Disk-Jet Connection in the Radio Galaxy 3C 120

We present the results of extensive multi-frequency monitoring of the radio galaxy 3C 120 between 2002 and 2007 at X-ray, optical, and radio wave bands, as well as imaging with the Very Long Baseline Array (VLBA). Over the 5 yr of observation, significant dips in the X-ray light curve are followed by ejections of bright superluminal knots in the VLBA images. Consistent with this, the X-ray flux and 37 GHz flux are anti-correlated with X-ray leading the radio variations. This implies that, in this radio galaxy, the radiative state of accretion disk plus corona system, where the X-rays are produced, has a direct effect on the events in the jet, where the radio emission originates. The X-ray power spectral density of 3C 120 shows a break, with steeper slope at shorter timescale and the break timescale is commensurate with the mass of the central black hole based on observations of Seyfert galaxies and black hole X-ray binaries. These findings provide support for the paradigm that black hole X-ray binaries and active galactic nuclei are fundamentally similar systems, with characteristic time and size scales linearly proportional to the mass of the central black hole. The X-ray and optical variations are strongly correlated in 3C 120, which implies that the optical emission in this object arises from the same general region as the X-rays, i.e., in the accretion disk-corona system. We numerically model multi-wavelength light curves of 3C 120 from such a system with the optical-UV emission produced in the disk and the X-rays generated by scattering of thermal photons by hot electrons in the corona. From the comparison of the temporal properties of the model light curves to that of the observed variability, we constrain the physical size of the corona and the distances of the emitting regions from the central BH.Comment: Accepted for publication in the Astrophysical Journal. 28 pages, 21 figures, 2 table

ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.Xi Luo, Simone Feurstein, Shruthi Mohan, Christopher C. Porter, Sarah A. Jackson, Sioban Keel ... et al

Regulation of apical membrane enrichment and retention of plasma membrane Ca2+ ATPase splice variants by the PDZ-domain protein NHERF2

The localization of plasma membrane calcium ATPase (PMCA) isoforms in specified membrane compartments is crucial for their function in local Ca2+ handling. PMCA2w/b is present in the apical membrane whereas alternative splice variants PMCA2x/b and 2z/b reside in the basolateral membrane in polarized epithelial cells. Here we found that the apical scaffolding protein NHERF2 greatly enhances the apical concentration of PMCA2w/b by tethering the pump to the underlying actin cytoskeleton. The interaction requires the C-terminal PDZ binding sequence in PMCA2b and results in increased membrane retention and decreased lateral mobility of the pump. In contrast, PMCA2x/b remains exclusively basolateral even when NHERF2 is overexpressed. Our results suggest that the alternatively spliced intracellular loop in PMCA2 imposes dominant membrane targeting information. NHERF2-mediated recruitment may be an effective means for polarized cells to regulate the abundance of PMCA2w/b in the apical membrane to meet an increased demand for local Ca2+ extrusion

Differential regulation of synchronous versus asynchronous neurotransmitter release by the C2 domains of synaptotagmin 1

Synaptic vesicle fusion at many synapses has been kinetically separated into two distinct Ca2+-dependent temporal components consisting of a rapid synchronous phase followed by a slower asynchronous component. Mutations in the synaptic vesicle Ca2+ sensor Synaptotagmin 1 (Syt 1) reduce synchronous neurotransmission while enhancing the slower asynchronous phase of release. Syt 1 regulation of vesicle fusion requires interactions mediated by its tandem cytoplasmic C2 domains (C2A and C2B). Although Ca2+ binding by Syt 1 is predicted to drive synchronous release, it is unknown if Ca2+ interactions with either C2 domain is required for suppression of asynchronous release. To determine if Ca2+ binding by Syt 1 regulates these two phases of release independently, we performed electrophysiological analysis of transgenically expressed Syt 1 mutated at Ca2+ binding sites in C2A or C2B in the background of Drosophila Syt 1-null mutants. Transgenic animals expressing mutations that disrupt Ca2+ binding to C2A fully restored the synchronous phase of neurotransmitter release, whereas the asynchronous component was not suppressed. In contrast, rescue with Ca2+-binding mutants in C2B displayed little rescue of the synchronous release component, but reduced asynchronous release. These results suggest that the tandem C2 domains of Syt 1 play independent roles in neurotransmission, as Ca2+ binding to C2A suppresses asynchronous release, whereas Ca2+ binding to C2B mediates synchronous fusion