Biology subjects

Jones, S. M.

Publications and source records attributed to Jones, S. M..

8 recordsLinked to original sources

bioRxiv2025

Taxonomy-free fecal microbiome profiles enable robust prediction of immunotherapy response and toxicity in melanoma

The gut microbiome has been causally linked to the efficacy of immune-checkpoint inhibitor therapy (ICI), prompting numerous clinical trials of microbiome-targeting strategies. Yet, mechanisms by which gut microbiota shape immune responses remain elusive as taxonomic biomarkers have failed to generalize across multiple cohorts. In this study, we develop a taxonomy-agnostic framework to identify microbial biomarkers of ICI response and immune-related adverse event (irAE) occurrence from metagenomic sequencing. Applying this approach to four independent melanoma cohorts from clinical centers across the United States, we uncover gut microbial proteins produced by diverse bacterial taxa that consistently predict ICI response. Notably, we uncover a previously uncharacterized operon involved in cellular redox homeostasis that is encoded by different bacteria and reliably predicts irAE occurrence. We further validated the predictive power of this operon in a prospectively sequenced melanoma cohort. Our results demonstrate that taxa-agnostic microbial protein biomarkers are robust, generalizable, and provide a path towards pretreatment risk stratification for melanoma patients initiating ICI therapy.

cancer biology↗

bioRxiv2025

Engineered yeast biofilms deliver plastic degrading enzymes to PET substrates

Enzymes that degrade PET and other plastics are being discovered with increasing pace, and engineering approaches further increase their activity. Most proposed applications for such enzymes require their purification, enabling the regeneration of monomeric subunits suitable for the production of new plastic. However, large amounts of plastics exist as environmental contaminants, and are unlikely to be suitable for standard recycling. Such waste may still be suitable for bioremediation using enzymatic activities, albeit without the economic incentives of a full recycling process. Here we develop a delivery system for PET hydrolases, based on engineered yeast biofilms that grow and secrete enzymes directly on the substrate to be degraded. The system does not require any enzyme purification steps, and the biofilms at least partially assimilate the degradation products into biomass. Our work provides proof-of-principle that demonstrates the potential of biofilm-based approaches.

bioengineering↗

bioRxiv2025

Carbohydrate consumption drives adaptive mutations in Escherichia coli associated with increased risk for systemic infection

Dissemination of organisms from the gut microbiota is a major contributor to sepsis and critical illness. Patients with cirrhosis are prone to systemic infections and are commonly prescribed the carbohydrate lactulose to manage hepatic encephalopathy (HE) 1. Commensal metabolism of lactulose is believed to reduce pathobiont colonization through short-chain fatty acid production, but its direct effects on gut pathobionts remain unexplored 2. Here, we show that lactulose consumption unexpectedly selects for mutations in Escherichia coli lactose (lac) operon regulation, enhancing its metabolic fitness and colonization capacity. This is mediated by selection for constitutive expression of the lac operon through mutations in its regulatory components. Using in vitro systems, murine models, and clinical samples, we demonstrate that these mutations enable E. coli to exploit lactulose as a carbon source, bypassing host carbohydrate metabolism and increasing its intestinal colonization. Despite its long-standing use in HE treatment, we find that lactulose has a paradoxical association with risk of infection hospitalization in patients with cirrhosis in a large epidemiologic study. The emergence of lactulose-adapted E. coli strains could be suppressed by a dietary oligosaccharide that competitively inhibits lactulose uptake. These findings reveal a mechanism by which dietary substrates exert selective pressure on the microbiome, with implications for diet-based strategies to modulate microbial evolution and infection risk.

microbiology↗

bioRxiv2024

Fate (or state) of CA2 neurons in a mineralocorticoid receptor knockout.

Hippocampal area CA2 has emerged as a functionally and molecularly distinct part of the hippocampus and is necessary for several types of social behavior, including social aggression. As part of the unique molecular profile of both mouse and human CA2, the mineralocorticoid receptor (MR; Nr3c2) appears to play a critical role in controlling CA2 neuron cellular and synaptic properties. To better understand the fate (or state) of the neurons resulting from MR conditional knockout, we used a spatial transcriptomics approach. We found that without MRs, CA2 neurons acquire a CA1-like molecular phenotype. Additionally, we found that neurons in this area appear to have a cell size and density more like that in CA1. These finding support the idea that MRs control at least CA2s state during development, resulting in a CA1-like fate.

neuroscience↗

bioRxiv2024

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

Immunotherapy leads to cancer eradication despite the tumors immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8+ T cells in the tumor. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8+ T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

cancer biology↗

bioRxiv2023

Spontaneous allelic variant in Ush1g resulting in an expanded phenotype

Strategies to reveal the discovery of the relationships between novel phenotypic behaviors and specific genetic alterations can be achieved via either target-specific, directed mutagenesis or phenotypic selection following random chemical mutagenesis. As an alternative approach, one can exploit deficiencies in DNA repair pathways that are responsible for the maintenance of genetic integrity in response to spontaneously-induced damage. In the genetic background of mice deficient in the DNA glycosylase NEIL1, elevated numbers of spontaneous mutations arise from translesion DNA synthesis past unrepaired, oxidatively-induced base damage. Several litters of Neil1 knockout mice included animals that were distinguished by their backwards-walking behavior in open-field environments, while maintaining frantic forward movements in their home cage environment. Other phenotypic manifestations included swim test failures, head tilting, and circling. Mapping of the mutation that conferred these behaviors revealed the introduction of a stop codon at amino acid 4 of the Ush1g gene; the allele was Ush1gbw, reflecting the backwards-walking phenotype. Ush1gbw/bw null mice displayed auditory and vestibular defects that are commonly seen with mutations affecting inner-ear hair-cell function, including a complete lack of auditory brainstem responses and vestibular-evoked potentials. As in other Usher syndrome type I mutant mouse lines, hair-cell phenotypes included disorganized and split hair bundles, as well as altered distribution of proteins for stereocilia that localize to the tips of row 1 or row 2. Disruption to the bundle and kinocilium displacement suggested that USH1G is essential for forming the hair cells kinocilial links. Due to the vestibular dysfunction, however, visual behavior as measured with optokinetic tracking could not be assessed in Ush1gbw/bw mice. Consistent with other Usher type 1 models, however, Ush1gbw/bw mice had no substantial retinal degeneration compared to Ush1gbw/+ controls out to six months. In contrast to previously-described Ush1g alleles, this new allele provides the first knockout model for this gene.

neuroscience↗

bioRxiv2019

Cytochrome P450 26b1-mediated specification of vestibular striola and central zones is required for transient responses in linear acceleration

Each vestibular sensory epithelia of the inner ear is divided into two zones, the striola and extrastriola in maculae of otolith organs and the central and peripheral zones in cristae of semicircular canals, that differ in morphology and physiology. We found that formation of striolar/central zones during embryogenesis requires Cytochrome P450 26b1 (Cyp26b1)-mediated degradation of retinoic acid (RA). In Cyp26b1 conditional knockout mice, the identities of the striolar/central zones were compromised, including abnormal innervating neurons and otoconia in otolith organs. Vestibular evoked potentials (VsEP) in response to jerk stimuli were largely absent. Vestibulo-ocular reflexes and standard motor performances such as forced swimming were unaffected, but mutants had head tremors and deficits in balance beam tests that were consistent with abnormal vestibular input. Thus, degradation of RA during embryogenesis is required for patterning highly specialized regions of the vestibular sensory epithelia that may provide acute feedback about head motion.

neuroscience↗

bioRxiv2019

Induction of the HIF pathway: Differential regulation by chemical hypoxia and oxygen glucose deprivation

The Hypoxia Inducible Factor (HIF) proteins are the master regulators in the cellular response to varying oxygen levels, including hypoxia. The HIF complex is stabilized and accumulates when oxygen levels drop through inhibition of a degradative enzyme. An active HIF complex can act as a transcriptional regulator of hundreds of genes. In turn, these genes determine the response of the cell by inducing pathways which can promote survival, or result in cell death. However, little is known about the regulation of the transcriptional process. We were interested in learning more about the time dependence of transcriptional activation in order to target those pathways which could enhance cell survival after ischemia. Using mouse hippocampal organotypic cultures (HOTCs), we compared oxygen-glucose deprivation with the hypoxia mimetic cobalt, which inhibits the oxygen dependent prolyl hydroylase and blocks degradation of the HIF proteins. We demonstrated that two of the most studied HIF target genes (VEGF, EPO) as well as HIF structural genes show complex time and dose-dependent expression patterns in response to the two different insults. Understanding of these molecular responses is crucial for the development of future treatments to enhance recovery from hypoxia and stroke.

neuroscience↗