Biology subjects

O'Connell, S.

Publications and source records attributed to O'Connell, S..

16 recordsLinked to original sources

bioRxiv2026

Aquamin: A Source of Bioavailable Calcium, Magnesium, and Additional Cationic Trace Elements in Colon Health and Beyond

Introduction: Aquamin is a calcium- and magnesium-rich natural product derived from marine red algae that contains multiple trace elements. Human and mouse studies have demonstrated potential health benefits. Methods: Aquamin and calcium carbonate were compared using a two-stage simulated gastric and intestinal digestion protocol. ICP-OES/ICP-MS was used to quantify cationic elements in soluble and insoluble fractions. Binding of dispersed mineral powders to human colon epithelial cells was assessed by light and scanning electron microscopy, and uptake was assessed by transmission electron microscopy. TMT-based proteomics identified protein changes in colon epithelial organoids following mineral exposure. Serum samples from 90- and 180-day Aquamin intervention trials were analyzed for changes in circulating cationic elements. Results: Both Aquamin and calcium carbonate were solubilized under simulated gastric conditions, although Aquamin was more acid-resistant. After transfer to neutral-pH intestinal conditions, limited precipitation occurred, and most calcium remained soluble. With Aquamin, magnesium and strontium also remained soluble, whereas several trace elements became partially or completely insoluble. Aquamin rapidly bound to colon epithelial cells, with ultrafine Aquamin particles detected between adjacent cells. Calcium carbonate bound more slowly and to fewer cells. Aquamin increased proteins involved in enterocyte cation uptake, intracellular trafficking, and basolateral secretion. Serum strontium levels increased in study participants after 90 or 180 days of Aquamin consumption; most other elements changed minimally, although serum iron increased modestly. Conclusions: Aquamin provides a bioavailable source of several cationic elements. Soluble calcium, magnesium, and strontium may be absorbed primarily through transcellular pathways, while less-soluble elements may also cross the colonic epithelium through paracellular mechanisms.

molecular biology↗

bioRxiv2026

DNT: Diploid Genomic Foundation Model

Clinical interpretation of genetic variation depends on the diploid genotype, including zygosity, allele dosage and whether multiple variants occur in cis on the same homologue or in trans on different homologues. Most genomic language models process haploid sequences or combine independently encoded haplotypes downstream, so they do not directly represent the paired genotype in a single sequence. We introduce a reference-aligned diploid encoding for single-nucleotide variants (SNVs) and short insertions and deletions (indels), together with unphased and phase-retaining tokenizers that accept phased genotypes and convert them to single-sequence diploid representation. Using Nucleotide Transformer v3 backbones, we continue training 8-million- and 100-million-parameter models and evaluate an auxiliary Contrastive Phase Loss (CPL) designed to retain the phasing information of the variants in contextual representations. We evaluate on a novel compound-heterozygous benchmark containing 9,460 examples. Models whose inputs did not distinguish relative phase remained near chance, whereas our diploidic models improved discrimination with AUROC 0.649, compared to 0.506 for the vocabulary-adapted control. These findings establish a method for making diploid genotype information accessible to genomic language models, rather than a universal improvement in variant prediction; validation in naturally observed, accurately phased clinical cohorts remains necessary.

bioinformatics↗

bioRxiv2026

Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML Subtypes

Transcriptional condensates anchored by chromatin readers are increasingly recognized as organizing hubs for gene expression, but how their assembly and stability are regulated remains poorly understood. Here, we identify an acetylation-dependent feed-forward circuit that controls the integrity of the Super Elongation Complex (SEC), a key driver of transcriptional elongation. We show that the SAGA histone acetyltransferase catalytic subunits KAT2A/KAT2B license acetylation of both histone H3 lysine 9 (H3K9ac) and SEC components themselves, including ENL, AFF1, and AFF3. Loss of this dual acetylation activity, achieved via a cereblon-recruiting PROTAC (GSK983/GSK699), displaces the chromatin reader ENL from target loci, dissolves ENL-anchored transcriptional condensates, and disrupts SEC-dependent transcriptional output - linking histone and non-histone acetylation to the physical integrity of a core transcriptional machine. Using genome-scale dependency data, we show that the SAGA complex is a selective chromatin dependency in acute myeloid leukemia (AML) AML and hematological malignancies and disrupting this feed-forward transcriptional circuit in AML demonstrates subtype independent antileukemia effects. KAT2A/B degradation drives potent, broad-spectrum antileukemic activity across genetically diverse AML cell lines, primary patient samples, and an isogenic KMT2A-rearranged model bearing cooperating oncogenic mutations, with H3K9ac loss concentrated asymmetrically at core AML oncogene loci such as MYC, MYB, and the HOXA cluster. Together, these findings define an acetylation-dependent circuit governing SEC integrity and establish KAT2A/B degradation as a mechanism-based, pan-AML therapeutic strategy, with implications for transcriptional condensate regulation beyond leukemia. HIGHLIGHTSO_LIThe SAGA complex is a selectively essential chromatin dependency across hematological malignancies and particularly in AML C_LIO_LIKAT2A/B degradation drives broad anti-leukemic activity across genetically diverse AML subtypes including chemo-refractory disease C_LIO_LIKAT2A/B degradation depletes H3K9ac at AML oncogene loci and dismantles ENL-anchored condensates C_LIO_LIKAT2A/B licenses regulation of super elongation complex acetylation and ENL interaction with SEC complex components C_LI

cancer biology↗

bioRxiv2026

GFMBench-API: A Standardized Interface for Benchmarking Genomic Foundation Models

The rapid scaling of Genomic Foundation Models (GFMs) has created a critical need for standardized evaluation frameworks. Current benchmarking practices are often fragmented, relying on model-specific preprocessing and inconsistent metric implementations that hinder reproducible comparisons. We present GFMBench-API, a high-level Python interface designed to unify the evaluation lifecycle of GFMs. GFMBench-API provides a modular "middleware" architecture that decouples model-specific tokenization and embedding logic from task-specific data streams and performance metrics. By standardizing the input/output schemas for common genomic tasks, such as regulatory element prediction, variant effect scoring, and long-range interaction mapping, GFMBench-API enables researchers to integrate new models or tasks with minimal "glue code." Our interface ensures mathematical consistency across evaluations, providing a robust foundation for the transparent and systematic benchmarking of GFMs.

genomics↗

bioRxiv2026

Aquamin a marine derived multi mineral attenuates toll like receptor mediated inflammatory responses in macrophages.

Toll-like receptors (TLRs) play a central role in innate immune responses through recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Activation of TLRs leads to the induction of inflammatory cytokines via MyD88- and TRIF-dependent signaling pathways. Aquamin, a multi-mineral supplement derived from the marine red algae Lithothamnion, is known for its anti-inflammatory properties. In this study, we demonstrate that Aquamin dose-dependently inhibits lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines (TNF-, IL-6, IL-1{beta}) and chemokines in both human peripheral blood mononuclear cells (hPBMCs) and murine bone marrow-derived macrophages (mBMDMs), without causing cytotoxicity. Mechanistic studies demonstrate that Aquamin specifically suppressed TRIF dependent IRF3 activation downstream of TLR3 and TLR4. These findings support Aquamin as a promising agent for use as an intervention in counteracting inflammatory diseases states where TLR signalling is implicated.

immunology↗

bioRxiv2026

High performance sorting of motor unit action potentials with EMUsort

Understanding how neural signals control muscle activity during behavior is a key challenge in motor neuroscience. To this end, recent advances in intramuscular multielectrode arrays have enabled high-quality multichannel recordings of many motor unit action potentials (MUAPs) in freely moving subjects. However, identifying individual MUAP events within multichannel recordings is a significant challenge for existing spike sorting methods, which are typically optimized for identifying action potentials from neurons in the brain. To overcome this challenge, we developed the Enhanced Motor Unit sorter (EMUsort), an extension of Kilosort4 (KS4) that achieves high-performance MUAP spike sorting. We applied EMUsort to high-resolution intramuscular recordings from rat forelimb during locomotion and monkey forelimb during a reaching task. EMUsort improves upon prior methods by addressing key challenges encountered with MUAP datasets, including: 1) long time delays across electrodes due to propagation along muscle fibers, 2) more complex waveform shapes compared to neuronal action potentials, and 3) a high degree of MUAP overlap due to cumulative motor unit recruitment. We compared EMUsort to existing spike sorting methods quantitatively using simulated datasets that closely emulated the rat and monkey datasets we recorded. EMUsort provided median error rate reductions of 67.5% and 49.9% during periods of high motor unit activation for the rat and monkey datasets, respectively. In sum, EMUsort provides a substantial improvement to MUAP spike sorter accuracy, especially during regions of high MUAP overlap, in an easy-to-use software package.

neuroscience↗

bioRxiv2025

High-content imaging reveals the ability of microexons to shape protein localisation

Alternative splicing provides a pervasive means to expand proteome complexity, yet how it reorganises protein interactions and constrains where proteins act within cell remains unclear. By constructing an interface-resolved interaction network composed of 17,660 experimentally defined contact sites, we reveal that tissue-specific alternative splicing remodels protein connectivity by reshaping modular protein architecture. Longer exons reshape local interaction patterns whereas microexons fine-tune key interfaces linking distinct cellular processes. Integration of subcellular localisation data further indicates that such rewiring can redistribute proteins within cells. To test this, we developed a high-content imaging approach to systematically evaluate the influence of individual exons on protein localisation and screened a targeted library of protein isoforms differing in individual exons. 38% of the tested isoform pairs altered localisation, with microexons, although typically shorter than five amino acids, accounting for a substantial proportion of these effects. Bioinformatic and structural analyses identified that microexons can extend secondary structural regions and reposition charged residues, suggesting a potential to modulate local electrostatic environments. Consistent with this, biochemical analysis of a four-amino acid microexon in sorting nexin 2 - identified through our screen - confirmed that residue insertion, rather than side chain chemistry, was driving differences in protein localisation through repositioning of a flanking, charged residue. Together, these findings describe a principle by which alternative splicing fine-tunes interface architecture to coordinate protein assembly, localisation, and proteome organisation.

molecular biology↗

bioRxiv2023

Immune memory shapes human polyclonal antibody responses to H2N2 vaccination

Influenza A virus subtype H2N2, which caused the 1957 influenza pandemic, remains a global threat. A recent phase I clinical trial investigating a ferritin nanoparticle displaying H2 hemagglutinin in H2-naive and H2-exposed adults. Therefore, we could perform comprehensive structural and biochemical characterization of immune memory on the breadth and diversity of the polyclonal serum antibody response elicited after H2 vaccination. We temporally map the epitopes targeted by serum antibodies after first and second vaccinations and show previous H2 exposure results in higher responses to the variable head domain of hemagglutinin while initial responses in H2-naive participants are dominated by antibodies targeting conserved epitopes. We use cryo-EM and monoclonal B cell isolation to describe the molecular details of cross-reactive antibodies targeting conserved epitopes on the hemagglutinin head including the receptor binding site and a new site of vulnerability deemed the medial junction. Our findings accentuate the impact of pre-existing influenza exposure on serum antibody responses. HighlightsO_LISerum Abs after first H2-F vaccination in H2-exposed donors bound variable HA head epitopes C_LIO_LISerum Abs after first H2-F vaccination in H2-naive donors bound conserved HA head and stem epitopes C_LIO_LIRBS-targeting VH1-69 cross-reactive antibodies were induced in H2-naive individuals C_LIO_LIThe medial junction is a previously uncharacterized conserved epitope on the HA head C_LI

immunology↗

bioRxiv2022

A baseline for the genetic stock identification of Atlantic herring, Clupea harengus, in ICES Divisions 6.a, 7.b-c

Atlantic herring in ICES Divisions 6.a, 7.b-c comprises at least three populations, distinguished by temporal and spatial differences in spawning, which have until recently been managed as two stocks defined by geographic delineators. Outside of spawning the populations form mixed aggregations, which are the subject of acoustic surveys. The inability to distinguish the populations has prevented the development of separate survey indices and separate stock assessments. A panel of 45 SNPs, derived from whole genome sequencing, were used to genotype 3,480 baseline spawning samples (2014-2021). A temporally stable baseline comprising 2,316 herring from populations known to inhabit Division 6.a was used to develop a genetic assignment method, with a self-assignment accuracy >90%. The long-term temporal stability of the assignment model was validated by assigning archive (2003-2004) baseline samples (270 individuals) with a high level of accuracy. Assignment of non-baseline samples (1,514 individuals) from Division 6.a, 7.b-c indicated previously unrecognised levels of mixing of populations outside of the spawning season. The genetic markers and assignment models presented constitute a toolbox that can be used for the assignment of herring caught in mixed survey and commercial catches in Division 6.a into their population of origin with a high level of accuracy.

zoology↗

bioRxiv2022

Convergent epitope specificities, V gene usage and public clones elicited by primary exposure to SARS-CoV-2 variants

An important consequence of infection with a SARS-CoV-2 variant is protective humoral immunity against other variants. The basis for such cross-protection at the molecular level is incompletely understood. Here we characterized the repertoire and epitope specificity of antibodies elicited by Beta, Gamma and ancestral variant infection and assessed their cross-reactivity to these and the more recent Delta and Omicron variants. We developed a high-throughput approach to obtain immunoglobulin sequences and produce monoclonal antibodies for functional assessment from single B cells. Infection with any variant elicited similar cross-binding antibody responses exhibiting a remarkably conserved hierarchy of epitope immunodominance. Furthermore, convergent V gene usage and similar public B cell clones were elicited regardless of infecting variant. These convergent responses despite antigenic variation may represent a general immunological principle that accounts for the continued efficacy of vaccines based on a single ancestral variant.

immunology↗

bioRxiv2021

A mechanistic investigation of enhanced nitrogen use efficiency in wheat seedlings after treatment with a precision engineered Ascophyllum nodosum biostimulant

Reduction in the emissions of the greenhouse gas nitrous oxide and nitrogen (N) pollution of ground water by improving nitrogen use efficiency (NUE) in crops is urgently required in pursuit of a sustainable agricultural future. Utilising an engineered biostimulant (PSI-362) derived from the brown seaweed Ascophyllum nodosum, we examined its effect on wheat seedling growth dynamics and mechanistic spatiotemporal changes at transcriptional and biochemical levels in relation to N uptake, assimilation and NUE. PSI-362-mediated biomass increase was associated with increased nitrate uptake and N assimilation in the form of glutamate, glutamine, free amino acids, soluble proteins and total chlorophyll. Phenotypical and biochemical analysis were supported by evaluation of differential expression of genetic markers involved in nitrate perception and transport (TaNRT1.1/NPF6.3), and assimilation (TaNR1 and TaNiR1, TaGDH2, TaGoGAT, TaGS1). Finally, a comparative analysis of the PSI-362 and two generic Ascophyllum nodosum extracts (ANEs) demonstrated that the NUE effect greatly differs depending on the ANE biostimulant used. In the current context of climate warming the transition of agriculture to a more sustainable model is urgently required. Application and adoption of precision biostimulants creates an opportunity for sustainable crop management, reduced production cost and environmental pollution, while maintaining yields.

plant biology↗

bioRxiv2021

Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates

Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 {micro}g of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.{beta} (heterologous), which encompasses the spike sequence of the B.1.351 (beta or {beta}) variant. Reciprocal ID50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the {beta} variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost {beta}-specific reciprocal ID50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the {beta} variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations. One-sentence summarymRNA-1273 boosted nonhuman primates have increased immune responses and are protected against SARS-CoV-2 beta infection.

immunology↗

bioRxiv2021

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates

BackgroundVaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. MethodsNonhuman primates received 30 or 100 {micro}g of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 {micro}g at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. ResultsEight weeks post-boost, 100 {micro}g x2 of mRNA-1273 induced reciprocal ID50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 {micro}g x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 {micro}g. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 {micro}g x2 of mRNA-1273, and there was a [~]2-log reduction in sgRNA in NHP that received two doses of 30 {micro}g compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 {micro}g x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. ConclusionsImmunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

immunology↗

bioRxiv2021

Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. The nonhuman primate (NHP) model of SARS-CoV-2 infection replicates key features of human infection and may be used to define immune correlates of protection following vaccination. Here, NHP received either no vaccine or doses ranging from 0.3 - 100 g of mRNA-1273, a mRNA vaccine encoding the prefusion-stabilized SARS-CoV-2 spike (S-2P) protein encapsulated in a lipid nanoparticle. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs following SARS-CoV-2 challenge in vaccinated animals and was most strongly correlated with levels of anti-S antibody binding and neutralizing activity. Consistent with antibodies being a correlate of protection, passive transfer of vaccine-induced IgG to naive hamsters was sufficient to mediate protection. Taken together, these data show that mRNA-1273 vaccine-induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP. One-Sentence SummarymRNA-1273 vaccine-induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP.

immunology↗

bioRxiv2021

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic. Safe and effective COVID-19 vaccines are now available, including mRNA-1273, which has shown 94% efficacy in prevention of symptomatic COVID-19 disease. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several variants have shown decreased susceptibility to neutralization by vaccine-induced immunity, most notably B.1.351 (Beta), although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of 2 updated mRNA vaccines designed to target SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the spike protein found in B.1.351 and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against B.1.351, while mRNA-1273.211 was effective at providing broad cross-variant neutralization. A third (booster) dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are being evaluated in pre-clinical challenge and clinical studies.

microbiology↗

bioRxiv2021

Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. Pseudovirus and live virus neutralizing IC50 titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3x106 PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.

immunology↗