Biology subjects

Whitmore, L.

Publications and source records attributed to Whitmore, L..

9 recordsLinked to original sources

bioRxiv2026

FLASH reduces radiation-induced oral mucositis in a mouse model of Fanconi anemia

Patients with Fanconi anemia (FA) are particularly susceptible to developing squamous cell carcinoma of the head and neck due to impaired DNA repair pathways. However, their hypersensitivity to DNA damaging agents can limit effective treatment with standard radiotherapy due to severe side effects and complications. In pre-clinical models, ultra-rapid FLASH radiotherapy (FLASH) reduces radiation-induced toxicity in normal tissues while maintaining similar tumor control compared to conventional dose rate radiotherapy (CONV). Here, we investigated the safety of FLASH for treatment of the head and neck in a mouse model of FA. 129/Sv wild-type (WT) and Fanca-deficient (Fanca-/-) mice received single-dose oral cavity irradiation with electron beam FLASH or CONV to evaluate radiation-induced toxicity in non-tumor-bearing mice. Fanca WT and Fanca-/- mice were irradiated with 25 and 18 Gy, respectively, of FLASH (190 Gy/sec) or CONV (0.2 Gy/sec), with tongues harvested at 12 hours (hpi) and 10 days (dpi) post-irradiation. At 10 dpi, FLASH-irradiated tongues in both genetic backgrounds demonstrated reduced ulceration at the dorsal tongue surface compared to CONV-irradiated counterparts. Histopathological analysis of the tongue revealed lower mucositis severity scores with decreased epithelial thinning and ulceration in FLASH-irradiated tongues compared to CONV-irradiated ones. Analysis of {gamma}-H2AX foci formation at 12 hpi demonstrated fewer foci in WT mice treated with FLASH compared to CONV, with a similar trend observed in Fanca-/- mice. These findings suggest a potential normal tissue-sparing effect with FLASH and hold important clinical implications for the treatment of patients with Fanconi anemia and head and neck cancers.

cancer biology↗

bioRxiv2025

Sea-ice microbial community succession and the potential role of parasitoids in the maintenance of diversity

Sea ice is a crucial, yet declining, habitat in high latitude ecosystems. Here we present a high-temporal resolution amplicon sequence data set collected during the spring ice-algal bloom near Utqia[g]vik, Alaska in 2021 to study sea-ice microbial dynamics. The ice-algal bloom peaked on May 8th, reaching 46.6 mg chlorophyll a m-2, and thereafter became limited by nitrate availability. A massive bloom of the oil-degrading bacterium, Oleispira (>80% relative abundance), coincided with the algal bloom raising questions about hydrocarbon exposure. The sea-ice algal bloom was dominated by diatoms, particularly Nitzschia spp., and transitioned into a flagellate dominated post-bloom community which aligned with melt-associated changes to the physicochemical environment. We explored the relationship between putative parasitoids, Chytridiomycetes, Thecofilosea (Cercozoa), Oomycetes, Syndiniales (Dinoflagellata), and Labyrinthulomycetes (Bigyra), and potential microalgal hosts. Chytrids peaked periodically suggesting synchronized infections and Cryothecomonas (Thecofilosea) was observed parasitizing Nitzschia spp. for the first time in Arctic sea ice. Co-occurrence analysis suggested that diatoms, especially Nitzschia, were the primary hosts of Pacific-Arctic parasitoids, and that top-down parasitoid control may dramatically alter community composition over short timescales, such as days. These results provide important insights into the drivers of spring bloom timing and maintenance of microalgal diversity in sea ice.

microbiology↗

bioRxiv2025

Computational design of dynamic biosensors for emerging synthetic opioids

Nitazenes are an emergent class of synthetic opioids that rival or exceed fentanyl in their potency. These compounds have been detected internationally in illicit drugs and are the cause of increasing numbers of hospitalizations and overdoses. New analogs are consistently released, making detection challenging - new ways of testing a wide range of nitazenes and their metabolic products are urgently needed. Here, we developed a computational protocol to redesign the plant abscisic acid receptor PYR1 to bind diverse nitazenes and maintain its dynamic transduction mechanism. The best design has a low nanomolar limit of detection in vitro against nitazene and menitazene. Deep mutational scanning yielded sensors able to recognize a range of clinically relevant nitazenes and the common metabolic byproduct in complex biological matrices with limited cross-specificity against unrelated opioids. Application of protein design tools on privileged receptors like PYR1 may yield general sensors for a wide range of applications in vitro and in vivo.

biochemistry↗

bioRxiv2024

The Human Neural Cell Atlas of Zika Infection in developing human brain tissue: viralpathogenesis, innate immunity, and lineage reprogramming

Zika virus (ZIKV) infection during pregnancy can lead to fetal brain infection and developmental anomalies collectively known as congenital Zika syndrome (CZS). To define the molecular features underlying CZS in a relevant human cell model, we evaluated ZIKV infection and neurodevelopment in primary fetal brain explants and induced pluripotent stem cell-derived mixed neural cultures at single cell resolution. We identified astrocytes as key innate immune sentinel cells detecting ZIKV and producing IFN-{beta}. In contrast, neural progenitor cells displayed impaired innate immunity and supported high levels of viral replication. ZIKV infection of neurons suppressed differentiation and synaptic signaling networks and programmed a molecular switch from neurogenesis to astrogliogenesis. We identified a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-{beta}. These findings reveal how innate immune signaling intersects with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.

immunology↗

bioRxiv2024

Dimensions of early life adversity are differentially associated with patterns of delayed and accelerated brain maturation

BackgroundDifferent types of early-life adversity have been associated with childrens brain structure and function. However, understanding the disparate influence of distinct adversity exposures on the developing brain remains a major challenge. MethodsThis study investigates the neural correlates of 10 robust dimensions of early-life adversity identified through exploratory factor analysis in a large community sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study. Brain age models were trained, validated, and tested separately on T1-weighted (T1; N = 9524), diffusion tensor (DTI; N = 8834), and resting-state functional (rs-fMRI; N = 8233) magnetic resonance imaging (MRI) data from two time points (mean age = 10.7 years, SD = 1.2, range = 8.9-13.8 years). ResultsBayesian multilevel modelling supported distinct associations between different types of early-life adversity exposures and younger- and older-looking brains. Dimensions generally related to emotional neglect, such as lack of primary and secondary caregiver support, and lack of caregiver supervision, were associated with lower brain age gaps (BAGs), i.e., younger-looking brains. In contrast, dimensions generally related to caregiver psychopathology, trauma exposure, family aggression, substance use and separation from biological parent, and socio-economic disadvantage and neighbourhood safety were associated with higher BAGs, i.e., older-looking brains. ConclusionsThe findings suggest that dimensions of early-life adversity are differentially associated with distinct neurodevelopmental patterns, indicative of dimension-specific delayed and accelerated brain maturation.

neuroscience↗

bioRxiv2023

Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in non-microcephalic infants, of which the pathogenesis remains poorly understood. We utilized an established pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We found prenatal ZikV exposure led to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses revealed marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals showed multi-focal decompaction consistent with perturbation or remodeling of previously formed myelin, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/561759v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@c0d423org.highwire.dtl.DTLVardef@1a76f40org.highwire.dtl.DTLVardef@178e509org.highwire.dtl.DTLVardef@4d581_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Sustained IL-15 response signature predicts RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work suggests that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including non-canonical T cell receptor (TCR), toll-lie receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly predicting protection. The IL-15 gene expression signature was further evaluated in an independent RM IL-15 treatment cohort, revealing that in whole blood the response to IL-15 is inclusive of innate and adaptive immune gene expression networks that link with RhCMV/SIV vaccine efficacy. We also show that this IL-15 response signature similarly tracks with vaccine protection in an independent RhCMV/SIV vaccination/SIV challenge RM validation cohort. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that enable vaccine-elicited CD8+ T cells to mediate protection against highly pathogenic SIV challenge. Author SummarySIV insert-expressing vaccine vectors based on strain 68-1 RhCMV elicit robust, highly effector-memory-biased T cell responses that are associated with an unprecedented level of SIV control after challenge (replication arrest leading to clearance) in slightly over half of vaccinated monkeys. Since efficacy is not predicted by standard measures of immunogenicity, we used functional genomics analysis of RhCMV/SIV vaccinated monkeys with known challenge outcomes to identify immune correlates of protection. We found that arrest of viral replication after challenge significantly correlates with a vaccine-induced response to IL-15 that includes modulation of T cell, inflammation, TLR signaling, and cell death programming. These data suggest that RhCMV/SIV efficacy is not based on chance, but rather, results from a coordinated and sustained vaccine-mediated induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ effector-memory T cell function, that enable vaccine-elicited CD8+ T cells to mediate efficacy.

genomics↗

bioRxiv2020

Evolution of the SARS-CoV-2 proteome in three dimensions (3D) during the first six months of the COVID-19 pandemic

Three-dimensional structures of SARS-CoV-2 and other coronaviral proteins archived in the Protein Data Bank were used to analyze viral proteome evolution during the first six months of the COVID-19 pandemic. Analyses of spatial locations, chemical properties, and structural and energetic impacts of the observed amino acid changes in >48,000 viral proteome sequences showed how each one of the 29 viral study proteins have undergone amino acid changes. Structural models computed for every unique sequence variant revealed that most substitutions map to protein surfaces and boundary layers with a minority affecting hydrophobic cores. Conservative changes were observed more frequently in cores versus boundary layers/surfaces. Active sites and protein-protein interfaces showed modest numbers of substitutions. Energetics calculations showed that the impact of substitutions on the thermodynamic stability of the proteome follows a universal bi-Gaussian distribution. Detailed results are presented for six drug discovery targets and four structural proteins comprising the virion, highlighting substitutions with the potential to impact protein structure, enzyme activity, and functional interfaces. Characterizing the evolution of the virus in three dimensions provides testable insights into viral protein function and should aid in structure-based drug discovery efforts as well as the prospective identification of amino acid substitutions with potential for drug resistance.

molecular biology↗

bioRxiv2020

Mutational, transcriptional and viral shedding dynamics of the marine turtle fibropapillomatosis tumor epizootic

Sea turtle populations are directly and indirectly under threat from a range of anthropogenic processes. Perhaps the most visibly apparent of these is the disfiguring tumor disease epizootic (animal epidemic) known as fibropapillomatosis. Fibropapillomatosis continues to spread geographically, with prevalence of the disease also growing at a number of affected sites globally. Environmental exposures seem key to inducing tumor development, possibly through weakening host immune systems to the point of enabling pathogen-induced tumor formation. However, we do not yet understand the precise molecular and mutational events driving fibropapillomatosis tumor formation and progression. Similarly, many open questions remain about the role of the herpesvirus (chelonid herpesvirus 5, ChHV5) associated with the disease as a potential co-trigger, and whether its occurrence within tumors is causative or opportunistic. Without improved understanding of the basic biology of this disease epizootic, treatment, containment and mitigation options are severely hampered. To address fundamental questions relating to the oncogenic signaling, mutational spectrum, viral load, viral transcriptional status (lytic or latent) and spread, we employed transcriptomic profiling, whole genome sequencing, immunohistochemistry and environmental (e)DNA-based monitoring of viral shedding. In particular we focused on the mutational landscape of tumors and assessing the transcriptional similarity of external (skin) and internal (visceral organs) tumors, and the oncogenic signaling events driving early stage tumor growth and post-surgical tumor regrowth. These analyses revealed that internal fibropapillomatosis tumors are molecularly distinct from the more common external tumors. However, our molecular analyses also revealed that there are a small number of conserved potentially therapeutically targetable molecular vulnerabilities in common between internal and external tumors, such as the MAPK, Wnt, TGF{beta} and TNF oncogenic signaling pathways. We also determined that the tumor genomes can harbor copy number gains, indicating potentially viral-independent oncogenic processes. Genes within such mutated genomic regions have known roles in human skin cancer, including MAPK-associated genes. Turtles attempt to mount an immune response, but in some animals this appears to be insufficient to prevent tumor development and growth. ChHV5 was transcriptionally latent in all tumor stages sequenced, including early stage and recurrent tumors. We also revealed that the tumors themselves are the primary source of viral shedding into the marine environment and, if they are surgically removed, the level of ChHV5 in the water column drops. Together, these results offer an improved understanding of fibropapillomatosis tumorigenesis and provide insights into the origins, therapeutic treatment, and appropriate quarantine responses for this wildlife epizootic. Furthermore, they provide insights into human pathogen-induced cancers, particularly mechanisms which are difficult to study in the human and terrestrial context, such as time-course quantification-based monitoring of viral shedding.

cancer biology↗