Biology subjects

Hill, M.

Publications and source records attributed to Hill, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Fishing pressure impacts on anchovy and hake off Peru

The Peruvian anchovy (Engraulis ringens) is a small pelagic fish. It is the largest singlespecies fishery in the world and it is used mainly for the production of fishmeal and fish oil. The Peruvian hake (Merluccius gayi) is a predatory demersal fish that is valued for direct human consumption, mainly as frozen products. In this study, I compared the response of both species to certain fishing mortality scenarios using a climatological set-up of the multispecies model OSMOSE for the northern Humboldt Current System. I observed that hake landings benefit from a decreased fishing pressure. In addition, the resilience of the anchovy fishery may increase if a higher threshold for their minimum catch size was implemented. The results of this study provide insights into better management strategies that could be beneficial for the two species based on their life-strategies.

ecology↗

bioRxiv2026

WNT8B and -9B promote the survival and dissemination of dormant ovarian cancer cells

Cancer cell dormancy and the resultant resistance to conventional therapies present significant challenges for the successful treatment of high-grade serous ovarian cancer (HGSC). We used genome wide, and specialized sgRNA, libraries in CRISPR-based screens to identify critical cell survival mechanisms in dormancy and metastasis. Our findings demonstrate that low expression Wnt ligands WNT8B and WNT9B are essential for sustaining cell survival during prolonged dormant spheroid culture conditions. These Wnt ligands utilize non-canonical signaling to activate expression of stem cell genes such as ALDH1A1, CD44 and others during spheroid dormancy. The loss of WNT8B and WNT9B reduced survival of xenografted ovarian cancer cells during early dissemination of disease that extended survival. Furthermore, treatment of WNT8B/9B deficient xenografts with carboplatin demonstrated increased sensitivity that further reduced dissemination and extended survival. These findings reveal that rare Wnt ligands can possess outsized functions in cancer pathogenesis and offer new avenues for improving treatment outcomes for HGSC through their inhibition.

cancer biology↗

bioRxiv2026

PTPRJ Drives Clonal Selection in CEBPA mutated AML

Transcription factor CEBPA is mutated in 10-15% of acute myeloid leukaemia (AML), a haematopoietic malignancy with high mortality. CEBPA mutations show a distinct pattern, and most patients are biallelic, carrying both an in-frame C-terminal mutation and a frameshift N-terminal mutation on opposing alleles. Rare N-terminal germline cases have 100% penetrance to AML, all with an acquired a C-terminal mutation. This suggests a selective pressure from one CEBPA mutation to develop another. Our zebrafish models faithfully recapitulate the human disease. All biallelic mutant combinations die by 4-6 weeks of age, with pre-leukaemic haematopoietic stem cell (HSC) expansion. C-terminal and N-terminal mutants show phenotypic differences in myeloid-primed HSC and differences in the myeloid differentiation block. RNA-Seq identified differentially expressed genes in opposing vectors. We identified phosphatase receptor PTPRJ as a candidate driver of clonal selection, with knock-out of ptprja in our fish accelerating pre-leukaemic expansion of HSC in C-terminal mutants, decelerating it in N-terminal mutants. Cebpa-mutant murine cells exhibit changes in differentiation and a clonal advantage with loss of Ptprj, which perturbs key signalling pathways. Our data suggest that PTPRJ contributes to the mechanism of leukaemogenesis in CEBPA mutant AML by driving the selective pressure from each mutation to develop the other.

cancer biology↗

bioRxiv2026

The role of EPS in the selective biosorption and desorption of REEs

Rare earth elements (REEs) are critical components of green technologies, but current mining and purification methods remain environmentally unsustainable due to their high energy consumption and intensive chemical requirements. Bio-hydrometallurgical processes have the potential to concentrate and recover REEs at a circumneutral pH. Work presented here uses bacteria at neutral pH to concentrate REEs from solution and subsequently recover those REEs using sodium citrate. Shewanella oneidensis MR-1 was incubated anaerobically in a culture media solution spiked with 14 REEs and yttrium for one to six days. REE concentrations remaining in solution were then compared to REE concentrations on cell pellets. For these same timepoints, the loosely bound extracellular polymeric substance (LB-EPS) was removed from cells prior to quantifying REEs on pellets to narrow down the location of REE binding. Moreover, cell pellets collected after 5 days in REE spiked solution were subjected to a time series desorption assay using sodium citrate. Shewanella oneidensis at a starting OD600 of 0.6 adsorbed 1.18mg/g of REE after 3 days. 80% of these REEs were located in the LB-EPS. In 10 minutes, 0.5 M sodium citrate desorbed about 75% of REEs from cells and over 95% after 24 hours. This method was also applied to Alaskan coal and showed that 68-86% of REEs were desorbed form S. oneidensis. This study elucidates the REE binding location and capacity of S. oneidensis, REE removal efficiency of sodium citrate overtime, and the application of this sustainable biotechnology for REE recovery at a circumneutral pH from Alaskan coal. ImportanceRare earth elements (REEs) are essential for technologies such as electric vehicles, wind turbines, batteries, and medical devices, but current methods for obtaining them are energy-intensive and can harm the environment with acidic waste. This study demonstrates a non-acidic sustainable approach using naturally occurring bacteria to capture REEs and then recover them with a biologically derived solution. The research also identifies where these elements attach to the bacteria, providing new insight into how the process works and how it can be improved. Importantly, the method successfully recovered REEs from Alaskan coal, highlighting its potential for real-world applications. By improving our understanding of microbial methods for rare earth element recovery, this work could help reduce the environmental impacts of mining and support more sustainable, secure supplies of the critical materials needed for clean energy and other advanced technologies.

microbiology↗

bioRxiv2026

Spatial Transcriptomic Profiling Reveals Microenvironment-Dependent Immune Signatures in a Lyme Arthritis model

Lyme arthritis, a manifestation of Lyme disease, is triggered by the spirochetal bacterium Borrelia burgdorferi (Bb), which is transmitted through the bite of the Ixodes tick. Although multiple studies have been conducted on the complex host immune response in Lyme arthritis, the spatial gene expression environment in the joint tissue remains unexplored. Here, we applied spatial transcriptomics to ankle joints of C3H mice infected with Bb, profiling tissues at peak inflammation (two weeks post infection) and after antibiotics (four weeks post-infection) during inflammation resolution. Analysis revealed spatially restricted signatures: pro-inflammatory responses dominated synovial and fibroblast populations two weeks post-infection, with elevated levels of Vimentin and I-Ek gene - and Vimentin protein - expression localized to these regions. By four weeks post-infection during the inflammation resolution phase, levels of Vimentin and I-Ek related gene and protein expression were reduced. Further, we noted an increase in the CD54+ and CD106+ double-positive population in infected mice joints compared to the vehicle treated controls. Notably, fibroblasts and synoviocytes in the medial joint regions adopted immune-like phenotypes during peak inflammation, while the same cell types in the exterior humeroradial joint displayed a more infection-resilient phenotype. These spatially resolved maps demonstrate that joint microenvironments play a crucial role in pathogenesis, offering unique insights into Lyme arthritis pathology.

microbiology↗

bioRxiv2026

Asymmetric population structure in Neoparamoeba perurans and its kinetoplastid symbiont

Secondary endosymbioses typically involve photosynthetic gain-of-function, at least initially. For Neoparamoeba perurans, the agent of Amoebic Gill Disease in Atlantic salmon, the evolutionary significance of its non-photosynthetic kinetoplastid endosymbiont, Perkinsela, remains a mystery. While such endosymbionts usually mirror organellar uniparental inheritance, departures from strict vertical transmission can significantly impact holobiont evolution and the spread of traits like drug resistance. However, genomic analysis of N. perurans is hampered by continual traffic of bacteria in and out of the amoeba, limiting our understanding of its population dynamics. Here, we developed a dual-target AmpSeq panel from a draft N. perurans genome, enabling simultaneous genotyping of host and symbiont directly from xenic biological samples. Analysis of 58 North Atlantic isolates revealed a striking asymmetry in population structure: the amoeba host forms a diverse, panmictic population with low linkage disequilibrium, whereas Perkinsela exhibits lower diversity and strong clonality. While cophylogenetic analyses confirm a global signal of vertical fidelity, fine-scale genotyping reveals frequent shuffling of host-symbiont pairs. These results suggest that strict host-symbiont co-inheritance is not absolute, perhaps reflecting a system characterised by long-term vertical stability punctuated by intermittent reassortment. Ultimately, we validate AmpSeq as a robust, scalable tool for decoupling complex host-symbiont trajectories and monitoring multi-partner disease dynamics in aquaculture environments.

genomics↗

bioRxiv2026

Cellular stemness identifies high-risk ductal carcinoma in situ and offers a therapeutic interception opportunity

Ductal carcinoma in situ (DCIS) exhibits substantial heterogeneity in its risk of progression to invasive breast cancer, yet the cellular and molecular determinants of high-risk lesions remain incompletely defined. Using spatially resolved single-cell transcriptomic and epigenomic profiling of 43 patient-derived DCIS and DCIS/invasive ductal carcinoma (IDC) samples, we delineate cellular programs, spatial organization, and epigenetic regulatory mechanisms associated with invasive potential. We identify an epithelial population with stemness features within luminal hormone-responsive (LumHR) cells that progressively expands from benign tissue to DCIS and IDC, and is strongly associated with invasive progression and recurrence-linked transcriptional programs. Spatial mapping reveals discrete DCIS niches enriched for stem-like LumHR cells, characterized by elevated CEACAM6 expression and enhanced ligand-receptor interactions, including CEACAM6-EGFR signaling between epithelial and stromal compartments, including cancer-associated fibroblasts, macrophages (APOC1-positive) and perivascular cells. These niches define a microenvironmental context that supports stemness and invasive potential. Epigenomic analyses implicate FOXA1 as a key regulator of these stem-like transcriptional states. Pharmacologic disruption of FOXA1-regulatory network using LSD1 inhibition suppresses stemness-associated transcriptional programs in vitro and significantly restrains tumor growth in vivo. Collectively, these findings define high-risk DCIS as a stemness-driven disease embedded within specialized microenvironments, and identify associated regulatory networks as candidate biomarkers and therapeutic vulnerabilities.

cancer biology↗

bioRxiv2026

Comparison of immunohistochemistry methods in embryonic chicken corneal tissue

Immunohistochemistry (IHC) is widely used to assess protein expression in corneal tissue, yet staining outcomes are strongly influenced by tissue preparation methods and regional differences within the cornea. This study aimed to systematically compare three processing techniques including paraffin (wax) embedding, wax embedding with antigen retrieval (wax AR), and cryosectioning for IHC analysis in embryonic day 18 chicken corneal tissue. Markers representing key biological functions were evaluated, including progenitor activity (PAX6, P40), tissue architecture (actin), and immune surveillance (TAP1, CD68), across central and limbal regions. Cryosectioning consistently produced the most specific staining for nuclear and antigen-sensitive markers. PAX6 and P40 exhibited strong, nuclear-localized expression in the corneal epithelium only under cryo conditions, whereas wax-based methods resulted in reduced specificity and irregular signal distribution. TAP1-positive immune cells were detectable in the limbal stroma exclusively in cryosections, highlighting improved antigen preservation. In contrast, actin staining, was best preserved with wax AR, and provided superior structural clarity and expected expression patterns across corneal layers. CD68 showed minimal or inconsistent staining in corneal tissue across all methods despite positive control validation. These findings demonstrate that optimal IHC outcomes in corneal tissue are marker-dependent and influenced by preparation methods and regional tissue context. Cryosectioning is recommended for detecting nuclear and immune-related antigens, while wax AR is preferable for preserving tissue architecture. This study provides a practical framework for improving reproducibility and interpretation of corneal immunostaining in avian models. HighlightsO_LICryosectioning preserves nuclear and immunity antigens in cornea C_LIO_LIWax AR improves structural markers such as actin in corneal tissue C_LIO_LIStaining outcomes depend on marker and tissue preparation method C_LIO_LICryosectioning enables detection of limbal immune-associated cells (TAP1) C_LIO_LICD68 shows limited corneal expression despite positive control staining C_LI

developmental biology↗

bioRxiv2026

Exercise Leverages a Post-Stress Therapeutic Window in Hypothalamic CRH Neurons to Enable Recovery from Threat Sensitization

Exercise provides a range of benefits for physical and mental health. It relieves stress, yet paradoxically, it recruits the bodys stress response system. Here we show that activation of corticotropin-releasing hormone cells of the paraventricular nucleus of the hypothalamus (CRHPVN) and the endocrine arm of the stress axis is necessary, but not sufficient for the beneficial effects of exercise. Specifically, glucocorticoids act synergistically with brain-derived neurotrophic factor (BDNF) on CRHPVN cells during exercise to reverse behavioral and synaptic sensitization after stress. In the absence of exercise, optogenetic activation of the tropomyosin-related kinase B (TrkB) receptor after stress is sufficient to reverse behavioral sensitization and synaptic metaplasticity. Our findings reveal a novel, time-sensitive mechanism by which exercise alleviates the impact of acute stress.

neuroscience↗

bioRxiv2025

Stable neuronal representations to repeated stimulation underlie cognitive resilience in Alzheimer's disease pathology

While Alzheimers Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.

neuroscience↗

bioRxiv2025

Spontaneous differentiation across cell lineages of separate germ layer origin during progenitor cell-mediated regeneration of the central nervous system

During CNS regeneration, neuroepithelial-derived oligodendrocyte progenitor cells (OPCs) can cross germ-layer boundaries to generate neural-crest-derived Schwann cells (SCs). However, the underlying mechanism and disease relevance of this unique phenomenon of cellular plasticity is unclear. Here, we combine single cell genomics in rodent models of CNS injury and samples from multiple sclerosis patients to characterise OPC-derived SCs. We discover that integrin signalling and bone morphogenetic protein (BMP) activation activate a core SOX10/OLIG2 transcriptional circuit to drive OPC-to-SC differentiation. We show that OPC-derived SCs myelinate in vitro and in vivo, and unlike peripheral SCs, can integrate into astrocyte-rich territories. Together, these findings define a conserved molecular mechanism of adult plasticity, enabling the control of OPC fate choices beyond their germ layer origin for CNS repair.

neuroscience↗

bioRxiv2025

Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction

It is well documented that disruption of circadian rhythms can cause metabolic dysregulation, but the specific mechanisms involved remain unclear. Our findings demonstrate that the negative metabolic effects of environmental circadian desynchronization (ECD) are dependent upon the cannabinoid receptor 1 (CB1r). The endocannabinoid system has not previously been implicated in mediating the effects of circadian disruption. We showed that ECD induced a positive correlation between the levels of the endocannabinoids AEA and 2-AG in both plasma and liver. While global CB1r knockout protects against the metabolic effects of ECD, behavioral and physiological response to ECD was strikingly similar between WT and CB1r KO mice and could not account for their distinct metabolic outcomes. Using liver-specific CB1r KO mice, we further specified that the ECD-induced metabolic hormone disruption, but not weight gain, is mediated through liver CB1r signaling. Finally, we showed that ECD upregulated transcription of genes involved in oxidative phosphorylation in the liver of WT, but not liver-specific CB1r KO mice. In summary, ECD led to modular metabolic dysfunction through CB1r signaling in multiple tissues, with the liver playing a critical role.

physiology↗

bioRxiv2025

Imaging progenitor cell differentiation during central nervous system remyelination using an MRI gene reporter

Demyelination, the loss of the myelin sheath from around otherwise intact axons, occurs in several diseases, most notably multiple sclerosis (MS). Demyelinated axons that are not remyelinated are vulnerable to irreversible degeneration and therefore therapies that enhance remyelination have been sought. However, there remains a paucity of suitable outcome measures to assess their efficacy. Magnetic Resonance Imaging (MRI) is a non-invasive imaging modality that is used both preclinically and clinically for the assessment of anatomy and tissue function. Here we describe an MRI technique for following the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes during the spontaneous regenerative process of remyelination in vivo. OPCs were transduced in situ with a lentiviral vector expressing an organic anion transporting polypeptide (Oatp1a1) under the control of the differentiation-specific Myelin Basic Protein (MBP) promoter. Oatp1a1 mediates cell uptake of a gadolinium-based MRI contrast agent (Primovist), allowing detection of the cells in T1-weighted MR images. Uptake of the contrast agent is restricted to MBP-expressing cells, which is most highly expressed during myelin sheath formation, thereby allowing progenitor-mediated, and potentially oligodendrocyte-mediated, remyelination to be monitored non-invasively in vivo using MRI. These findings provide the foundation for the development of direct methods for assessing the efficacy of pro-remyelination therapies.

neuroscience↗

bioRxiv2025

Effects of nicotinic receptor antagonism on nicotine and THC self-administration in a model of polysubstance use

BackgroundMost substance users are polysubstance users; however, little is known about how the combined use of different drugs affects the course of substance use disorder or effectiveness of treatment. Notably, co-use of cannabis and nicotine is very common, and we previously demonstrated that nicotine enhances the self-administration of a synthetic cannabinoid receptor agonist and the primary psychoactive phytocannabinoid in cannabis, {Delta}-9-tetrahydrocannabinol (THC). MethodsHere we aimed to further investigate the patterns of nicotine and THC self-administration when available in a concurrent choice model, and to determine the effects of nicotinic acetylcholine receptor (nAchR) antagonists on nicotine-enhanced THC self-administration in male and female rats. ResultsDuring concurrent choice, nicotine availability increased THC self-administration in females without affecting THC metabolism, while THC availability decreased nicotine self-administration and preference in females relative to when nicotine and saline were concurrently available. In females, THC self-administration was reduced by the {beta}2/4 subunit-containing nAchR antagonist dihydro-beta-erythroidine (DH{beta}E) in both nicotine and saline concurrent availability groups; while nicotine self-administration was reduced in both sexes by the 7nAchR antagonist methylylcaconitine (MLA), but only in rats that had concurrent access to THC. The nonspecific nAchR antagonist mecamylamine had minimal effects in the concurrent choice model, but it prevented nicotine-induced enhancement of THC self-administration when nicotine was given prior to a single choice THC only self-administration session. ConclusionsThus, behavioral regulation of self-administration is differentially influenced by nAchR subtypes depending on the availability of other substances, which has implications for the efficacy of treatments in the context of polysubstance use. Significance StatementPolysubstance use is extremely common, but very understudied in both clinical and preclinical research. The results presented here highlight that pharmacological modulators of drug reinforcement can differ when multiple drugs are available simultaneously, highlighting the importance of investigating potential treatments for substance use disorders in the context of polysubstance use.

animal behavior and cognition↗

bioRxiv2025

CA2 neurons show abnormal responses to social stimuli in a rat model of Fragile X syndrome

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is highly comorbid with autism spectrum disorders and can cause abnormal social behaviors. The CA2 subregion of the hippocampus is essential for social memory processing and social recognition. A social interaction induces changes in CA2 neuronal firing; however, it is unknown whether these changes are impaired in FXS models. Here, we examined CA2 activity in a rat model of Fragile X Syndrome (Fmr1 knockout rats). In Fmr1 knockout rats, we observed impaired CA2 cell responses to social stimuli, despite similar social behaviors. Further, in CA2 of Fmr1 knockout rats, we found reduced expression of oxytocin receptors and impaired whole cell responses to oxytocin. Together, these results raise the possibility that abnormal CA2 activity contributes to impaired social behavior in FXS and may suggest novel treatment targets for FXS patients. Significance statementFragile X Syndrome (FXS) is a neurodevelopmental disorder that can result in abnormal social behaviors, including social avoidance. Activity in the CA2 subregion of the hippocampus is believed to support social recognition and social cognition. Yet, the extent to which the CA2 subregion of the hippocampus is affected by FXS is poorly understood. In this study, we identified specific impairments in CA2 neuronal responses to social stimuli in a rat model of FXS. Further, we provide evidence suggesting that CA2 responses to oxytocin, a neuropeptide released during social interactions, are abnormal in FXS.

neuroscience↗

bioRxiv2025

Sequence-Based Generative AI-Guided Design of Versatile Tryptophan Synthases

Enzymes offer unparalleled selectivity and sustainability for chemical synthesis, yet their widespread industrial application is often hindered by the slow and uncertain process of discovering and optimizing suitable biocatalysts. While directed evolution remains the gold standard for enzyme optimization, its success hinges on the availability of a starting enzyme with measurable activity, a persistent bottleneck for many desired functions. Designing libraries likely to contain such functional starting points remains a major challenge. In this work, we use the GenSLM protein language model (PLM) along with a series of filters to generate novel sequences of the {beta}-subunit of tryptophan synthase (TrpB) that express in Escherichia coli, are stable, and are catalytically active in the absence of a TrpA partner. Many generated TrpBs also demonstrated significant substrate promiscuity, accepting non-canonical substrates typically inaccessible to natural TrpBs. Remarkably, several outperformed both natural and laboratory-optimized TrpBs on native and non-canonical substrates. Comparative analysis of the most active and promiscuous generated TrpB and its closest natural homolog confirmed that this enhanced functional versatility does not stem from the natural enzyme, highlighting the creative potential of generative models. Our results demonstrate that the model can generate enzymes which not only preserve natural structure and function but also acquire non-natural properties, establishing PLMs as powerful tools for biocatalyst discovery and engineering, with the potential in some cases to bypass further optimization.

biochemistry↗

bioRxiv2025

Lower Bounds on the Sample Complexity of Species Tree Estimation when Substitution Rates Vary Across Loci

In this paper we analyze the effect of substitution rate heterogenity on the sample complexity of species tree estimation. We consider a model based on the multi-species coalescent (MSC), with the addition that gene trees exhibit random i.i.d. rates of substitution. Our first result is a lower bound on the number of loci needed to distinguish 2-leaf trees (i.e., pairwise distances) with high probability, when substitution rates satisfy a growth condition. In particular, we show that to distinguish two distances differing by length f with high probability, one requires O(f-2) loci, a significantly higher bound than the constant rate case. The second main result is a lower bound on the amount of data needed to reconstruct a 3-leaf species tree with high probability, when mutation rates are gamma distributed. In this case as well, we show that the number of gene trees must grow as O(f-2).

evolutionary biology↗

bioRxiv2024

A lineage-resolved multimodal single-cell atlas reveals the genomic dynamics of early C. elegans development

Multimodal single-cell profiling provides a powerful approach for unravelling the gene regulatory mechanisms that drive development, by simultaneously capturing cell-type- specific transcriptional and chromatin states. However, its inherently destructive nature hampers the ability to trace regulatory dynamics between mother and daughter cells. Taking advantage of the invariant cell lineage of Caenorhabditis elegans, we constructed a lineage- resolved single-cell multimodal map of pre-gastrulation development, which allows the tracing of chromatin and gene expression changes across cell divisions and regulatory cascades. We characterise the early dynamics of genome regulation, revealing that zygotic genome activation occurs on an accessible chromatin landscape pre-patterned both maternally and zygotically, and we identify a redundant family of transcriptional regulators that drive a transient pre-gastrulation program. Our findings demonstrate the power of a lineage-resolved atlas for dissecting the genome regulatory events of development.

genomics↗