Calcium Regulates the Nuclear Localization of Protein Arginine Deiminase 2

Protein arginine deiminases (PADs) are calcium-dependent enzymes that mediate the post-translational conversion of arginine into citrulline. Dysregulated PAD activity is associated with numerous autoimmune disorders and cancers. In breast cancer, PAD2 citrullinates histone H3R26 and activates the transcription of estrogen receptor target genes. However, PAD2 lacks a canonical nuclear localization sequence, and it is unclear how this enzyme is transported into the nucleus. Here, we show for the first time that PAD2 translocates into the nucleus in response to calcium signaling. Using BioID2, a proximity-dependent biotinylation method for identifying interacting proteins, we found that PAD2 preferentially associates with ANXA5 in the cytoplasm. Binding of calcium to PAD2 weakens this cytoplasmic interaction, which generates a pool of calcium-bound PAD2 that can interact with Ran. We hypothesize that this latter interaction promotes the translocation of PAD2 into the nucleus. These findings highlight a critical role for ANXA5 in regulating PAD2 and identify an unusual mechanism whereby proteins translocate between the cytosol and nucleus

Molecular Gas in the NGC 6240 Merging Galaxy System at the Highest Spatial Resolution

We present the highest-resolution—15 pc (0.”03)—ALMA ¹²CO(2–1) line emission and 1.3 mm continuum maps, tracers of the molecular gas and dust, respectively, in the nearby merging galaxy system NGC 6240, which hosts two supermassive black holes growing simultaneously. These observations provide an excellent spatial match to existing Hubble Space Telescope (HST) optical and near-infrared observations of this system. A significant molecular gas mass, ~9 × 10⁹ M⊙, is located between the two nuclei, forming a clumpy stream kinematically dominated by turbulence, rather than a smooth rotating disk, as previously assumed from lower-resolution data. Evidence for rotation is seen in the gas surrounding the southern nucleus but not in the northern one. Dynamical shells can be seen, likely associated with nuclear supernova remnants. We further detect the presence of significant high-velocity outflows, some of them reaching velocities >500 km s⁻¹, affecting a significant fraction, ~11%, of the molecular gas in the nuclear region. Inside the spheres of influence of the northern and southern supermassive black holes, we find molecular masses of 7.4 × 10⁸ and 3.3 × 10⁹ M⊙, respectively. We are thus directly imaging the reservoir of gas that can accrete onto each supermassive black hole. These new ALMA maps highlight the critical need for high-resolution observations of molecular gas in order to understand the feeding of supermassive black holes and its connection to galaxy evolution in the context of a major galaxy merger

Reference Array and Design Consideration for the next-generation Event Horizon Telescope

We describe the process to design, architect, and implement a transformative enhancement of the Event Horizon Telescope (ngEHT). This program - the next-generation Event Horizon Telescope (ngEHT) - will form a networked global array of radio dishes capable of making high-fidelity real-time movies of supermassive black holes (SMBH) and their emanating jets. This builds upon the EHT principally by deploying additional modest-diameter dishes to optimized geographic locations to enhance the current global mm/submm wavelength Very Long Baseline Interferometric (VLBI) array, which has, to date, utilized mostly pre-existing radio telescopes. The ngEHT program further focuses on observing at three frequencies simultaneously for increased sensitivity and Fourier spatial frequency coverage. Here, the concept, science goals, design considerations, station siting and instrument prototyping are discussed, and a preliminary reference array to be implemented in phases is described.Comment: Submitted to the journal Galaxie

The SLUGGS Survey: kinematics for over 2500 globular clusters in twelve early-type galaxies

We present a spectrophotometric survey of 2522 extragalactic globular clusters (GCs) around 12 early-type galaxies, nine of which have not been published previously. Combining space-based and multicolour wide-field ground-based imaging, with spectra from the Keck/DEep Imaging Multi-Object Spectrograph (DEIMOS) instrument, we obtain an average of 160 GC radial velocities per galaxy, with a high-velocity precision of ∼15 km s−1 per GC. After studying the photometric properties of the GC systems, such as their spatial and colour distributions, we focus on the kinematics of metal-poor (blue) and metal-rich (red) GC subpopulations to an average distance of ∼8 effective radii from the galaxy centre. Our results show that for some systems the bimodality in GC colour is also present in GC kinematics. The kinematics of the red GC subpopulations are strongly coupled with the host galaxy stellar kinematics. The blue GC subpopulations are more dominated by random motions, especially in the outer regions, and decoupled from the red GCs. Peculiar GC kinematic profiles are seen in some galaxies: the blue GCs in NGC 821 rotate along the galaxy minor axis, whereas the GC system of the lenticular galaxy NGC 7457 appears to be strongly rotation supported in the outer region. We supplement our galaxy sample with data from the literature and carry out a number of tests to study the kinematic differences between the two GC subpopulations. We confirm that the GC kinematics are coupled with the host galaxy properties and find that the velocity kurtosis and the slope of their velocity dispersion profiles are different between the two GC subpopulations in more massive galaxies

Key Science Goals for the Next-Generation Event Horizon Telescope

The Event Horizon Telescope (EHT) has led to the first images of a supermassive black hole, revealing the central compact objects in the elliptical galaxy M87 and the Milky Way. Proposed upgrades to this array through the next-generation EHT (ngEHT) program would sharply improve the angular resolution, dynamic range, and temporal coverage of the existing EHT observations. These improvements will uniquely enable a wealth of transformative new discoveries related to black hole science, extending from event-horizon-scale studies of strong gravity to studies of explosive transients to the cosmological growth and influence of supermassive black holes. Here, we present the key science goals for the ngEHT and their associated instrument requirements, both of which have been formulated through a multi-year international effort involving hundreds of scientists worldwide

The persistent shadow of the supermassive black hole of M 87

In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3−3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30° relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5 × 109 M⊙. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet

Development of a Selective Inhibitor of Protein Arginine Deiminase 2.

Protein arginine deiminase 2 (PAD2) plays a key role in the onset and progression of multiple sclerosis, rheumatoid arthritis, and breast cancer. To date, no PAD2-selective inhibitor has been developed. Such a compound will be critical for elucidating the biological roles of this isozyme and may ultimately be useful for treating specific diseases in which PAD2 activity is dysregulated. To achieve this goal, we synthesized a series of benzimidazole-based derivatives of Cl-amidine, hypothesizing that this scaffold would allow access to a series of PAD2-selective inhibitors with enhanced cellular efficacy. Herein, we demonstrate that substitutions at both the N-terminus and C-terminus of Cl-amidine result in \u3e100-fold increases in PAD2 potency and selectivity (30a, 41a, and 49a) as well as cellular efficacy (30a). Notably, these compounds use the far less reactive fluoroacetamidine warhead. In total, we predict that 30a will be a critical tool for understanding cellular PAD2 function and sets the stage for treating diseases in which PAD2 activity is dysregulated