealed higher variance in heart rate and blood pressure during rest and activity compared to wildtype (WT) mice, and smaller responses to chemoreceptor activation when anesthetized. In the working heart brainstem preparation of the Cx36 KO mouse, respiratory-coupled sympathetic nerve discharge was attenuated and responses to chemoreceptor stimulation and noxious stimulation were blunted compared to WT mice. Using whole cell patch recordings, sympathetic preganglionic neurons in spinal cord slices of Cx36 KO mice displayed lower levels of spikelet activity compared to WT mice, indicating reduced gap junction coupling between neurons. Cx36 deletion therefore disrupts normal regulation of sympathetic outflow with effects on cardiovascular parameters

Detection of Potential Transit Signals in the First Three Quarters of Kepler Mission Data

We present the results of a search for potential transit signals in the first three quarters of photometry data acquired by the Kepler Mission. The targets of the search include 151,722 stars which were observed over the full interval and an additional 19,132 stars which were observed for only 1 or 2 quarters. From this set of targets we find a total of 5,392 detections which meet the Kepler detection criteria: those criteria are periodicity of the signal, an acceptable signal-to-noise ratio, and a composition test which rejects spurious detections which contain non-physical combinations of events. The detected signals are dominated by events with relatively low signal-to-noise ratio and by events with relatively short periods. The distribution of estimated transit depths appears to peak in the range between 40 and 100 parts per million, with a few detections down to fewer than 10 parts per million. The detected signals are compared to a set of known transit events in the Kepler field of view which were derived by a different method using a longer data interval; the comparison shows that the current search correctly identified 88.1% of the known events. A tabulation of the detected transit signals, examples which illustrate the analysis and detection process, a discussion of future plans and open, potentially fruitful, areas of further research are included

The Star Formation and Extinction Co-Evolution of UV-Selected Galaxies over 0.05<z<1.2

We use a new stacking technique to obtain mean mid IR and far IR to far UV flux ratios over the rest near-UV/near-IR color-magnitude diagram. We employ COMBO-17 redshifts and COMBO-17 optical, GALEX far and near UV, Spitzer IRAC and MIPS Mid IR photometry. This technique permits us to probe infrared excess (IRX), the ratio of far IR to far UV luminosity, and specific star formation rate (SSFR) and their co-evolution over two orders of magnitude of stellar mass and redshift 0.1<z<1.2. We find that the SSFR and the characteristic mass (M_0) above which the SSFR drops increase with redshift (downsizing). At any given epoch, IRX is an increasing function of mass up to M_0. Above this mass IRX falls, suggesting gas exhaustion. In a given mass bin below M_0 IRX increases with time in a fashion consistent with enrichment. We interpret these trends using a simple model with a Schmidt-Kennicutt law and extinction that tracks gas density and enrichment. We find that the average IRX and SSFR follows a galaxy age parameter which is determined mainly by the galaxy mass and time since formation. We conclude that blue sequence galaxies have properties which show simple, systematic trends with mass and time such as the steady build-up of heavy elements in the interstellar media of evolving galaxies and the exhaustion of gas in galaxies that are evolving off the blue sequence. The IRX represents a tool for selecting galaxies at various stages of evolution.Comment: Accepted for publication in GALEX Special Ap.J.Suppl., December, 200

Detection of Potential Transit Signals in Sixteen Quarters of Kepler Mission Data

We present the results of a search for potential transit signals in four years of photometry data acquired by the Kepler Mission. The targets of the search include 111,800 stars which were observed for the entire interval and 85,522 stars which were observed for a subset of the interval. We found that 9,743 targets contained at least one signal consistent with the signature of a transiting or eclipsing object, where the criteria for detection are periodicity of the detected transits, adequate signal-to-noise ratio, and acceptance by a number of tests which reject false positive detections. When targets that had produced a signal were searched repeatedly, an additional 6,542 signals were detected on 3,223 target stars, for a total of 16,285 potential detections. Comparison of the set of detected signals with a set of known and vetted transit events in the Kepler field of view shows that the recovery rate for these signals is 96.9%. The ensemble properties of the detected signals are reviewed.Comment: Accepted by ApJ Supplemen

Planetary Candidates Observed by Kepler. VIII. A Fully Automated Catalog with Measured Completeness and Reliability Based on Data Release 25

We present the Kepler Object of Interest (KOI) catalog of transiting exoplanets based on searching 4 yr of Kepler time series photometry (Data Release 25, Q1–Q17). The catalog contains 8054 KOIs, of which 4034 are planet candidates with periods between 0.25 and 632 days. Of these candidates, 219 are new, including two in multiplanet systems (KOI-82.06 and KOI-2926.05) and 10 high-reliability, terrestrial-size, habitable zone candidates. This catalog was created using a tool called the Robovetter, which automatically vets the DR25 threshold crossing events (TCEs). The Robovetter also vetted simulated data sets and measured how well it was able to separate TCEs caused by noise from those caused by low signal-to-noise transits. We discuss the Robovetter and the metrics it uses to sort TCEs. For orbital periods less than 100 days the Robovetter completeness (the fraction of simulated transits that are determined to be planet candidates) across all observed stars is greater than 85%. For the same period range, the catalog reliability (the fraction of candidates that are not due to instrumental or stellar noise) is greater than 98%. However, for low signal-to-noise candidates between 200 and 500 days around FGK-dwarf stars, the Robovetter is 76.7% complete and the catalog is 50.5% reliable. The KOI catalog, the transit fits, and all of the simulated data used to characterize this catalog are available at the NASA Exoplanet Archive

Planetary Candidates Observed by Kepler V: Planet Sample from Q1-Q12 (36 Months)

The Kepler mission discovered 2842 exoplanet candidates with 2 years of data. We provide updates to the Kepler planet candidate sample based upon 3 years (Q1-Q12) of data. Through a series of tests to exclude false-positives, primarily caused by eclipsing binary stars and instrumental systematics, 855 additional planetary candidates have been discovered, bringing the total number known to 3697. We provide revised transit parameters and accompanying posterior distributions based on a Markov Chain Monte Carlo algorithm for the cumulative catalogue of Kepler Objects of Interest. There are now 130 candidates in the cumulative catalogue that receive less than twice the flux the Earth receives and more than 1100 have a radius less than 1.5 Rearth. There are now a dozen candidates meeting both criteria, roughly doubling the number of candidate Earth analogs. A majority of planetary candidates have a high probability of being bonafide planets, however, there are populations of likely false-positives. We discuss and suggest additional cuts that can be easily applied to the catalogue to produce a set of planetary candidates with good fidelity. The full catalogue is publicly available at the NASA Exoplanet Archive.Comment: Accepted for publication, ApJ