Biology subjects

Cameron, M.

Publications and source records attributed to Cameron, M..

9 recordsLinked to original sources

bioRxiv2026

Human 3D epithelioids enable continuous long-term clonal evolution studies across multiple epithelial tissues

Modeling human epithelia in vitro remains challenging because current systems do not fully preserve the combination of architecture, heterogeneity, clonal composition, and long-term dynamics shown in vivo. While 3D approaches such as organoids and organotypic cultures capture important aspects of lineage differentiation and niche signaling, they often lose stable organization over time, limiting studies of long-lasting processes such as clonal evolution and cell competition. Here, we present human epithelioids as continuous long-term, 3D epithelial cultures efficiently derived from eight adult human epithelia, including trachea, skin, buccal mucosa, esophagus, blader, urethra, submandibular gland and endometrium. Using immunostaining, electron microscopy, single-cell RNA sequencing, functional assays and somatic mutation analyses, we deeply characterized human epithelioids and confirmed that they recapitulate native architecture and cell diversity, sustain regenerative capacity, and preserve donor-specific mutational landscapes, establishing a robust and versatile platform for longitudinal interrogation of clonal evolution, tissue dynamics and responses to clinically relevant perturbations, including radiotherapy and chemotherapy, over extended timescales.

cancer biology↗

bioRxiv2026

Balancing Stability and Flow in Hippocampal Networks via Inductive Bias and Learned Symmetry Breaking

The hippocampus must balance stable memory representations with internally generated sequential dynamics underlying replay and prediction. How hippocampal circuitry achieves both remains unclear. Here, we show that recurrent neural networks trained on prediction tasks converge to a mixed-symmetry dynamical regime, in which dominant symmetric recurrence stabilizes an attractor while a weaker antisymmetric component induces directed flow. This structure accelerates learning and supports robust replay and prediction. We further show that such symmetry breaking can arise from biologically plausible spike-timing-dependent plasticity (STDP) rules, yielding a tilted Mexican-hat connectivity profile without explicit architectural constraints. Initializing networks with CA3-like structured connectivity biases learning toward this regime, and improves optimization efficiency and performance. These results suggest that hippocampal computation reflects an interaction between biologically constrained circuit structure and task-driven learning, with partial symmetry breaking providing a low-dimensional control principle for balancing stability and flow in sequence generation. Subject Areascomputational neuroscience, systems neuroscience, neural dynamics, learning, memory

neuroscience↗

bioRxiv2025

A SARS-CoV-2 entry inhibitor trimerizes to lock the spike protein in a closed conformation

The SARS-CoV-2 spike protein binds its receptor ACE2 to initiate target-cell infection. To engage ACE2, at least one of the three receptor-binding domains (RBDs) of the spike must adopt the up orientation. Here we describe S22, a potent, bioavailable, and non-toxic inhibitor of BA.2 and all subsequent Omicron variants. Cryo-EM analyses showed that S22 assembled as a trimer in a previously uncharacterized pocket of the spike apex, stabilizing all three RBDs in the down orientation, thereby preventing ACE2 association. Binding studies, especially those using mixed S22-sensitive and -resistant spikes, imply a cooperative assembly of three S22 molecules with three RBDs, resulting in an unusually slow S22 off-rate. Consistent with its slow dissociation and favorable pharmacokinetics, S22 suppressed viral replication 100-fold in the lungs of XBB.1.5-infected mice. Thus, S22 potently inhibits Omicron entry through a distinct mechanism whereby a small compound assembles cooperatively as a trimer to stabilize spike in an inactive conformation.

microbiology↗

bioRxiv2025

Impact of Voluntary Wheel Running on Gene Expression of Histone 3 Lysine 27-Modifying Enzymes in Mouse Skeletal Muscle

Skeletal muscle is highly plastic and capable of remodelling its contractile and metabolic properties depending on physical demands. Such remodelling requires modification of chromatin structure to support transcriptional activation and suppression of gene programs. Chromatin dynamics depend, in part, on the acetylation and methylation of histone 3 lysine 27 (H3K27), which is controlled by several H3K27-specific acetyltransferases, deacetylases, methyltransferases and demethylases. Several histone post-translational modifications in muscle have been shown to be modulated by exercise. Here, we sought to examine whether major H3K27 regulators are altered by endurance training. Male and female C57BL/6J mice were provided with voluntary running wheels for 6 weeks and compared to sex-matched sedentary controls with locked running wheels. Gene expression of various slow/oxidative and fast/glycolytic skeletal muscles was then measured. We found voluntary running induced modest changes in H3K27 acetyltransferases, along with several components of the polycomb-repressive complex 2 in a muscle- and sex-specific manner. Our findings indicate that the capacity for both acetylation and methylation of H3K27 is modulated by chronic endurance exercise, suggesting that chromatin dynamics are a mechanistic component of exercise-induced muscle remodelling.

physiology↗

bioRxiv2025

CD11b Activation Reduces Myeloid Brain Infiltration and Mitigates Synucleinopathy in a Model of Parkinson's Disease

The pathology of Parkinsons disease is defined by -synuclein (-syn) aggregation into neuronal Lewy bodies, which may lead to chronic neuroinflammation and dopaminergic neurodegeneration. Misfolded -syn activates Toll-like receptor signaling in microglia, leading to downstream activation of NF-{kappa}B and subsequent release of pro-inflammatory cytokines. These cytokines recruit pro-inflammatory myeloid cells from circulation, thereby amplifying neuroinflammation. Thus, reducing microglial activation and myeloid cell infiltration has the potential to reduce neuroinflammation and PD pathology. Here, we investigated a targeted immunomodulatory strategy using LA1, a novel, small-molecule agonist of CD11b, a {beta}2 integrin receptor highly and selectively expressed on myeloid cells and microglia. CD11b has key roles in cell adhesion, migration, and phagocytosis. Previous work has demonstrated that CD11b agonism via LA1 transiently enhances integrin-mediated adhesion that limits immune cell transmigration and tissue infiltration. CD11b agonism also suppresses TLR-driven inflammatory signaling and myeloid cell activation. To evaluate its efficacy in vivo, we utilized pre-clinical Parkinsons disease model by stereotaxically delivering AAV2-SYN to induce -synuclein overexpression in the murine midbrain. Mice were treated with oral LA1 for four or eight weeks and analyzed. LA1 treatment significantly reduced microglial activation and decreased brain infiltration of peripheral immune cells, thereby attenuating -synuclein-induced neuroinflammation. These findings suggest that CD11b agonism may offer a dual-action therapeutic approach in Parkinsons disease by dampening pro-inflammatory responses by central and peripheral myeloid cells.

neuroscience↗

bioRxiv2024

MT-125 Inhibits Non-Muscle Myosin IIA and IIB, Synergizes with Oncogenic Kinase Inhibitors, and Prolongs Survival in Glioblastoma

We have identified a NMIIA and IIB-specific small molecule inhibitor, MT-125, and have studied its effects in GBM. MT-125 has high brain penetrance and retention and an excellent safety profile; blocks GBM invasion and cytokinesis, consistent with the known roles of NMII; and prolongs survival as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor significantly improves survival in orthotopic GBM models over either drug alone, and in the case of sunitinib, markedly prolongs survival in [~]40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM. HighlightsO_LIMT-125 is a highly specific small molecule inhibitor of non-muscle myosin IIA and IIB, is well-tolerated, and achieves therapeutic concentrations in the brain with systemic dosing. C_LIO_LITreating preclinical models of glioblastoma with MT-125 produces durable improvements in survival. C_LIO_LIMT-125 stimulates PDGFR- and MAPK-driven signaling in glioblastoma and increases dependency on these pathways. C_LIO_LICombining MT-125 with an FDA-approved PDGFR inhibitor in a mouse GBM model synergizes to improve median survival over either drug alone, and produces tumor free, prolonged survival in over 40% of mice. C_LI

cancer biology↗

bioRxiv2023

Identifying the core genome of the nucleus-forming bacteriophage family and characterization of Erwinia phage RAY

We recently discovered that some bacteriophages establish a nucleus-like replication compartment (phage nucleus), but the core genes that define nucleus-based phage replication and their phylogenetic distribution were unknown. By studying phages that encode the major phage nucleus protein chimallin, including previously sequenced yet uncharacterized phages, we discovered that chimallin-encoding phages share a set of 72 highly conserved genes encoded within seven distinct gene blocks. Of these, 21 core genes are unique to this group, and all but one of these unique genes encode proteins of unknown function. We propose that phages with this core genome comprise a novel viral family we term Chimalliviridae. Fluorescence microscopy and cryo-electron tomography studies of Erwinia phage vB_EamM_RAY confirm that many of the key steps of nucleus-based replication encoded in the core genome are conserved among diverse chimalliviruses, and reveal that non-core components can confer intriguing variations on this replication mechanism. For instance, unlike previously studied nucleus-forming phages, RAY doesnt degrade the host genome, and its PhuZ homolog appears to form a five-stranded filament with a lumen. This work expands our understanding of phage nucleus and PhuZ spindle diversity and function, providing a roadmap for identifying key mechanisms underlying nucleus-based phage replication.

microbiology↗

bioRxiv2021

A Promising Chemical Series of Positive Allosteric Modulators of the μ-Opioid Receptor that Enhance the Antinociceptive Efficacy of Opioids but not their Adverse Effects

Positive allosteric modulators (PAMs) of the {micro}-opioid receptor (MOR) have been proposed to exhibit therapeutic potential by maximizing the analgesic properties of clinically used opioid drugs while limiting their adverse effects or risk of overdose as a result of using lower drug doses. We herein report in vitro and in vivo characterization of two small molecules from a chemical series of MOR PAMs that exhibit: (i) MOR PAM activity and receptor subtype selectivity in vitro, (ii) a differential potentiation of the antinociceptive effect of oxycodone, morphine, and methadone in mouse models of pain that roughly correlates with in vitro activity, and (iii) a lack of potentiation of adverse effects associated with opioid administration, such as somatic withdrawal, respiratory depression, and analgesic tolerance. This series of MOR PAMs holds promise for the development of adjuncts to opioid therapy to mitigate against overdose and opioid use disorders.

neuroscience↗

bioRxiv2021

Male sex and age biases viral burden, viral shedding, and type 1 and 2 interferon responses during SARS-CoV-2 infection in ferrets

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and the elderly. Here we investigated the impact of male sex and age by infecting adult male, aged male, and adult female ferrets with SARS-CoV-2. Aged male ferrets had a decrease in temperature which was accompanied by prolonged viral replication with increased pathology in the upper respiratory tract after infection. Transcriptome analysis of the nasal turbinates and lungs indicated that female ferrets had significant increases in interferon response genes (OASL, MX1, ISG15, etc.) on day 2 post infection which was delayed in aged males. In addition, genes associated with taste and smell such as RTP1, CHGA, and CHGA1 at later time points were upregulated in males but not in females. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses.

microbiology↗