Metal Ion-dependent Heavy Chain Transfer Activity of TSG-6 Mediates Assembly of the Cumulus-Oocyte Matrix

The matrix polysaccharide hyaluronan (HA) has a critical role in the expansion of the cumulus cell-oocyte complex (COC), a process that is necessary for ovulation and fertilization in most mammals. Hyaluronan is organized into a cross-linked network by the cooperative action of three proteins, inter-α-inhibitor (IαI), pentraxin-3, and TNF-stimulated gene-6 (TSG-6), driving the expansion of the COC and providing the cumulus matrix with its required viscoelastic properties. Although it is known that matrix stabilization involves the TSG-6-mediated transfer of IαI heavy chains (HCs) onto hyaluronan (to form covalent HC·HA complexes that are cross-linked by pentraxin-3) and that this occurs via the formation of covalent HC·TSG-6 intermediates, the underlying molecular mechanisms are not well understood. Here, we have determined the tertiary structure of the CUB module from human TSG-6, identifying a calcium ion-binding site and chelating glutamic acid residue that mediate the formation of HC·TSG-6. This occurs via an initial metal ion-dependent, non-covalent, interaction between TSG-6 and HCs that also requires the presence of an HC-associated magnesium ion. In addition, we have found that the well characterized hyaluronan-binding site in the TSG-6 Link module is not used for recognition during transfer of HCs onto HA. Analysis of TSG-6 mutants (with impaired transferase and/or hyaluronan-binding functions) revealed that although the TSG-6-mediated formation of HC·HA complexes is essential for the expansion of mouse COCs in vitro, the hyaluronan-binding function of TSG-6 does not play a major role in the stabilization of the murine cumulus matrix

THE K2-ESPRINT PROJECT. V. A SHORT-PERIOD GIANT PLANET ORBITING A SUBGIANT STAR

We report on the discovery and characterization of the transiting planet K2-39b (EPIC 206247743b). With an orbital period of 4.6 days, it is the shortest-period planet orbiting a subgiant star known to date. Such planets are rare, with only a handful of known cases. The reason for this is poorly understood but may reflect differences in planet occurrence around the relatively high-mass stars that have been surveyed, or may be the result of tidal destruction of such planets. K2-39 (EPIC 206247743) is an evolved star with a spectroscopically derived stellar radius and mass of 3.88 [subscript -0.42] [superscript +0.48] R [subscript ⊙] and 1.53[subscript-0.12] [superscript +0.13] M[subscript ⊙], respectively, and a very close-in transiting planet, with a/R [subscript asterisk]= 3.4 Radial velocity (RV) follow-up using the HARPS, FIES, and PFS instruments leads to a planetary mass of 50.3 [subscript -9.4] [superscript +9.7] M [subscript ⊙]. In combination with a radius measurement of 8.3 ± 1.1 R [subscript oplus], this results in a mean planetary density of 0.50 [subscript -0.17] [superscript +0.29] g cm [superscript -3]. We furthermore discover a long-term RV trend, which may be caused by a long-period planet or stellar companion. Because K2-39b has a short orbital period, its existence makes it seem unlikely that tidal destruction is wholly responsible for the differences in planet populations around subgiant and main-sequence stars. Future monitoring of the transits of this system may enable the detection of period decay and constrain the tidal dissipation rates of subgiant stars

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hydrographic and Acoustic Doppler Current Profiler (ADCP) data from the Farallones Shelf and Slope study : 13-18 February 1991

This data report presents hydrographic (CTD) and Acoustic Doppler Current Profiler (ADCP) data from a cruise to the Continental Shelf and slope region near the Gulf of the Farallones National Marine Sanctuary during 13-18 February 1991. The study area encompassed a region from 75 km south of San Francisco (Pigeon Point) north to about 38 deg 0.0' N (Point Reyes) extending from the coast to about 90 km offshore. The sampling grid consisted of five across-shore transects 20 km apart, with nine or ten CTD stations from 5 to 15 km apart each transect. A total of forty-eight CTD's were made to within approximately 25 m of the bottom. ADCP data were collected during the occupation of the sampling grid as well during a separate ADCP survey conducted at the end of the cruise. The data are presented as vertical sections, property distributions on horizontal surfaces, and waterfall plots. Environmental Protection Agency, Farallones National Marine Sanctuary, CTD data, hydrographic data, ADCP data, shelf currents, slope currentshttp://archive.org/details/hydrographicacou00jessN