HIV-1 Nef limits communication between linker of activated T cells and SLP-76 to reduce formation of SLP-76-signaling microclusters following TCR stimulation

Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1-infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef's ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76-signaling MCs.

Discovery of Main-Belt Comet P/2006 VW139 by Pan-STARRS 1

The main-belt asteroid (300163) 2006 VW139 (later designated P/2006 VW139) was discovered to exhibit comet-like activity by the Pan-STARRS1 (PS1) survey telescope using automated point-spread-function analyses performed by PS1's Moving Object Processing System. Deep follow-up observations show both a short (~10'') antisolar dust tail and a longer (~60'') dust trail aligned with the object's orbit plane, similar to the morphology observed for another main-belt comet (MBC), P/2010 R2 (La Sagra), and other well-established comets, implying the action of a long-lived, sublimation-driven emission event. Photometry showing the brightness of the near-nucleus coma remaining constant over ~30 days provides further evidence for this object's cometary nature, suggesting it is in fact an MBC, and not a disrupted asteroid. A spectroscopic search for CN emission was unsuccessful, though we find an upper limit CN production rate of Q CN 100 Myr, while a search for a potential asteroid family around the object reveals a cluster of 24 asteroids within a cutoff distance of 68 m s-1. At 70 m s-1, this cluster merges with the Themis family, suggesting that it could be similar to the Beagle family to which another MBC, 133P/Elst-Pizarro, belongs.

The Pan-STARRS Moving Object Processing System

We describe the Pan-STARRS Moving Object Processing System (MOPS), a modern software package that produces automatic asteroid discoveries and identifications from catalogs of transient detections from next-generation astronomical survey telescopes. MOPS achieves >99.5% efficiency in producing orbits from a synthetic but realistic population of asteroids whose measurements were simulated for a Pan-STARRS4-class telescope. Additionally, using a nonphysical grid population, we demonstrate that MOPS can detect populations of currently unknown objects such as interstellar asteroids. MOPS has been adapted successfully to the prototype Pan-STARRS1 telescope despite differences in expected false detection rates, fill-factor loss, and relatively sparse observing cadence compared to a hypothetical Pan-STARRS4 telescope and survey. MOPS remains highly efficient at detecting objects but drops to 80% efficiency at producing orbits. This loss is primarily due to configurable MOPS processing limits that are not yet tuned for the Pan-STARRS1 mission. The core MOPS software package is the product of more than 15 person-years of software development and incorporates countless additional years of effort in third-party software to perform lower-level functions such as spatial searching or orbit determination. We describe the high-level design of MOPS and essential subcomponents, the suitability of MOPS for other survey programs, and suggest a road map for future MOPS development.

The main-belt comets: The Pan-STARRS1 perspective

We analyze a set of 760 475 observations of 333 026 unique main-belt objects obtained by the Pan-STARRS1(PS1) survey telescope between 2012 May 20 and 2013 November 9, a period during which PS1 discoveredtwo main-belt comets, P/2012 T1 (PANSTARRS) and P/2013 R3 (Catalina-PANSTARRS). PS1 cometdetection procedures currently consist of the comparison of the point spread functions (PSFs) of movingobjects to those of reference stars, and the flagging of objects that show anomalously large radial PSFwidths for human evaluation and possible observational follow-up. Based on the number of missed discoveryopportunities among comets discovered by other observers, we estimate an upper limit comet discoveryefficiency rate of 70% for PS1. Additional analyses that could improve comet discovery yields infuture surveys include linear PSF analysis, modeling of trailed stellar PSFs for comparison to trailed movingobject PSFs, searches for azimuthally localized activity, comparison of point-source-optimized photometryto extended-source-optimized photometry, searches for photometric excesses in objects withknown absolute magnitudes, and crowd-sourcing. Analysis of the discovery statistics of the PS1 surveyindicates an expected fraction of 59 MBCs per 106 outer main-belt asteroids (corresponding to a totalexpected population of 140 MBCs among the outer main-belt asteroid population with absolute magnitudesof 12 < HV < 19:5), and a 95% confidence upper limit of 96 MBCs per 106 outer main-belt asteroids(corresponding to a total of 230 MBCs), assuming a detection efficiency of 50%. We note howeverthat significantly more sensitive future surveys (particularly those utilizing larger aperture telescopes)could detect many more MBCs than estimated here. Examination of the orbital element distribution ofall known MBCs reveals an excess of high eccentricities (0:1 < e < 0:3) relative to the background asteroidpopulation. Theoretical calculations show that, given these eccentricities, the sublimation rate for atypical MBC is orders of magnitude larger at perihelion than at aphelion, providing a plausible physicalexplanation for the observed behavior of MBCs peaking in observed activity strength near perihelion.These results indicate that the overall rate of mantle growth should be slow, consistent with observationalevidence that MBC activity can be sustained over multiple orbit passages.

Absolute Magnitudes of Pan-STARRS PS1 Asteroids

Absolute magnitude (H) of an asteroid is a fundamental parameter describing the size and the apparent brightness of the body. Because of its surface shape, properties and changing illumination, the brightness changes with the geometry and is described by the phase function governed by the slope parameter (G). Although many years have been spent on detailed observations of individual asteroids to provide H and G, vast majority of minor planets have H based on assumed G and due to the input photometry from multiple sources the errors of these values are unknown. We compute H of ~ 180 000 and G of few thousands asteroids observed with the Pan-STARRS PS1 telescope in well defined photometric systems. The mean photometric error is 0.04 mag. Because on average there are only 7 detections per asteroid in our sample, we employed a Monte Carlo (MC) technique to generate clones simulating all possible rotation periods, amplitudes and colors of detected asteroids. Known asteroid colors were taken from the SDSS database. We used debiased spin and amplitude distributions dependent on size, spectral class distributions of asteroids dependent on semi-major axis and starting values of G from previous works. H and G (G12 respectively) were derived by phase functions by Bowell et al. (1989) and Muinonen et al. (2010). We confirmed that there is a positive systematic offset between H based on PS1 asteroids and Minor Planet Center database up to -0.3 mag peaking at 14. Similar offset was first mentioned in the analysis of SDSS asteroids and was believed to be solved by weighting and normalizing magnitudes by observatory codes. MC shows that there is only a negligible difference between Bowell's and Muinonen's solution of H. However, Muinonen's phase function provides smaller errors on H. We also derived G and G12 for thousands of asteroids. For known spectral classes, slope parameters agree with the previous work in general, however, the standard deviation of G in our sample is twice as larger, most likely due to sparse phase curve sampling. In the near future we plan to complete the H and G determination for all PS1 asteroids (500,000) and publish H and G values online. This work was supported by NASA grant No. NNX12AR65G.

Absolute Magnitudes of Pan-STARRS 1 Asteroids

It is well known that the absolute magnitudes (H) in the MPCORB and ASTORB orbital element catalogs suffer from a systematic offset. Juric at al. (2002) found 0.4 mag offset in the SDSS data and detailed light curve studies of WISE asteroids by Pravec et al. (2012) revealed size-dependent offsets of up to 0.5 mag. The offsets are thought to be caused by systematic errors introduced by earlier surveys using different photometric catalogs and filters. The next generation asteroid surveys provide an order of magnitude more asteroids and well-defined and calibrated magnitudes. The Pan-STARRS 1 telescope (PS1) has observed hundreds of thousands asteroids, submitted more than 2 million detections to the Minor Planet Center (MPC) and discovered almost 300 NEOs since the beginning of operations in late 2010. We transformed the observed apparent magnitudes of PS1-detected asteroids from the gP1,rP1,iP1,yP1,zP1 and wP1-bands into Johnson photometric system by assuming the mean S and C-type asteroid color (Fitzsimmons 2011 - personal communication, Schlafly et al. 2012, Magnier et al. 2012 - in preparation) and calculated the absolute magnitude (H) in the V-band and its uncertainty (Bowell et al., 1989) for more than 200,000 known asteroids having on average 6.7 detections per object. The H error with respect to the MPCORB catalog revealed a mean offset of -0.49+0.30 mag in good agreement with published values. We will also discuss the statistical and systematical errors in H and slope parameter G.

Absolute magnitudes and slope parameters for 250,000 asteroids observed by Pan-STARRS PS1 - preliminary results

We present the results of a Monte Carlo technique to calculate the absolute magnitudes (H) and slope parameters (G) of about 240,000 asteroids observed by the Pan-STARRS1 telescope during the first 15 months of its 3-year all-sky survey mission. The system's exquisite photometry with photometric errors asteroids rotation period, amplitude and color to derive the most-likely H and G, but its major advantage is in estimating realistic statistical+systematic uncertainties and errors on each parameter. The method was confirmed by comparison with the well-established and accurate results for about 500 asteroids provided by Pravec et al. (2012) and then applied to determining H and G for the Pan-STARRS1 asteroids using both the Muinonen et al. (2010) and Bowell et al. (1989) phase functions. Our results confirm the bias in MPC photometry discovered by ( Jurić et al., 2002).

Pan-retinal photocoagulation and other forms of laser treatment and drug therapies for non-proliferative diabetic retinopathy: systematic review and economic evaluation

BACKGROUND: Diabetic retinopathy is an important cause of visual loss. Laser photocoagulation preserves vision in diabetic retinopathy but is currently used at the stage of proliferative diabetic retinopathy (PDR).

OBJECTIVES: The primary aim was to assess the clinical effectiveness and cost-effectiveness of pan-retinal photocoagulation (PRP) given at the non-proliferative stage of diabetic retinopathy (NPDR) compared with waiting until the high-risk PDR (HR-PDR) stage was reached. There have been recent advances in laser photocoagulation techniques, and in the use of laser treatments combined with anti-vascular endothelial growth factor (VEGF) drugs or injected steroids. Our secondary questions were: (1) If PRP were to be used in NPDR, which form of laser treatment should be used? and (2) Is adjuvant therapy with intravitreal drugs clinically effective and cost-effective in PRP?

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) for efficacy but other designs also used.

REVIEW METHODS: Systematic review and economic modelling.

RESULTS: The Early Treatment Diabetic Retinopathy Study (ETDRS), published in 1991, was the only trial designed to determine the best time to initiate PRP. It randomised one eye of 3711 patients with mild-to-severe NPDR or early PDR to early photocoagulation, and the other to deferral of PRP until HR-PDR developed. The risk of severe visual loss after 5 years for eyes assigned to PRP for NPDR or early PDR compared with deferral of PRP was reduced by 23% (relative risk 0.77, 99% confidence interval 0.56 to 1.06). However, the ETDRS did not provide results separately for NPDR and early PDR. In economic modelling, the base case found that early PRP could be more effective and less costly than deferred PRP. Sensitivity analyses gave similar results, with early PRP continuing to dominate or having low incremental cost-effectiveness ratio. However, there are substantial uncertainties. For our secondary aims we found 12 trials of lasers in DR, with 982 patients in total, ranging from 40 to 150. Most were in PDR but five included some patients with severe NPDR. Three compared multi-spot pattern lasers against argon laser. RCTs comparing laser applied in a lighter manner (less-intensive burns) with conventional methods (more intense burns) reported little difference in efficacy but fewer adverse effects. One RCT suggested that selective laser treatment targeting only ischaemic areas was effective. Observational studies showed that the most important adverse effect of PRP was macular oedema (MO), which can cause visual impairment, usually temporary. Ten trials of laser and anti-VEGF or steroid drug combinations were consistent in reporting a reduction in risk of PRP-induced MO.

LIMITATION: The current evidence is insufficient to recommend PRP for severe NPDR.

CONCLUSIONS: There is, as yet, no convincing evidence that modern laser systems are more effective than the argon laser used in ETDRS, but they appear to have fewer adverse effects. We recommend a trial of PRP for severe NPDR and early PDR compared with deferring PRP till the HR-PDR stage. The trial would use modern laser technologies, and investigate the value adjuvant prophylactic anti-VEGF or steroid drugs.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42013005408.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.