Biology subjects

Stevens, G.

Publications and source records attributed to Stevens, G..

5 recordsLinked to original sources

bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗

bioRxiv2026

Genetic Identification of Dopamine Neurons Required for Circadian Food Anticipatory Activity in Mice

Anticipating daily food availability is a conserved circadian behavior that persists even in animals lacking the suprachiasmatic nucleus, yet its neural substrates remain poorly defined. Previous studies implicated dopamine signaling in food anticipatory activity (FAA) but lacked the resolution to identify the responsible neuronal population. Here, we conditionally deleted tyrosine hydroxylase (Th) from molecularly defined dopamine neuron populations in mice. Broad deletion of Th in dopamine transporter-expressing neurons nearly abolished FAA, whereas restoration of Th in substantia nigra dopamine neurons rescued anticipatory locomotion. Surprisingly, deletion of Th from several large dopamine neuron populations had little effect on FAA. In contrast, deletion using Calb1Cre, targeting only [~]25% of substantia nigra dopamine neurons, produced a profound FAA deficit. Notably, these mice exhibited a profound loss of anticipatory locomotion while retaining substantial anticipatory food-seeking behavior. These findings identify a small Calbindin1+ dopamine population required for anticipatory locomotion and demonstrate that distinct behavioral components of food anticipation can be genetically dissociated.

neuroscience↗

bioRxiv2021

ToxoNet: A high confidence map of protein-protein interactions in Toxoplasma gondii reveals novel virulence factors implicated in host cell invasion

The apicomplexan intracellular parasite Toxoplasma gondii is a major food borne pathogen with significant impact in children and during pregnancy. The majority of the T. gondii proteome remains uncharacterized and the organization of proteins into complexes is unclear. To overcome this knowledge gap, we utilize a biochemical fractionation strategy coupled with mass spectrometry to predict interactions by correlation profiling. Key to this approach is the integration of additional datasets based on gene co-expression as well as phylogenetic profiles that eliminate poorly supported interactions and reduce the number of false positive interactions. In addition to a supervised machine learning strategy, we employed an unsupervised approach in data integration, based on similarity network fusion, to overcome the deficit of high-quality training data in non-model organisms. The resulting high confidence network, we term ToxoNet, comprises 2,063 interactions connecting 652 proteins. Clustering of this network identifies 93 protein complexes, predicting both novel complexes as well as new components for previously known complexes. In particular, we identified clusters enriched in mitochondrial machinery that include previously uncharacterized proteins that likely represent novel adaptations to oxidative phosphorylation. Furthermore, complexes enriched in proteins localized to secretory organelles and the inner membrane complex, predict additional novel components representing novel targets for detailed functional characterization. We present ToxoNet as a publicly available resource with the expectation that it will help drive future hypotheses within the research community.

microbiology↗

bioRxiv2020

Dynamic regulation of hierarchical heterogeneity in Acute Myeloid Leukemia serves as a tumor immunoevasion mechanism

Acute Myeloid Leukemia, a hematological malignancy with poor clinical outcome, is composed of hierarchically heterogeneous cells. We examine the contribution of this heterogeneity to disease progression in the context of anti-tumor immune responses and investigate whether these responses regulate the balance between stemness and differentiation in AML. Combining phenotypic analysis with proliferation dynamics and fate-mapping of AML cells in a murine AML model, we demonstrate the presence of a terminally differentiated, chemoresistant population expressing high levels of PDL1. We show that PDL1 upregulation in AML cells, following exposure to IFN{gamma} from activated T cells, is coupled with AML differentiation and the dynamic balance between proliferation, versus differentiation and immunosuppression, facilitates disease progression in the presence of immune responses. This microenvironment-responsive hierarchical heterogeneity in AML may be key in facilitating disease growth at the population level at multiple stages of disease, including following bone marrow transplantation and immunotherapy.

cancer biology↗

bioRxiv2018

Phylogenomics and species delimitation of mobulid rays reveals cryptic diversity and a new species of manta ray

Practical biodiversity conservation relies on delineation of biologically meaningful units, particularly with respect to global conventions and regulatory frameworks. Traditional approaches have typically relied on morphological observation, resulting in artificially broad delineations and non-optimal species units for conservation. More recently, species delimitation methods have been revolutionised with High-Throughput Sequencing approaches, allowing study of diversity within species radiations using genome-wide data. The highly mobile elasmobranchs, manta and devil rays (Mobula spp.), are threatened globally by targeted and bycatch fishing pressures resulting in recent protection under several global conventions. However, a lack of global data, morphological similarities, a succession of recent taxonomic changes and ineffectual traceability measures combine to impede development and implementation of a coherent and enforceable conservation strategy. Here, we generate genome-wide Single Nucleotide Polymorphism (SNP) data from among the most globally and taxonomically representative set of mobulid tissues. The resulting phylogeny and delimitation of species units represents the most comprehensive assessment of mobulid diversity with molecular data to date. We find a mismatch between current species classifications, and optimal species units for effective conservation. Specifically, we find robust evidence for an undescribed species of manta ray in the Gulf of Mexico and show that species recently synonymised are reproductively isolated. Further resolution is achieved at the population level, where cryptic diversity is detected in geographically distinct populations, and indicates potential for future traceability work determining regional location of catch. We estimate the optimal species tree and uncover substantial incomplete lineage sorting, where standing variation in extinct ancestral populations is identified as a driver of phylogenetic uncertainty, with further conservation implications. Our study provides a framework for molecular genetic species delimitation that is relevant to wide-ranging taxa of conservation concern, and highlights the potential for genomic data to support effective management, conservation and law enforcement strategies.

genomics↗