Biology subjects

Moore, A. R.

Publications and source records attributed to Moore, A. R..

11 recordsLinked to original sources

bioRxiv2026

The small GTPase Rem2 modulates sex-dependent spatial learning by regulating CA1 glutamate receptor composition

The small GTPase Rem2 is a key signaling molecule involved in synaptic formation, dendritic complexity, spine formation, and regulation of CaMKII-dependent long-term potentiation (LTP). However, it remains unclear how Rem2 explicitly impacts learning and memory. To address this issue, we deleted Rem2 specifically in dorsal CA1 neurons of male and female mice and assessed spatial learning using a spatial object recognition (SOR) task. We found that males outperform females in this behavioral assay and that deleting Rem2 did not impact spatial learning in males. In contrast, Rem2 deletion significantly improved spatial learning in females enabling them to perform as well as males in the SOR task. Using an automated Western blot system to assess all known AMPA- and NMDA-mediated glutamate receptor (AMPAR and NMDAR) subunits in each mouse, we found that the sex-dependent change in SOR we observed was likely due to Rem2 increasing GluN2D expression in the interneurons of female mice only. Furthermore, using S-statistics to compare the overall AMPAR and NMDAR composition among groups, we found that males and females normally have divergent covariance structures but this divergence is eliminated when Rem2 is deleted from CA1 neurons. These results reveal an unexpected role of Rem2 in maintaining sex differences in glutamate receptor composition and spatial learning abilities. To our knowledge, this is the first demonstration of a signaling molecule that confers sexual dimorphism to excitatory synapses. As such, Rem2 may play a critical role in understanding how sex-dependent symptoms of neurodevelopmental and neurodegenerative disorders arise.

neuroscience↗

bioRxiv2025

A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response

Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with the increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature, is associated with each of these risk factors prior to infection. Furthermore, we found this conserved immune signature is modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted patients with sepsis that would be harmed from hydrocortisone treatment, and patients with asthma that will not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of baseline immune state and response to chronic, subacute, and acute illnesses.

immunology↗

bioRxiv2024

International multi-cohort analysis identifies novel framework for quantifying immune dysregulation in critical illness: results of the SUBSPACE consortium

Progress in the management of critical care syndromes such as sepsis, Acute Respiratory Distress Syndrome (ARDS), and trauma has slowed over the last two decades, limited by the inherent heterogeneity within syndromic illnesses. Numerous immune endotypes have been proposed in sepsis and critical care, however the overlap of the endotypes is unclear, limiting clinical translation. The SUBSPACE consortium is an international consortium that aims to advance precision medicine through the sharing of transcriptomic data. By evaluating the overlap of existing immune endotypes in sepsis across over 6,000 samples, we developed cell-type specific signatures to quantify dysregulation in these immune compartments. Myeloid and lymphoid dysregulation were associated with disease severity and mortality across all cohorts. This dysregulation was not only observed in sepsis but also in ARDS, trauma, and burn patients, indicating a conserved mechanism across various critical illness syndromes. Moreover, analysis of randomized controlled trial data revealed that myeloid and lymphoid dysregulation is linked to differential mortality in patients treated with anakinra or corticosteroids, underscoring its prognostic and therapeutic significance. In conclusion, this novel immunology-based framework for quantifying cellular compartment dysregulation offers a valuable tool for prognosis and therapeutic decision-making in critical illness.

immunology↗

bioRxiv2023

Evolutionary analysis of mammalian Rem2, a member of the RGK (Rem, Rem2, Rad, and Gem/Kir) family of small GTPases, reveals the role of selection and epistasis in shaping protein functional constraints.

Rad And Gem-Like GTP-Binding Protein 2 (Rem2), is a member of the RGK family of Ras-like GTPases and has been identified in various mammalian species. Rem2 has been implicated in Huntingtons disease and Long QT Syndrome and is highly expressed in the brain and in endocrine cells. In this study, we examined the evolutionary history of Rem2 across mammals, focusing on the role of purifying selection and epistasis in shaping its sequence and structure. In our analysis of Rem2 sequences across 175 mammalian species, we found evidence for strong purifying selection in 70% of non-invariant codon sites of the protein, characteristic of essential proteins that play critical roles in biological processes and is consistent with Rem2s role in the regulation of neuronal development and function. We inferred epistatic effects in 49 pairs of coevolving codon sites in Rem2, some of which are predicted to have deleterious effects on human health. Additionally, we reconstructed the ancestral evolutionary history of mammalian Rem2 using protein structure prediction of extinct and extant sequences. This analysis revealed the dynamics of how substitutions that change the genetic distance of Rem2 can impact protein structure in variable regions while maintaining core functional mechanisms. By understanding the selective pressures, protein- and genetic-interactions that have shaped the sequence and structure of the Rem2 protein, we may gain a stronger understanding of its biological and functional constraints.

neuroscience↗

bioRxiv2023

Winning a competitive research award decreases time to degree in bioscience PhD programs, but not for everyone

Time to degree completion is an important metric of academic progress and success for doctoral students. It is also a common way for educational stakeholders to compare programs even if the content of the degree programs varies. But what types of behaviors and experiences are associated with faster times to degree? In this education article, we examine the relationship between receiving competitive research awards (e.g. grant writing) and time to degree for PhD students. We organize our analyses by student identities, specifically gender and underrepresented minority (URM) status, to examine differences in time to degree based on student demographics. Our dataset included students that graduated between academic years 2008-09 through 2018-19. We also interviewed students currently enrolled in these same programs. We find that URM women who won competitive research awards graduate faster than all other students who also won awards but also report lower levels of advisor support. We also find that URM women and all URM students tended to graduate faster compared to other groups of students who did not win awards. Students who reported feeling supported by their advisors, most of which reflected hands-on guidance through the writing process, in the interviews were more likely to apply for grants. Combined, these results highlight that writing grants and specific types of advisor support may influence faster times to degree for bioscience PhD students. This study suggests similar introspective analyses at other institutions and databases are needed.

scientific communication and education↗

bioRxiv2021

Gestationally-Dependent Immune Organization at the Maternal-Fetal Interface

The immune system and placenta have a dynamic relationship across gestation to accommodate fetal growth and development. High-resolution characterization of this maternal- fetal interface is necessary to better understand the immunology of pregnancy and its complications. We developed a single-cell framework to simultaneously immuno-phenotype circulating, endovascular, and tissue-resident cells at the maternal-fetal interface throughout gestation, discriminating maternal and fetal contributions. Our data reveal distinct immune profiles across the endovascular and tissue compartments with tractable dynamics throughout gestation that respond to a systemic immune challenge in a gestationally-dependent manner. We uncover that mononuclear phagocytes and neutrophils drive the temporal immune composition of the placenta with remarkably diverse populations, including PD-L1-expressing subsets having compartmental and early gestational bias. Our approach and accompanying datasets provide a resource for additional investigations into gestational immunology and evoke a more significant role for the innate immune system in establishing the microenvironment of early pregnancy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/449807v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@6235corg.highwire.dtl.DTLVardef@fba572org.highwire.dtl.DTLVardef@12b0af4org.highwire.dtl.DTLVardef@dc44da_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

The NOTCH3 Downstream Target HEYL Regulates Human Airway Epithelial Club Cell Differentiation

Basal cells (BC) are the resident stem/progenitor cells of the adult pseudostratified airway epithelium, whose differentiation program is orchestrated by the NOTCH signaling pathway. NOTCH3 receptor mediated signaling regulates BC to club cell differentiation; however, the downstream responses that regulate this process are largely unknown. In the present study we used an in vitro air-liquid interface model of the human pseudostratified airway epithelium to identify the NOTCH3-dependent downstream genes/pathways that regulate human BC to club cell differentiation. Activation of NOTCH3 signaling in BC via lentivirus-mediated over-expression of the active NOTCH3 intracellular domain (NICD3) promoted club cell differentiation. Bulk RNA-seq analysis of control vs NICD3-transduced cells, identified 692 NICD3 responsive genes enriched for pathways linked to airway epithelial biology and differentiation including Wnt/{beta}-catenin Signaling. Expression of the classical NOTCH target HEYL increased in response to NOTCH3 activation and positively correlated with expression of the club cell marker SCGB1A1. Further, using single-cell RNA-seq, we report that HEYL+ cells primarily clustered with SCGB1A1+ and NOTCH3+ cells. Moreover, HEYL protein co-localized with SCGB1A1 in ALI cultures in vitro and in the human and mouse airway epithelium in vivo. siRNA-mediated knockdown of HEYL in BC led to changes in epithelial structure including altered morphology and significant reductions in transepithelial electrical resistance and expression of tight junction related genes. Finally, HEYL knockdown significantly reduced the number of SCGB1A1+ club cells, along with a corresponding increase in KRT8+ BC-intermediate cells. Overall, our data identifies NOTCH3-HEYL signaling as a key regulator of BC to club cell differentiation.

cell biology↗

bioRxiv2019

Experience-dependent development of dendritic arbors in mouse visual cortex

Despite the importance of dendritic arbors for proper neuronal function, our knowledge of how sensory experience influences these structures during postnatal cortical development is incomplete. We present a large-scale dataset of 849 three-dimensional reconstructions of pyramidal neuron basal arbors collected across early postnatal development in the mouse visual cortex. We found that the basal arbor underwent a 45% increase in total length between postnatal day 7 (P7) and P30. Surprisingly, comparisons of dark-reared and typically-reared mice revealed that only 15% of arbor length could be attributed to visual experience. Furthermore, we characterized the role of the activity-regulated small GTPase Rem2, showing that Rem2 is an experience-dependent negative regulator of dendritic segment number during the visual critical period. These data establish a detailed, quantitative analysis of the basal arbor that has high utility for understanding circuit development and providing a framework for computationalists wishing to generate anatomically accurate neuronal models.

neuroscience↗

bioRxiv2019

Uveal Melanoma Oncogene CYSLTR2 Encodes a Constitutively Active GPCR Highly Biased Toward Gq Signaling

The G protein-coupled receptor (GPCR) cysteinyl-leukotriene receptor 2 (CysLTR2) with a single amino acid mutation at position 3.43 (Leu replaced with Gln at position 129 in transmembrane helix 3) causes uveal melanoma in humans. The ability of CysLTR2-L129Q to cause malignant transformation has been hypothesized to result from constitutive activity. We show that CysLTR2-L129Q is a constitutively active mutant (CAM) that strongly drives Gq/11 signaling pathways in melan-a melanocytes and in HEK293T cells in culture. However, the mutant receptor only very weakly recruits beta-arrestins 1 and 2. The mutant receptor displays profound signaling bias while avoiding arrestin-mediated downregulation. The mechanism of the signaling bias results from the creation of a hydrogen-bond network that stabilizes the active G protein signaling state through novel interactions with the highly-conserved NPxxY motif on helix 7. Furthermore, the mutation destabilizes a putative allosteric sodium-binding site that usually stabilizes the inactive state of GPCRs. Thus, the mutation has a dual role of promoting the active state while destabilizing inactivating allosteric networks. The high degree of constitutive activity renders existing orthosteric antagonist ligands of CysLTR2 ineffective as inverse agonists of the mutant. CysLTR2 is the first example of a GPCR oncogene that encodes a GPCR with constitutive highly biased signaling that can escape cellular downregulation mechanisms.

cancer biology↗

bioRxiv2017

Rem2 regulates distinct homeostatic mechanisms in visual circuit plasticity

Activity-regulated genes sculpt neural circuits in response to sensory experience. These calcium-sensitive genes generally fall into two categories: transcription factors and proteins that function at synapses. Yet little is known about activity-regulated, cytosolic proteins that transduce signals between the neuronal membrane and the nucleus. Using the visual system as a model, we investigated the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in vivo. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the circuit level, cortical layer 2/3 neurons in Rem2-/- mice show deficits in both postsynaptic scaling up of excitatory synapses and misregulation of intrinsic excitability. Further, we reveal that Rem2 plays a novel, cell-autonomous role in regulating neuronal intrinsic excitability. Thus, Rem2 is a critical regulator of neural circuit function and distinct homeostatic plasticity mechanisms in vivo.\n\nHIGHLIGHTSO_LIRem2 is required in excitatory cortical neurons for normal ocular dominance plasticity\nC_LIO_LIRem2 regulates postsynaptic homoeostatic synaptic scaling up\nC_LIO_LIRem2 alters the intrinsic excitability of neurons in a cell-autonomous manner\nC_LI

neuroscience↗

bioRxiv2017

Comparison Of The Human Gastric Microbiota In Hypochlorhydric States Arising As A Result Of Helicobacter pylori-Induced Atrophic Gastritis, Autoimmune Atrophic Gastritis And Proton Pump Inhibitor Use

ObjectiveSeveral conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk.\n\nDesign95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq).\n\nResultsSamples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase.\n\nConclusionAutoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.\n\nSIGNIFICANCE OF THIS STUDY 1. What is already known about this subject?O_LISome conditions which result in reduced gastric acid secretion and hypochlorhydria are associated with an increased risk of gastric tumourigenesis.\nC_LIO_LIThis risk is different in patients with H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and chronic proton pump inhibitor use.\nC_LIO_LIHypochlorhydria and H. pylori infection cause alterations in the composition of the gastric microbiota.\nC_LI\n\n2. What are the new findings?O_LIWe used 16S rRNA sequencing to characterise the microbiota in gastric corpus biopsies from a well characterised cohort of patients.\nC_LIO_LIThe gastric microbiota was different in patients who were hypochlorhydric as a result of H. pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.\nC_LIO_LIBiochemical pathways associated with gastric carcinogenesis such as the fumarate reductase pathway were predicted to be altered in patients with atrophic gastritis.\nC_LI\n\n3. How might it impact on clinical practice in the foreseeable future?O_LIUnderstanding how the microbiota that colonise the hypochlorhydric stomach influence gastric carcinogenesis may ultimately permit stratification of patients subsequent tumour risk.\nC_LIO_LIInterventions that alter the composition of the gastric microbiome in hypochlorhydric patients with atrophic gastritis should be tested to investigate whether they alter the subsequent risk of developing gastric malignancy.\nC_LI

microbiology↗