Degradation of the cancer genomic DNA deaminase APOBEC3B by SIV Vif

APOBEC3B is a newly identified source of mutation in many cancers, including breast, head/neck, lung, bladder, cervical, and ovarian. APOBEC3B is a member of the APOBEC3 family of enzymes that deaminate DNA cytosine to produce the promutagenic lesion, uracil. Several APOBEC3 family members function to restrict virus replication. For instance, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H combine to restrict HIV-1 in human lymphocytes. HIV-1 counteracts these APOBEC3s with the viral protein Vif, which targets the relevant APOBEC3s for proteasomal degradation. While APOBEC3B does not restrict HIV-1 and is not targeted by HIV-1 Vif in CD4-positive T cells, we asked whether related lentiviral Vif proteins could degrade APOBEC3B. Interestingly, several SIV Vif proteins are capable of promoting APOBEC3B degradation, with SIVmac239 Vif proving the most potent. This likely occurs through the canonical polyubiquitination mechanism as APOBEC3B protein levels are restored by MG132 treatment and by altering a conserved E3 ligase-binding motif. We further show that SIVmac239 Vif can prevent APOBEC3B mediated geno/cytotoxicity and degrade endogenous APOBEC3B in several cancer cell lines. Our data indicate that the APOBEC3B degradation potential of SIV Vif is an effective tool for neutralizing the cancer genomic DNA deaminase APOBEC3B. Further optimization of this natural APOBEC3 antagonist may benefit cancer therapy

Follow-up Imaging of Disk Candidates from the Disk Detective Citizen Science Project: New Discoveries and False Positives in WISE Circumstellar Disk Surveys

The Disk Detective citizen science project aims to find new stars with excess 22 m emission from circumstellar dust in the All WISE data release from the Wide-field Infrared Survey Explorer. We evaluated 261 Disk Detective objects of interest with imaging with the Robo-AO adaptive optics instrument on the 1.5 m telescope at Palomar Observatory and with RetroCam on the 2.5 m du Pont Telescope at Las Campanas Observatory to search for background objects at 0 1512 separations from each target. Our analysis of these data leads us to reject 7% of targets. Combining this result with statistics from our online image classification efforts implies that at most7.9%0.2% of All WISE-selected infrared excesses are good disk candidates. Applying our false-positive rates to other surveys, we find that the infrared excess searches of McDonald et al. and Marton et al. all have false-positiverates >70%. Moreover, we find that all 13 disk candidates in Theissen & West with W4 signal-to-noise ratio >3are false positives. We present 244 disk candidates that have survived vetting by follow-up imaging. Of these,213 are newly identified disk systems. Twelve of these are candidate members of comoving pairs based on Gaia astrometry, supporting the hypothesis that warm dust is associated with binary systems. We also note the discovery of 22 m excess around two known members of the ScorpiusCentaurus association, and we identifyknown disk host WISEA J164540.79-310226.6 as a likely Sco-Cen member. Thirty of these disk candidates arecloser than 125 pc (including 26 debris disks), making them good targets for both direct-imaging exoplanetsearches

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest

SARS-CoV-2 infection in central North Carolina: Protocol for a population-based longitudinal cohort study and preliminary participant results

Public health surveillance systems likely underestimate the true prevalence and incidence of SARS-CoV-2 infection due to limited access to testing and the high proportion of subclinical infections in community-based settings. This ongoing prospective, observational study aimed to generate accurate estimates of the prevalence and incidence of, and risk factors for, SARS-CoV-2 infection among residents of a central North Carolina county. From this cohort, we collected survey data and nasal swabs every two weeks and venous blood specimens every month. Nasal swabs were tested for the presence of SARS-CoV-2 virus (evidence of active infection), and serum specimens for SARS-CoV-2-specific antibodies (evidence of prior infection). As of June 23, 2021, we have enrolled a total of 153 participants from a county with an estimated 76,285 total residents. The anticipated study duration is at least 24 months, pending the evolution of the pandemic. Study data are being shared on a monthly basis with North Carolina state health authorities and future analyses aim to compare study data to state-wide metrics over time. Overall, the use of a probability-based sampling design and a well-characterized cohort will enable collection of critical data that can be used in planning and policy decisions for North Carolina and may be informative for other states with similar demographic characteristics

Follow-up Imaging of Disk Candidates from the Disk Detective Citizen Science Project: New Discoveries and False Positives in WISE Circumstellar Disk Surveys

The Disk Detective citizen science project aims to find new stars with excess 22 μm emission from circumstellar dust in the AllWISE data release from the Wide-field Infrared Survey Explorer. We evaluated 261 Disk Detective objects of interest with imaging with the Robo-AO adaptive optics instrument on the 1.5 m telescope at Palomar Observatory and with RetroCam on the 2.5 m du Pont Telescope at Las Campanas Observatory to search for background objects at 0.”15–12'' separations from each target. Our analysis of these data leads us to reject 7% of targets. Combining this result with statistics from our online image classification efforts implies that at most 7.9% ± 0.2% of AllWISE-selected infrared excesses are good disk candidates. Applying our false-positive rates to other surveys, we find that the infrared excess searches of McDonald et al. and Marton et al. all have false-positive rates >70%. Moreover, we find that all 13 disk candidates in Theissen & West with W4 signal-to-noise ratio >3 are false positives. We present 244 disk candidates that have survived vetting by follow-up imaging. Of these, 213 are newly identified disk systems. Twelve of these are candidate members of comoving pairs based on Gaia astrometry, supporting the hypothesis that warm dust is associated with binary systems. We also note the discovery of 22 μm excess around two known members of the Scorpius–Centaurus association, and we identify known disk host WISEA J164540.79-310226.6 as a likely Sco-Cen member. Thirty of these disk candidates are closer than ~125 pc (including 26 debris disks), making them good targets for both direct-imaging exoplanet searches

The WiggleZ Dark Energy Survey: High Resolution Kinematics of Luminous Star-Forming Galaxies

We report evidence of ordered orbital motion in luminous star-forming galaxies at z~1.3. We present integral field spectroscopy (IFS) observations, performed with the OH Suppressing InfraRed Imaging Spectrograph (OSIRIS) system, assisted by laser guide star adaptive optics on the Keck telescope, of 13 star-forming galaxies selected from the WiggleZ Dark Energy Survey. Selected via ultraviolet and [OII] emission, the large volume of the WiggleZ survey allows the selection of sources which have comparable intrinsic luminosity and stellar mass to IFS samples at z>2. Multiple 1-2 kpc size sub-components of emission, or 'clumps', are detected within the Halpha spatial emission which extends over 6-10 kpc in 4 galaxies, resolved compact emission (r<3 kpc) is detected in 5 galaxies, and extended regions of Halpha emission are observed in the remaining 4 galaxies. We discuss these data in the context of different snapshots in a merger sequence and/or the evolutionary stages of coalescence of star-forming regions in an unstable disk. We find evidence of ordered orbital motion in galaxies as expected from disk models and the highest values of velocity dispersion (\sigma>100 km/s) in the most compact sources. This unique data set reveals that the most luminous star-forming galaxies at z>1 are gaseous unstable disks indicating that a different mode of star formation could be feeding gas to galaxies at z>1, and lending support to theories of cold dense gas flows from the intergalactic medium.Comment: 25 pages, 11 figures, accepted for publication in MNRA

Productive Hepatitis C Virus Infection of Stem Cell-Derived Hepatocytes Reveals a Critical Transition to Viral Permissiveness during Differentiation

Primary human hepatocytes isolated from patient biopsies represent the most physiologically relevant cell culture model for hepatitis C virus (HCV) infection, but these primary cells are not readily accessible, display individual variability, and are largely refractory to genetic manipulation. Hepatocyte-like cells differentiated from pluripotent stem cells provide an attractive alternative as they not only overcome these shortcomings but can also provide an unlimited source of noncancer cells for both research and cell therapy. Despite its promise, the permissiveness to HCV infection of differentiated human hepatocyte-like cells (DHHs) has not been explored. Here we report a novel infection model based on DHHs derived from human embryonic (hESCs) and induced pluripotent stem cells (iPSCs). DHHs generated in chemically defined media under feeder-free conditions were subjected to infection by both HCV derived in cell culture (HCVcc) and patient-derived virus (HCVser). Pluripotent stem cells and definitive endoderm were not permissive for HCV infection whereas hepatic progenitor cells were persistently infected and secreted infectious particles into culture medium. Permissiveness to infection was correlated with induction of the liver-specific microRNA-122 and modulation of cellular factors that affect HCV replication. RNA interference directed toward essential cellular cofactors in stem cells resulted in HCV-resistant hepatocyte-like cells after differentiation. The ability to infect cultured cells directly with HCV patient serum, to study defined stages of viral permissiveness, and to produce genetically modified cells with desired phenotypes all have broad significance for host-pathogen interactions and cell therapy

The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance

In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.</p