Biology subjects

Byrd, K.

Publications and source records attributed to Byrd, K..

6 recordsLinked to original sources

bioRxiv2025

STARComm Scalably Detects Emergent Modules of Spatial Cell-Cell Communication in Inflammation and Cancer.

In humans, cell-cell communication orchestrates tissue organization, immune coordination, and repair, yet spatially mapping these interactions remains a challenge for biology. We introduce STARComm, a scalable-interpretable computational method that identifies Multicellular Communication Interaction Modules (MCIMs) by detecting spatially co-located receptor-ligand activity from high-plex spatial transcriptomics in 2D and 3D. Applied to an atlas of >14million cells across 8 cancers, STARComm revealed 24 conserved and tumor-specific MCIMs, including a fibro-immune module with targetable axes linked to immune exclusion and immunotherapy resistance. In chronic graft-versus-host disease, STARComm identified three salivary gland MCIMs predictive of patient death and two druggable axes (CXCL12-CXCR4, CCL5-SDC4), both with FDA-approved therapeutics. STARComm demonstrated that peripheral tissue profiling can forecast fatality nearly 3 years in advance using minor salivary glands. By enabling scalable biomarker discovery, drug targeting, and spatially resolved precision profiling, STARComm bridges the gap between spatial biology and clinical translation, advancing the field of spatial medicine. SUMMARYDespite major advances in spatial biology, no framework has yet linked spatially resolved intercellular communication networks, independent of cell types, to clinical outcomes in human disease. Here, we present STARComm, a scalable method that identifies Multicellular Interaction MCIMs (MCIMs). Applying STARComm to minor salivary gland biopsies from patients with chronic graft-versus-host disease (GVHD), we identify MCIMs that not only distinguish healthy from diseased tissue but also stratify patient survival. High-risk MCIMs are enriched for actionable immune and stromal pathways, including those targetable with existing therapies. These findings establish the first outcome-linked spatial communication framework in any human disease and highlight the translational potential of oral tissues as minimally invasive platforms for real-time immune diagnostics, prognostic modeling, and therapeutic screening.

bioinformatics↗

bioRxiv2025

SAME: Topology-flexible transforms enable robust integration of multimodal spatial omics

Spatial omics technologies provide complementary and layered molecular insights that span proteins, transcripts, and metabolites. However, aligning and integrating these modalities across serial tissue sections remains a computational challenge. Existing alignment methods are primarily unimodal and assume preserved topology, often failing with tissue distortions like tears, folds, or anatomical changes. Here, we present SAME (Spatial Alignment of Multimodal Expression) that introduces space-tearing transforms, a framework for controlling localized topological disruptions during cross-sectional alignment. Using integer linear programming to maximize cell type matches across the modalities, we enhance cell-type alignment accuracy by 20% compared to existing methods while preserving biologically meaningful spatial relationships. Applied to protein-RNA integration in healthy tongue tissue and lung adenocarcinoma, SAME revealed cryptic immune subpopulations that were otherwise missed by RNA-only or protein-only classification. In a separate lung adenocarcinoma study, we assayed and integrated protein and metabolomic profiles, uncovering localized mevalonic acid upregulation specifically within tumor-macrophage spatial niches and identifying targeted metabolic crosstalk invisible to single-modality approaches. SAME enables unprecedented experimental designs that leverage each modality independently while computationally recovering cross-modal spatial structure, unlocking multimodal discoveries in complex tissues.

bioinformatics↗

bioRxiv2025

Stereotypy is strongly linked to multiple biomarkers of oxidative stress--a potential common etiology for Abnormal Repetitive Behaviors

Spontaneous stereotypies (abnormal, repetitive, and seemingly goal-less behaviors) in captive animals resemble stereotypies documented in patients with neurodevelopmental disorders, including evidence of homologous cortico-striatal dysfunction and shared behavioral deficits. While environmental risk factors for stereotypies are well documented, their developmental pathophysiology remains unclear. However, as previously found for compulsive behavior, there is growing evidence that REDOX imbalance may be linked to stereotypy. To examine the nature of this relationship, we first tested whether plasma glutathione level, the gold-standard biomarker of REDOX imbalance, is predictive of stereotypy severity in N=19 C57BL/6 mice. After confirming the presence of this relationship, we used a proteomics approach (Olink) to identify a broader biomarker profile of dysfunction. We found expression of 9 proteins to correlate with plasma glutathione level, and expression of 15 proteins to correlate with stereotypy severity. A subset of these proteins additionally correlated with stereotypy severity in a validation cohort of CD1 mice (N=28). Further supporting a role for REDOX imbalance in the developmental pathophysiology of stereotypies, the identified proteins were associated with REDOX physiology, dopamine physiology, and stereotypy-presenting human neurodevelopmental disorders. These data suggest REDOX imbalance may contribute to the developmental pathophysiology of abnormal repetitive behaviors and highlight promising novel targets for intervention.

animal behavior and cognition↗

bioRxiv2024

Etomidate as an Effective Alternative Method of Euthanizing Adult Zebrafish (Danio Rerio)

We assessed the efficacy of etomidate in euthanizing adult zebrafish. The aims of this study were to investigate: 1) the efficacy of 2 concentrations and 2) the effects at 2 densities. Aim 1-Fish (n=10 fish/group) were immersed in either 6 mg/L (Eto-6) or 10 mg/L (Eto-10) etomidate. Aim 2- either 5 or 10 fish were immersed in Eto-6. Tanks were video recorded and scored by two blinded observers. The parameters monitored included: 1) loss of righting reflex (LORR); 2) undulation cessation; 3) cessation of operculation (COO); and 4) loss of startle reflex. After the 30 minute immersion, fish were transferred to recovery tanks and monitored once every 5 minutes for 60 minutes. Results - Aim 1, the time to undulation cessation, COO, and loss of startle reflex was significantly shorter in the Eto-10 group and there was no difference in LORR. Aim 2, the time to LORR and undulation cessation was significantly shorter in the 5 fish/L group and there was no significant difference in time to COO or loss of startle reflex. No aversive behaviors were noted and fish in all groups were effectively euthanized by 30 minutes. This study indicates that Eto-6 or Eto-10 effectively euthanizes adult zebrafish.

animal behavior and cognition↗

bioRxiv2021

BET inhibitors synergize with anti-PD1 by rescuing TCF1+ progenitor exhausted CD8+ T cells in Acute Myeloid Leukemia

Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid derived suppressor cells (MDSCs), suppressive regulatory T cells (Tregs) and dysfunctional T cells. We have developed a mouse model of AML driven by Flt3-ITD and Tet2 deficiency displays these immune-related features, including CD8+ T cells exhibiting a terminally exhausted phenotype (TEx). This T cell subset has been shown to be refractory to immune checkpoint blockade (ICB) monotherapy. Here we show that small molecule inhibitors which target bromodomain and extra-terminal domain (BET) proteins affect both tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor exhausted T cells (TPEx). This reversal is enhanced by combined BETi and anti-PD1 treatment. Finally, we show that BETi synergizes with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow, and increased expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. In total, we show the potential efficacy of combining BETi and ICB therapy in the treatment of AML.

cancer biology↗

bioRxiv2018

Integrating water, sanitation, handwashing, and nutrition interventions to reduce child soil-transmitted helminth and Giardia infections: a cluster-randomized controlled trial in rural Kenya

Background.Helminth and protozoan infections affect >1 billion children globally. Improved water, sanitation, handwashing, and nutrition could be more sustainable control strategies for parasite infections than mass drug administration (MDA), while providing other quality of life benefits.\n\nMethods and Findings.We enrolled geographic clusters of pregnant women into a cluster-randomized controlled trial that tested six interventions: disinfecting drinking water(W), improved sanitation(S), handwashing with soap(H), combined WSH, improved nutrition(N), and combined WSHN. We assessed intervention effects on parasite infections by measuring Ascaris lumbricoides, Trichuris trichiura, hookworm, and Giardia duodenalis among individual children born to enrolled mothers and their older siblings (ClinicalTrials.gov NCT01704105). We collected stool specimens from 9077 total children in 622 clusters, including 2346 children in control, 1117 in water, 1160 in sanitation, 1141 in handwashing, 1064 in WSH, 1072 in nutrition, and 1177 in WSHN. In the control group, 23% of children were infected with Ascaris lumbricoides, 1% with Trichuris trichuria, 2% with hookworm and 39% with Giardia duodenalis. After two years of intervention exposure, Ascaris infection prevalence was 18% lower in the water treatment arm (95% confidence interval (CI) 0%, 33%), 22% lower in the WSH arm (CI 4%, 37%), and 22% lower in the WSHN arm (CI 4%, 36%) compared to control. Individual sanitation, handwashing, and nutrition did not significantly reduce Ascaris infection on their own, and integrating nutrition with WSH did not provide additional benefit. Trichuris and hookworm were rarely detected, resulting in imprecise effect estimates. No intervention reduced Giardia. Reanalysis of stool samples by quantitative polymerase chain reaction (qPCR) confirmed the reductions in Ascaris infections measured by microscopy in the WSH and WSHN groups. Lab technicians and data analysts were blinded to treatment assignment, but participants and sample collectors were not blinded. The trial was funded by the Bill & Melinda Gates Foundation and USAID.\n\nConclusions.Our results suggest integration of improved water quality, sanitation, and handwashing could contribute to sustainable control strategies for Ascaris infections, particularly in similar settings with recent or ongoing deworming programs. Water treatment alone was similarly effective to integrated WSH, providing new evidence that drinking water should be given increased attention as a transmission pathway for Ascaris.

clinical trials↗