Mutations in Park8, encoding for the multidomain Leucine-rich repeat kinase 2 (LRRK2) protein, comprise the predominant genetic cause of Parkinson's disease (PD). G2019S, the most common amino acid substitution activates the kinase two- to threefold. This has motivated the development of LRRK2 kinase inhibitors; however, poor consensus on physiological LRRK2 substrates has hampered clinical development of such therapeutics. We employ a combination of phosphoproteomics, genetics, and pharmacology to unambiguously identify a subset of Rab GTPases as key LRRK2 substrates. LRRK2 directly phosphorylates these both in vivo and in vitro on an evolutionary conserved residue in the switch II domain. Pathogenic LRRK2 variants mapping to different functional domains increase phosphorylation of Rabs and this strongly decreases their affinity to regulatory proteins including Rab GDP dissociation inhibitors (GDIs). Our findings uncover a key class of bona-fide LRRK2 substrates and a novel regulatory mechanism of Rabs that connects them to PD.DOI: http://dx.doi.org/10.7554/eLife.12813.001

The Zwicky Transient Facility (ZTF) is a new robotic time-domain survey currently in progress using the Palomar 48-inch Schmidt Telescope. ZTF uses a 47 square degree field with a 600 megapixel camera to scan the entire northern visible sky at rates of ∼3760 square degrees/hour to median depths of g∼20.8 and r∼20.6 mag (AB, 5σ in 30 sec). We describe the Science Data System that is housed at IPAC, Caltech. This comprises the data-processing pipelines, alert production system, data archive, and user interfaces for accessing and analyzing the products. The real-time pipeline employs a novel image-differencing algorithm, optimized for the detection of point-source transient events. These events are vetted for reliability using a machine-learned classifier and combined with contextual information to generate data-rich alert packets. The packets become available for distribution typically within 13 minutes (95th percentile) of observation. Detected events are also linked to generate candidate moving-object tracks using a novel algorithm. Objects that move fast enough to streak in the individual exposures are also extracted and vetted. We present some preliminary results of the calibration performance delivered by the real-time pipeline. The reconstructed astrometric accuracy per science image with respect to Gaia DR1 is typically 45 to 85 milliarcsec. This is the RMS per-axis on the sky for sources extracted with photometric S/N10 and hence corresponds to the typical astrometric uncertainty down to this limit. The derived photometric precision (repeatability) at bright unsaturated fluxes varies between 8 and 25 millimag. The high end of these ranges corresponds to an airmass approaching ∼2-the limit of the public survey. Photometric calibration accuracy with respect to Pan-STARRS1 is generally better than 2%. The products support a broad range of scientific applications: fast and young supernovae; rare flux transients; variable stars; eclipsing binaries; variability from active galactic nuclei;

The Multiband Imaging Photometer for Spitzer (MIPS) provides long-wavelength capability for the mission in imaging bands at 24, 70, and 160 m and measurements of spectral energy distributions between 52 and 100 m at a spectral resolution of about 7%. By using true detector arrays in each band, it provides both critical sampling of the Spitzer point-spread function and relatively large imaging fields of view, allowing for substantial advances in sensitivity, angular resolution, and efficiency of areal coverage compared with previous space far-infrared capabilities. The 24 m array has excellent photometric properties, and measurements with rms relative errors of about 1% can be obtained. The two longer-wavelength arrays use detectors with poor photometric stability, but a system of onboard stimulators used for relative calibration, combined with a unique data pipeline, produce good photometry with rms relative errors of less than 10%.

Many X-ray binaries remain undetected in the mid-infrared, a regime where emission from their compact jets is likely to dominate. Here, we report the detection of the black hole binary GX 339-4 with the Widefield Infrared Survey Explorer (WISE) during a very bright, hard accretion state in 2010. Combined with a rich contemporaneous multiwavelength dataset, clear spectral curvature is found in the infrared, associated with the peak flux density expected from the compact jet. An optically-thin slope of ∼-0.7 and a jet radiative power of >6×10 35 erg s −1 (d/8 kpc) 2 are measured. A ∼24 h WISE light curve shows dramatic variations in mid-infrared spectral slope on timescales at least as short as the satellite orbital period ∼95 mins. There is also significant change during one pair of observations spaced by only 11 s. These variations imply that the spectral break associated with the transition from self-absorbed to optically-thin jet synchrotron radiation must be varying across the full wavelength range of ∼3-22 µm that WISE is sensitive to, and more. Based on fourband simultaneous mid-infrared detections, the break is constrained to frequencies of ≈4.6 +3.5 −2.0 ×10 13 Hz in at least two epochs of observation, consistent with a magnetic field B≈1.5(±0.8)×10 4 G assuming a single-zone synchrotron emission region. The observed variability implies that either B, or the size of the acceleration zone above the jet base, are being modulated by factors of ∼10 on relatively-short timescales.