Biology subjects

Loomis, C. A.

Publications and source records attributed to Loomis, C. A..

5 recordsLinked to original sources

bioRxiv2026

Cyclin D-CDK4/6 couple proliferation to membrane and mitochondrial protein supply through a DeSI1 phospho-switch

Cyclin D-CDK4/6 complexes drive cell-cycle entry through an RB-E2F-dependent transcriptional program, but how they coordinate proliferation with the membrane and organelle protein supply required for growth is unclear. We identify DeSI1 as a cyclin D-CDK4/6 substrate whose phosphorylation at S25 converts a latent homodimer into an active monomeric deubiquitylase that recognizes hydrophobic proteins such as those bearing transmembrane domains and mitochondrial targeting sequences. Phosphorylated DeSI1 extends the lifetime of newly synthesized hydrophobic proteins that support membrane and mitochondrial capacity. Constitutive DeSI1 activation uncouples this proteostatic program from metabolic supply, creating a cytidine-nucleotide supply-demand imbalance associated with impaired CTP-dependent phospholipid homeostasis, cardiolipin depletion, and mitochondrial decompensation - defects that cytidine reverses. In mice, constitutive DeSI1 activation causes progressive cerebellar degeneration with membrane-protein accumulation, respiratory-chain loss, and phospholipid depletion. These findings define a post-translational mechanism coupling cell-cycle entry to membrane and mitochondrial capacity, and reveal the cost of uncoupling this program from its metabolic support.

cell biology↗

bioRxiv2026

IFNγ-Driven Inflammatory Responses in the Nasal Mucosa Drive Influenza Virus Shedding and Transmission

What determines host infectiousness during influenza A virus (IAV) infection remains a fundamental unanswered question in virology. While upper respiratory tract (URT) replication is necessary for transmission, its insufficient to explain host-to-host variation in contagiousness. Using the infant mouse model of influenza transmission, we show that viruses containing H3 hemagglutinin shed at higher levels than non-H3-containing viruses, despite comparable URT replication. H3-containing virus infection was associated with higher URT inflammation, characterized by increased cytokine production, immune cell recruitment, and mucus hypersecretion, which directly correlated with shedding efficiency. Transcriptomic profiling identified enrichment of interferon-stimulated gene programs, with a dominant interferon gamma (IFN{gamma}) signature during H3 infections. Functional studies demonstrated that IFN{gamma} deficiency reduced mucus production, shedding, and transmission, whereas IFN{gamma} supplementation restored these phenotypes. Together, these findings identify IFN{gamma}-driven mucosal inflammation key host determinant of influenza infectiousness, reframing contagiousness as a consequence of host inflammatory clearance rather than viral replication alone.

microbiology↗

bioRxiv2025

Non-segmented unsupervised learning of multispectral whole slide images for robust analysis of tissue repair and regeneration

Analyzing whole tissue architecture remains challenging due to the inherent complexity of multicellular organization, variable morphology, and the limitations of conventional segmentation-based image analysis. Traditional approaches often rely on partial sampling or nuclear/cytoplasmic boundaries, which risk introducing bias and fail to capture the contextual interplay of diverse tissue compartments. To overcome these barriers, we developed a segmentation free framework for analyzing multispectral whole slide images (WSIs). By tiling WSIs into fixed sized regions and extracting quantitative tile features, we applied unsupervised machine learning to systematically reveal patterns of tissue organization at scale. This approach preserved spatial context without the need for cell-level delineation, recapitulating expected compartments such as epidermis, adipose, and scab, while also revealing subtle but coherent substructures within stromal and granulation regions. Applied to murine wound healing, the method distinguished wild type from diabetic repair dynamics without prior labels, uncovering both gross and nuanced differences in tissue composition. Together, this work establishes a robust, unbiased strategy for whole-tissue analysis that circumvents the limitations of segmentation, leverages unsupervised learning for discovery, and advances the study of tissue repair and regenerative pathology.

cell biology↗

bioRxiv2023

Targeting host sialic acids in the upper respiratory tract with a broadly-acting neuraminidase to inhibit influenza virus transmission

The ongoing transmission of influenza A viruses (IAV) for the past century continues to be a burden to humans. IAV binds terminal sialic acids (SA) of sugar molecules present within the upper respiratory tract (URT) in order to successfully infect hosts. The two most common SA structures that are important for IAV infection are those with 2,3- and 2,6-linkages. While mice were once considered to be an unsuitable system for studying IAV transmission due to their lack of 2,6-SA in the trachea, we have successfully demonstrated that IAV transmission in infant mice is remarkably efficient. This finding led us to reevaluate the SA composition of the URT of mice using in situ immunofluorescence and examine its in vivo contribution to transmission for the first time. We demonstrate that mice express both 2,3- and 2,6-SA in the URT and that the difference in expression between infants and adults contribute to the variable transmission efficiencies observed. Furthermore, selectively blocking 2,3-SA or 2,6-SA within the URT of infant mice using lectins was necessary but insufficient at inhibiting transmission, and simultaneous blockade of both receptors was crucial in achieving the desired inhibitory effect. By employing a broadly-acting neuraminidase (ba-NA) to indiscriminately remove both SA moieties in vivo, we effectively suppressed viral shedding and halted the transmission of different strains of influenza viruses. These results emphasize the utility of the infant mouse model for studying IAV transmission, and strongly indicate that broadly targeting host SA is an effective approach that inhibits IAV contagion. IMPORTANCEInfluenza virus transmission studies have historically focused on viral mutations that alter hemagglutinin binding to sialic acid (SA) receptors in vitro. However, SA binding preference doesnt fully account for the complexities of IAV transmission in humans. Our previous findings reveal that viruses that are known to bind 2,6-SA in vitro have different transmission kinetics in vivo, suggesting that diverse SA interactions may occur during their life-cycle. In this study, we examine the role of host SA on viral replication, shedding, and transmission in vivo. We highlight the critical role of SA presence during virus shedding, such that attachment to SA during virion egress is equally important as detachment from SA during virion release. These insights support the potential of broadly-acting neuraminidases as therapeutic agents capable of restraining viral transmission in vivo. Our study unveils intricate virus-host interactions during shedding, highlighting the necessity to develop innovative strategies to effectively target transmission.

microbiology↗

bioRxiv2022

Single-Cell RNA Sequencing Reveals the Effects of Chemotherapy on Human Pancreatic Adenocarcinoma and its Tumor Microenvironment

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) is a complex ecosystem that drives tumor progression; however, in-depth single cell characterization of the PDAC TME and its role in response to therapy is lacking. We performed single-cell RNA sequencing on freshly collected human PDAC samples either before or after chemotherapy. Overall, we found a heterogeneous mixture of basal and classical cancer cell subtypes, along with distinct cancer-associated fibroblast and macrophage subpopulations. Strikingly, classical and basal-like cancer cells exhibited similar transcriptional responses to chemotherapy, and did not demonstrate a shift towards a basal-like transcriptional program among treated samples. We observed decreased ligand-receptor interactions in treated samples, particularly TIGIT on CD8+ T cells and its receptor on cancer cells, and identified TIGIT as the major inhibitory checkpoint molecule of CD8+ T cells. Our results suggest that chemotherapy profoundly impacts the PDAC TME and may promote resistance to immunotherapy.

cancer biology↗