Scholarly Works, Biological Sciences

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Using Water Quality as a Proxy to Estimate Microplastic Concentrations in the New River, VA, via Sentinel 2
Rodriguez Sequeira, Luisana; Allen, George H.; Gray, Austin D. (New River Symposium, 2024-04-12)
Microplastics (<5mm), are pervasive in Earth’s environments, and rivers are a major transport pathway. Microplastic detection methods that rely on counting individual particles are time consuming and require laborious field collection, inhibiting real-time insights over large spatial extents, which are needed in order to better understand the issue. Satellite remote sensing has been used to estimate water quality in rivers with relatively high spatial and temporal coverage. Finding a correlation between water quality and microplastics could allow us to estimate microplastics in rivers via satellite imagery using water quality as a proxy. Though a handful of these assessments have been done, a wide-variety of study sites are needed to form a coherent model. We focused our study in the New River near Blacksburg, VA, and collected weekly water quality measurements and surface-water microplastic samples. We combined these in situ measurements with cotemporal remotely-sensed water quality index observations from Sentinel-2 to develop a model estimating microplastic concentration. We validated the model using in-situ spectrometry and water quality measurements. By providing more observations than what can be done with in situ sampling alone, we can improve large-scale microplastic analyses and modeling leading to better assessments of mismanaged plastic waste in Earth’s rivers.
A silent spring, or a new cacophony? Invasive plants as maestros of modern soundscapes
Barney, Jacob N.; O'Malley, Grace; Ripa, Gabrielle N.; Drake, Joseph; Franusich, David; Mims, Meryl C. (Wiley, 2024-04-01)
Sound plays a key role in ecosystem function and is a defining part of how humans experience nature. In the seminal book Silent Spring (Carson 1962), Rachel Carson warned of the ecological and environmental harm of pesticide usage by envisioning a future without birdsong. Soundscapes, or the acoustic patterns of a landscape through space and time, encompass both biological and physical processes (Pijanowski et al. 2011). Yet, they are often an underappreciated element of the natural world and the ways in which it is perceived. Scientists are only beginning to quantify changes to soundscapes, largely in response to anthropogenic sounds, but soundscape alteration is likely linked to many dimensions of global change. For example, invasive non-native species (hereafter, invasive species) are near-ubiquitous members of ecosystems globally and threaten both natural and managed ecosystems at great expense. Their impacts to soundscapes may be an important, yet largely unknown, threat to ecosystems and the human and economic systems they support.
Altered DNA methylation underlies monocyte dysregulation and immune exhaustion memory in sepsis
Caldwell, Blake A.; Wu, Yajun; Wang, Jing; Li, Liwu (Elsevier, 2024-03)
Monocytes can develop an exhausted memory state characterized by reduced differentiation, pathogenic inflammation, and immune suppression that drives immune dysregulation during sepsis. Chromatin alterations, notably via histone modifications, underlie innate immune memory, but the contribution of DNA methylation remains poorly understood. Using an ex vivo sepsis model, we show altered DNA methylation throughout the genome of exhausted monocytes, including genes implicated in immune dysregulation during sepsis and COVID-19 infection (e.g., Plac8). These changes are recapitulated in septic mice induced by cecal slurry injection. Methylation profiles developed in septic mice are maintained during ex vivo culture, supporting the involvement of DNA methylation in stable monocyte exhaustion memory. Methylome reprogramming is driven in part by Wnt signaling inhibition in exhausted monocytes and can be reversed with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Our study demonstrates the significance of altered DNA methylation in the maintenance of stable monocyte exhaustion memory.
Coordination of rhythmic RNA synthesis and degradation orchestrates 24-and 12-h RNA expression patterns in mouse fibroblasts
Unruh, Benjamin A.; Weidemann, Douglas E.; Miao, Lin; Kojima, Shihoko (National Academy of Sciences, 2024)
Circadian RNA expression is essential to ultimately regulate a plethora of downstream rhythmic biochemical, physiological, and behavioral processes. Both transcriptional and posttranscriptional mechanisms are considered important to drive rhythmic RNA expression; however, the extent to which each regulatory process contributes to the rhythmic RNA expression remains controversial. To systematically address this, we monitored RNA dynamics using metabolic RNA labeling technology during a circadian cycle in mouse fibroblasts. We find that rhythmic RNA synthesis is the primary contributor of 24-h RNA rhythms, while rhythmic degradation is more important for 12-h RNA rhythms. These rhythms were predominantly regulated by Bmal1 and/or the core clock mechanism, and the interplay between rhythmic synthesis and degradation has a significant impact in shaping rhythmic RNA expression patterns. Interestingly, core clock RNAs are regulated by multiple rhythmic processes and have the highest amplitude of synthesis and degradation, presumably critical to sustain robust rhythmicity of cell-autonomous circadian rhythms. Our study yields invaluable insights into the temporal dynamics of both 24-and 12-h RNA rhythms in mouse fibroblasts.
Can Common Pool Resource Theory Catalyze Stakeholder-Driven Solutions to the Freshwater Salinization Syndrome?
Grant, Stanley B.; Rippy, Megan A.; Birkland, Thomas A.; Schenk, Todd; Rowles, Kristin; Misra, Shalini; Aminpour, Payam; Kaushal, Sujay; Vikesland, Peter J.; Berglund, Emily; Gomez-Velez, Jesus D.; Hotchkiss, Erin R.; Perez, Gabriel; Zhang, Harry X.; Armstrong, Kingston; Bhide, Shantanu V.; Krauss, Lauren; Maas, Carly; Mendoza, Kent; Shipman, Caitlin; Zhang, Yadong; Zhong, Yinman (American Chemical Society, 2022-09-14)
Freshwater salinity is rising across many regions of the United States as well as globally, a phenomenon called the freshwater salinization syndrome (FSS). The FSS mobilizes organic carbon, nutrients, heavy metals, and other contaminants sequestered in soils and freshwater sediments, alters the structures and functions of soils, streams, and riparian ecosystems, threatens drinking water supplies, and undermines progress toward many of the United Nations Sustainable Development Goals. There is an urgent need to leverage the current understanding of salinization's causes and consequences?in partnership with engineers, social scientists, policymakers, and other stakeholders?into locally tailored approaches for balancing our nation's salt budget. In this feature, we propose that the FSS can be understood as a common pool resource problem and explore Nobel Laureate Elinor Ostrom's social-ecological systems framework as an approach for identifying the conditions under which local actors may work collectively to manage the FSS in the absence of top-down regulatory controls. We adopt as a case study rising sodium concentrations in the Occoquan Reservoir, a critical water supply for up to one million residents in Northern Virginia (USA), to illustrate emerging impacts, underlying causes, possible solutions, and critical research needs.
Anoxia begets anoxia: A positive feedback to the deoxygenation of temperate lakes
Lewis, Abigail S. L.; Lau, Maximilian P.; Jane, Stephen F.; Rose, Kevin C.; Be'eri-Shlevin, Yaron; Burnet, Sarah H.; Clayer, François; Feuchtmayr, Heidrun; Grossart, Hans-Peter; Howard, Dexter W.; Mariash, Heather; Delgado Martin, Jordi; North, Rebecca L.; Oleksy, Isabella; Pilla, Rachel M.; Smagula, Amy P.; Sommaruga, Ruben; Steiner, Sara E.; Verburg, Piet; Wain, Danielle; Weyhenmeyer, Gesa A.; Carey, Cayelan C. (Wiley, 2023)
Declining oxygen concentrations in the deep waters of lakes worldwide pose a pressing environmental and societal challenge. Existing theory suggests that low deep-water dissolved oxygen (DO) concentrations could trigger a positive feedback through which anoxia (i.e., very low DO) during a given summer begets increasingly severe occurrences of anoxia in following summers. Specifically, anoxic conditions can promote nutrient release from sediments, thereby stimulating phytoplankton growth, and subsequent phytoplankton decomposition can fuel heterotrophic respiration, resulting in increased spatial extent and duration of anoxia. However, while the individual relationships in this feedback are well established, to our knowledge, there has not been a systematic analysis within or across lakes that simultaneously demonstrates all of the mechanisms necessary to produce a positive feedback that reinforces anoxia. Here, we compiled data from 656 widespread temperate lakes and reservoirs to analyze the proposed anoxia begets anoxia feedback. Lakes in the dataset span a broad range of surface area (1–126,909 ha), maximum depth (6–370 m), and morphometry, with a median time-series duration of 30 years at each lake. Using linear mixed models, we found support for each of the positive feedback relationships between anoxia, phosphorus concentrations, chlorophyll a concentrations, and oxygen demand across the 656-lake dataset. Likewise, we found further support for these relationships by analyzing time-series data from individual lakes. Our results indicate that the strength of these feedback relationships may vary with lake-specific characteristics: For example, we found that surface phosphorus concentrations were more positively associated with chlorophyll a in high-phosphorus lakes, and oxygen demand had a stronger influence on the extent of anoxia in deep lakes. Taken together, these results support the existence of a positive feedback that could magnify the effects of climate change and other anthropogenic pressures driving the development of anoxia in lakes around the world.
BubR1 recruitment to the kinetochore via Bub1 enhances spindle assembly checkpoint signaling
Banerjee, Anand; Chen, Chu; Humphrey, Lauren; Tyson, John J.; Joglekar, Ajit P. (American Society for Cell Biology, 2022-06-29)
During mitosis, unattached kinetochores in a dividing cell activate the spindle assembly checkpoint (SAC) and delay anaphase onset by generating the anaphase-inhibitory mitotic checkpoint complex (MCC). These kinetochores generate the MCC by recruiting its constituent proteins, including BubR1. In principle, BubR1 recruitment to signaling kinetochores should increase its local concentration and promote MCC formation. However, in human cells BubR1 is mainly thought to sensitize the SAC to silencing. Whether BubR1 localization to signaling kinetochores by itself enhances SAC signaling remains unknown. Therefore, we used ectopic SAC activation (eSAC) systems to isolate two molecules that recruit BubR1 to the kinetochore, the checkpoint protein Bub1 and the KI and MELT motifs in the kinetochore protein KNL1, and observed their contribution to eSAC signaling. Our quantitative analyses and mathematical modeling show that Bub1-mediated BubR1 recruitment to the human kinetochore promotes SAC signaling and highlight BubR1’s dual role of strengthening the SAC directly and silencing it indirectly.
Neuromuscular Dysfunction Precedes Cognitive Impairment in a Mouse Model of Alzheimer's Disease
Brisendine, Matthew H.; Nichenko, Anna S.; Bandara, Aloka B.; Willoughby, Orion S.; Amiri, Niloufar; Weingrad, Zach; Specht, Kalyn S.; Bond, Jacob M.; Addington, Adele; Jones III, Ronald G.; Murach, Kevin A.; Poelzing, Steven; Craige, Siobhan M.; Grange, Robert W.; Drake, Joshua C. (Oxford University Press, 2023-12-04)
Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD.
Mathematical modeling of mechanosensitive reversal control in Myxococcus xanthus
Chen, Yirui; Topo, Elias J.; Nan, Beiyan; Chen, Jing (Frontiers, 2024-01-08)
Adjusting motility patterns according to environmental cues is important for bacterial survival. Myxococcus xanthus, a bacterium moving on surfaces by gliding and twitching mechanisms, modulates the reversal frequency of its front-back polarity in response to mechanical cues like substrate stiffness and cell-cell contact. In this study, we propose that M. xanthus’s gliding machinery senses environmental mechanical cues during force generation and modulates cell reversal accordingly. To examine our hypothesis, we expand an existing mathematical model for periodic polarity reversal in M. xanthus, incorporating the experimental data on the intracellular dynamics of the gliding machinery and the interaction between the gliding machinery and a key polarity regulator. The model successfully reproduces the dependence of cell reversal frequency on substrate stiffness observed in M. xanthus gliding. We further propose reversal control networks between the gliding and twitching motility machineries to explain the opposite reversal responses observed in wild type M. xanthus cells that possess both motility mechanisms. These results provide testable predictions for future experimental investigations. In conclusion, our model suggests that the gliding machinery in M. xanthus can function as a mechanosensor, which transduces mechanical cues into a cell reversal signal.
A fine balance among key biophysical factors is required for recovery of bipolar mitotic spindle from monopolar and multipolar abnormalities
Li, Xiaochu; Bloomfield, Mathew; Bridgeland, Alexandra; Cimini, Daniela; Chen, Jing (American Society for Cell Biology, 2023-06-21)
During mitosis, equal partitioning of chromosomes into two daughter cells requires assembly of a bipolar mitotic spindle. Because the spindle poles are each organized by a centrosome in animal cells, centrosome defects can lead to monopolar or multipolar spindles. However, the cell can effectively recover the bipolar spindle by separating the centrosomes in monopolar spindles and clustering them in multipolar spindles. To interrogate how a cell can separate and cluster centrosomes as needed to form a bipolar spindle, we developed a biophysical model, based on experimental data, which uses effective potential energies to describe key mechanical forces driving centrosome movements during spindle assembly. Our model identified general biophysical factors crucial for robust bipolarization of spindles that start as monopolar or multipolar. These factors include appropriate force fluctuation between centrosomes, balance between repulsive and attractive forces between centrosomes, exclusion of the centrosomes from the cell center, proper cell size and geometry, and a limited centrosome number. Consistently, we found experimentally that bipolar centrosome clustering is promoted as mitotic cell aspect ratio and volume decrease in tetraploid cancer cells. Our model provides mechanistic explanations for many more experimental phenomena and a useful theoretical framework for future studies of spindle assembly.
Anti-inflammatory cytokine stimulation of HMC3 cells: Proteome dataset
Ahuja, Shreya; Lazar, Iulia M. (Elsevier, 2023-07-20)
The immunoprotective functions of microglia in the brain are mediated by the inflammatory M1 phenotype. This phenotype is challenged by anti-inflammatory cytokines which polarize the microglia cells to an immunosuppressive M2 phenotype, a trait that is often exploited by cancer cells to evade immune recognition and promote tumor growth. Investigating the molecular determinants of this behavior is crucial for advancing the understanding of the mechanisms that cancer cells use to escape immune attack. In this article, we describe liquid chromatography (LC)-mass spectrometry (MS)/proteomic data acquired with an EASY-nanoLC 1200-Q ExactiveTM OrbitrapTM mass spectrometer that reflect the response of human microglia cells (HMC3) to stimulation with potential cancer-released anti-inflammatory cytokines known to be key players in promoting tumorigenesis in the brain (IL-4, IL-13, IL-10, TGFB and MCP-1). The MS files were processed with the Proteome Discoverer v.2.4 software package. The cell culture conditions, the sample preparation protocols, the MS acquisition parameters, and the data processing approach are described in detail. The RAW and processed MS files associated with this work were deposited in the PRIDE partner repository of the ProteomeXchange Consortium with the dataset identifiers PXD023163 and PXD023166, and the analyzed data in the Mendeley Data cloud-based repository with DOI 10.17632/fvhw2zwt5d.1. The biological interpretation of the data can be accessed in the research article “Systems-Level Proteomics Evaluation of Microglia Response to Tumor-Supportive Anti-inflammatory Cytokines” (Shreya Ahuja and Iulia M. Lazar, Frontiers in Immunology 2021 [1]). The proteome data described in this article will benefit researchers who are either interested in re-processing the data with alternative search engines and filtering criteria, and/or exploring the data in more depth to advance the understanding of cancer progression and the discovery of novel biomarkers or drug targets.
Small molecules below-ground: the role of specialized metabolites in the rhizosphere
Massalha, Hassan; Korenblum, Elisa; Tholl, Dorothea; Aharoni, Asaph (2017-03)
Soil communities are diverse taxonomically and functionally. This ecosystem experiences highly complex networks of interactions, but may also present functionally independent entities. Plant roots, a metabolically active hotspot in the soil, take an essential part in below-ground interactions. While plants are known to release an extremely high portion of the fixated carbon to the soil, less information is known about the composition and role of C-containing compounds in the rhizosphere, in particular those involved in chemical communication. Specialized metabolites (or secondary metabolites) produced by plants and their associated microbes have a critical role in various biological activities that modulate the behavior of neighboring organisms. Thus, elucidating the chemical composition and function of specialized metabolites in the rhizosphere is a key element in understanding interactions in this below-ground environment. Here, we review key classes of specialized metabolites that occur as mostly non-volatile compounds in root exudates or are emitted as volatile organic compounds (VOCs). The role of these metabolites in below-ground interactions and response to nutrient deficiency, as well as their tissue and cell type-specific biosynthesis and release are discussed in detail.
Secondary metabolite biosynthetic pathways shared between plants and animals: convergent mechanisms and functions
Beran, Franziska; Koellner, Tobias G.; Gershenzon, Jonathan; Tholl, Dorothea (2019)
Despite the phylogenetic distance between plants and insects, these two groups of organisms produce some secondary metabolites in common. Identical structures belonging to chemical classes such as the simple monoterpenes and sesquiterpenes, iridoid monoterpenes, cyanogenic glycosides, benzoic acid derivatives, benzoquinones and naphthoquinones are sometimes found in both plants and insects. In addition, very similar glucohydrolases involved in activating twocomponent defenses, such as glucosinolates and cyanogenic glycosides, occur in both plants and insects. Although this trend was first noted many years ago, researchers have long struggled to find convincing explanations for such co-occurrence. In some cases, identical compounds may be produced by plants to interfere with their function in insects. In others, plant and insect compounds may simply have parallel functions, probably in defense or attraction, and their cooccurrence is a coincidence. The biosynthetic origin of such co-occurring metabolites may be very different in insects as compared to plants. Plants and insectsmayhave different pathways to the same metabolite, or similar sequences of intermediates, but different enzymes. Further knowledge of the ecological roles and biosynthetic pathways of secondary metabolites may shed more light on why plants and insects produce identical substances.
Range expansion can promote the evolution of plastic generalism in coarse-grained landscapes
Miller, Caitlin M.; Draghi, Jeremy A. (Oxford University Press, 2023-12-14)
Phenotypic plasticity is one way for organisms to deal with variable environments through generalism. However, plasticity is not found universally and its evolution may be constrained by costs and other limitations such as complexity: the need for multiple mutational steps before the adaptation is realized. Theory predicts that greater experienced heterogeneity, such as organisms may encounter when spatial heterogeneity is fine-grained relative to dispersal, should favor the evolution of a broader niche. Here we tested this prediction via simulation. We found that, contrary to classical predictions, coarse-grained landscapes can be the most favorable for the evolution of plasticity, but only when populations encounter those landscapes through range expansion. During these range expansions, coarse-grained landscapes select for each step in the complex mutational pathway to plastic generalism by blocking the dispersal of specialists. These circumstances provide ecological opportunities for innovative mutations that change the niche. Our results indicate a new mechanism by which range expansion and spatially structured landscapes interact to shape evolution and reveal that the environments in which a complex adaptation has the highest fitness may not be the most favorable for its evolution.
Mitotic checkpoint gene expression is tuned by codon usage bias
Esposito, Eric; Weidemann, Douglas E.; Rogers, Jessie M.; Morton, Claire M.; Baybay, Erod Keaton; Chen, Jing; Hauf, Silke (Wiley, 2022-08-01)
The mitotic checkpoint (also called spindle assembly checkpoint, SAC) is a signaling pathway that safeguards proper chromosome segregation. Correct functioning of the SAC depends on adequate protein concentrations and appropriate stoichiometries between SAC proteins. Yet very little is known about the regulation of SAC gene expression. Here, we show in the fission yeast Schizosaccharomyces pombe that a combination of short mRNA half-lives and long protein half-lives supports stable SAC protein levels. For the SAC genes mad2+ and mad3+, their short mRNA half-lives are caused, in part, by a high frequency of nonoptimal codons. In contrast, mad1+ mRNA has a short half-life despite a higher frequency of optimal codons, and despite the lack of known RNA-destabilizing motifs. Hence, different SAC genes employ different strategies of expression. We further show that Mad1 homodimers form co-translationally, which may necessitate a certain codon usage pattern. Taken together, we propose that the codon usage of SAC genes is fine-tuned to ensure proper SAC function. Our work shines light on gene expression features that promote spindle assembly checkpoint function and suggests that synonymous mutations may weaken the checkpoint.
Systematic literature review identifying bacterial constituents in the core intestinal microbiome of rainbow trout (Oncorhynchus mykiss)
Hines, Ian S.; Marshall, Maggie A.; Smith, Stephen A.; Kuhn, David D.; Stevens, Ann M. (Wiley, 2023-08-11)
Fish aquaculture has become the fastest growing sector in global food production. Thus, ensuring the sustainability of aquaculture practices is of the utmost importance. Studies in higher vertebrates (i.e. mammals) have demonstrated the role of the host microbiome in physiological processes from nutrient acquisition to pathogen protection. Therefore, analysis of fish microbiomes is an important factor to consider with regard to overall animal health and welfare. Rainbow trout (Oncorhynchus mykiss) are an economically valued fish cultured worldwide. Several studies have identified microbial constituents inhabiting the intestinal tract of rainbow trout. To better elucidate some of the core constituents of the rainbow trout intestinal microbiome, this systematic literature review analysed the relative abundance results from 25 articles published on the rainbow trout intestinal microbiome from 2017 to 2021. Bacteria classified within the phyla Firmicutes and Proteobacteria were observed in every study. At the family level, Lactobacillaceae was consistently observed. Additionally, bacteria in the Actinobacteria, Bacteroides, and Tenericutes phyla were identified in at least 50% of the studies. Interestingly, Mycoplasma spp. were occasionally the most dominant organisms present in the microbiome. Overall, the results here identify bacteria that are commonly found members of the rainbow trout intestinal microbiome.
Robust and Transparent Silver Oxide Coating Fabricated at Room Temperature Kills Clostridioides difficile Spores, MRSA, and Pseudomonas aeruginosa
Hosseini, Mohsen; Huang, Jinge; Williams, Myra D.; Gonzalez, Gerardo Alexander; Jiang, Xiuping; Falkinham, Joseph O.; Ducker, William A. (MDPI, 2023-12-31)
Antimicrobial coatings can inhibit the transmission of infectious diseases when they provide a quick kill that is achieved long after the coating application. Here, we describe the fabrication and testing of a glass coating containing Ag₂O microparticles that was prepared from sodium silicate at room temperature. The half-lives of both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa on this coating are only 2–4 min. The half-life of Clostridioides difficile spores is about 9–12 min, which is extremely short for a spore. Additional tests on MRSA demonstrate that the coating retains its antimicrobial activity after abrasion and that an increased loading of Ag₂O leads to a shorter half-life. This coating combines the properties of optical transparency, robustness, fast kill, and room temperature preparation that are highly desirable for an antimicrobial coating.
TRAM deletion attenuates monocyte exhaustion and alleviates sepsis severity
Wang, Jing; Wu, Yajun; Lin, Ruici; Zhang, Yao; Li, Liwu (Frontiers, 2023-12-15)
Monocyte exhaustion characterized by immune-suppressive features can develop during sepsis and contribute to adverse patient outcomes. However, molecular mechanisms responsible for the establishment of immune-suppressive monocytes with reduced expression of immune-enhancing mediators such as CD86 during sepsis are not well understood. In this study, we identified that the TLR4 intracellular adaptor TRAM plays a key role in mediating the sustained reduction of CD86 expression on exhausted monocytes and generating an immune-suppressive monocyte state. TRAM contributes to the prolonged suppression of CD86 through inducing TAX1BP1 as well as SARM1, collectively inhibiting Akt and NFκB. TRAM deficient mice are protected from cecal slurry-induced experimental sepsis and retain immune-competent monocytes with CD86 expression. Our data reveal a key molecular circuitry responsible for monocyte exhaustion and provide a viable target for rejuvenating functional monocytes and treating sepsis.
Tollip deficiency exaggerates airway type 2 inflammation in mice exposed to allergen and influenza A virus: role of the ATP/IL-33 signaling axis
Nouri, Hamid Reza; Schaunaman, Niccolette; Kraft, Monica; Li, Liwu; Numata, Mari; Chu, Hong Wei (Frontiers, 2023-12-06)
Toll-interacting protein (Tollip) is a negative regulator of the pro-inflammatory response to viruses, including influenza A virus (IAV). Genetic variation of Tollip has been associated with reduced airway epithelial Tollip expression and poor lung function in patients with asthma. Whether Tollip deficiency exaggerates type 2 inflammation (e.g., eosinophils) and viral infection in asthma remains unclear. We sought to address this critical, but unanswered question by using a Tollip deficient mouse asthma model with IAV infection. Further, we determined the underlying mechanisms by focusing on the role of the ATP/IL-33 signaling axis. Wild-type and Tollip KO mice were intranasally exposed to house dust mite (HDM) and IAV with or without inhibitors for IL-33 (i.e., soluble ST2, an IL-33 decoy receptor) and ATP signaling (i.e., an antagonist of the ATP receptor P2Y13). Tollip deficiency amplified airway type 2 inflammation (eosinophils, IL-5, IL-13 and mucins), and the release of ATP and IL-33. Blocking ATP receptor P2Y13 decreased IL-33 release during IAV infection in HDM-challenged Tollip KO mice. Furthermore, soluble ST2 attenuated airway eosinophilic inflammation in Tollip KO mice treated with HDM and IAV. HDM challenges decreased lung viral load in wild-type mice, but Tollip deficiency reduced the protective effects of HDM challenges on viral load. Our data suggests that during IAV infection, Tollip deficiency amplified type 2 inflammation and delayed viral clearance, in part by promoting ATP signaling and subsequent IL-33 release. Our findings may provide several therapeutic targets, including ATP and IL-33 signaling inhibition for attenuating excessive airway type 2 inflammation in human subjects with Tollip deficiency and IAV infection.
An extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano
Sonani, Ravi R.; Palmer, Lee K.; Esteves, Nathaniel C.; Horton, Abigail A.; Sebastian, Amanda L.; Kelly, Rebecca J.; Wang, Fengbin; Kreutzberger, Mark A. B.; Russell, William K.; Leiman, Petr G.; Scharf, Birgit E.; Egelman, Edward H. (Springer, 2024-01-26)
A contractile sheath and rigid tube assembly is a widespread apparatus used by bacteriophages, tailocins, and the bacterial type VI secretion system to penetrate cell membranes. In this mechanism, contraction of an external sheath powers the motion of an inner tube through the membrane. The structure, energetics, and mechanism of the machinery imply rigidity and straightness. The contractile tail of Agrobacterium tumefaciens bacteriophage Milano is flexible and bent to varying degrees, which sets it apart from other contractile tail-like systems. Here, we report structures of the Milano tail including the sheath-tube complex, baseplate, and putative receptor-binding proteins. The flexible-to-rigid transformation of the Milano tail upon contraction can be explained by unique electrostatic properties of the tail tube and sheath. All components of the Milano tail, including sheath subunits, are crosslinked by disulfides, some of which must be reduced for contraction to occur. The putative receptor-binding complex of Milano contains a tailspike, a tail fiber, and at least two small proteins that form a garland around the distal ends of the tailspikes and tail fibers. Despite being flagellotropic, Milano lacks thread-like tail filaments that can wrap around the flagellum, and is thus likely to employ a different binding mechanism.

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