The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene... Show moreThe autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and classs-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome. Show less
Research indicates that knowledge sharing promotes teacher professional learning opportunities and development. However, it is yet to be known what motivates teachers in rural schools in sharing... Show moreResearch indicates that knowledge sharing promotes teacher professional learning opportunities and development. However, it is yet to be known what motivates teachers in rural schools in sharing their knowledge as they may face more challenges than teachers in urban areas when sharing. This study examined factors explaining rural teachers' sharing behavior regarding digital educational resources, both within and outside school, as posited by combining motivation theory and the integrative model of behavior prediction. Self-reported questionnaires from 709 rural teachers were collected and analyzed employing the Structural Equation Modeling. Different motivational factors were found to be related to sharing behavior within school and outside school. More specifically, internal motivation was positively and external motivation was negatively related to sharing behavior in both contexts. Moreover, sharing intention and sharing climate significantly explained teachers' sharing behavior, but only outside school. A mediation analysis using a bias-corrected bootstrapping method revealed that the effect of internal motivation on sharing intention within school was mediated through self-efficacy and attitudes whereas the effect of external motivation on sharing intention outside school was only mediated by attitudes. These findings contribute to a better understanding of how to support teachers’ sharing behavior in different contexts. Show less
Context. Methods used to detect giant exoplanets can be broadly divided into two categories: indirect and direct. Indirect methods are more sensitive to planets with a small orbital period, whereas... Show moreContext. Methods used to detect giant exoplanets can be broadly divided into two categories: indirect and direct. Indirect methods are more sensitive to planets with a small orbital period, whereas direct detection is more sensitive to planets orbiting at a large distance from their host star. This dichotomy makes it difficult to combine the two techniques on a single target at once.Aims. Simultaneous measurements made by direct and indirect techniques offer the possibility of determining the mass and luminosity of planets and a method of testing formation models. Here, we aim to show how long-baseline interferometric observations guided by radial-velocity can be used in such a way.Methods. We observed the recently-discovered giant planet beta Pictoris c with GRAVITY, mounted on the Very Large Telescope Interferometer.Results. This study constitutes the first direct confirmation of a planet discovered through radial velocity. We find that the planet has a temperature of T=125050 K and a dynamical mass of M=8.2 +/- 0.8 M-Jup. At 18.5 +/- 2.5 Myr, this puts beta Pic c close to a 'hot start' track, which is usually associated with formation via disk instability. Conversely, the planet orbits at a distance of 2.7 au, which is too close for disk instability to occur. The low apparent magnitude (M-K=14.3 +/- 0.1) favours a core accretion scenario.Conclusions. We suggest that this apparent contradiction is a sign of hot core accretion, for example, due to the mass of the planetary core or the existence of a high-temperature accretion shock during formation. Show less
Lagrange, A.M.; Rubini, P.; Nowak, M.; Lacour, S.; Grandjean, A.; Boccaletti, A.; ... ; Woillez, J. 2020
Context. The nearby and young β Pictoris system hosts a well resolved disk, a directly imaged massive giant planet orbiting at '9 au, as well as an inner planet orbiting at '2.7 au, which was... Show moreContext. The nearby and young β Pictoris system hosts a well resolved disk, a directly imaged massive giant planet orbiting at '9 au, as well as an inner planet orbiting at '2.7 au, which was recently detected through radial velocity (RV). As such, it offers several unique opportunities for detailed studies of planetary system formation and early evolution. Aims. We aim to further constrain the orbital and physical properties of β Pictoris b and c using a combination of high contrast imaging, long base-line interferometry, and RV data. We also predict the closest approaches or the transit times of both planets, and we constrain the presence of additional planets in the system. Methods. We obtained six additional epochs of SPHERE data, six additional epochs of GRAVITY data, and five additional epochs of RV data. We combined these various types of data in a single Markov-chain Monte Carlo analysis to constrain the orbital parameters and masses of the two planets simultaneously. The analysis takes into account the gravitational influence of both planets on the star and hence their relative astrometry. Secondly, we used the RV and high contrast imaging data to derive the probabilities of presence of additional planets throughout the disk, and we tested the impact of absolute astrometry. Results. The orbital properties of both planets are constrained with a semi-major axis of 9.8 ± 0.4 au and 2.7 ± 0.02 au for b and c, respectively, and eccentricities of 0.09 ± 0.1 and 0.27 ± 0.07, assuming the HIPPARCOS distance. We note that despite these low fitting error bars, the eccentricity of β Pictoris c might still be over-estimated. If no prior is provided on the mass of β Pictoris b, we obtain a very low value that is inconsistent with what is derived from brightness-mass models. When we set an evolutionary model motivated prior to the mass of β Pictoris b, we find a solution in the 10–11 MJup range. Conversely, β Pictoris c’s mass is well constrained, at 7.8 ± 0.4 MJup, assuming both planets are on coplanar orbits. These values depend on the assumptions on the distance of the β Pictoris system. The absolute astrometry HIPPARCOS-Gaia data are consistent with the solutions presented here at the 2σ level, but these solutions are fully driven by the relative astrometry plus RV data. Finally, we derive unprecedented limits on the presence of additional planets in the disk. We can now exclude the presence of planets that are more massive than about 2.5 MJup closer than 3 au, and more massive than 3.5 MJup between 3 and 7.5 au. Beyond 7.5 au, we exclude the presence of planets that are more massive than 1–2 MJup. Conclusions. Combining relative astrometry and RVs allows one to precisely constrain the orbital parameters of both planets and to give lower limits to potential additional planets throughout the disk. The mass of β Pictoris c is also well constrained, while additional RV data with appropriate observing strategies are required to properly constrain the mass of β Pictoris b. Show less
The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because... Show moreThe main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclo-hexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus. Show less
Duchêne, G.; Rice, M.; Hom, J.; Zalesky, J.; Esposito, T.M.; Millar-Blanchaer, M.A.; ... ; Ward-Duong, K. 2020
Endothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic... Show moreEndothelial cell (EC) metabolism is an emerging target for anti-angiogenic therapy in tumor angiogenesis and choroidal neovascularization (CNV), but little is known about individual EC metabolic transcriptomes. By single-cell RNA sequencing 28,337 murine choroidal ECs (CECs) and sprouting CNV-ECs, we constructed a taxonomy to characterize their heterogeneity. Comparison with murine lung tumor ECs (TECs) revealed congruent marker gene expression by distinct EC phenotypes across tissues and diseases, suggesting similar angiogenic mechanisms. Trajectory inference predicted that differentiation of venous to angiogenic ECs was accompanied by metabolic transcriptome plasticity. ECs displayed metabolic transcriptome heterogeneity during cell- cycle progression and in quiescence. Hypothesizing that conserved genes are important, we used an integrated analysis, based on congruent transcriptome analysis, CEC-tailored genome-scale metabolic modeling, and gene expression meta-analysis in cross-species datasets, followed by in vitro and in vivo validation, to identify SQLE and ALDH18A1 as previously unknown metabolic angiogenic targets. Show less
Heterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single... Show moreHeterogeneity of lung tumor endothelial cell (TEC) phenotypes across patients, species (human/mouse), and models (in vivo/in vitro) remains poorly inventoried at the single-cell level. We single-cell RNA (scRNA)-sequenced 56,771 endothelial cells from human/mouse (peri)-tumoral lung and cultured human lung TECs, and detected 17 known and 16 previously unrecognized phenotypes, including TECs putatively regulating immune surveillance. We resolved the canonical tip TECs into a known migratory tip and a putative basement-membrane remodeling breach phenotype. Tip TEC signatures correlated with patient survival, and tip/breach TECs were most sensitive to vascular endothelial growth factor blockade. Only tip TECs were congruent across species/models and shared conserved markers. Integrated analysis of the scRNA-sequenced data with orthogonal multi-omics and meta-analysis data across different human tumors, validated by functional analysis, identified collagen modification as a candidate angiogenic pathway. Show less
Vliet, O.P. van; Caminada, C.L.J.; Goudswaard, K.P.; Wang, J. 2020
