Cracking the DNA Code for V(D)J Recombination

To initiate V(D) J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpinforming complexes up to 2.75 angstrom resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation. Two intertwined RAG1 subunits crisscross four times between the asymmetric pair of severely bent 12/23-RSS DNAs. Location-sensitive bending of 60 degrees and 150 degrees in 12- and 23-RSS spacers, respectively, must occur for RAG1/2 to capture the nonamers and pair the hep-tamers for symmetric double-strand breakage. DNA pairing is thus sequence-context dependent and structure specific, which partly explains the "beyond 12/23'' restriction. Finally, catalysis in crystallo reveals the process of DNA hairpin formation and its stabilization by interleaved base stacking.116Ysciescopu

Aqueous electrosynthesis of an electrochromic material based water-soluble EDOT-MeNH2 hydrochloride

2\u27-Aminomethyl-3,4-ethylenedioxythiophene (EDOT-MeNH2) showed unsatisfactory results when its polymerization occurred in organic solvent in our previous report. Therefore, a water-soluble EDOT derivative was designed by using hydrochloric modified EDOT-MeNH2 (EDOT-MeNH2·HCl) and electropolymerized in aqueous solution to form the corresponding polymer with excellent electrochromic properties. Moreover, the polymer was systematically explored, including electrochemical, optical properties and structure characterization. Cyclic voltammetry showed low oxidation potential of EDOT-MeNH2·HCl (0.85 V) in aqueous solution, leading to the facile electrodeposition of uniform the polymer film with outstanding electroactivity. Compared with poly(2′-aminomethyl- 3,4-ethylenedioxythiophene) (PEDOT-MeNH2), poly(2′-aminomethyl-3,4-ethylenedioxythiophene salt) (PEDOT-MeNH3 +A-) revealed higher efficiencies (156 cm2 C-1), lower bandgap (1.68 eV), and faster response time (1.4 s). Satisfactory results implied that salinization can not only change the polymerization system, but also adjust the optical absorption, thereby increase the electrochromic properties

Aqueous electrosynthesis of an electrochromic material based water-soluble EDOT-MeNH2 hydrochloride

2\u27-Aminomethyl-3,4-ethylenedioxythiophene (EDOT-MeNH2) showed unsatisfactory results when its polymerization occurred in organic solvent in our previous report. Therefore, a water-soluble EDOT derivative was designed by using hydrochloric modified EDOT-MeNH2 (EDOT-MeNH2·HCl) and electropolymerized in aqueous solution to form the corresponding polymer with excellent electrochromic properties. Moreover, the polymer was systematically explored, including electrochemical, optical properties and structure characterization. Cyclic voltammetry showed low oxidation potential of EDOT-MeNH2·HCl (0.85 V) in aqueous solution, leading to the facile electrodeposition of uniform the polymer film with outstanding electroactivity. Compared with poly(2′-aminomethyl- 3,4-ethylenedioxythiophene) (PEDOT-MeNH2), poly(2′-aminomethyl-3,4-ethylenedioxythiophene salt) (PEDOT-MeNH3 +A-) revealed higher efficiencies (156 cm2 C-1), lower bandgap (1.68 eV), and faster response time (1.4 s). Satisfactory results implied that salinization can not only change the polymerization system, but also adjust the optical absorption, thereby increase the electrochromic properties

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

Ad-hoc recovery in workflow systems : formal model and a prototype system

A workflow management system (WFMS) facilitates business processing (workflow) across distributed nodes. State-of-the-art WFMSs do not have adequate support for the dynamic changes during the workflow execution. This thesis focuses on one of the dynamic problems, ad-hoc recovery. It is a phenomenon that occurs in workflow applications when an agent needs to alter the control flow prescribed in the original definition. Specifically, we are interested in the backward ad-hoc recoveries, in which the control flow is redirected backward. When this happens, some tasks will be re-executed and consistency problems may arise. In our proposed ad-hoc recovery model, the key components of the ad-hoc recovery are defined and some constraints are given to ensure the correctness of the workflow execution. We also present a WFMS prototype, describing its design strategy and implementation method, as well as a related protocol, as one application of this model. The protocol is exemplified by a hospital workflow. Some performance issues are also discussed

Analyzing the Error Pattern of InSAR-Based Mining Subsidence Estimation Caused by Neglecting Horizontal Movements

It is common to estimate underground mining-induced subsidence from interferometric synthetic aperture radar (InSAR) displacement observations by Neglecting hOrizontal moVements (NOV). Such a strategy would cause large errors in the NOV-estimated subsidence. This issue was proven and the theoretical equation of the resulting errors has been deduced before. However, the systematic analysis of the error pattern (e.g., spatial distribution) and its relationship between some critical influence factors (e.g., lithology of overlying rock strata) is lacking to date. To circumvent this, a method was first presented to assess the errors of the NOV-estimated mining subsidence in this study. Then, the error pattern and the influence factors of the NOV-estimated mining subsidence were discussed. The results suggest that the errors of the NOV-estimated mining subsidence spatially follow a “peak-to-valley” shape, with an absolute “peak-to-valley angle” of 5–15°. In addition, for the same underground mining geometry, the error magnitudes of the NOV-estimated mining subsidence under hard lithology of overlying rock strata are smaller than those under soft lithology, and vice versa. These results would be beneficial to guide the scientific use of the NOV method for understanding the deformation mechanism and controlling the geohazards associated with underground mining and other similar anthropogenic activities

Analyzing the Error Pattern of InSAR-Based Mining Subsidence Estimation Caused by Neglecting Horizontal Movements

It is common to estimate underground mining-induced subsidence from interferometric synthetic aperture radar (InSAR) displacement observations by Neglecting hOrizontal moVements (NOV). Such a strategy would cause large errors in the NOV-estimated subsidence. This issue was proven and the theoretical equation of the resulting errors has been deduced before. However, the systematic analysis of the error pattern (e.g., spatial distribution) and its relationship between some critical influence factors (e.g., lithology of overlying rock strata) is lacking to date. To circumvent this, a method was first presented to assess the errors of the NOV-estimated mining subsidence in this study. Then, the error pattern and the influence factors of the NOV-estimated mining subsidence were discussed. The results suggest that the errors of the NOV-estimated mining subsidence spatially follow a &ldquo;peak-to-valley&rdquo; shape, with an absolute &ldquo;peak-to-valley angle&rdquo; of 5&ndash;15&deg;. In addition, for the same underground mining geometry, the error magnitudes of the NOV-estimated mining subsidence under hard lithology of overlying rock strata are smaller than those under soft lithology, and vice versa. These results would be beneficial to guide the scientific use of the NOV method for understanding the deformation mechanism and controlling the geohazards associated with underground mining and other similar anthropogenic activities

La mobilisation sanitaire des pouvoirs publics locaux : le cas de la ville de Wuhan

International audienceEn Chine, ce sont les gouvernements locaux, en particulier celui de la ville de Wuhan, épicentre de l’épidémie, qui ont joué un rôle clé durant la crise sanitaire. D’une part, c’est à cette échelle que les décisions importantes ont été prises ; d’autre part, la majorité des dépenses liées à la lutte contre le Covid-19, y compris les primes versées aux professionnels de santé mobilisés, a été majoritairement supportée par les gouvernements locaux. Le rôle de l’État central, sans être marginal, a consisté à coordonner la mobilisation des professionnels de santé et du matériel entre les territoires, à mobiliser l’industrie et à financer une partie limitée des dépenses liées à l’action publique. Ce régime de mobilisation des ressources, s’il a permis d’être au plus proche du terrain, pose problème en termes d’équité territoriale et de capacité d’endettement des gouvernements locaux, notamment pour les régions les plus pauvres

Modeling Seasonal Variations in Vertical GPS Coordinate Time Series Using Independent Component Analysis and Varying Coefficient Regression

Common seasonal variations in Global Positioning System (GPS) coordinate time series always exist, and the modeling and correction of the seasonal signals are helpful for many geodetic studies using GPS observations. A spatiotemporal model was proposed to model the common seasonal variations in vertical GPS coordinate time series, based on independent component analysis and varying coefficient regression method. In the model, independent component analysis (ICA) is used to separate the common seasonal signals in the vertical GPS coordinate time series. Considering that the periodic signals in GPS coordinate time series change with time, a varying coefficient regression method is used to fit the separated independent components. The spatiotemporal model was then used to fit the vertical GPS coordinate time series of 262 global International GPS Service for Geodynamics (IGS) GPS sites. The results show that compared with least squares regression, the varying coefficient method can achieve a more reliable fitting result for the seasonal variation of the separated independent components. The proposed method can accurately model the common seasonal variations in the vertical GPS coordinate time series, with an average root mean square (RMS) reduction of 41.6% after the model correction