Biology subjects

James, E.

Publications and source records attributed to James, E..

11 recordsLinked to original sources

bioRxiv2026

Wildfire smoke delays breeding and alters reproductive outcomes in cavity-nesting songbirds

Smoke from spring boreal wildfires increasingly impacts eastern North America, exposing breeding birds to hazardous air pollution that may impact reproductive outcomes. Using data collected in 2018-2025 from 70,979 monitored nests of four widespread cavity-nesting songbirds, we found strong evidence that smoke greatly delays egg laying and can extend incubation and nestling duration. We further found that while smoke is associated with increased clutch sizes, in some species smoke exposure strongly decreases hatching or fledging success. Our results demonstrate that extreme smoke can have wide-ranging impacts on breeding birds, from altering phenology to impacting fitness. While the exact mechanisms underlying these results remain elusive, the full suite of effects suggests that modifications to adult behavior under smoky conditions is the most likely cause. As fire regimes shift, birds and other wildlife are at greater risk of exposure to toxic smoke during the breeding season, which may further exacerbate the biodiversity crisis.

ecology↗

bioRxiv2026

Morphological and functional characterization of the ptychocyte, a stingless stinging cell

Cnidocytes (stinging cells), unique to cnidarians (corals, anemones, jellyfish), have diversified into distinct types with variable forms and functions. Nematocytes, cnidocytes found in all cnidarians, are used for prey capture and defense. When triggered, a pressurized capsule inside the nematocyte releases a harpoon-like structure attached to a hollow tubule that pierces prey and delivers venom. Ptychocytes, a cnidocyte unique to tube anemones (sister to corals and sea anemones) discharge a long spineless tubule used exclusively to build the tube in which the animal lives. Given that nematocytes and ptychocytes are specialized for different functions, we hypothesized that they might respond to firing cues in different ways. To test this, we examined the morphology, function, and distribution of nematocytes and ptychocytes in the North American Tube Anemone, Ceriantheopsis americana. We determined that ptychocytes have apical sensory structures like the cones previously described on nematocytes. Surprisingly, the body wall has a dense population of multiciliated cells that appear to function in tube formation. To determine how divergent selection pressures may have affected firing dynamics, we compared the discharge kinematics of cnidocytes from C. americana and the model sea anemone, Nematostella vectensis. Both nematocytes and ptychocytes from C. americana fired slower than nematocytes from N. vectensis, suggesting the rapid discharge speed of sea anemone nematocytes resulted from modification to these cells after sea anemones and tube anemones diverged from their common ancestor. By comparing the morphology and function of different cnidocytes, we can reconstruct the steps that gave rise to cnidocyte diversity.

evolutionary biology↗

bioRxiv2026

Single-Cell Profiling Reveals Developmental Trajectories and identifies SYK and TIM3 as Targets in some T Cell Lymphomas

T cell lymphomas (TCL) are a heterogeneous collection of malignancies whose origins and pathogenesis are poorly understood and for which few efficacious therapeutic options exist. Here, we conduct single-cell transcriptomic profiling spanning eight TCL entities and describe entity-associated programmes. We predict the cell of origin for these tumours through an integrative analysis of transcriptome and T cell receptor (TCR) maturation states. By identifying tumours with TCR states ranging from the pre-TCR through non-productive and productive TCR alpha and beta chain rearrangements we shed new light on their developmental origins. Furthermore, we apply our drug2cell computational drug target predictions with drug screens using patient-derived cell models, systematically benchmarking the performance of drug2cell and validating compounds and targets. This process identifies SYK inhibitors as a therapeutic opportunity and prioritises TIM3 for immunotherapy based on combined spatial transcriptomics analysis. Overall, our data provide a resource for diagnostics and therapies for tumours of critical unmet need.

cancer biology↗

bioRxiv2025

Detergent-Triggered Membrane Remodelling Monitored via Intramembrane Fluorescence De-Quenching

Detergent-induced membrane solubilization is important for several biotechnological applications including membrane protein isolation, cell lysis and virus inactivation. The thermodynamic details of the underlying process have been previously examined, but the mechanistic details remain largely underexplored owing in part, to a lack of suitable technologies capable of assessing nanoscopic membrane disruption events. Key open questions include: how do detergents remodel the membrane structure at sub-solubilizing concentrations? And what is the sequence of morphological transitions that lead up to solubilization? Here, we introduce a single-colour assay based on the fluorescence de-quenching of membrane-integrated fluorophores as a sensitive and generalizable tool to probe nanoscale membrane remodelling events induced by detergents. We demonstrate, using fluorescence spectroscopy and time-correlated single photon counting, that the widely used detergent Triton X-100 triggers substantial morphological changes at concentrations below its critical micellar concentration. Moreover, by taking advantage of single vesicle fluorescence lifetime imaging and scanning electron microscopy, we reveal that the swelling step involves a morphological transition from spherical vesicles to toroidal structures, providing direct evidence for detergent-driven membrane reorganization prior to solubilization. Our findings support and refine a multistep model of detergent-induced membrane solubilization, positioning fluorescence de-quenching as a tool for detecting conformational intermediates. We show that the fluorescence de-quenching approach performs robustly across multiple cyanine-based probes and experimental conditions and its nanoscale sensitivity provides a platform from which to interrogate membrane perturbations induced by a wide variety of molecular disruptors, including those with important biomedical significance.

biophysics↗

bioRxiv2024

Stochasticity in dietary restriction-mediated lifespan outcomes in Drosophila

Dietary restriction (DR) is widely considered to be one of the most potent approaches to extend healthy lifespan across various species, yet it has become increasingly apparent that DR-mediated longevity is influenced by biological and non-biological factors. We propose that current priorities in the field should include understanding the relative contributions of these factors to elucidate the mechanisms underlying the beneficial effects of DR. Our work conducted in two laboratories, represents an attempt to unify DR protocols in Drosophila and to investigate the stochastic effects of DR. Across 64 pairs of survival data (DR/ad libitum, or AL), we find that DR does not universally extend lifespan. Specifically, we observed that DR conferred a significant lifespan extension in only 26.7% (17/64) of pairs. Our pooled data show that the overall lifespan difference between DR and AL groups is statistically significant, but the median lifespan increase under DR (7.1%) is small. The effects of DR were overshadowed by stochastic factors and genotype. Future research efforts directed toward gaining a comprehensive understanding of DR-dependent mechanisms should focus on unraveling the interactions between genetic and environmental factors. This is essential for developing personalized healthspan-extending interventions and optimizing dietary recommendations for individual genetic profiles.

genetics↗

bioRxiv2024

FGFR2 promotes resistance to ALK tyrosine kinase inhibitors and its inhibition acts synergistically with lorlatinib in the treatment of ALK-expressing neuroblastoma

Anaplastic Lymphoma Kinase inhibitors (ALK TKIs) are approved for the treatment of ALK-positive non-small cell lung cancer (NSCLC) and are in clinical trial for ALK-aberrant high-risk neuroblastoma (NB) patients, particularly loratinib. However, resistance to ALK inhibitors can occur in patients, via the activation of bypass-signalling pathways, and there is a need to identify these mechanisms as well as drugs that inhibit them to design therapeutic approaches that prevent resistance, and to treat ALK TKI relapsed/refractory disease. Using genome-wide CRISPR-Cas9 overexpression screens, we identified and validated FGFR2 as a desensitizer to lorlatinib in aberrant ALK-expressing high-risk NB. FGFR2 and FGFR2-associated pathways are up-regulated in lorlatinib-resistant NB cells. Moreover, high-throughput screens using a library of 1,430 FDA approved drugs identified kinase inhibitors including those targeting FGFR2 as efficacious in reducing the survival of lorlatinib resistant NB cells. Hence, the FGFR pathway was investigated as a therapeutic target applying the pan-FGFR inhibitor erdafitinib or the multi-kinase inhibitor ponatinib, resulting in reduced survival of lorlatinib-resitant cells in comparison to their lorlatinib-sensitive counterparts. Moreover, both FGFR inhibitors act synergistically with lorlatinib in vitro and in vivo, using patient-derived xenografts (PDXs) and genetically engineered models (GEMM) of ALK-expressing NB. FGFR2 mRNA expression also correlate with a poorer prognosis for NB patients, regardless of sub-type, suggesting that a broader range of patients may benefit from FGFR inhibitors. Overall, our data suggests that FGFR2 potentially plays roles in lorlatinib resistance in NB and that combined pharmacological inhibition of ALK and FGFR constitutes a therapeutic approach to treat high-risk NB.

cancer biology↗

bioRxiv2024

Heterozygous Eif4nif1 Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype in Women

We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The Eif4enif1 C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.1286C>G stop-gain mutation in exon 10. The hybrid offspring of CMV-Cre mice with Eif4enif1WT/flx mice were designated Eif4enif1WT/{Delta} for simplicity. A subset of female heterozygotes (Eif4enif1WT/{Delta}) had no litters. In those with litters, the final litter was earlier (5.4{+/-}2.6 vs. 10.5{+/-}0.7 months; p=0.02). Heterozygous breeding pair (Eif4enif1WT/{Delta} x Eif4enif1WT/{Delta}) litter size was 60% of WT litter size (3.9{+/-}2.0 vs. 6.5{+/-}3.0 pups/litter; p<0.001). The genotypes were 35% Eif4enif1WT/flx and 65% Eif4enif1WT/{Delta}, with no homozygotes. Homozygote embryos did not develop beyond the 4-8 cell stage. The number of follicles in ovaries from Eif4enif1WT/{Delta} mice was lower starting at the primordial (499{+/-}290 vs. 1445{+/-}381) and primary follicle stage (1069{+/-}346 vs. 1450{+/-}193) on day 10 (p<0.05). The preantral follicle number was lower starting on day 21 (213{+/-}86 vs. 522{+/-}227; p<0.01). Examination of ribosome protected mRNAs (RPR) demonstrated altered mRNA expression. The Eif4enif1 stop-gain mice replicate the POI phenotype in women. The unique mouse model provides a platform to study regulation of protein translation across oocyte and embryo development in mammals.

developmental biology↗

bioRxiv2021

The chromatin remodelling factor Chd7 protects auditory neurons and sensory hair cells from stress-induced degeneration

Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission1-4. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear5,6. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms.

developmental biology↗

bioRxiv2019

Spatial, climate, and ploidy factors drive genomic diversity and resilience in the widespread grass Themeda triandra

O_LIFragmented grassland ecosystems, and the species that shape them, are under immense pressure. Restoration and management strategies should include genetic diversity and adaptive capacity to improve success but these data are generally unavailable. Therefore, we use the foundational grass, Themeda triandra, to test how spatial, environmental, and ploidy factors shape patterns of genetic variation. C_LIO_LIWe used reduced-representation genome sequencing on 487 samples from 52 locations to answer fundamental questions about how the distribution of genomic diversity and ploidy polymorphism supports adaptation to harsher climates. We explicitly quantified isolation-by-distance (IBD), isolation-by-environment (IBE), and predicted population genomic vulnerability in 2070. C_LIO_LIWe found that a majority (54%) of the genomic variation could be attributed to IBD, while 22% of the genomic variation could be explained by four climate variables showing IBE. Results indicate that heterogeneous patterns of vulnerability across populations are due to genetic variation, multiple climate factors, and ploidy polymorphism, which lessened genomic vulnerability in the most susceptible populations. C_LIO_LIThese results indicate that restoration and management of T. triandra should incorporate knowledge of genomic diversity and ploidy polymorphisms to increase the likelihood of population persistence and restoration success in areas that will become hotter and more arid. C_LI

genomics↗

bioRxiv2018

Protective low avidity anti-tumour CD8+ T cells are selectively attenuated by regulatory T cells

Regulatory T cells (Treg) play a major role in the suppression of protective anti-tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, Tregs differentially suppress responses to two characterised CD8+ T epitopes, AH1 and GSW11, which results in an absence of detectable IFN-{gamma} producing GSW11- specific T cells in the spleen and lymph nodes of tumour challenged mice. Activation of GSW11-specific T cells correlates with protection against tumour growth. Here we show that GSW11-specific T cells are in fact induced in Treg-replete, CT26-bearing mice, where they make up the majority of tumour infiltrating CD8+ lymphocytes, but exhibit a dysfunctional exhausted phenotype. This dysfunctional phenotype is induced early in the anti-tumour response in draining lymph nodes, spleens and tumours and is significantly more pronounced in GSW11-specific T cells compared to other tumour-specific T cell responses. Depletion of Tregs prior to tumour challenge significantly reduces the induction of exhaustion in GSW11-specific T cells and correlates with altered T cell receptor (TcR) usage. Moreover, the avidity of GSW11- specific TcRs that expanded in the absence of Tregs was significantly lower compared to TcRs of cytotoxic T lymphocyte (CTL) populations that were diminished in protective anti-tumour responses. This indicates that Tregs suppress the induction of protective anti-tumour T cell responses and may signify that the induction of low avidity T cells, while being more susceptible to exhaustion are the most efficacious in tumour rejection.

immunology↗

bioRxiv2018

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis.

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed \"MHC-I-opathy\" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n=360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: OR[95% CI]=2.07[1.58-2.71], p=1.24 x 10(-7)) and rs2287987 (OR[95% CI]: =2.01 [1.51-2.67], p=1.41 x 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 x 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

genetics↗