Biology subjects

Fields, M.

Publications and source records attributed to Fields, M..

6 recordsLinked to original sources

bioRxiv2026

Provisional extracellular matrix signaling network regulates tumor lymphoneogenesis and response to immunotherapy

Tertiary lymphoid structures (TLS) predict response to checkpoint inhibition, and conventional dendritic cells (cDC) are required to build and maintain them. What renders a niche permissive for their assembly is unknown: chemokines recruit the cellular constituents but do not specify how they organize. Here we show that the organizing signal is a matrix fragment. Proteolysis of the proteoglycan versican (VCAN) releases the matrikine versikine, constitutively in germinal center light zones and inducibly in tumor stroma. Versikine activates CD11b+ cDC and expands cDC1 to assemble TLS-archetypal triads, apposed DC: CD4+ T: CD8+ T units. Versikine-conditioned DC engage progenitor-exhausted CD8+ T cells (Tpex) and Th1-polarized follicular helper CD4+ T cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine supplied as mRNA or recombinant protein sensitizes refractory tumors to PD-L1 blockade. VCAN proteolysis prospectively predicted outcomes after PD-1 blockade in metastatic colorectal cancer. Matrikines organize chemokine-recruited cells into functional immune niches.

immunology↗

bioRxiv2025

Multiblock Integration and Modeling of Localized Microbiome, Metabolome, and Clinical Metadata to Identify Biomarkers Predictive of Outcome in Veterans with Non-Healing Wounds

The chronic wound microenvironment consists of a complex milieu of host cells, microbial species, and metabolites. While much is known about wound microbiomes, our knowledge of metabolic landscapes influencing wound healing is limited. Furthermore, integrating complex datasets into predictive models of wound healing is almost non-existent. Microbial rRNA and total metabolites were extracted from 45 diabetic foot ulcers (DFU) debridement samples from 13 patients, with 25 from non-healing wounds and 20 from healing wounds that remained closed for over 30 days. 16S rRNA sequencing and global metabolomics were performed and clinical metadata collected. Healing outcome was modeled as a function of three blocks of features (N = 21 clinical, 634 microbiome, and 865 metabolome) using DIABLO (Data Integration Analysis for Biomarker Discovery using Latent Components). The final model selected 176 features (N = 15 clinical, 8 microbiome, and 153 metabolome) and the correct clinical outcome was predicted with an accuracy of nearly 94%. These results indicate that integrating multi-omics data with clinical metadata can predict clinical wound healing with low error rates. Furthermore, the biomarkers selected within the model offer novel insights into wound microenvironment composition which may reveal innovative therapeutic approaches and improve treatment efficacy in difficult-to-heal wounds.

systems biology↗

bioRxiv2024

Modest functional diversity decline and pronounced composition shifts of microbial communities in a uranium-contaminated aquifer

BackgroundMicrobial taxonomic diversity declines with increased environmental stress. Yet, few studies have explored whether phylogenetic and functional diversities track taxonomic diversity along the stress gradient. Here, we investigated bacterial communities within an aquifer in Oak Ridge, Tennessee, USA, which is characterized by a broad spectrum of stressors, including extremely high levels of nitrate, heavy metals like cadmium and chromium, radionuclides such as uranium, and extremely low pH (<3). ResultsBoth taxonomic and phylogenetic -diversities were reduced in the most impacted wells, while the decline in functional -diversity was modest and statistically insignificant, indicating a more robust buffering capacity to environmental stress. Differences in functional gene composition (i.e., functional {beta}-diversity) were pronounced in highly contaminated wells, while convergent functional gene composition was observed in uncontaminated wells. The relative abundances of most carbon degradation genes were decreased in contaminated wells, but genes associated with denitrification, adenylylsulfate reduction, and sulfite reduction were increased. Compared to taxonomic and phylogenetic compositions, environmental variables played a more significant role in shaping functional gene composition, suggesting that niche selection could be more closely related to microbial functionality than taxonomy. ConclusionsOverall, we demonstrated that despite a reduced taxonomic -diversity, microbial communities under stress maintained functionality underpinned by environmental selection.

microbiology↗

bioRxiv2023

The Septin Cytoskeleton is Required for Plasma Membrane Repair

Mammalian cells are frequently exposed to mechanical and biochemical stressors resulting in plasma membrane injuries. Repair mechanisms reseal the plasma membrane to restore homeostasis and prevent cell death. In the present work, a silencing RNA screen was performed to uncover plasma membrane repair mechanisms of cells exposed to a pore-forming toxin (listeriolysin O). This screen identified molecules previously known to repair the injured plasma membrane such as annexin A2 (ANXA2) as well as novel plasma membrane repair candidate proteins. Of the novel candidates, we focused on septin 7 (SEPT7) because the septins are an important family of conserved eukaryotic cytoskeletal proteins. Using diverse experimental approaches, we established for the first time that SEPT7 plays a general role in plasma membrane repair of cells perforated by pore-forming toxins and mechanical wounding. Remarkably, upon cell injury, the septin cytoskeleton is extensively redistributed in a Ca2+-dependent fashion, a hallmark of plasma membrane repair machineries. The septins reorganize into subplasmalemmal domains arranged as knob and loop (or ring) structures containing F-actin, myosin II, and annexin A2 (ANXA2) and protrude from the cell surface. Importantly, the formation of these domains correlates with the plasma membrane repair efficiency. Super-resolution microscopy shows that septins and actin are arranged in intertwined filaments associated with ANXA2. Silencing SEPT7 expression prevented the formation of the F-actin/myosin II/ANXA2 domains, however, silencing expression of ANXA2 had no observable effect on their formation. These results highlight the key structural role of the septins in remodeling the plasma membrane and in the recruitment of the repair molecule ANXA2. Collectively, our data support a novel model in which the septin cytoskeleton acts as a scaffold to promote the formation of plasma membrane repair domains containing contractile F-actin and annexin A2.

cell biology↗

bioRxiv2020

The Guaymas Basin Subseafloor Sedimentary Archaeome Reflects Complex Environmental Histories

We explore archaeal distribution and environmental niche differentiation in sedimentary subseafloor habitats of Guaymas Basin and the adjacent Sonora Margin, located in the Gulf of California, Mexico. Specifically, we survey diverse subseafloor habitats on the Guaymas Basin flanking regions that are extending from the spreading center, termed here "off-axis" sites. Sampling locations include (i) control sediments without hydrothermal or seep influence, (ii) Sonora Margin sediments underlying oxygen minimum zone water, (iii) compacted, highly reduced sediments from a pressure ridge with numerous seeps at the base of the Sonora Margin, and (iv) sediments impacted by hydrothermal circulation at the off-axis Ringvent site. Generally, archaeal 16S rRNA gene datasets are largely comprised of Bathyarchaeal lineages, members of the Hadesarchaea, MBG-D, TMEG, and ANME-1 groups. The most frequently observed 25 OTUs belong to members of these lineages, and correspond to approx. 40 to 80% of the sequence dataset in each sediment sample. Differential distribution patterns of these archaeal groups in downcore sediments uniquely characterize each major sedimentary environment. Variations in archaeal community composition reflect locally specific environmental challenges throughout the greater Guaymas Basin area. Background sediments are divided into surface and subsurface niches, reflecting increased selection of the archaeal community downcore. In sum, the environmental setting and history of a particular site, not isolated biogeochemical properties out of context, control the subseafloor archaeal communities in Guaymas Basin and Sonora Margin sediments.

ecology↗

bioRxiv2019

A global perspective on microbial diversity in the terrestrial deep subsurface

While recent efforts to catalogue Earths microbial diversity have focused upon surface and marine habitats, 12% to 20% of Earths bacterial and archaeal biomass is suggested to inhabit the terrestrial deep subsurface, compared to [~]1.8% in the deep subseafloor 1-3. Metagenomic studies of the terrestrial deep subsurface have yielded a trove of divergent and functionally important microbiomes from a range of localities 4-6. However, a wider perspective of microbial diversity and its relationship to environmental conditions within the terrestrial deep subsurface is still required. Here, we show the diversity of bacterial communities in deep subsurface groundwater is controlled by aquifer lithology globally, by using 16S rRNA gene datasets collected across five countries on two continents and from fifteen rock types over the past decade. Furthermore, our meta-analysis reveals that terrestrial deep subsurface microbiota are dominated by Betaproteobacteria, Gammaproteobacteria and Firmicutes, likely as a function of the diverse metabolic strategies of these taxa. Despite this similarity, evidence was found not only for aquifer-specific microbial communities, but also for a common small consortium of prevalent Betaproteobacteria and Gammaproteobacterial OTUs across the localities. This finding implies a core terrestrial deep subsurface community, irrespective of aquifer lithology, that may play an important role in colonising and sustaining microbial habitats in the deep terrestrial subsurface. An in-silico contamination-aware approach to analysing this dataset underscores the importance of downstream methods for assuring that robust conclusions can be reached from deep subsurface-derived sequencing data. Understanding the global panorama of microbial diversity and ecological dynamics in the deep terrestrial subsurface provides a first step towards understanding the role of microbes in global subsurface element and nutrient cycling.

microbiology↗