Biology subjects

Brown, R.

Publications and source records attributed to Brown, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Livestock depredation frequency is negatively associated with wolf body mass

Foraging theory predicts that behavioral decisions are state-dependent, with individuals expected to alter foraging strategies according to physiological condition. Although livestock depredation by carnivores is often attributed to seasonal changes in prey availability and livestock exposure, less attention has been given to predator state. We evaluated whether seasonal variation in wolf body mass was associated with monthly livestock depredation frequency using 17 years of monitoring data from gray wolves (Canis lupus) in Oregon, USA. Using 329 body-mass measurements from 274 wolves, we modeled age- and season-related variation in body mass and generated standardized monthly population-level predictions. Predicted body mass declined through spring and summer, reached its lowest values in late summer, and increased into winter. Monthly depredation frequency decreased as predicted population-level body mass increased; a one-standard-deviation increase in predicted mass was associated with a 36.7% decrease in expected monthly depredation frequency (95% confidence interval: 22.7-48.1% decrease). The negative association persisted across sensitivity analyses based on predicted population-level body mass. When season was modeled explicitly, the association remained negative, but uncertainty increased substantially because predicted body mass and season contained limited independent temporal information. Livestock depredations were therefore most frequent during the portion of the annual cycle when wolves were predicted to have their lowest body mass. The observed association is consistent with state-dependent foraging theory, but the available data could not determine whether body mass itself contributed to depredation frequency or whether other seasonal ecological processes drove the association. Our results identify predator state as a potentially important but understudied component of carnivore-livestock interactions. Integrating measures of predator state with established drivers of conflict, including livestock exposure, husbandry, native prey, and landscape conditions, may help determine whether predator state provides additional information for understanding and anticipating carnivore-livestock conflict.

animal behavior and cognition↗

bioRxiv2026

Parental death destabilizes wolf packs despite the benefits of larger pack size

1. Cooperative breeding is a fundamental feature of many animal family groups. However, few studies have quantified whether variation in group size meaningfully buffers social and reproductive consequences following parental death. 2. Using 17 years of data from a gray wolf (Canis lupus) population in Oregon, USA, we evaluated how parental death (the death of one or both parents) influenced pack dissolution, reproductive failure, and pup recruitment, and whether larger pack sizes mitigated these effects. 3. Across 303 pack-years, we recorded 69 parental deaths, 39 pack dissolutions, and 112 reproductive failures. Packs that experienced parental death were nearly five times more likely to dissolve (95% CI: 2.12-11.12), nearly 16 times more likely to fail reproductively (95% CI: 5.34-47.26), and recruited 66% fewer pups (95% CI: 49-78% fewer) than packs in which both parents survived. 4. Larger packs were associated with improved demographic outcomes overall, but these group-size benefits were insufficient to fully offset the elevated risks associated with parental death. 5. Our results show that numerous individuals can provide generalized pack-level demographic resilience but do not functionally replace parental roles, highlighting the importance of evaluating social structure in addition to population size. 6. By clarifying the limits of social buffering in a cooperatively breeding carnivore, this study advances understanding of how social systems respond to parental death.

animal behavior and cognition↗

bioRxiv2026

Distinct Motor Cortex Somatotopy in Experimental Alzheimers Disease

Alzheimers Disease (AD) and related dementias (AD/RDs) impact cortical motor and sensory biology whereas the precise changes to these systems, and their clinical relevance, remain under debate. We hypothesized that cortical representations of complex and simple movements are differently altered during disease progression in 5XFAD mice, a well-established model of AD. Motor cortex somatotopy was determined in 5XFAD and Wild-Type Control (WT Control) mice at 6 and 12 months (mos.) of age using long-duration intracortical microstimulation (LD-ICMS) to systematically identify cortical sites evoking complex and simple forelimb movements. At 6 mos. of age, 5XFAD mice exhibited a significant expansion of motor cortical sites representing simple movements, specifically Elbow Flexion (p=0.0004) and Wrist Flexion (p=0.024). The over-sized territory for Elbow Flexion significantly distinguished 5XFAD from WT mice (Receiver Operating Characteristic [ROC] area under the curve [AUC]= 0.94, p= 0.0009) whereas discriminative performance of Wrist Flexion was a non-significant trend (AUC=0.75, p=0.059). By 12 mos. of age, motor cortex organization was markedly reorganized in 5XFAD mice, with significantly fewer cortical sites evoking complex Advance movement (p<0.0001) as well as simple Shoulder (p=0.0001), Elbow Extension (p=0.024), and Wrist Extension (p=0.003) movements. The number of sites for simple Wrist Flexion was significantly increased (p=0.011) in 12 mo. old 5XFAD mice. At 12 mos., territory size of several of these movement zones highly distinguished 5XFAD from WT mice, including Advance (AUC= 0.96, p= 0.0005), Shoulder (AUC= 0.97, p= 0.0004), Elbow Extension (AUC=0.78, p=0.034), Wrist Extension (AUC=0.85, p= 0.0082), and Wrist Flexion (AUC=0.80, p= 0.023). These findings demonstrate progressive, age-dependent remodeling of motor cortex somatotopy in 5XFAD mice, characterized by early expansion of specific simple movement cortical sites followed by deterioration of both complex and simple motor cortical maps as disease advances. Motor cortex somatotopic remodeling may provide a sensitive biomarker of AD/RDs progression.

neuroscience↗

bioRxiv2026

A sequence variation between two orthologues alters functional expression of the potassium channel Kesv of Ectocarpus siliculosus virus

The potassium channel Kesv encoded by the Ectocarpus siliculosus virus (Kesv 1) differs by seven amino acid residues from its host-derived homolog (Kesv 2), resulting from lysogenic integration. When expressed in Xenopus laevis oocytes, Kesv 1 displayed significantly higher ion conductance and functional expression than Kesv 2, as demonstrated by GFP fluorescence and voltage clamp measurements. This study provides the first structural and functional analysis of Kesv 2, uncovering key differences between the original and host-derived variant. The systematic residue substitutions - based on location- from Kesv 2 to the corresponding residues in Kesv 1 illustrated that two amino acid exchanges in close proximity to the pore region (Q61H and T66A), albeit not individually but in combination, significantly resulted in a loss-of-function phenotype in Kesv 1. AlphaFold predictions and subsequent molecular dynamics simulations did not reveal significant differences between Kesv 1 and Kesv 2 structural models, suggesting that the loss of function cannot be attributed to differences at the structural level. Instead, a reduced surface expression of Kesv 2, caused by the sequence modulations in the brown algal host, appears more plausible. Notably, the pharmacological profiling with Linopirdine and Sotalol highlights differences in drug sensitivity, establishing these minimalist channels (core channel structure without regulatory domains) as tractable models for dissecting novel fundamental principles of ion channel function and drug interaction, while highlighting key differences from more complex channel systems. Significance StatementPotassium channels are essential for cellular excitability, yet their large size and structural complexity limit our understanding of the core features underlying channel function. Here, we identified and established an orthologous model to compare the effects of evolutionarily acquired mutations in two voltage-sensing potassium channels-the viral potassium channel from Ectocarpus siliculosus virus (Kesv 1) and its host-homolog derivative (Kesv 2) as simplified model systems for understanding ion channel physiology and host-viral interactions. We provide the first functional characterization of Kesv 2 in Xenopus laevis oocytes using two-electrode voltage-clamp and site-directed mutagenesis, revealing that, despite sharing an identical SVGYG selectivity-filter motif and differing by only 7 residues, they exhibit distinct ion-conduction properties.

pharmacology and toxicology↗

bioRxiv2026

Exposure to P. falciparum and common cold viruses shape vaccine responses in early life

Vaccine immunogenicity is consistently lower in low-income countries than in high-income settings, yet the factors driving this disparity remain incompletely understood. Using multiplexed electrochemiluminescence serology, we measured IgG and IgA responses to Expanded Program on Immunization (EPI) vaccines and common childhood viral infections in 89 Ugandan infants. We integrated detailed parasitological surveillance and maternal clinical data to examine how P. falciparum infection history, concurrent parasitemia, maternal gravidity, and early-life viral exposures shaped serological profiles. We found that infants mounted robust responses to most EPI vaccines, but critical gaps in protection persisted for diphtheria, measles and rubella. Children born to primigravid mothers had lower antibody levels at 8 weeks of age, independent of placental malaria and only partially explained by maternal age. Contrary to expectation, cumulative P. falciparum exposure was positively associated with antibody concentrations to diphtheria and varicella, and concurrent parasitemia was positively correlated with responses to multiple antigens. Seroconversion to rhinovirus C was associated with higher IgG and IgA levels to several vaccines. Together, these findings suggest that common microbial exposures during infancy, including respiratory viruses and P. falciparum may positively modulate vaccine responsiveness.

immunology↗

bioRxiv2026

Phenotype-dependent subtyping exposes high MYC activity as a targetable dependency in LuAd

C-MYC (MYC) occupies a critical nexus of oncogenic signalling and deregulated expression of MYC is widespread across most human cancer types, suggesting that MYC should be an attractive target for therapeutic intervention. Although 30-40% of human Non-Small Cell lung cancers show low level amplification of c-MYC and genetic evidence has shown that c-Myc is a key downstream effector of KRas-driven lung tumourigenesis in mouse models, the functional contribution of MYC to human lung cancer remains unclear. We applied a phenotype-based classifier to the TCGA Lung Adenocarcinoma (LuAd) cohort and found that high MYC transcriptional activity identifies a subset of LuAd with significantly reduced survival. Application of the same methodology to a panel of genetically engineered mouse models identified multiple genotypes that give rise to the high MYC activity phenotype, disease positioning such models as reflective of a distinct subset of human LuAd. We show that high MYC activity predicts sensitivity to a small molecule dual-inhibitor of the MYC co-factors, EZH2 and G9A, HKMTi-1-005, and that treatment with HKMTi-1-005 strongly reduced MYC protein expression, induced B cell-mediated immune surveillance and suppressed growth of autochthonous KRasG12D-driven lung tumours. Statement of significanceThis work establishes the principle of indirectly targeting MYC in LuAd, via inhibition of associated enzymatic cofactors, EZH2 and G9A, and identifies a large subset of aggressive human LuAd with a high MYC activity signature that may benefit from this approach.

cancer biology↗

bioRxiv2026

Sex differences in neural circuits driving binge drinking: A female-specific role for an amygdalo-striatal pathway

BackgroundRates of binge drinking have converged significantly between the sexes over recent decades, driven by increased rates of alcohol misuse in women. However, understanding of fundamental circuitry and neurobiology driving alcohol use in females, or how this may differ from male subjects remains underexplored. MethodsWe quantified c-Fos expression across 40 brain regions in alcohol naive, alcohol anticipating and binge drinking male and female mice. In vivo fiber photometry examined sex differences in basolateral amygdala (BLA) activity changes to alcohol intake. Chemogenetic BLA inhibition investigated a functional role in binge drinking. We then assessed sex differences in BLA efferent projection activation following binge drinking. Finally, we functionally interrogated the BLA to nucleus accumbens core (AcbC) projection in binge drinking. ResultsBinge drinking reduced network modularity (number of communities with similar activation patterns) in both sexes relative to alcohol naive and anticipating same-sex counterparts. Female binge drinking mice had increased BLA c-Fos expression compared to female naive and male binge drinking counterparts. In vivo fiber photometry revealed greater and more prolonged BLA responsivity at the onset of alcohol intake in females. Global BLA inhibition reduced reward intake in both sexes. However, the BLA to AcbC projection was preferentially activated in female binge drinking mice, and inhibition of this pathway reduced binge alcohol intake exclusively in females. ConclusionsWe identified sex differences in the neural circuits engaged in binge drinking, highlighting the BLA to AcbC projection may in part underpin sex differences in alcohol misuse. This provides further evidence of distinct neurobiological drivers of alcohol-related behaviors between the sexes.

neuroscience↗

bioRxiv2026

An in vivo model of Amyloid-Related Imaging Abnormalities (ARIA) predicts ARIA incidence of anti-Aβ antibodies seen in clinical trials

Amyloid-related imaging abnormality (ARIA) is the most common adverse event associated with amyloid-beta (A{beta}) immunotherapy. The neuropathology underlying active ARIA lesions has been studied in only a few rare fatal cases. A faithful translational model of ARIA should allow a better understanding of pathogenic mechanisms and enable development of mitigation strategies. Since bapineuzumab induced the most frequent and severe forms of ARIA in humans, we assessed the ability of its murine precursor, 3D6, to induce ARIA-like lesions by applying clinically-validated MRI sequences in a mouse model with extensive amyloid deposition. Using this paradigm we documented ARIA-like changes based on their imaging features, location, and temporal evolution and established postmortem histopathologic correlates. We observed that ARIA-like lesions were ubiquitously induced with 3D6, including T2-hyperintense leptomeningeal effusions, T2-hyperintense parenchymal lesions and T2* hypointense parenchymal lesions. Histological assays demonstrated meningovascular inflammation as well as vascular mural permeation and microvascular lesions, including microhemorrhages and microinfarcts. Compared to 3D6-treated mice, animals treated with mouse analogues of aducanumab and gantenerumab showed less frequent radiologic and histopathologic ARIA-like lesions with delayed onset. Our results align well with the differential incidence of ARIA observed in humans treated with different anti-A{beta} antibodies. Collectively, our studies demonstrate that: i) anti-A{beta} antibodies chronically administered to 5xFAD mice can induce MRI lesions reminiscent of human ARIA; ii) this paradigm allows identification of transient lesions other than microhemorrhages, and (iii) the incidence and severity of ARIA-like lesions induced with three clinically tested antibodies faithfully recapitulates that seen in humans. One Sentence SummaryMRI and histological correlation in a preclinical ARIA mouse model treated with anti-A{beta} antibodies that recapitulates results seen in humans.

neuroscience↗

bioRxiv2026

Localisation of corticosteroids in male mouse kidney by mass spectrometry imaging

Renal sodium balance is important for blood pressure homeostasis and is regulated by corticosteroids, chiefly aldosterone but also glucocorticoids. Abundance of these hormones in functional subregions of the kidney is unknown, previous work being limited to measurements in plasma and urine, and in microdialysate from kidney medulla. Here mass spectrometry imaging (MSI) was applied to map corticosteroids in kidney to understand how their distribution overlays with functional targets. Male C57BL6 mice, aged 10 weeks, were fed diets containing 0.03%, 0.3% or 3% w:w sodium for two weeks and kidneys harvested at cull. Steroids were localised as Girard T derivatives on cryosections using Matrix assisted laser desorption ionisation Fourier transform ion cyclotron MSI, with confirmation by liquid extraction surface analysis. Co-registration was performed on sections stained with hematoxylin and eosin. Corticosterone localised along the papilla, medulla and inner cortex, whereas 11-dehydrocorticosterone was concentrated in the medulla. Higher amounts of aldosterone were present in medulla and outer cortex. Distribution patterns were unchanged by dietary salt, but amounts of corticosterone were elevated, particularly in outer cortex with low salt diet. MSI holds great promise to dissect corticosteroid signalling in functional zones of the kidney.

biochemistry↗

bioRxiv2025

A Mechanism-Aware Dual Attention Deep Model for Molecular-Protein Binding Affinity Prediction with Enhanced Generalizability and Interpretability

Accurate prediction of molecular-protein binding affinity (MPBA) is paramount in drug discovery, yet current computational models often lack generalizability, interpretability, and explicit mechanistic understanding. To address these limitations, we introduce BindMecNet (Binding Mechanism Network), a novel mechanism-aware, multi-scale deep model. BindMec-Nets core innovation lies in its Interfacial Interaction Prediction Module, which explicitly predicts an atom-residue level interaction map, serving as a crucial mechanistic inductive bias. This map guides a Mechanism-Aware Dual Attention Interaction Module, ensuring that information exchange between protein and ligand representations is focused on genuinely interacting regions, fostering a deeper understanding of binding mechanisms. We employ a robust two-stage training strategy: initial pre-training on PDBBind with a multi-task loss (affinity and interaction prediction), followed by fine-tuning on challenging generalization datasets using predicted protein and ligand structures. Our comprehensive evaluations on unseen protein families using predicted binding conformations demonstrate BindMecNets superior performance, significantly outperforming state-of-the-art deep learning baselines. Ablation studies confirm that both the PDBBind pre-training and the explicit mechanistic inductive bias are critical for achieving this enhanced generalizability and accuracy. Furthermore, BindMecNets predicted interaction maps offer valuable, interpretable insights into binding hotspots, paving the way for more rational and mechanism-driven drug design.

bioinformatics↗

bioRxiv2025

Divergent Macrophage-Regulated T cell States Determine Response to Bacillus Calmette-Guerin (BCG) in High-Risk Bladder Cancer

The primary therapy for high-risk bladder cancer (BCa) is repeated instillations of the tuberculosis vaccine, Bacillus Calmette-Guerin (BCG). While BCG decreases the risk of recurrence by more than half, the concerted mechanisms of immune activation from BCG are unknown. Our objective was to investigate how the immune response differs between responders and non-responders to BCG therapy. We performed single-cell RNA-sequencing of isolated immune cells adjacent to high-risk bladders before and after BCG in BCG responders and non-responders. We identify an increase in Th17-like Th1 cells in BCG responders, characterized by greater expression of pro-inflammatory cytokines. Alternatively, non-responders had increased CD8+ T-cell exhaustion and T-regulatory cells. We identify that the primary mechanism of divergent T cell activity is driven by altered polarization and immunosuppressive signaling with myeloid cells. Through a machine-learning-based approach, we identified a Th17-like Th1 cytokines, such as IL17, IL21, and IL26, were predictive of a response, which were then validated in a separate BCG-treated BCa cohort. Together, this suggests that dynamic regulation of myeloid-T cell interactions can be targeted to improve BCG activity.

immunology↗

bioRxiv2025

CRISPRi Screening Identifies SON and MAP4K1 as Regulators of Type III Cytokine Expression in Innate Lymphoid Cells

The cytokines interleukin (IL)-22 and IL-17 are secreted by innate and adaptive immune cells to drive "type III" responses that protect against extracellular pathogens, promote mucosal barrier integrity, and foster microbiota homeostasis. However, dysregulation of IL-22 and/or IL-17 contributes to autoimmunity, chronic inflammation, and malignancy. Thus, a deeper understanding of mechanisms regulating type III cytokine production could provide new therapeutic targets for a spectrum of immune-mediated diseases. Toward this goal, we performed a genome-wide CRISPR inhibition (CRISPRi) screen to identify factors that regulate IL-22/IL-17 expression in a murine type III innate lymphoid cell (ILC3) model, MNK3, following stimulation with IL-23 and IL-1b. In addition to previously known regulators of type III cytokines, including IL-23 receptor components IL23R and IL12RB1, the screen identified a large set of new factors that either potentiate or attenuate expression of IL-22 and/or IL-17. A subset of these novel factors was chosen for validation, from which two were selected for further study. The nuclear protein, SON, which binds both DNA and RNA, impaired expression of IL12RB1 at the levels of de novo transcription and RNA processing. The second, MAP4K1 (HPK1), is a serine/threonine kinase that is required for IL-22 but not IL-17 expression. Depletion of MAP4K1 in MNK3 also enhanced expression of the type I cytokine, IFNg, which was co-expressed with IL-17, a phenotype reminiscent of pathogenic Th17 cells. Together, results from the CRISPRi screen broaden our understanding of the factors involved in type III immune responses and offer new targets for modulating IL-22/17 expression.

immunology↗

bioRxiv2025

Attention robustly dissociates objective performance and subjective visibility reports

Visual experience can sometimes depart from visual performance, providing a powerful lens into the mechanisms generating conscious perception. In one proposed dissociation--subjective inflation--unattended locations in the periphery appear stronger than attended ones despite equated performance. Subjective inflation has played a central role in motivating theories of consciousness that reject the sufficiency of sensory signals for conscious perception. Yet the empirical basis for subjective inflation is limited. Here, in a large-scale adversarial collaboration, we conducted four simultaneously-replicated experiments testing the strength, character, and extent of subjective inflation under inattention. We used a new analytic approach to quantify inattentional inflation over full psychometric functions, beyond single matched-performance levels. We found robust inattentional inflation for contrast-dependent and texture-based perception, at and above the visual threshold. However at suprathreshold, we found inattentional inflation for the overall stimulus but not the specific feature relevant for performance. Finally, we establish the unifying principle that inattentional inflation occurs if and only if attention reduces performance thresholds more than visibility thresholds. Thus what we think we see may regularly exceed what we can visually discriminate, placing constraints on theories of conscious perception.

neuroscience↗

bioRxiv2025

Epithelial tumor cells utilize mast cell-derived histamine to regulate perineural invasion

Cancer dissemination by perineural invasion (PNI) is associated with poor outcomes in epithelial malignancies, yet the cellular interactions critical to this process are not fully defined. Single-cell transcriptomic analysis of cutaneous squamous cell carcinoma (cSCC) with PNI highlighted KITLG-KIT signaling activation between keratinocytes and mast cells. Additionally, we observed increased expression of HRH1 on tumor cells, which encodes the H1 histamine receptor. We confirmed these changes in other cancers, including PNI-positive hepatobiliary and oral mucosal tumors. Histamine enhanced tumor invasion into nerve in organoids that recapitulate key features of PNI, an effect rescued by H1-antihistamines. Mechanistically, broad upregulation of matrix metalloproteinases (MMPs) through P38 activation underscored histamine-mediated PNI by enabling collagen degradation in the nerve sheath. Examination of multiple cancer types with PNI showed co-expression of HRH1 and MMP2 on tumor cells as well as type IV collagen loss in involved nerves. Retrospective analysis of >15,000 patient health records in two independent databases demonstrated that H1-antihistamine use improved overall survival and immunotherapy response in cancers that spread by PNI. Together, these data reveal a critical role for mast cells in PNI and present a new therapeutic strategy for targeting this process in epithelial cancers.

cancer biology↗

bioRxiv2025

300 billion years of angiosperm evolution at risk of extinction

Extinction results in not only loss of species, but also loss of the unique evolutionary history that they represent and the irreplaceable features they exhibit. There is broad consensus regarding the necessity to optimise the preservation of the tree of life by including evolutionary information in conservation prioritisation, a notion also endorsed by major policy frameworks1-4. However, evolutionarily-informed prioritisations are lacking for most plants, resulting in a taxonomic imbalance in the evolutionary information incorporated in global biodiversity analyses, which has undermined conservation for decades. Here, we use comprehensive species-level phylogenetic trees, and extinction risk estimates, to generate the first global assessment of angiosperm evolutionary history at risk, and to identify phylogenetically-informed conservation priorities for the worlds flowering plants. We estimate that more than one fifth of angiosperm evolutionary history is at risk of extinction in the short term. Using the Evolutionarily Distinct and Globally Endangered5,6 approach, we identify 9,945 threatened plant species that disproportionately account for total evolutionary history at risk. Species and area prioritisations incorporating evolutionary history are urgently needed to correct imbalances between plants and animals, monitor the effectiveness of conservation efforts, and optimise conservation resource allocation in the face of increasing human pressures on Earths biodiversity.

evolutionary biology↗

bioRxiv2025

The origin, invasion history and resistance architecture of Anopheles stephensi in Africa.

The invasion of Africa by the Asian urban malaria vector, Anopheles stephensi, endangers 126 million people across a rapidly urbanising continent where malaria is primarily a rural disease. Control of An. stephensi requires greater understanding of its origin, invasion dynamics, and mechanisms of widespread resistance to vector control insecticides. We present a genomic surveillance study of 551 An. stephensi sampled across the invasive and native ranges in Africa and Asia. Our findings support a hypothesis that an initial invasion from Asia to Djibouti seeded separate incursions to Sudan, Ethiopia, and Yemen before spreading inland, aided by favourable temperature, vegetation cover, and human transit conditions. Insecticide resistance in invasive An. stephensi is conferred by detoxification genes introduced from Asia. These findings, and a companion genomic data catalogue, will form the foundation of an evidence base for surveillance and management strategies for An. stephensi.

genomics↗

bioRxiv2024

G-quadruplex structures regulate long-range transcriptional reprogramming to promote drug resistance in ovarian cancer

Epigenetic evolution is a common mechanism used by cancer cells to evade the therapeutic effects of drug treatment. In ovarian cancers, epigenetically-driven resistance may be responsible for a large number of late-stage patient deaths. Here, we describe the first investigation into the role of G-quadruplex (G4) DNA secondary structures in mediating epigenetic regulation in drug-resistant ovarian cancer cells. Through genome-wide mapping of G4s in paired drug-sensitive and drug-resistant cell lines, we find that increased G4 formation is associated with significant increase in gene expression, with high enrichment in signalling pathways previously established to promote drug-resistant states. However, in contrast to previous studies, the expression-enhancing effects of G4s were not found at gene promoters, but intergenic and intronic regions, indicating that G4s promote long-range transcriptional regulation in drug-resistant cells. Furthermore, we discovered that clusters of G4s (super-G4s) are associated with particularly high levels of transcriptional enhancement that surpass the effects of super-enhancers, which act as well established regulatory sites in many cancers. Finally, we demonstrate that targeting G4s with small molecules results in significant down-regulation of pathways associated with drug-resistance, which results in resensitisation of resistant cells to chemotherapy agents. These findings indicate that G4 structures are critical for the epigenetic regulatory networks of drug-resistant cells and may represent a promising target to treat drug-tolerant ovarian cancer.

cancer biology↗

bioRxiv2024

Pseudomonas fluorescens 15 small RNA Pfs1 mediates transgenerational epigenetic inheritance of pathogen avoidance in C. elegans through the Ephrin receptor VAB-1

C. elegans are exposed to a variety of pathogenic and non-pathogenic bacteria species in their natural environment. Correspondingly, C. elegans has evolved an ability to discern between nutritive and infectious bacterial food sources. Here we show that C. elegans can learn to avoid the pathogenic bacteria Pseudomonas fluorescens 15 (PF15), and that this learned avoidance behavior is passed on to progeny for four generations, as we previously demonstrated for Pseudomonas aeruginosa (PA14) and Pseudomonas vranovensis, using similar mechanisms, including the involvement of both the TGF-{beta} ligand DAF-7 and Cer1 retrotransposon-encoded virus-like particles. PF15 small RNAs are both necessary and sufficient to induce this transgenerational avoidance behavior. Unlike PA14 or P. vranovensis, PF15 does not use P11, Pv1, or a small RNA with maco-1 homology for this avoidance; instead, an unrelated PF15 small RNA, Pfs1, that targets the C. elegans vab-1 Ephrin receptor gene is necessary and sufficient for learned avoidance, suggesting the evolution of yet another bacterial sRNA/C. elegans gene target pair involved in transgenerational inheritance of pathogen avoidance. As VAB-2 Ephrin receptor ligand and MACO-1 knockdown also induce PF15 avoidance, we have begun to understand the genetic pathway involved in small RNA targeted pathogenic avoidance. Moreover, these data show that axon guidance pathway genes (VAB-1 and VAB-2) have previously unknown adult roles in regulating neuronal function. C. elegans may have evolved multiple bacterial specificity-encoded small RNA-dependent mechanisms to avoid different pathogenic bacteria species, thereby providing progeny with a survival advantage in a dynamic environment.

genetics↗