Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia

Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and cofactor required for A3 degradation : Maedi-visna virus Vif interactions with cellular factors

Funding and additional information K. M. K. was supported by the predoctoral program in Biophysics NIH T32 GM008283. This work was supported by the National Institutes of Health grant AI116313 (to Y. X.) and University of Iceland Research Fund (to S. R. J). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory proteincalled the virion infectivity factor (Vif), which recruits A3 proteins to cullin–RING E3 ubiquitin ligases such as cullin-5 (Cul5) for ubiquitylation and subsequent proteasomal degradation. Although Vif proteins from primate lentiviruses such as HIV-1 utilize the transcription factor core-binding factor subunit beta as a noncanonical cofactor to stabilize the complex, the maedi–visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Because core-binding factor subunit beta and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for the MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that although some common motifs between the HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in the MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.Peer reviewe

ILC Reference Design Report Volume 1 - Executive Summary

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2s^-1. This report is the Executive Summary (Volume I) of the four volume Reference Design Report. It gives an overview of the physics at the ILC, the accelerator design and value estimate, the detector concepts, and the next steps towards project realization

ILC Reference Design Report Volume 4 - Detectors

This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics.This report, Volume IV of the International Linear Collider Reference Design Report, describes the detectors which will record and measure the charged and neutral particles produced in the ILC's high energy e+e- collisions. The physics of the ILC, and the environment of the machine-detector interface, pose new challenges for detector design. Several conceptual designs for the detector promise the needed performance, and ongoing detector R&D is addressing the outstanding technological issues. Two such detectors, operating in push-pull mode, perfectly instrument the ILC interaction region, and access the full potential of ILC physics

ILC Reference Design Report Volume 3 - Accelerator

The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC.The International Linear Collider (ILC) is a 200-500 GeV center-of-mass high-luminosity linear electron-positron collider, based on 1.3 GHz superconducting radio-frequency (SCRF) accelerating cavities. The ILC has a total footprint of about 31 km and is designed for a peak luminosity of 2x10^34 cm^-2 s^-1. The complex includes a polarized electron source, an undulator-based positron source, two 6.7 km circumference damping rings, two-stage bunch compressors, two 11 km long main linacs and a 4.5 km long beam delivery system. This report is Volume III (Accelerator) of the four volume Reference Design Report, which describes the design and cost of the ILC

International Linear Collider Reference Design Report Volume 2: PHYSICS AT THE ILC

This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described.This article reviews the physics case for the ILC. Baseline running at 500 GeV as well as possible upgrades and options are discussed. The opportunities on Standard Model physics, Higgs physics, Supersymmetry and alternative theories beyond the Standard Model are described