Biology subjects

Payne, T.

Publications and source records attributed to Payne, T..

6 recordsLinked to original sources

bioRxiv2026

Targeting Synaptic Vesicle Endocytosis in Nociceptors Provides Sustained Pain Relief

Endocytosis replenishes synaptic vesicle (SV) pools that are required for persistent transmission of chronic pain signals within nociceptive spinal circuits. The nociceptor-specific contribution of SV endocytosis to pain and the therapeutic potential of endocytosis inhibitors are unclear. We identified SV endocytosis in nociceptors as a critical driver of ongoing pain and developed a gene-based strategy to target this mechanism. Nociceptor-specific adeno-associated virus-mediated knockdown of adaptor-associated kinase 1 (AAK1) or dynamin 1 (Dnm1) in dorsal root ganglia Nav1.8-positive neurons inhibited postoperative and neuropathic hypersensitivity without affecting baseline mechanical or thermal sensitivity, locomotion or spontaneous behavior. Electrophysiological recordings from spinal neurons combined with optogenetic activation of nociceptor afferents showed that AAK1 or Dnm1 downregulation blocked the sustained synaptic transmission between nociceptors and dorsal horn neurons by disrupting SV recycling and reducing neurotransmitter release probability. Lipid nanoparticle (LNP)-encapsulated CRISPR/dCas9-repressor mRNA constructs (dCas9-R) were engineered to achieve sustained and reversible transcriptional and epigenetic repression of Aak1 or Dnm1 following intrathecal delivery. LNP-mediated gene modulation produced sustained downregulation of Aak1 or Dnm1 mRNA in sensory neurons and resulted in robust and long-lasting analgesia in preclinical models of postoperative, inflammatory, neuropathic and osteoarthritis pain without impairing acute nociception or locomotor activity. Mechanistically, targeting endocytic machinery disrupted SV recycling at nociceptor terminals, thereby reducing excitatory neurotransmission within spinal pain circuits. Together, these findings establish presynaptic endocytic regulation as a convergent mechanism underlying chronic pain and demonstrate the translational potential of LNP-delivered CRISPR/dCas9-R as a durable, non-opioid pain therapy that surmounts inherent redundancy of pain signaling mechanisms. One Sentence SummarySynaptic vesicle endocytosis in nociceptors is a critical mechanism driving ongoing pain and targeting this process with intrathecal LNP-delivered CRISPR/dCas9-mediated gene repression produces durable, non-opioid analgesia across multiple chronic pain models.

neuroscience↗

bioRxiv2026

Revealing the Hidden Landscape of Public Metabolomics Data Reuse in MetaboLights

Public data reuse is a key driver of progress in omics sciences, including increasingly metabolomics data. In this study, we present a validated analysis of confirmed reuse of datasets from the MetaboLights data repository, one of the leading resources in the field. Candidate publications were collected via dataset identifiers (MTBLS#) using a Python-based retrieval pipeline across major publisher databases. They were next manually validated to distinguish active reuse from citation-only mentions. Overall, 272 unique publications were confirmed to have reused at least one MetaboLights dataset. Reuse is dominated by Method/Tool Development, with smaller contributions from Secondary Biological Analysis and Data Integration/Meta-analysis. LC-MS datasets account for the majority of reuse, whereas NMR and GC-MS also contribute but at a lower level. Data reuse has increased over time, with a noticeable acceleration in the most recent years. At the dataset level, reuse follows a long-tail distribution, where a small subset of datasets accounts for repeated reuse, mainly as community benchmarks. These results provide a conservative estimate of public metabolomics data reuse and show that public datasets are predominantly used for methodological and computational applications. They also indicate that reuse is under-detected when dataset identifiers are not consistently reported, highlighting the need for standardised dataset citation to improve traceability and recognition of reuse. Statement of significance of the studyThe impact of public metabolomics repositories has been difficult to assess due to the lack of reliable evidence distinguishing true data reuse from simple literature citations. This study addresses that gap by providing a conservative, manually validated baseline for confirmed reuse of datasets from the MetaboLights data repository. The analysis clarifies how MetaboLights datasets are used in practice, showing that reuse is concentrated to a limited number of datasets and is dominated by computational and methodological applications.

bioinformatics↗

bioRxiv2026

Type IV pilus length determines virulence by regulating a hidden subpopulation of non-contributing filaments

Many clinically important bacterial pathogens, including Pseudomonas, Vibrio, Neisseria, and Acinetobacter species, employ dynamic extracellular appendages called type IV pili (T4P) to facilitate virulence through cyclical extension and retraction of pilus filaments. To dissect how T4P dynamics govern pathogenesis, we engineered a genetic system to precisely tune pilus length across a continuum. We demonstrate that pilus length critically determines four major T4P-dependent virulence traits in Pseudomonas aeruginosa (motility, surface sensing, biofilm formation, and phage infection) and reveal a hidden subpopulation of pili that are unable to interact with environmental substrates or host cells, rendering them non-contributing to any T4P-mediated function. Integrating molecular dynamics simulations, we show that low inner-membrane abundance of the major pilin forces the extension mechanism into transient idle states, restricting both velocity and final length. Molecularly, this finding reveals how two key biophysical parameters, pilin abundance and diffusion, impose a fundamental physical constraint on T4P assembly, and that regulating pilin abundance presents a strong lever over regulating pilus count for controlling the amount of functionally contributing filaments. Contrary to the prevailing view that retraction force generation primarily dictates T4P-mediated behaviors, our results establish extension dynamics as the overlooked bottleneck constraining all retraction-enabled virulence traits, with population heterogeneity in length enabling adaptive bet-hedging.

microbiology↗

bioRxiv2024

A Versatile Antibody Capture System that Drives Precise In Vivo Delivery of mRNA loaded Lipid Nanoparticles and Enhances Gene Expression

Efficient and precise delivery of mRNA is critical to advance mRNA therapies beyond their current use as vaccines. Lipid nanoparticles (LNP) efficiently encapsulate and protect mRNA, but non-specific cellular uptake may lead to off-target delivery and minimal delivery to target cells. Functionalizing LNPs with antibodies enables targeted mRNA delivery, but traditional modification techniques require complex conjugation and purification, which often reduces antibody affinity. Here, we present a simple method for capturing antibodies in their optimal orientation on LNPs, without antibody modification or complex purification. This strategy uses an optimally oriented anti-Fc nanobody on the LNP surface to capture antibodies, resulting in protein expression levels >1000 times higher than non-targeted LNPs and >8 times higher than conventional antibody functionalization techniques. These precisely targeted LNPs showed highly efficient in vivo targeting to T cells, with minimal delivery to other immune cells. This approach enables the rapid development of targeted LNPs and has the potential to broaden the use of mRNA therapies.

bioengineering↗

bioRxiv2019

Genomic insights into the Archaea inhabiting an Australian radioactive legacy site

During the 1960s, small quantities of radioactive materials were co-disposed with chemical waste at the Little Forest Legacy Site (LFLS, Sydney, Australia). The microbial function and population dynamics in a waste trench during a rainfall event have been previously investigated using shotgun metagenomics. This revealed a broad abundance of candidate and potentially undescribed taxa in this iron-rich, radionuclide-contaminated environment. Here, applying genome-based metagenomic methods, we recovered 37 refined archaeal MAGs ([≥]50% completeness, [≤]10% redundancy) from 10 different major lineages. They were, mainly, included in four DPANN lineages without standing nomenclature (LFWA-I to IV) and Methanoperedenaceae (ANME-2D). While most of the new DPANN lineages show reduced genomes with limited central metabolism typical of other DPANN, the orders under the LFWA-III lineage, Ca. Gugararchaeales and Ca. Anstonellales, may constitute distinct orders with a more comprehensive central metabolism and anabolic capabilities within the Micrarchaeota phylum. The new Methanoperedens spp. MAGs, together with previously published data, suggests metal ions as the ancestral electron acceptors during the anaerobic oxidation of methane while the respiration of nitrate/nitrite via molybdopterin oxidoreductases would have been a secondary acquisition. The presence of genes for the biosynthesis of polyhydroxyalkanoates in most Methanoperedens also appears to be a widespread characteristic of the genus for carbon accumulation. We formally propose 22 new candidate taxa based on data analysed in this manuscript, as well as four missing formal taxa definitions and two new candidate species based on extant data. We present evidence of four new DPANN lineages and six non-conspecific Methanoperedens, while exploring their uniqueness, potential role in elemental cycling, and evolutionary history.

microbiology↗

bioRxiv2019

A Proteomic Atlas of Senescence-Associated Secretomes for Aging Biomarker Development

The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of, and promising therapeutic target for, multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the SASP Atlas, a comprehensive proteomic database of soluble and exosome SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins, but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including GDF15, STC1 and SERPINs, which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging. Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus and tissue of origin of senescent cells in vivo.\n\nAbbreviationsATV, atazanavir treatment; BLSA, Baltimore Longitudinal Study of Aging; CTL, control; DDA, data-dependent acquisition; DAMP, damage-associated molecular pattern; DIA, data-independent acquisition; eSASP, extracellular vesicle senescence associated secretory phenotype; EVs, extracellular vesicles; IR, X-irradiation; MS, mass spectrometry; RAS, inducible RAS overexpression; SA-{beta}-Gal, senescence-associated {beta}-galactosidase; SEN, senescent; sSASP, soluble senescence associated secretory phenotype.

cell biology↗