Production of all the r-process nuclides in the dynamical ejecta of neutron star mergers

Recent studies suggest that binary neutron star (NS-NS) mergers robustly produce the heavy r-process nuclei above the atomic mass number A ~ 130 because of their ejecta consisting of almost pure neutrons (electron fraction of Y_e < 0.1). However, little production of the lighter r-process nuclei (A = 90-120) conflicts with the spectroscopic results of r-process-enhanced Galactic halo stars. We present, for the first time, the result of nucleosynthesis calculations based on the fully general-relativistic simulation of a NS-NS merger with approximate neutrino transport. It is found that the bulk of the dynamical ejecta are appreciably shock-heated and neutrino-processed, resulting in a wide range of Y_e (= 0.09-0.45). The mass-averaged abundance distribution of calculated nucleosynthesis yields is in reasonable agreement with the full-mass range (A = 90-240) of the solar r-process curve. This implies, if our model is representative of such events, that the dynamical ejecta of NS-NS mergers can be the origin of the Galactic r-process nuclei. Our result also shows that the radioactive heating after ~ 1 day from the merging, giving rise to r-process-powered transient emission, is dominated by the beta-decays of several species close to stability with precisely measured half-lives. This implies that the total radioactive heating rate for such an event can be well constrained within about a factor of two if the ejected material has a solar-like r-process pattern.Comment: 6 pages, 5 figures, accepted for publication in ApJL. Section 2 was significantly changed according to the referee's advices. Our result was unchange

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells.

The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development and lead to altered DNA methylation landscapes and an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type-specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed acute myeloid leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we provide evidence that loss of TET2 leads to attenuation of chromatin binding of members of the basic helix-loop-helix (bHLH) TF family. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provides an example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.K.D.R. was supported by a postdoctoral fellowship from the Danish Medical Research Council (FSS 1333-00120B), K.N. was supported by Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, JSPS (S2704), and L.S.-C. was supported by a Marie Sklodowska-Curie individual fellowship (Horizon 2020 Framework Programme, grant agreement no. H2020-MSCA-IF-2017-796341). The work in the Helin laboratory was supported by grants to K.H. from The European Research Council (294666_DNAMET), the Danish Cancer Society, the Danish National Research Foundation (DNRF82), and through a center grant from the Novo Nordisk Foundation (NNF17CC0027852). This work was also supported by the National Institutes of Health (NIH, P30 CA008748)

Cdk1-mediated DIAPH1 phosphorylation maintains metaphase cortical tension and inactivates the spindle assembly checkpoint at anaphase

Animal cells undergo rapid rounding during mitosis, ensuring proper chromosome segregation, during which an outward rounding force abruptly increases upon prometaphase entry and is maintained at a constant level during metaphase. Initial cortical tension is generated by the actomyosin system to which both myosin motors and actin network architecture contribute. However, how cortical tension is maintained and its physiological significance remain unknown. We demonstrate here that Cdk1-mediated phosphorylation of DIAPH1 stably maintains cortical tension after rounding and inactivates the spindle assembly checkpoint (SAC). Cdk1 phosphorylates DIAPH1, preventing profilin1 binding to maintain cortical tension. Mutation of DIAPH1 phosphorylation sites promotes cortical F-actin accumulation, increases cortical tension, and delays anaphase onset due to SAC activation. Measurement of the intra-kinetochore length suggests that Cdk1-mediated cortex relaxation is indispensable for kinetochore stretching. We thus uncovered a previously unknown mechanism by which Cdk1 coordinates cortical tension maintenance and SAC inactivation at anaphase onset

Systematic evaluation of AML-associated antigens identifies anti-U5 SNRNP200 therapeutic antibodies for the treatment of acute myeloid leukemia.

Despite recent advances in the treatment of acute myeloid leukemia (AML), there has been limited success in targeting surface antigens in AML, in part due to shared expression across malignant and normal cells. Here, high-density immunophenotyping of AML coupled with proteogenomics identified unique expression of a variety of antigens, including the RNA helicase U5 snRNP200, on the surface of AML cells but not on normal hematopoietic precursors and skewed Fc receptor distribution in the AML immune microenvironment. Cell membrane localization of U5 snRNP200 was linked to surface expression of the Fcγ receptor IIIA (FcγIIIA, also known as CD32A) and correlated with expression of interferon-regulated immune response genes. Anti-U5 snRNP200 antibodies engaging activating Fcγ receptors were efficacious across immunocompetent AML models and were augmented by combination with azacitidine. These data provide a roadmap of AML-associated antigens with Fc receptor distribution in AML and highlight the potential for targeting the AML cell surface using Fc-optimized therapeutics

APC(CDH1) targets MgcRacGAP for destruction in the late M phase.

Male germ cell RacGTPase activating protein (MgcRacGAP) is an important regulator of the Rho family GTPases--RhoA, Rac1, and Cdc42--and is indispensable in cytokinesis and cell cycle progression. Inactivation of RhoA by phosphorylated MgcRacGAP is an essential step in cytokinesis. MgcRacGAP is also involved in G1-S transition and nuclear transport of signal transducer and activator of transcription 3/5 (STAT3/5). Expression of MgcRacGAP is strictly controlled in a cell cycle-dependent manner. However, the underlying mechanisms have not been elucidated.Using MgcRacGAP deletion mutants and the fusion proteins of full-length or partial fragments of MgcRacGAP to mVenus fluorescent protein, we demonstrated that MgcRacGAP is degraded by the ubiquitin-proteasome pathway in the late M to G1 phase via APC(CDH1). We also identified the critical region for destruction located in the C-terminus of MgcRacGAP, AA537-570, which is necessary and sufficient for CDH1-mediated MgcRacGAP destruction. In addition, we identified a PEST domain-like structure with charged residues in MgcRacGAP and implicate it in effective ubiquitination of MgcRacGAP.Our findings not only reveal a novel mechanism for controlling the expression level of MgcRacGAP but also identify a new target of APC(CDH1). Moreover our results identify a C-terminal region AA537-570 of MgcRacGAP as its degron