Biology subjects

Bartelle, B. B.

Publications and source records attributed to Bartelle, B. B..

12 recordsLinked to original sources

bioRxiv2026

Systemic endotoxemia induces integrated sickness physiology in female BALB/c mice

Sickness is an organismal response to inflammation, yet its immune, metabolic, neural, and behavioral components are often studied separately and predominantly in male C57BL/6 mice. In this study, we characterized these responses to systemic lipopolysaccharide (LPS) in female BALB/c mice. Mice received intraperitoneal LPS at moderate concentrations and outcomes were assessed during the acute and resolving phases of endotoxemia. LPS caused rapid disappearance of resident peritoneal macrophages, followed by neutrophil accumulation and increased circulating TNF- and IL-6. In the liver, LPS induced inflammatory, acute-phase, and anti-inflammatory transcripts while suppressing genes involved in lipid, cholesterol, and xenobiotic metabolism. Hepatic glutathione was reduced, whereas total superoxide dismutase activity was unchanged. These peripheral responses were followed by transient hypothermia, reduced food intake, and body weight loss. Regional brain mapping showed increased c-Fos labeling in the area postrema, nucleus of the solitary tract, external lateral parabrachial nucleus, paraventricular nucleus of the hypothalamus, and arcuate nucleus. In parallel, LPS selectively promoted IBA1-positive area in the median eminence and arcuate nucleus, whereas several other regions showed no changes, indicating that neuronal and microglial responses are regionally distinct. Behaviorally, LPS reduced locomotion and exploration, increased freezing, and increased forced-swim immobility. Changes in spatial exploration were most pronounced during the acute phase, whereas locomotor suppression and passive stress-coping persisted longer and varied in magnitude with the timing of inflammatory challenge. Together, these findings show that systemic LPS produces a coordinated sickness state in female BALB/c mice that links peripheral inflammation and hepatic metabolic and redox changes with region-specific neuronal and microglial responses, altered thermoregulation and feeding, and behavioral suppression.

immunology↗

bioRxiv2026

Biomimetic MRI Nanoprobe for Mapping Cerebrovascular Inflammation After Traumatic Brain Injury

Cerebrovascular inflammation is a critical driver of secondary injury following traumatic brain injury (TBI), yet no noninvasive tool currently exists to map its spatial heterogeneity across the injured brain. Here, we report MoNP-SPION, a monocyte-mimetic nanoprobe that selectively targets activated cerebrovascular endothelium after TBI and enables quantitative MRI of spatiotemporally heterogeneous cerebrovascular inflammation. MoNP-SPION binding to inflamed brain endothelium scaled with activation state, enabling rapid, spatially heterogeneous targeting of injured cerebral vasculature. MoNP-SPION-enhanced MRI revealed dynamic reductions in T2* throughout the brain that extended beyond the injury penumbra and captured both subacute vascular injury and therapy-induced recovery. Importantly, spatiotemporal reductions in T2* strongly correlated with VCAM1 upregulation, supporting MoNP-SPION as a molecularly specific readout of endothelial activation. Together, these findings establish MoNP-SPION as a promising platform for longitudinal, noninvasive monitoring of cerebrovascular inflammation in TBI and other neurological disorders involving vascular dysfunction. TEASERCell-mimicking MRI nanoprobe maps cerebrovascular injury and recovery dynamics following brain trauma.

bioengineering↗

bioRxiv2026

The Microglia Forebrain Assembloid Model Recapitulates Human Brain Development and Neuroimmune Biology.

Microglia are innate immune cells of the CNS whose dysfunction contributes to inflammation and metabolic changes across neurodegenerative and CNS disorders. Across all stages of life, microglia are essential for immune surveillance, neural homeostasis, and synaptic pruning; however, their role in neurodevelopment is less understood. Microglia invade the brain during early neurogenesis, prior to neuronal/glial differentiation, but their potential role at this stage remains undescribed. To model neuroimmune interactions during human cortical development, we created an "assembloid" of human ESC-derived forebrain organoids combined with developmentally matched microglia during cortex formation. Functional contributions of microglia were compared to control organoids using histology and metabolomics.

neuroscience↗

bioRxiv2026

Representation Methods of Transcriptomics with Applications in Neuroimmune Biology

Interpretable representations of gene expression are used to define cellular identities and the molecular programs active within cells, two related, but distinct phenomena. In the case of microglia, a cell type with high transcriptomic, functional, and morphological heterogeneity, the predominant representation of transcriptomic data presumes the adoption of distinct molecular identities, despite a lack of easily separable transcriptional states. Here, we explore alternative transcriptomic representations by comparing two single-cell analysis methods: differential expression analysis for identities and co-expression network analysis for molecular programs. For microglia, co-expression network analysis identifies highly significant functional ontologies not resolved by differential expression analysis. The identified co-expression modules are preserved across transcriptomic datasets and suggest reducible functional programs that activate and modulate depending on context. We conclude that co-expression analysis constitutes a best practice for single cell analysis of an individual cell type and describing microglia function as concurrent molecular programs offers a more parsimonious model of microglia function.

bioinformatics↗

bioRxiv2026

Surface Display For Phage Assisted Continuous Evolution: A Platform For Evolving / Screening Nanobodies In Prokaryote Systems

Despite >50 years of methods development, specific antibodies are still generated at low throughput and remain in high demand across biotechnology. Most biologics and immunoprobes are monoclonal antibodies, developed using a combination of inoculating animals with a target antigen, engineered candidate libraries, and multiple rounds of selection using phage or yeast display. Here we introduce a synthetic biology scheme to eliminate the need for nearly all of these steps, by combining Surface display on E. coli and Phage display with the microvirus {Phi}X174, Assisting Continuous Evolution (SurPhACE). Instead of building libraries for screening, SurPhACE runs a closed evolutionary program. A typical experiment can have 1011 mutant candidates under active selection, with complete turnover of the mutant population every 30min, or >5x1012 unique mutants per day, using less than 100mL of bacterial culture media. We demonstrate SurPhACE for optimizing a nanobody to a related epitope, and develop novel nanobodies for an arbitrary target using a minimal starting library to establish a proof of concept and identify best practices for this scalable method for generating protein binders.

synthetic biology↗

bioRxiv2026

O-GlcNAcylation regulates PPAR-driven metabolic programming in intestinal stem cells

Diet deeply influences health and disease risk by reshaping cellular metabolism. In the intestine, dietary nutrients directly affect intestinal stem cell (ISC) behavior, yet the regulatory mechanisms linking metabolism to transcriptional control remain poorly defined. Because mitochondria function as central metabolic hubs, we focused on mitochondrial signaling to understand how nutrient utilization governs ISC function. Using the MITO-Tag mouse, we isolated metabolites specifically from ISC mitochondria and found that the sugar-derived metabolite UDP-GlcNAc was reduced in ISCs from mice fed a high-fat diet. Moreover, we identified that reducing O-GlcNAcylation (OGN) rapidly increased stem cell frequency, proliferation, regenerative capacity, and the abundance of PPAR target proteins. Mechanistically, these effects depend on PPAR signaling, as genetic loss of Ppar-d/a blocks the ISC phenotypes induced by reduced OGN. These results reveal an OGN-PPAR signaling axis that translates dietary metabolic cues into transcriptional programs governing fuel utilization and ISC behavior in the intestine. Collectively, our findings highlight that OGN is a previously unrecognized regulator of PPAR signaling in intestinal stem cells.

cell biology↗

bioRxiv2026

Maternal obesity induces developmental programming of Intestinal stem cells through an IL-17A/PPAR immune-epithelial axis

Maternal obesity is associated with increased risk of sporadic colorectal cancer (CRC) in offspring, suggesting that early-life environmental exposures durably shape disease susceptibility. Intestinal stem cells (ISCs), long-lived drivers of epithelial renewal and tumor initiation, are well poised to mediate this effect; however, how maternal obesity influences ISC programming during development remains poorly understood. Using mouse models of diet-induced obesity, we show that exposure to a maternal high-fat Western diet (mHFD) during pre- and postnatal development stably programs colonic ISCs. Offspring exhibit increased ISC proliferation, enhanced self-renewal, a hypermetabolic state, and altered epithelial lineage composition that persists into adulthood despite dietary normalization. These changes are accompanied by increased tumor burden following loss of Apc heterozygosity. Mechanistically, we identify the pro-inflammatory cytokine IL-17A as a key extrinsic driver and PPARd/a nuclear receptors as intrinsic mediators of the mHFD phenotype, revealing an immune-epithelial axis that programs ISC function during early life. Together, our findings demonstrate that maternal metabolic environments durably enhance stem cell fitness, providing a mechanistic link between developmental exposure and adult disease risk.

cell biology↗

bioRxiv2026

Diet-induced chromatin states influence intestinal stem cell memory

Intestinal stem cells (ISCs) integrate dietary cues through a metabolic-transcriptional axis, but whether these mechanisms create a lasting epigenetic memory remains unclear. Here, we investigate diet-induced chromatin adaptations in ISCs using a high-fat Western diet (HFD) mouse model. HFD broadly remodels chromatin accessibility, altering pre-existing open regulatory regions. Many differentially accessible regions (DARs) persist during the differentiation of ISCs into transient amplifying cells (TACs). Notably, HFD-induced DARs are retained following diet normalization despite phenotypic reversibility, and HFD re-exposure enhances ISC self-renewal and adenoma growth compared with naive HFD exposure. The HFD-induced chromatin changes require Ppar-d/a nuclear receptors but are independent of their transcriptional targets. Although a subset of HFD-induced DARs is maintained following Apc loss, extensive chromatin remodeling driven by tumor suppressor inactivation largely overrides diet-dependent differences in Lgr5 ISCs. Together, these findings demonstrate that ISCs retain a chromatin-based memory of dietary fat exposure.

cell biology↗

bioRxiv2025

GPU-accelerated, self-optimizing processing for 3D multiplexed iterative RNA-FISH experiments

Imaging-based spatial transcriptomic approaches rely on iterative labeling and imaging of carefully prepared samples, followed by solving a computational inverse problem to determine the location and identity of the targeted RNA. Because these approaches require high-resolution optics, the Nyquist-Shannon determined voxel size is small relative to typical tissue sample footprints. A common solution to speed up both experiments and computation is to increase the distance in between focal planes, trading off local information content to sample a larger imaging area in a reasonable time. In this work we introduce a GPU-accelerated computational framework, merfish3d-analysis, designed to speed up the computational processing of barcoded, in situ imaging-based spatial transcriptomics. Using this framework, we quantify the information lost due to axial sampling changes in simulated imaging-based spatial transcriptomic experiments, robustly reprocess publicly available multiplexed error-robust fluorescence in situ hybridization (MERFISH) datasets, and analyze new MERFISH experiments performed on a post-mortem human olfactory bulb sample. To improve the quality of experimental data in the post-mortem human sample, we designed a multi-step autofluorescence quenching protocol specific for in situ imaging-based spatial transcriptomic strategies. Taken together, we hope that the sample preparation protocols and single workstation, GPU-accelerated processing will further democratize imaging-based spatial transcriptomic experiments.

bioinformatics↗

bioRxiv2023

Ts-Biotag, a multimodal reporter of Tie2 expression, labels microglia in a model of neuro injury.

The Ts-Biotag transgenic mouse reports the expression of receptor tyrosine kinase Tie2, a known marker of angiogenic states for both vascular endothelial cells and macrophages. We demonstrate Ts-Biotag labeling and Tie2 expression in a neural injury model to find the majority of labeling occurs in the myeloid derived and brain resident cell type, microglia. Additionally the ligand of Tie2, Ang1, is dynamically expressed, first in astrocytes then neural progenitor during wound signaling and healing. These results offer a Tie2 specific, in vivo view of a neuroimmune response to injury, suggesting a microglia/neural progenitor intercellular interaction guides recovery from a brain lesion. Graphical AbstractThe Ts-Biotag mouse reports expression of Tie2 for any imaging modality compatible with avidinated agents. Mice were given a transcranial cryo-injury and Ts-Biotag activity was followed for 7 days with MRI and histology, showing local and systemic Ts-Biotag labeling. Histology of WT and labeled bone marrow chimeras showed the protein Tie2 expressed in microglia, which assembled at the border of the lesion 1-2d post injury before invading by day 7. The main ligand of Tie2, Ang1, was first expressed systemically by astrocytes, then by neural progenitor cells proximal to and within the lesion. These results elucidate an axis of intercellular signaling involved in the resolution of inflammation and partial healing of a CNS injury. O_FIG O_LINKSMALLFIG WIDTH=180 HEIGHT=200 SRC="FIGDIR/small/527655v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@c11887org.highwire.dtl.DTLVardef@1316a54org.highwire.dtl.DTLVardef@13be2a5org.highwire.dtl.DTLVardef@9cf9bd_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2021

Improved Unsupervised Representation Learning of Spatial Transcriptomic Data with Sparse Filtering

Unsupervised learning methods are commonly used to detect features within transcriptomic data and ultimately derive meaningful representations of biology. Contributions of individual genes to any feature however becomes convolved with each learning step, requiring followup analysis and validation to understand what biology might be represented by a cluster on a low dimensional plot. We sought learning methods that could preserve the gene information of detected features, using the spatial transcriptomic data and anatomical labels of the Allen Mouse Brain Atlas as a test dataset with verifiable ground truth. We established metrics for accurate representation of molecular anatomy to find sparse learning approaches were uniquely capable of generating anatomical representations and gene weights in a single learning step. Fit to labeled anatomy was highly correlated with intrinsic properties of the data, offering a means to optimize parameters without established ground truth. Once representations were derived, complementary gene lists could be further compressed to generate a low complexity dataset, or to probe for individual features with >95% accuracy. We demonstrate the utility of sparse learning as a means to derive biologically meaningful representations from transcriptomic data and reduce the complexity of large datasets while preserving intelligible gene information throughout the analysis.

bioinformatics↗

bioRxiv2020

Functional dissection of neural circuitry using a genetic reporter for fMRI

The complex connectivity of the mammalian brain underlies its function, but understanding how interconnected brain regions interact in neural processing remains a formidable challenge. Here we address this problem by introducing a genetic probe that permits selective functional imaging of neural circuit elements defined by their synaptic interrelationships throughout the brain. The probe is an engineered enzyme that transduces cytosolic calcium dynamics of probe-expressing cells into localized hemodynamic responses that can be selectively visualized by functional magnetic resonance imaging. Using a viral vector that undergoes retrograde transport, we apply the probe to characterize a brain-wide network of monosynaptic inputs to the striatum activated in a deep brain stimulation paradigm in rats. The results reveal engagement of surprisingly diverse projection sources and inform an integrated model of striatal function relevant to reward behavior and therapeutic neurostimulation approaches. Our work thus establishes a potent strategy for mechanistic analysis of distributed neural systems.

neuroscience↗