Structural insights into the mechanism of negative regulation of single-box high mobility group proteins by the acidic tail domain.

The Drosophila and plant (maize) functional counterparts of the abundant vertebrate chromosomal protein HMGB1 (HMG-D and ZmHMGB1, respectively) differ from HMGB1 in having a single HMG box, as well as basic and acidic flanking regions that vary greatly in length and charge. We show that despite these variations, HMG-D and ZmHMGB1 exist in dynamic assemblies in which the basic HMG boxes and linkers associate with their intrinsically disordered, predominantly acidic, tails in a manner analogous to that observed previously for HMGB1. The DNA-binding surfaces of the boxes and linkers are occluded in "auto-inhibited" forms of the protein, which are in equilibrium with transient, more open structures that are "binding-competent." This strongly suggests that the mechanism of auto-inhibition may be a general one. HMG-D and ZmHMGB1 differ from HMGB1 in having phosphorylation sites in their tail and linker regions. In both cases, in vitro phosphorylation of serine residues within the acidic tail stabilizes the assembled form, suggesting another level of regulation for interaction with DNA, chromatin, and other proteins that is not possible for the uniformly acidic (hence unphosphorylatable) tail of HMGB1.This work was supported by the Biotechnology and Biological Sciences Research Council through the award of Grant BB/D002257/1 (to J. O. T.) and a grant from the Deutsche Forschungsgemeinschaft (DFG) (to K. D. G.).This is the final published version. It first appeared at http://www.jbc.org/content/289/43/29817.long

Safety and immunogenicity of H1/IC31®, an adjuvanted TB subunit vaccine, in HIV-infected adults with CD4+ lymphocyte counts greater than 350 cells/mm3: a phase II, multi-centre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Novel tuberculosis vaccines should be safe, immunogenic, and effective in various population groups, including HIV-infected individuals. In this phase II multi-centre, double-blind, placebo-controlled trial, the safety and immunogenicity of the novel H1/IC31 vaccine, a fusion protein of Ag85B-ESAT-6 (H1) formulated with the adjuvant IC31, was evaluated in HIV-infected adults. METHODS: HIV-infected adults with CD4+ T cell counts >350/mm3 and without evidence of active tuberculosis were enrolled and followed until day 182. H1/IC31 vaccine or placebo was randomly allocated in a 5:1 ratio. The vaccine was administered intramuscularly at day 0 and 56. Safety assessment was based on medical history, clinical examinations, and blood and urine testing. Immunogenicity was determined by a short-term whole blood intracellular cytokine staining assay. RESULTS: 47 of the 48 randomised participants completed both vaccinations. In total, 459 mild or moderate and 2 severe adverse events were reported. There were three serious adverse events in two vaccinees classified as not related to the investigational product. Local injection site reactions were more common in H1/IC31 versus placebo recipients (65.0% vs. 12.5%, p = 0.015). Solicited systemic and unsolicited adverse events were similar by study arm. The baseline CD4+ T cell count and HIV viral load were similar by study arm and remained constant over time. The H1/IC31 vaccine induced a persistent Th1-immune response with predominately TNF-α and IL-2 co-expressing CD4+ T cells, as well as polyfunctional IFN-γ, TNF-α and IL-2 expressing CD4+ T cells. CONCLUSION: H1/IC31 was well tolerated and safe in HIV-infected adults with a CD4+ Lymphocyte count greater than 350 cells/mm3. The vaccine did not have an effect on CD4+ T cell count or HIV-1 viral load. H1/IC31 induced a specific and durable Th1 immune response. TRIAL REGISTRATION: Pan African Clinical Trials Registry (PACTR) PACTR201105000289276

A comparison of daily water use estimates derived from constant-heat sap-flow probe values and gravimetric measurements in pot-grown saplings.

Use of Granier-style heat dissipation sensors to measure sap flow is common in plant physiology, ecology and hydrology. There has been concern that any change to the original Granier design invalidates the empirical relationship between sap flux density and the temperature difference between the probes. Here, we compared daily water use estimates from gravimetric measurements with values from variable length heat dissipation sensors, which are a relatively new design. Values recorded during a one-week period were compared for three large pot-grown saplings of each of the tropical trees Pseudobombax septenatum (Jacq.) Dugand and Calophyllum longifolium Willd. For five of the six individuals, P values from paired t-tests comparing the two methods ranged from 0.12 to 0.43 and differences in estimates of total daily water use over the week of the experiment averaged < 3%. In one P. septenatum sapling, the sap flow sensors underestimated water use relative to the gravimetric measurements. This discrepancy could have been associated with naturally occurring gradients in temperature that reduced the difference in temperature between the probes, which would have caused the sensor method to underestimate water use. Our results indicate that substitution of variable length heat dissipation probes for probes of the original Granier design did not invalidate the empirical relationship determined by Granier between sap flux density and the temperature difference between probes.Keywords: validation, variable-length probeKeywords: validation, variable-length prob

Radial decoupling of small and large dust grains in the transitional disk RX J1615.3-3255

We present H-band (1.6 {\mu}m) scattered light observations of the transitional disk RX J1615.3-3255, located in the ~1 Myr old Lupus association. From a polarized intensity image, taken with the HiCIAO instrument of the Subaru Telescope, we deduce the position angle and the inclination angle of the disk. The disk is found to extend out to 68 $\pm$ 12 AU in scattered light and no clear structure is observed. Our inner working angle of 24 AU does not allow us to detect a central decrease in intensity similar to that seen at 30 AU in the 880 {\mu}m continuum observations. We compare the observations with multiple disk models based on the Spectral Energy Distribution (SED) and submm interferometry and find that an inner rim of the outer disk at 30 AU containing small silicate grains produces a polarized intensity signal which is an order of magnitude larger than observed. We show that a model in which the small dust grains extend smoothly into the cavity found for large grains is closer to the actual H-band observations. A comparison of models with different dust size distributions suggests that the dust in the disk might have undergone significant processing compared to the interstellar medium.Comment: 8 pages, 7 figures, 4 tables. Accepted for publication in A&

Extreme Asymmetry in the Disk of V1247 Ori

We present the first near-infrared scattered-light detection of the transitional disk around V1247 Ori, which was obtained using high-resolution polarimetric differential imaging observations with Subaru/HiCIAO. Our imaging in the H band reveals the disk morphology at separations of ~0.14"-0.86" (54-330 au) from the central star. The polarized intensity (PI) image shows a remarkable arc-like structure toward the southeast of the star, whereas the fainter northwest region does not exhibit any notable features. The shape of the arm is consistent with an arc of 0.28" $\pm$ 0.09" in radius (108 au from the star), although the possibility of a spiral arm with a small pitch angle cannot be excluded. V1247 Ori features an exceptionally large azimuthal contrast in scattered, polarized light; the radial peak of the southeastern arc is about three times brighter than the northwestern disk measured at the same distance from the star. Combined with the previous indication of an inhomogeneous density distribution in the gap at $\lesssim$46 au, the notable asymmetry in the outer disk suggests the presence of unseen companions and/or planet-forming processes ongoing in the arc.Comment: 21 pages, 5 figures, accepted for publication in PAS