Biology subjects

Carter, K.

Publications and source records attributed to Carter, K..

14 recordsLinked to original sources

bioRxiv2026

A stromal metabolic program suppresses NK-cell immunity to drive tumor progression in HER2-low breast cancer

Cancer-associated fibroblasts (CAFs) are major regulators of the tumor microenvironment, yet how distinct CAF states suppress innate immunity in HER2-low breast cancer remains poorly understood. Here, we identify an S100A4-enriched CAF population that expands during HER2-low breast tumor progression and establishes a metabolically immunosuppressive niche. Spatial transcriptomics and multiplex imaging of human HER2-low tumors reveal progressive CAF accumulation and an inverse spatial association between S100A4-enriched CAFs and immune infiltration, including natural killer (NK) cells. Using an immunocompetent HER2-low mammary tumor model, we show that S100A4-enriched CAFs promote tumor initiation and progression while suppressing NK-cell cytotoxicity, IFN-{gamma} production, perforin, and granzyme B. Fractionation of CAF-conditioned media and metabolic profiling identify a low-molecular-weight immunosuppressive program characterized by enhanced branched-chain amino acid catabolism and accumulation of branched-chain -keto acids (BCKAs). Mechanistically, BCKAs directly suppress NK-cell IFN-{gamma} production, whereas inhibition of the branched-chain aminotransferase BCAT1 reduces CAF-mediated NK-cell suppression and restores antitumor cytotoxicity. BCAT1 inhibition also suppresses HER2-low tumor growth in vivo, an effect attenuated by NK-cell depletion, establishing NK-cell restoration as a functional component of its antitumor activity. Together, these findings uncover a CAF-driven metabolic immune checkpoint in which S100A4-enriched CAFs exploit BCAT1-dependent BCKA production to suppress NK-cell surveillance and promote HER2-low breast tumor progression. Targeting stromal BCAT1 therefore represents a potential strategy to dismantle CAF-mediated immune suppression and restore innate antitumor immunity.

cancer biology↗

bioRxiv2026

Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression

Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

cancer biology↗

bioRxiv2026

Gut microbiome changes over the course of multiple sclerosis differentially influence autoimmune neuroinflammation

Multiple sclerosis (MS) is the leading inflammatory and demyelinating disease of the central nervous system (CNS). MS begins with systemic inflammation and over time is compartmentalized within the CNS. Studies in humans, supported by animal experiments, suggest that the gut microbiome plays an important role in MS development. However, despite the dynamic nature of the disease, little is known on how the microbiome evolves over the course of MS and how these microbiome changes influence immune responses and disease progression. Here, using high-throughput sequencing, we identified distinct gut microbial communities with differential functional potential in MS patients stratified by time since disease onset. Importantly, using a humanized mouse model, we demonstrate that differences in microbial composition significantly impact disease outcomes. Microbiota from more recently diagnosed MS patients induced severe neuroimmune disease in mice, whereas microbiota from long-term MS patients and healthy individuals elicited only mild disease. Accordingly, we found that microbiota from earlier diagnosed MS patients exhibit a higher inflammatory potential. This was characterized by a reduced capacity to induce regulatory T cells in mice and an increased induction of pro-inflammatory cytokines in human peripheral blood mononuclear cells. Together, our results suggest that the ability of the gut microbiome to promote systemic inflammation and trigger MS pathology shifts over the course of the disease and is primarily critical during its early stages. These findings indicate that a limited therapeutic window should be considered when designing microbiome-based interventions for MS.

immunology↗

bioRxiv2025

Populus trichocarpa associated microbiomes vary across a natural temperature, elevation and rainfall gradient

Abiotic stresses associated with warming and drought are increasing in frequency and severity due to climate change. However, microbial associations can partially mitigate their adverse effects on plant physiology. We examined the bacterial/archaeal and fungal communities with 16S rRNA and ITS2 gene region amplicon sequencing of bulk soil, rhizosphere soil, and root endosphere samples of Populus trichocarpa trees from 11 sites along a 200 km transect with highly variable precipitation, temperature, and soil conditions over the Cascade Mountains in Washington, USA. Foliar stress response was examined with qRT-PCR and field physiological measurements. Soil conditions were examined with physiochemical sample analysis and site climate conditions were approximated using DAYMET. For each niche sampled, bacterial/archaeal and fungal communities clustered into three distinct micro-climate groups: a high-precipitation, low-stress community on the western side of the range, and two stressed climate communities: a high-elevation community nearer the crest of the pass, and a warmer and drier community along the eastern slope. The differences between these micro-climate communities, though still distinct, were notably diminished within the P. trichocarpa root endosphere, indicating that P. trichocarpa likely has a homogenizing effect on the microbiome under stress, but climate plays a major role in shaping these microbial communities.

ecology↗

bioRxiv2025

Aging-Associated Microbiota Drives Treg Dysfunction via TNF Signaling

Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF-dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.

immunology↗

bioRxiv2025

Microbial Modulation of Host Plant Proteasome Activity Improves Heat Stress Tolerance

Global climate change marked by rising temperatures and increasingly frequent, severe heat waves, threatens plant health, productivity, and ecosystem function. Beneficial plant-microbe associations are increasingly recognized for their role in mitigating abiotic stress, yet the molecular mechanisms underlying microbially-conferred thermotolerance remain poorly understood. Here, we developed a population-based assay using Sphagnum peat mosses, a key species in peatland ecosystems that sequester 33-50% of the worlds soil carbon as recalcitrant peat, to perform microbiome transfers and assess microbial contributions to heat resilience. Strain-based assays in Sphagnum and Arabidopsis identified Variovorax as a key thermotolerance-enhancing microbe and identified ECM29, a proteasome-associated protein, as critical for this interaction. In Arabidopsis, Variovorax sp. CF313 association led to ECM29 preferentially binding the RPT1 subunit of the 19S regulatory particle, inhibiting 20S proteasome gate opening and slightly reducing proteasomal activity. This results in the accumulation of ubiquitinated proteins and induces HSP70 transcription, priming the host for heat shock stress even in the absence of prior heat exposure. These findings establish ECM29 as a key regulator of proteasome activity in response to microbial interactions, highlighting a previously unknown mechanism by which microbes enhance plant thermotolerance. More broadly, this work highlights the importance of leveraging natural systems and ecologically relevant models to identify strategies for enhancing plant and ecosystem resilience to a changing climate. Significance StatementGlobal climate change poses severe threats to plant health and productivity, with cascading impacts on ecosystems. Beneficial plant-microbe interactions offer promising strategies to mitigate abiotic stress, yet the molecular mechanisms often remain unclear. This study uncovers a novel thermotolerance mechanism mediated by Variovorax modulating the plant host proteasome. Using a QTL derived from Sphagnum peat mosses, and tested within a genetically tractable Arabidopsis model, we identified ECM29, a highly conserved protein across diverse plant species, as a key regulator of proteasome activity. ECM29 primes plants for heat stress by inducing HSP70 transcription through proteasome modulation. Additionally, we demonstrated that ECM29 is required for the host to receive microbially conferred thermotolerance, but is not necessary for innate priming to heat stress. These findings highlight the potential of leveraging natural systems and ecologically relevant species to develop innovative genetic models, advancing plant resilience and productivity in a warming world.

plant biology↗

bioRxiv2025

B cells maintain the homeostasis of splenic marginal zone antigen-presenting cells to promote the anti-viral CD8+ T cell response

Natural killer and CD8+ T cells are critical in the elimination of blood-borne viruses such as cytomegalovirus (CMV); however, the role of B cells in this process is less clear. Here, using the murine CMV (MCMV) infection model, we demonstrated that the B cell-deficient mice mounted a weaker primary virus-specific CD8+ T cell response than their wild-type counterparts, which was associated with increased viral transcription. Notably, we found that the contribution of B cells to the CD8+ T-cell-mediated anti-viral response was not associated with their ability to generate antibodies but with their ability to sustain Langerin+ type 1 conventional dendritic cells (cDC1s), a dendritic cells (DC) subset known for being involved in viral and bacterial clearance in the marginal zone of the spleen. Furthermore, we found that the presence of Langerin+ cDC1s is dependent on B cells expressing lymphotoxin (LT{beta}) to maintain CD169+ marginal metallophilic macrophages (MMMs). We further discovered, using ligand-receptor interaction analyses, that the communication between MMMs and Langerin+ cDC1s was mediated via VCAM1 - ITGA4/ITGB1 interaction. Thus, our data reveals that B cell regulate the development of MMMs in the spleen via LT{beta} expression and consequently sustain Langerin+ cDC1s homeostasis for effective initiation of an anti-viral CD8+ T cell response. Overall, our study offers a new perspective on how B cells maintain the homeostasis of antigen-presenting cells in the splenic marginal zone and thus indirectly affect the virus-specific CD8+ T cell response, which could potentially be extended to other infectious and autoimmune diseases as well as tumors.

immunology↗

bioRxiv2024

Fluence rate-dependent kinetics of light-triggered liposomal doxorubicin assessed by quantitative fluorescence-based endoscopic probe

Liposomal doxorubicin (Dox), a treatment option for recurrent ovarian cancer, often suffers from suboptimal biodistribution and efficacy, which might be addressed with precision drug delivery systems. Here, we introduce a catheter-based endoscopic probe designed for multispectral, quantitative monitoring of light-triggered drug release. This tool utilizes red-light photosensitive porphyrin-phospholipid (PoP), which is encapsulated in liposome bilayers to enhance targeted drug delivery. By integrating diffuse reflectance and fluorescence spectroscopy, our approach not only corrects the effects of tissue optical properties but also ensures accurate drug delivery to deep-seated tumors. Pre-liminary results validate the probe effectiveness in controlled settings, highlighting its potential for future clinical adaptation. This study sets the stage for in vivo applications, enabling the exploration of next-generation treatment paradigms for the management of cancer by optimizing chemotherapy administration with precision and control.

bioengineering↗

bioRxiv2022

Candesartan treatment preserves learning and working memory in female TgF344-AD rats

BackgroundTargeting the renin angiotensin system, especially with angiotensin receptor II blockers (ARB), and related vascular dysfunction is a promising therapeutic intervention for cognitive impairment including Alzheimers Disease (AD). The underlying mechanisms of the effects of ARB is unclear. This study sought to examine if treatment with candesartan, an ARB, affects neurobehavioral manifestation and the underlying neuro- and vascular mechanisms in male and female TgF344-AD rats. MethodsCandesartan or vehicle was administered to TgF344-AD rats (n=127) daily from 12-months to 18-months of age. Behavioral assays (spontaneous alternation test, novel object recognition, water radial arm maze) and neuropathologic assessment were completed along with brain proteome and measures of contractility in 12- and 18-month rat brains. ResultsUntreated 18-month TgF344-AD showed impairments in learning and increased perseverative working memory errors on the water radial arm maze (WRAM). These behavioral changes were corrected with candesartan treatment in female rats only. Treatment with candesartan was also associated with improved vascular reactivity and reduced blood pressure in both wild type and TgF344-AD male and female rats. Although there was no effect on amyloid-{beta}, treatment with candesartan reduced whole brain clusterin, an AD-risk associated protein, and GFAP in female TgF344-AD. ConclusionsOur results demonstrate that candesartan administered in the early stages of AD has a sexual dimorphic response in Tgf344-AD rat, where it reduced cognitive disturbances only in female TgF344-AD rat. These effects appear to be independent of changes in blood pressure and amyloid-{beta} reduction and are likely mediated through mechanisms related to clusterin and GFAP pathways.

neuroscience↗

bioRxiv2021

Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

ABSTRACT AND KEYWORDSThere is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old- SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.

physiology↗

bioRxiv2020

Global transcriptomics analyses reveal specialized roles for splicing regulatory proteins in the macrophage innate immune response

Pathogen sensing via pattern recognition receptors triggers massive reprogramming of macro-phage gene expression. While the signaling cascades and transcription factors that activate these responses are well-known, the role of post-transcriptional RNA processing in modulating innate immune gene expression remains understudied. Recent phosphoproteomics analyses revealed that members of the SR and hnRNP families of splicing regulatory proteins are dynamically post-translationally modified in infected macrophages. To begin to test if these splicing factors play a privileged role in controlling the innate immune transcriptome, we analyzed steady state gene expression and alternatively spliced isoform production in ten SR/hnRNP knockdown RAW 264.7 macrophage cell lines following infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (Salmonella). We identified thousands of transcripts whose abundance was increased or decreased by SR/hnRNP knockdown in macrophages. We observed that different SR/hnRNPs control the expression of distinct gene regulons in uninfected and Salmonella-infected macrophages, with several key innate immune genes (Nos2, Mx1, Il1a) relying on multiple SR/hnRNPs to maintain proper induction and/or repression. Knockdown of SR/hnRNPs promoted differential isoform usage (DIU) for a number of key immune sensors and signaling molecules and many of these splicing changes were again, distinct in uninfected and Salmonella-infected macrophages. Finally, after observing a surprising degree of similarity between the DEGs and DIUs in hnRNP K and U knockdown macrophages, we found that these cells are better able to restrict vesicular stomatitis virus replication than control cells, supporting a role for these hnRNPs in controlling infection outcomes in macrophages ex vivo. Based on these findings, we conclude that many innate immune genes have evolved to rely on one or more splicing regulatory factors to ensure the proper timing and magnitude of their induction, bolstering a model wherein pre-mRNA splicing is a critical regulatory node in the innate immune response.

immunology↗

bioRxiv2019

Microbial Community Dissimilarity for Source Tracking with Application in Forensic Studies

Microbial source-tracking is a useful tool for trace evidence analysis in Forensics. Community-wide massively parallel sequencing profiles can bypass the need for satellite microbes or marker sets which are unreliable when handling unstable samples. We propose a method utilizing Aitchison distance to select important suspects/sources and then propose several methods to estimate the proportions of microbial communities/samples coming from important suspects/sources. A series of comprehensive simulation studies show that these methods are capable of accurate selection and improve the performance of current methods Bayesian SourceTracker and FEAST in the presence of noise microbial sources.

bioinformatics↗

bioRxiv2019

Giraffe Translocation Population Viability Analysis

Most populations of giraffes have declined in recent decades, leading to the recent decision to upgrade the species to vulnerable status, and some subspecies to endangered. Translocations have been used as a conservation tool to re-introduce giraffes to previously occupied areas or establish new populations, but guidelines for founding populations are lacking. To provide general guidelines for translocation projects regarding feasibility, we simulated various scenarios of translocated giraffe populations to identify viable age and sex distributions of founding populations using Population Viability Analysis (PVA) implemented in Vortex software. We explored the parameter space for demography (population growth rates: {lambda} = 1.001, 1.010, 1.024), and the genetic load (number of lethal equivalents: LE = 2.5, 6.29, 12.6), examining how variation in founding numbers (N = 5 to 80 females) and sex ratios (M:F = 0.1 to 0.5) affected 100-year probability of extinction and genetic diversity. We found that even very small numbers of founders (N [≤]10 females) can appear to be successful in the first decades due to transient positive population growth, but with moderate population growth rate and moderate genetic load, long-term population viability (probability of extinction <0.01) was only achieved with [≥]30 females and [≥]3 males released. To maintain >95% genetic diversity of the source population in an isolated population, 50 females and 5 males are recommended to comprise the founding population. Sensitivity analyses revealed first-year survival and reproductive rate were the simulation parameters with the greatest proportional influence on probability of extinction and genetic diversity. These simulations highlight important considerations for translocation success, and data gaps including true genetic load in wild giraffe populations.

ecology↗

bioRxiv2017

The phylogeography of westslope cutthroat trout

Identifying units of conservation of aquatic species is fundamental to informed natural resources science and management. We used a combination of mitochondrial and nuclear molecular methods to identify potential units of conservation of westslope cutthroat trout, a taxon native to montane river basins of the northwestern U.S. and southwestern Canada. Mitogenomic sequencing identified two major lineages composed of nine monophyletic clades, and a well-supported subclade within one of these, largely delineated by river basins. Analyses of microsatellites and single nucleotide polymorphisms corroborated most of these groupings, sometimes with less resolution but demonstrating more complex connections among clades. The mitochondrial and nuclear analyses revealed that Pleistocene glacial cycles profoundly influenced the distribution and divergence of westslope cutthroat trout, that this taxon crossed the Continental Divide in two separate events, and that genetically pure but nonindigenous fish were widely distributed. Herein, we recognize nine geographically discrete, cytonuclear lineages largely circumscribed by major river basins as potential units of conservation: 1) John Day; 2) Coeur dAlene; 3) St. Joe; 4) North Fork Clearwater; 5) Salmon; 6) Clearwater headwaters; 7) Clearwater-eastern Cascades; 8) neoboreal, consisting of most of the Columbia upstream from central Washington, the Fraser in British Columbia, and the South Saskatchewan in Alberta; and 9) Missouri.

evolutionary biology↗