Biology subjects

Armstrong, M. L.

Publications and source records attributed to Armstrong, M. L..

7 recordsLinked to original sources

bioRxiv2025

Parallel polygenic urban adaptation despite high gene flow in a coastal marine invertebrate

Urbanization results in novel environments, offering a unique opportunity to investigate natural selection on small spatiotemporal scales. Although each city is different, geographically distinct cities can in some ways represent evolutionary replicates, allowing for the investigation of parallel and predictable evolutionary responses to urban environments. Additionally, there are few examples of urban adaptation in high gene flow marine systems, whose patterns might differ markedly from aquatic and terrestrial systems. Using whole genomes from Pacific purple sea urchins (Strongylocentrotus purpuratus) across three coastal cities spanning >2000km, we investigated genomic signals for adaptation to urban environments. We found genetic variants differentiating urban and nonurban sites within each city region, despite high gene flow and little evidence for differentiation across latitudinal gradients. While these SNP-level candidates for selection were largely non-overlapping, polygenic approaches uncover a distinct parallel signal of urban adaptation across the sampled range. Our results suggest that adaptation over small scale urbanization gradients is possible even in high gene flow systems and the polygenic architecture of adaptation is, at least in part, parallel. More broadly, our work highlights the importance of polygenic methods in ecological genomics in expanding our understanding of how evolutionary forces operate in natural systems.

genomics↗

bioRxiv2024

The primary mechanism for highly potent inhibition of HIV-1 maturation by lenacapavir

Lenacapavir (LEN) is a highly potent, long-acting antiretroviral medication for treating people infected with muti-drug-resistant HIV-1 phenotypes. The inhibitor targets multifaceted functions of the viral capsid protein (CA) during HIV-1 replication. Previous studies have mainly focused on elucidating LENs mode of action during viral ingress. Additionally, the inhibitor has been shown to interfere with mature capsid assembly during viral egress. However, the mechanism for how LEN affects HIV-1 maturation is unknown. Here, we show that pharmacologically relevant LEN concentrations do not impair proteolytic processing of Gag in virions. Instead, we have elucidated the primary mechanism for highly potent inhibition of HIV-1 maturation by sub-stoichiometric LEN:CA ratios. The inhibitor exerts opposing effects on formation of CA pentamers versus hexamers, the key capsomere intermediates in mature capsid assembly. LEN impairs formation of pentamers, whereas it induces assembly of hexameric lattices by imposing an opened CA conformation and stabilizing a dimeric form of CA. Consequently, LEN treatment results in morphologically atypical virus particles containing malformed, hyper-stable CA assemblies, which fail to infect target cells. Moreover, we have uncovered an inverse correlation between inhibitor potency and CA levels in cell culture assays, which accounts for LENs ability to potently (with pM EC50 values) inhibit HIV-1 maturation at clinically relevant drug concentrations. Author SummaryLenacapavir (LEN) is the first-in-class HIV-1 capsid targeting antiretroviral that exhibits multimodal modality to inhibit both early and late steps of viral replication. Our studies here have elucidated previously undescribed structural and mechanistic bases for a highly potent antiviral activity of LEN during viral egress. These findings will inform clinical applications of LEN as a potent HIV-1 maturation inhibitor and aid the development of second-generation inhibitors targeting assembly of the mature viral capsid.

microbiology↗

bioRxiv2024

Appearance of green tea compounds in plasma following green tea consumption is modulated by the gut microbiome in mice

Studies have suggested that phytochemicals in green tea have systemic anti-inflammatory and neuroprotective effects. However, the mechanisms behind these effects are poorly understood, possibly due to differential metabolism of phytochemicals resulting from variation in gut microbiome composition. To unravel this complex relationship, our team utilized a novel combined microbiome analysis and metabolomics approach applied to low complexity microbiome (LCM) and human colonized (HU) gnotobiotic mice treated with an acute dose of powdered matcha green tea. A total of 20 LCM mice received 10 distinct human fecal slurries for an n=2 mice per human gut microbiome; 9 LCM mice remained un-colonized with human slurries throughout the experiment. We performed untargeted metabolomics on green tea and plasma to identify green tea compounds that were found in plasma of LCM and HU mice that had consumed green tea. 16S ribosomal RNA gene sequencing was performed on feces of all mice at study end to assess microbiome composition. We found multiple green tea compounds in plasma associated with microbiome presence and diversity (including acetylagmatine, lactiflorin, and aspartic acid negatively associated with diversity). Additionally, we detected strong associations between bioactive green tea compounds in plasma and specific gut bacteria, including associations between spiramycin and Gemmiger, and between wildforlide and Anaerorhabdus. Additionally, some of the physiologically relevant green tea compounds are likely derived from plant-associated microbes, highlighting the importance of considering foods and food products as meta-organisms. Overall, we describe a novel workflow for discovering relationships between individual food compounds and composition of the gut microbiome. ImportanceFoods contain thousands of unique and biologically important compounds beyond the macro- and micro-nutrients listed on nutrition facts labels. In mammals, many of these compounds are metabolized by the community of microbes in the colon. These microbes may impact the thousands of biologically important compounds we consume; therefore, understanding microbial metabolism of food compounds will be important for understanding how foods impact health. We used metabolomics to track green tea compounds in plasma of mice with and without complex microbiomes. From this, we can start to recognize certain groups of green tea-derived compounds that are impacted by mammalian microbiomes. This research presents a novel technique for understanding microbial metabolism of food-derived compounds in the gut, which can be applied to other foods.

systems biology↗

bioRxiv2023

Identifying drivers of sewage-associated pollutants in pollinators across urban landscapes

Human sewage can introduce pollutants into food webs and threaten ecosystem integrity. Among the many sewage-associated pollutants, pharmaceuticals and personal care products (PPCPs) are useful indicators of sewage in ecosystems and can also cause potent ecological consequences even at minute concentrations (e.g., ng/L). Despite increased study over the past three decades, PPCPs in terrestrial systems have been less studied than those in aquatic ecosystems. To evaluate PPCP prevalence and drivers in a terrestrial ecosystem, we analyzed managed and native bees collected from agroecosystems in Washington State (USA) for PPCPs. Caffeine, paraxanthine, cotinine, and acetaminophen were detected in all three evaluated taxa (Bombus vosnesenskii, Agapostemon texanus, and Apis mellifera), with B. vosnesenskii and A. texanus having a higher probability of PPCP detection relative to A. mellifera. The probability for PPCP presence in all three taxa increased in landscapes with more human development or greater plant abundance, with significant but negative interactions among these factors. These results suggest that human activity, availability of resources, and species-specific traits affect the introduction and mobilization of PPCPs in terrestrial ecosystems. Consequently, monitoring PPCPs and their ecological responses in terrestrial ecosystems creates opportunities to synthesize consequences of sewage pollution across terrestrial and aquatic ecosystems and organism types.

ecology↗

bioRxiv2021

Coordinated regulation of CB1 cannabinoid receptors and anandamide metabolism stabilize network activity during homeostatic scaling down

Neurons express overlapping homeostatic mechanisms to regulate synaptic function and network properties in response to perturbations of neuronal activity. Endocannabinoids (eCBs) are bioactive lipids synthesized in the post-synaptic compartments to regulate synaptic transmission, plasticity, and neuronal excitability primarily through retrograde activation of pre- synaptic cannabinoid receptor type 1 (CB1). The eCB system is well-situated to regulate neuronal network properties and coordinate pre- and post-synaptic activity. However, the role of the eCB system in homeostatic adaptations to neuronal hyperactivity is unknown. To address this issue, we used western blot and targeted lipidomics to measure adaptations in eCB system to bicuculline (BCC)-induced chronic hyperexcitation in mature (>DIV21) cultured rat cortical neurons, and used multielectrode array recording and live-cell imaging of glutamate dynamics to test the effects of pharmacological manipulations of eCB on network activities. We show that BCC-induced chronic hyperexcitation triggers homeostatic downscaling and a coordinated adaptation to enhance tonic eCB signaling. Hyperexcitation triggers first the downregulation of fatty acid amide hydrolase (FAAH), the lipase that degrades the eCB anandamide, then an accumulation of anandamide and related metabolites, and finally a delayed upregulation of surface and total CB1. Additionally, we show that BCC-induced downregulation of surface AMPA-type glutamate receptors (AMPARs) and upregulation of CB1 occur through independent mechanisms. Finally, we show that endocannabinoids support baseline network activities before and after downscaling and is engaged to suppress network activities during adaptation to hyperexcitation. We discuss the implications of our findings in the context of downscaling and homeostatic regulation of oscillatory network activities. Significance statementNeurons are remarkably resilient to perturbations in network activities thanks to the expression of overlapping homeostatic adaptations. In response to network hyperactivity or silencing, neurons respond through regulating excitatory and inhibitory post-synaptic neurotransmitter receptors density, probability of pre-synaptic neurotransmitter release, and/or membrane excitability. The endocannabinoid system is a prominent signaling pathway at many synapses that is known to be involved in multiple forms of short- and long-term synaptic plasticity. Here we find that components of the endocannabinoid system are upregulated in response to chronic hyperexcitation of cultured cortical neurons, and that endocannabinoid signaling is required to maintain network activity but also suppresses network events during hyperexcitation. This work supports a novel tonic homeostatic function for the endocannabinoid system in neurons.

neuroscience↗

bioRxiv2021

Tonic endocannabinoid signaling supports sleep through development in both sexes.

Sleep is an essential behavior that supports brain function and cognition throughout life, in part by acting on neuronal synapses. The synaptic signaling pathways that mediate the restorative benefits of sleep are not fully understood, particularly in the context of development. Endocannabinoids (eCBs) including 2-arachidonyl glycerol (2-AG) and anandamide (AEA), are bioactive lipids that activate cannabinoid receptor, CB1, to regulate synaptic transmission and mediate cognitive functions and many behaviors, including sleep. We used targeted mass spectrometry to measure changes in forebrain synaptic eCBs during the sleep/wake cycle in developing and adult mice. We find that eCBs are downregulated in response to acute sleep deprivation in juvenile mice, while in young adults eCBs are upregulated during the sleep phase in a circadian manner. Next we manipulated the eCB system using selective pharmacology and measured the effects on sleep behavior in developing and adult mice of both sexes using a non-invasive piezoelectric home-cage recording apparatus. Enhancement of eCB signaling through inhibition of 2-AG or AEA degradation, increased dark phase sleep amount and bout length in developing and adult males, but not in females. Inhibition of CB1 by injection of the antagonist AM251 reduced sleep time and caused sleep fragmentation in developing and adult males and females. Our data suggest that males are more sensitive to the sleep promoting effects of enhanced eCBs but that tonic eCB signaling supports sleep behavior through multiple stages of development in both sexes. This work informs the further development of cannabinoid-based therapeutics for sleep disruption.

animal behavior and cognition↗

bioRxiv2019

Dietary fat and fiber impacts intestinal microbiome resilience to antibiotics and Clostridoides difficile infection in mice

Clostridioides difficile infection (CDI), is the leading cause of hospital-acquired diarrhea and emerging evidence has linked dietary components with CDI pathogenesis, suggesting that dietary modulation may be an effective strategy for prevention. Here, we show that mice fed a high-fat/low-fiber "Western type" diet (WD) had dramatically increased mortality in a murine model of antibiotic-induced CDI compared to a low-fat/low-fiber (LF/LF) diet and standard mouse chow controls. We found that the WD had a pro- C. difficile bile acid composition that was driven in part by higher levels of primary bile acids that are produced to digest fat, and a lower level of secondary bile acids that are produced by the gut microbiome. This lack of secondary bile acids was associated with a greater disturbance to the gut microbiome with antibiotics in both the WD and LF/LF diet compared to mouse chow. Mice fed the WD also had the highest level of toxin TcdA just prior to the onset of mortality, but not of TcdB or increased inflammation. These findings indicate that dietary intervention to decrease fat may complement previously proposed dietary intervention strategies to prevent CDI in high-risk individuals. One Sentence SummaryA high-fat/low-fiber Western type diet promoted mortality in a mouse model of antibiotic-induced C. difficile infection compared to a low-fat/low-fiber diet and chow diet, suggesting that lower dietary fat may be an effective strategy for preventing C. difficile pathology.

microbiology↗