Biology subjects

McCann, K.

Publications and source records attributed to McCann, K..

11 recordsLinked to original sources

bioRxiv2026

Identification of pre-existing ubiquitous neoantigen-reactive tumor-infiltrating T-cells in a patient with metastatic pancreatic neuroendocrine tumor

BackgroundMutation-derived neoantigens, typically identified in primary tumors, are emerging therapeutic targets for personalized cancer vaccines and adoptive T-cell therapies. However, clinical efficacy of neoantigen-directed therapies in patients with metastatic disease remains limited, partly due to inter-site genetic heterogeneity. We investigated whether ubiquitous neoantigens-derived from mutations shared across all tumor sites-could provide more effective, durable targets, particularly in patients undergoing resection of metastatic lesions. MethodsWhole-exome and RNA sequencing were performed on 14 tumor samples (primary and 13 synchronous nodal metastases) from a treatment-naive patient with pancreatic neuroendocrine tumor (PNET). Ubiquitous mutations were identified bioinformatically, and their immunogenicity assessed using in-vitro stimulation of autologous peripheral blood mononuclear cells followed by IFN-{gamma} ELISpot assay. Neoantigen-specific T-cell clonotypes were further identified by HLA-tetramer staining and single-cell RNA/TCR sequencing. Neoantigen-reactive clonotypes identified in peripheral blood were tracked across multiple metastatic sites using bulk TCR{beta} repertoire sequencing. ResultsAmong 1,195 non-synonymous mutations detected, eight were shared across all 14 tumor sites. Of these, one encoded a neoantigen that elicited a reproducible IFN-{gamma} ELISpot response in peripheral blood, confirming its immunogenicity. Further, we identified the corresponding neoantigen-reactive TCR clonotypes in blood. Comparison with bulk TCR{beta} repertoires from eight metastatic sites showed that these clonotypes were present in every site analyzed, with evidence of local clonal expansion. ConclusionThis study provides direct evidence that a single ubiquitous mutation-derived neoantigen can generate systemic T-cell responses and clonotype expansion across multiple metastatic sites in a TMB-low, TIL-low tumor. Our findings support incorporating mutation-sharing status across metastases as a key criterion for neoantigen selection in cancer vaccines and adoptive T-cell therapies. This approach could inform the design of neoantigen-directed immunotherapies in metastatic PNET and potentially other metastatic solid tumors. What is already known on this topicNeoantigen-directed therapies, such as personalized cancer vaccines or adoptive T-cell transfer, can induce anti-tumor responses but have shown limited success in metastatic disease. One major barrier is genetic heterogeneity between tumor sites, suggesting that targeting ubiquitous mutations-those shared across all tumor sites-may improve the efficacy of such therapies. What this study addsIn one patient with metastatic pancreatic neuroendocrine tumor involving 13 lymph nodes, we identified eight ubiquitous mutations, one of which generated a detectable neoantigen-specific T-cell response in blood. The corresponding T-cell clonotypes were found across all metastatic sites analyzed and showed evidence of clonal expansion, providing direct evidence of systemic and local recognition of a shared neoantigen in a TMB-low/TIL-low cancer. How this study might affect research, practice or policyThese findings support incorporating mutation sharing across metastases as a key criterion in neoantigen selection for cancer vaccines and adoptive T-cell therapies. This strategy could enhance the relevance and durability of neoantigen- directed approaches in patients with metastatic disease.

immunology↗

bioRxiv2026

Activity Patterns Structure Food Web Interactions Through Time

Many mobile animals move to locate and consume resources, making energy gain and growth dependent on activity. Yet the role of activity in shaping predator-prey interactions in food webs has not been broadly considered. Here, we synthesize empirical examples to examine how three activity traits (mean, variance, and timing) vary among taxa (fish, mammals, birds) and between predators and prey across temporal scales. We then use predator-prey models to explore how these diverse activity patterns influence stability. Motivated by emerging activity patterns, our theory shows that fluctuating activity rates can drive predator-prey interaction strengths with major consequences for stability. Future research is needed on activity trait patterning, links between activity and attack rates, and the consequences of activity for predator-prey interactions to whole food webs. This is especially critical as human-driven changes to abiotic cues increasingly alter animal activity rates and may rewire food webs.

animal behavior and cognition↗

bioRxiv2026

Nuclear tau aggregates inhibit RNA export and form by secondary seeding from cytosolic tau aggregates.

Tau aggregates contribute to multiple neurodegenerative diseases including frontotemporal dementia and Alzheimers disease (AD). In models of tauopathy and in patient tissue, tau aggregates can form in the cytoplasm, perinuclear region, and nucleus. Using a HEK293T tau biosensor system, we identified that cytoplasmic tau aggregates formed first, followed by perinuclear-ring-like tau assemblies, and then nuclear tau aggregates formed in nuclear speckles. Nuclear tau aggregates only form in cells with pre-existing cytoplasmic tau aggregates and mostly form independently of cells traversing mitosis. Finally, nuclear tau aggregates do not contain exogenous tau seeds and arise by a secondary seeding event dependent on VCP. Nuclear tau aggregates inhibit mRNA export and show a twofold increase in poly-adenylated mRNAs in the nucleus. Together, these findings indicate that nuclear tau aggregation alters RNA biogenesis and occurs by a secondary seeding event from cytoplasmic tau aggregates, which could contribute to tau pathology.

neuroscience↗

bioRxiv2025

Transient dynamics and counterintuitive competitive performance in periodic environments

Despite the rapid pace of global change altering temporal environmental patterning, we lack a general understanding of how periodic environments structure ecological communities. In fluctuating environments, nonlinear dynamics associated with temporal trade-offs between competing species can create the potential for both niche differentiation (coexistence) and seemingly unexpected outcomes (exclusion) that deviate from deterministic coexistence theory. Yet, the mechanisms behind these outcomes are not fully understood. Here, we show that periodic fluctuations between times of high and low growth (e.g., seasons), and adaptive temporal trade-offs within and between species, can drive counterintuitive over- and under-performance of competing species. Most notable is the counterintuitive outcome of seasonally-mediated competitive exclusion that would not occur in either season alone, but is rather the direct result of environmental variability itself. We find that seasonal trade-offs in species growth rates, seasonal differences in competition strength, and functional similarity between competing species have the potential to drive nonlinear responses in coexistence to changing seasonality under global change. These biological conditions collectively influence our models transient dynamics, further explaining the mechanisms behind counterintuitive outcomes and highlighting the importance of non-equilibrium theory for global change ecology. Importantly, the seasonal patterns and species trade-offs that magnify these results are biologically realistic, therefore providing important insight into the implications for the maintenance of biodiversity under global change.

ecology↗

bioRxiv2025

Deconvolution of the on-target activity of plasmepsin V peptidomimetics in P. falciparum parasites

Plasmepsin V (PMV), an essential aspartyl protease, plays a critical role during the asexual blood stage of infection of Plasmodium by enabling the export of parasite proteins into the host red blood cell. This export is vital for parasite survival and pathogenesis, making PMV an attractive target for antimalarial drug development. Peptidomimetic inhibitors designed to mimic the natural substrate of PMV have demonstrated potent parasite-killing activity by blocking protein export. While these compounds have been instrumental in validating PMV as a bona fide antimalarial target, inconsistencies between their biochemical potency and cellular activity have raised questions regarding their precise mechanism of action. In this study, we employed chemoproteomic approaches, including solvent induced protein precipitation (SIP) and intact-cell thermal PISA profiling, to demonstrate PMV target engagement by the peptidomimetics. To further support these findings, we generated parasite lines exhibiting reduced sensitivity to peptidomimetics. Through whole-genome sequencing of these parasite lines, a single nucleotide variant (SNV) within the pmv gene was revealed. This mutation was later validated using reverse genetics, confirming its role in mediating resistance. Together, these data provide strong evidence that the peptidomimetics exert their antimalarial activity by directly targeting PMV. These findings further support the potential of PMV as a validated and promising target for future antimalarial drug development.

cell biology↗

bioRxiv2025

Polyserine-tau interactions modulate tau fibrilization

Tau aggregates are the defining feature of multiple neurodegenerative diseases and contribute to the pathology of disease. However, the molecules affecting tau aggregation in cells are unclear. We previously determined that polyserine-rich domain containing proteins enrich in tau aggregates, assemble into puncta that can serve as sites of tau aggregation, and exacerbate tau aggregation in cells and mice. Herein, we show that polyserine domains are sufficient to define assemblies as sites of tau aggregation, in part, through localization of tau seeds. Purified polyserine self-assembles and directly interacts with monomeric and fibrillar tau. Moreover, polyserine-tau assemblies recruit RNA, leading to faster rates of tau fibrillization in vitro. Using polyserine variants, we found that enrichment in tau aggregates and stimulation of tau aggregation are separable functions of polyserine domains, with polyserine self-assembly stimulating tau aggregation. Together, our results show that polyserine self-assembles and directly interacts with tau to form preferred sites of tau aggregation.

biochemistry↗

bioRxiv2023

A pyridyl-furan series developed from Open Global Health Library blocks red blood cell invasion and protein trafficking in Plasmodium falciparum through potential inhibition of the parasites PI4KIIIb enzyme.

With resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250, was prioritised for further optimisation. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasites life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB which clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies which showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.

microbiology↗

bioRxiv2023

Coexistence in Periodic Environments

Climate change and other anthropogenic impacts are rapidly altering natural environmental periodicities on a variety of time scales. Despite this, a general theoretical foundation describing the role of periodic environmental variation in structuring species interactions and ecological communities is still underdeveloped. Alarmingly, this leaves us unprepared to understand and predict implications for the maintenance of biodiversity under global change. Here, we extend a two-species Lotka-Volterra competition model that incorporates periodic forcing between seasons of high and low production to investigate the effects of changing environmental patterns on species coexistence. Towards this, we define coexistence criteria for periodic environments by approximating isocline solutions akin to classical coexistence outcomes. This analytical approach illustrates that periodic environments (i.e., seasonality) in and of themselves can mediate different competitive outcomes, and these patterns are general across varying time scales. Importantly, species coexistence may be incredibly sensitive to changes in these abiotic periods, suggesting that climate change has the potential to drastically impact the maintenance of biodiversity in the future.

ecology↗

bioRxiv2020

Subsidy Accessibility Drives Asymmetric Food Web Responses

Global change is fundamentally altering flows of natural and anthropogenic subsidies across space and time. After a pointed call for research on subsidies in the 1990s, an industry of empirical work has documented the ubiquitous role subsidies play in ecosystem structure, stability and function. Here, we argue that physical constraints (e.g., water temperature) and species traits can govern a species accessibility to resource subsidies, and that these physical constraints have been largely overlooked in the subsidy literature. We examined the input of a high quality, point-source anthropogenic subsidy into a recipient freshwater lake food web (i.e., released net-pen aquaculture feed in Parry Sound, Lake Huron), to demonstrate the importance of subsidy accessibility in governing recipient whole food web responses. By using a combined bio-tracer approach, we detect a gradient in accessibility of the anthropogenic subsidy within the surrounding food web driven by the thermal tolerances of three constituent species. This thermally-driven accessibility gradient drives asymmetrical changes in food web structure, effectively rewiring the recipient lake food web and altering patterns in secondary production with yet unknown stability consequences. Since aquaculture is predicted to increase significantly in coming decades to support growing human populations, and global change is altering temperature regimes, then this form of food web alteration may be expected to occur frequently. We argue that subsidy accessibility is a key characteristic of recipient food web interactions that must be considered when trying to understand the impacts of subsidies on ecosystem stability and function under continued global change.

ecology↗

bioRxiv2020

Ecosystem Entanglement and the Propagation of Nutrient-Driven Instability

Almost 50 years ago, Michael Rosenzweig pointed out that nutrient addition can destabilize food webs, leading to loss of species and reduced ecosystem function through the paradox of enrichment. Around the same time, David Tilman demonstrated that increased nutrient loading would also be expected to cause competitive exclusion leading to deleterious changes in food web diversity. While both concepts have greatly illuminated general diversity-stability theory, we currently lack a coherent framework to predict how nutrients influence food web stability across a landscape. This is a vitally important gap in our understanding, given mounting evidence of serious ecological disruption arising from anthropogenic displacement of resources and organisms. Here, we combine contemporary theory on food webs and meta-ecosystems to show that nutrient additions are indeed expected to drive loss in stability and function in human-impacted regions. However, this loss in stability occurs not just from wild oscillations in population abundance, but more frequently from the complete loss of an equilibrium due to edible plant species being competitively excluded. In highly modified landscapes, spatial nutrient transport theory suggests that such instabilities can be amplified over vast distances from the sites of nutrient addition. Consistent with this theoretical synthesis, the empirical frequency of these distant propagating ecosystem imbalances appears to be growing. This synthesis of theory and empirical data suggests that human modification of the Earths ecological connectivity is "entangling" once distantly separated ecosystems, causing rapid, expansive, and costly nutrient-driven instabilities over vast areas of the planet. The corollary to this spatial nutrient theory, though -- akin to weak interaction theory from food web networks -- is that slow spatial nutrient pathways can be potent stabilizers by moderating flows across a landscape.

ecology↗

bioRxiv2019

Winter in water: Differential responses and the maintenance of biodiversity

The ecological consequences of winter in freshwater systems are an understudied but rapidly emerging research area. Here, we argue that winter periods of reduced temperature and light (and potentially oxygen and resources) could play an underappreciated role in mediating the coexistence of species. This may be especially true for temperate and subarctic lakes, where seasonal changes in the thermal environment might fundamentally structure species interactions. With climate change already shortening ice-covered periods on temperate and polar lakes, consideration of how winter conditions shape biotic interactions is urgently needed. Using freshwater fishes in northern temperate lakes as a case study, we demonstrate how physiological trait differences (e.g., thermal preference, light sensitivity) drive differential behavioral responses to winter among competing species. Specifically, some species have a higher capacity for winter activity than others. Existing and new theory is presented to argue that such differential responses to winter can promote species coexistence. Importantly, if winter is a driver of niche differences that weaken competition between relative to within species, then shrinking winter periods could threaten coexistence by tipping the scales in favor of certain sets of species over others.

ecology↗