Multi-Epoch Spectroscopy of Dwarf Galaxies with AGN Signatures: Identifying Sources with Persistent Broad H Α Emission

We use time-domain optical spectroscopy to distinguish between broad emission lines powered by accreting black holes (BHs) or stellar processes (i.e., supernovae) for 16 galaxies identified as AGN candidates by Reines \etal (2013). Our study is primarily focused on those objects with narrow emission-line ratios dominated by star formation. Based on follow-up spectra taken with the Magellan Echellette Spectrograph (MagE), the Dual Imaging Spectrograph, and the Ohio State Multi-Object Spectrograph, we find that the broad Hα emission has faded or was ambiguous for all of the star-forming objects (14/16) over baselines ranging from 5 to 14 years. For the two objects in our follow-up sample with narrow-line AGN signatures (RGG 9 and RGG 119), we find persistent broad Hα emission consistent with an AGN origin. Additionally, we use our MagE observations to measure stellar velocity dispersions for 15 objects in the Reines et al. (2013) sample, all with narrow-line ratios indicating the presence of an AGN. Stellar masses range from ∼5×108 to 3×109~\msun, and we measure σ∗ ranging from 28−71 km s−1. These σ∗ correspond to some of the lowest-mass galaxies with optical signatures of AGN activity. We show that RGG 119, the one object which has both a measured σ∗ and persistent broad Hα emission, falls near the extrapolation of the MBH−σ⋆ relation to the low-mass end

Multi-Epoch Spectroscopy of Dwarf Galaxies with AGN Signatures: Identifying Sources with Persistent Broad H Α Emission

We use time-domain optical spectroscopy to distinguish between broad emission lines powered by accreting black holes (BHs) or stellar processes (i.e., supernovae) for 16 galaxies identified as AGN candidates by Reines \etal (2013). Our study is primarily focused on those objects with narrow emission-line ratios dominated by star formation. Based on follow-up spectra taken with the Magellan Echellette Spectrograph (MagE), the Dual Imaging Spectrograph, and the Ohio State Multi-Object Spectrograph, we find that the broad Hα emission has faded or was ambiguous for all of the star-forming objects (14/16) over baselines ranging from 5 to 14 years. For the two objects in our follow-up sample with narrow-line AGN signatures (RGG 9 and RGG 119), we find persistent broad Hα emission consistent with an AGN origin. Additionally, we use our MagE observations to measure stellar velocity dispersions for 15 objects in the Reines et al. (2013) sample, all with narrow-line ratios indicating the presence of an AGN. Stellar masses range from ∼5×108 to 3×109~\msun, and we measure σ∗ ranging from 28−71 km s−1. These σ∗ correspond to some of the lowest-mass galaxies with optical signatures of AGN activity. We show that RGG 119, the one object which has both a measured σ∗ and persistent broad Hα emission, falls near the extrapolation of the MBH−σ⋆ relation to the low-mass end

Multi-Epoch Spectroscopy of Dwarf Galaxies with AGN Signatures: Identifying Sources with Persistent Broad H Α Emission

We use time-domain optical spectroscopy to distinguish between broad emission lines powered by accreting black holes (BHs) or stellar processes (i.e., supernovae) for 16 galaxies identified as AGN candidates by Reines \etal (2013). Our study is primarily focused on those objects with narrow emission-line ratios dominated by star formation. Based on follow-up spectra taken with the Magellan Echellette Spectrograph (MagE), the Dual Imaging Spectrograph, and the Ohio State Multi-Object Spectrograph, we find that the broad Hα emission has faded or was ambiguous for all of the star-forming objects (14/16) over baselines ranging from 5 to 14 years. For the two objects in our follow-up sample with narrow-line AGN signatures (RGG 9 and RGG 119), we find persistent broad Hα emission consistent with an AGN origin. Additionally, we use our MagE observations to measure stellar velocity dispersions for 15 objects in the Reines et al. (2013) sample, all with narrow-line ratios indicating the presence of an AGN. Stellar masses range from ∼5×108 to 3×109~\msun, and we measure σ∗ ranging from 28−71 km s−1. These σ∗ correspond to some of the lowest-mass galaxies with optical signatures of AGN activity. We show that RGG 119, the one object which has both a measured σ∗ and persistent broad Hα emission, falls near the extrapolation of the MBH−σ⋆ relation to the low-mass end

Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families

Nonstandard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Genotype-phenotype correlation in PRKN-associated Parkinson's disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p &lt; 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials

Genotype–phenotype correlation in PRKN- associated Parkinson’s disease

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials

Modelling the molecular mechanisms of ageing

This document is the Accepted Manuscript version of a published work that appeared in final form in Bioscience reports. To access the final edited and published work see http://www.bioscirep.org/content/37/1/BSR20160177.The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field