Biology subjects

Moore, C. M.

Publications and source records attributed to Moore, C. M..

25 records · Page 2Linked to original sources

bioRxiv2021

Heme oxygenase-2 (HO-2) binds and buffers labile heme, which is largely oxidized, in human embryonic kidney cells

Heme oxygenases (HO) detoxify heme by oxidatively degrading it into carbon monoxide, iron, and biliverdin, which is reduced to bilirubin and excreted. Humans express two isoforms: inducible HO-1, which is up-regulated in response to various stressors, including excess heme, and constitutive HO-2. While much is known about the regulation and physiological function of HO-1, comparatively little is known about the role of HO-2 in regulating heme homeostasis. The biochemical necessity for expressing constitutive HO-2 is largely dependent on whether heme is sufficiently abundant and accessible as a substrate under conditions in which HO-1 is not induced. By measuring labile heme, total heme, and bilirubin in human embryonic kidney HEK293 cells with silenced or over-expressed HO-2, and various HO-2 mutant alleles, we found that endogenous heme is too limiting to support HO-2 catalyzed heme degradation. Rather, we discovered that a novel role for HO-2 is to bind and buffer labile heme. Taken together, in the absence of excess heme, we propose that HO-2 regulates heme homeostasis by acting as a heme buffering factor in control of heme bioavailability. When heme is in excess, HO-1 is induced and both HO-2 and HO-1 can provide protection from heme toxicity by enzymatically degrading it. Our results explain why catalytically inactive mutants of HO-2 are cytoprotective against oxidative stress. Moreover, the change in bioavailable heme due to HO-2 overexpression, which selectively binds ferric over ferrous heme, is consistent with the labile heme pool being oxidized, thereby providing new insights into heme trafficking and signaling.

cell biology↗

bioRxiv2020

Human Ribosomal G-Quadruplexes Regulate Heme Bioavailability

The in vitro formation of stable G-quadruplexes (G4s) in human ribosomal RNA (rRNA) was recently reported. However, their formation in cells and their cellular roles have not been resolved. Here, by taking a chemical biology approach that integrates results from immunofluorescence, G4 ligands, heme affinity reagents, and a genetically encoded fluorescent heme sensor, we report that human ribosomes can form G4s in vivo that regulate heme bioavailability. Immunofluorescence experiments indicate that the vast majority of extra-nuclear G4s are associated with rRNA. Moreover, titrating human cells with a G4 ligand alters the ability of ribosomes to bind heme and disrupts cellular heme bioavailability as measured by a genetically encoded fluorescent heme sensor. Overall, these results suggest ribosomes are central hubs of heme metabolism.

biochemistry↗

bioRxiv2020

Divided Attention in Perception:A Unified Analysis of Dual-Task Deficits and Congruency Effects

How well can one perceive simultaneous stimuli at two widely spaced visual locations? Are the stimuli processed independently? If not, does the dependency affect perception, disrupt signals in later stages, or both? To address these questions, we measured effects of divided attention using a dual-task paradigm with stimuli presented in noise on either side of fixation. This paradigm was applied to detecting Gabor patches and to the semantic categorization of words. We measured dual-task deficits which are a decline in mean performance for a dual task compared to a single task. There was such a deficit for categorizing two words but relatively little deficit for detecting two Gabors. We also measured congruency effects which are when performance at one location depends on whether the stimulus at the other location requires the same response. There was such a congruency effect for detecting two Gabors but relatively little congruency effect for categorizing two words. Further experiments were consistent with the dual-task deficit in word categorization being perceptual, but the congruency effect in Gabor detection being due to later processes. Results of additional experiments showed that the congruency effect was consistent with either graded selection errors or with all-or-none selection followed by graded interactive processing. To answer our opening question: for Gabor detection, perceptual processes were largely independent but later processes caused congruency effects; for word categorization, perceptual processes had capacity limits but even in combination with later processes caused relatively little congruency effects. In summary, there was evidence for two different kinds of dependency. Such complementary dependencies are inconsistent with theories of divided attention that depend on a single dependency such as a single resource or single source of interactive processing.

neuroscience↗

bioRxiv2019

Architecture of the chromatin remodeler RSC and insights into its nucleosome engagement

Eukaryotic DNA is packaged into nucleosome arrays, which are repositioned by chromatin remodeling complexes to control DNA accessibility1,2. The Saccharomyces cerevisiae RSC (Remodeling the Structure of Chromatin) complex, a member of the SWI/SNF chromatin remodeler family, plays critical roles in genome maintenance, transcription, and DNA repair2-4. Here we report cryo-electron microscopy (cryo-EM) and crosslinking mass spectrometry (CLMS) studies of yeast RSC complex and show that RSC is composed of a rigid tripartite core and two flexible lobes. The core structure is scaffolded by an asymmetric Rsc8 dimer and built with the evolutionarily conserved subunits Sfh1, Rsc6, Rsc9 and Sth1. The flexible ATPase lobe, composed of helicase subunit Sth1, Arp7, Arp9 and Rtt102, is anchored through the interactions between the N-terminus of Sth1 and the core. Our cryo-EM analysis also shows that in addition to the expected nucleosome-Sth1 interactions, RSC engages histones and nucleosomal DNA through one arm of the core structure, composed of Rsc8 SWRIM domains, Sfh1 and Npl6. Our findings provide structural insights into the conserved assembly process for all members of the SWI/SNF family of remodelers, and illustrate how RSC selects, engages, and remodels nucleosomes.

molecular biology↗

bioRxiv2018

Resting-state functional connectivity, cortical GABA and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic imaging and resonance study

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (1H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p=0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p=0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r=+0.661, p=0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r=+0.522, p=0.000; left amygdala: r=+0.651, p=0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p=0.03) and positively correlated with intra DMPFC connectivity (r=+0.548, p=0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.

neuroscience↗

bioRxiv2017

The mismatch in distributions of vertebrates and the plants that they disperse

Little is known about how mutualistic interactions affect the distribution of species richness on broad geographic scales. It has been predicted that the richness of species involved in obligate mutualisms should be positively associated across their range. Whereas, if mutualisms are facilitative, the distribution of mutualists should be correlated with other factors. This study is the first study to compare the co-distribution of mutualist species in general and seed dispersal mutualisms specifically. We used geographic distributions of plant and animal mutualists to investigate the co-distribution and patterns of seed dispersal mutualisms. We found the mutualism between dispersers and plants does not account for the distribution of either group. In fact, there is a mismatch of richness between plants and the animals that disperse their seeds. Environmental factors are better predictors of both animal distribution and seed dispersal mutualisms across North America.\n\nStatement of authorshipJD, CM, and SV conceived the original project idea. Plant data were compiled and analyzed by CM and SV, and JD compiled animal and environmental data. JD standardized and formatted all geographical data, and JD and CM performed all statistical analyses. JD wrote the first draft of the manuscript, and all authors contributed significantly to the revisions.

ecology↗

bioRxiv2017

Population dynamics of mutualism and intraspecific density dependence:how θ-logistic-like density dependence affects mutualistic positive feedback

Mutualism describes the biological phenomenon where two or more species are reciprocally beneficial, regardless of their ecological intimacy or evolutionary history. Classic theory shows that mutualistic benefit must be relatively weak, or else it overpowers the stabilizing influence of intraspecific competition and leads to unrealistic, unbounded population growth. Interestingly, the conclusion that strong positive interactions lead to runaway population growth is strongly grounded in the behavior of a single model. This model [-] the Lotka-Volterra competition model with a sign change to generate mutualism rather than competition between species [-] assumes logistic growth of each species plus a linear interaction term to represent the mutualism. While it is commonly held that the linear interaction term is to blame for the models unrealistic behavior, we show here that a linear mutualism added to a{theta} -logistic model of population growth can prevent unbounded growth. We find that when density dependence is decelerating, the benefit of mutualism at equilibrium is greater than when density dependence is accelerating. Although there is a greater benefit, however, decelerating density dependence tends to destabilize populations whereas accelerating density dependence is always stable. We interpret these findings tentatively, but with promise for the understanding of the population ecology of mutualism by generating several predictions relating growth rates of mutualist populations and the strength of mutualistic interaction.

ecology↗