Biology subjects

Nelson, A.

Publications and source records attributed to Nelson, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Structural variation in repeat elements is widespread in normal human tissues and in tumorigenesis

Somatic mosaicism contributes to genomic variation, yet postzygotic structural variants remain under-characterized. We performed long- and short-read WGS from multiple individuals (n=47 normal tissues; n=168 samples) and identified mosaic structural variants in all individuals and germ layers, impacting a median 285.2 kb/genome. Nearly half of breakpoints were independently validated, with tissue distributions reflecting both early and late developmental origins. Most mosaic variants were repeat-mediated and 8.3% overlapped functional elements, an enrichment compared to germline variants. To extend these analyses in samples where long-read sequencing is infeasible, we measured repeat alterations from short-read sequencing, recapitulating mosaic tissue-specific differences. We characterized tumor- and tissue- specific variation in repeats across 15 cancer types and found tumor-related repeat variation to be similar in scale to that of normal mosaic variation. Tracking repeat changes in cell-free DNA provided a noninvasive approach for tumor monitoring. Our analyses revealed widespread repeat-driven structural variation in health and disease.

genomics↗

bioRxiv2026

Widespread detection of Polyethylene glycol reveals chronic human exposure through pharmaceutical drugs

Polyethylene glycol (PEG) is a synthetic polymer ubiquitous in pharmaceuticals, personal care products, food additives, and industrial manufacturing. Despite its widespread use and potential importance as an exposure chemical, the prevalence of PEG exposure and its excretion in human populations remain largely uncharacterized. Moreover, PEG detected in human biofluids is frequently assumed to arise from analytical contamination during sample preparation, potentially obscuring its contribution to the human exposome and confounding metabolic phenotyping studies. Here, we show that PEG is as component of the human xenobiotic exposome and is further metabolized into PEG hydoxy acid and diacid metabolites in humans. We further find that PEG exposure is associated with alterations in microbiome composition and short-chain fatty acid metabolism, suggesting its biological impact of its exposure. We identify PEG exposure in approximately 2.3% of publicly available metabolomics data files and provide a reusable 85,484 candidate PEG and PEGylated MS/MS spectral library for future use for the metabolomic community. Together, these findings establish PEG signal in human biofluids can reflect genuine exposure, and that PEG exposure is neither metabolically inert nor biologically silent.

biochemistry↗

bioRxiv2026

TALAVE in Breast Cancer: BRCA1/2 Mutation-Dependent Immune Remodeling after PARP Inhibition with Limited Checkpoint Engagement

PARP inhibitors (PARPi) drive efficacy in BRCA-mutant breast cancer (BC) via DNA damage-induced synthetic lethality and immune activation, supporting their combination with immune checkpoint blockade. In the TALAVE study, patients with advanced BRCA-mutant or wild-type (WT) HER2-negative BC received talazoparib followed by talazoparib plus avelumab. Only BRCA-mutant BC responded clinically. Serial multi-omic profiling revealed BRCA-dependent tumor-immune remodeling, including sustained H2AX-pTBK1 signaling with increased CD8+ T cells, tumor cell depletion, and enrichment of CD163+ macrophages. In contrast, BRCA-WT tumors remained compact and immunosuppressed with reduced T cells after therapy. PD-1+ T cells localized to CD4+-rich neighborhoods and correlated with longer progression-free survival in BRCA-mutant tumors. However, PD-L1+ cells were rapidly depleted or confined to immune-excluded regions, spatially segregating them from PD-1+ T cells, impairing effective checkpoint blockade. These findings suggest limited benefit of PD-1/PD-L1 blockade in augmenting PARPi activity and highlight the need for alternative strategies to sustain PARPi-induced immunity.

cancer biology↗

bioRxiv2026

A cargo receptor entrapment complex is a therapeutic node for genetically and clinically distinct proteinopathies

Severe proteinopathies--such as retinitis pigmentosa, a form of inherited blindness--are driven by genetic mutations that overwhelm the quality control of the post-endoplasmic reticulum (post-ER) secretory pathway, causing toxic protein accumulation. Here, we identify a therapeutic node defined by a hetero-oligomeric cargo receptor complex consisting of TMED7, 2, 9, and 10. This "entrapment complex" anchors structurally and functionally diverse mutant clients within the early secretory pathway via TMED7 binding to the integral Golgi protein GRASP55. Disruption of the entrapment complex results in the clearance of accumulated protein cargoes. In vivo ablation of the entrapment node via inducible genetic deletion or via the small molecule BRD7635 reverses histopathological hallmarks and rescues functional deficits in clinically distinct proteinopathies of the kidney and the eye, including mitigating vision loss in a mouse model of retinitis pigmentosa.

cell biology↗

bioRxiv2026

Network Formation Dynamics in Thiol-ene Crosslinked Hyaluronic Acid Hydrogels: Design Principles for In Vitro Tissue Models

Hydrogels are widely used as three-dimensional cell culture systems to understand the impact of cellular mechanotransduction for tissue engineering applications. Photoinitiated thiol-ene click chemistry is a commonly utilized hydrogel crosslinking mechanism that provides spatial and temporal control over hydrogel network formation and resulting mesh size and compressive properties. Despite historically documented efficiency as step-growth reactions, these reactions do not always proceed as predicted. To understand the impact of cell confinement and microenvironmental mechanics on cellular function, thiol-ene network formation must be thoroughly characterized. To this end, the objective of this work was to investigate the crosslinking dynamics to determine hydrogel network formation as assessed via mesh size and mechanical properties using a pentenoate-functionalized hyaluronic acid thiol-ene reaction. Hydrogel parameters including polymer concentration and thiol:-ene crosslinker molar ratio were modulated (4, 6, or 8 polymer weight percent and 0.15:1, 0.5:1, or 1:1 molar ratio of thiol groups to reactive -ene groups) to tune network properties including shear storage modulus and relative mesh size. Molecular Dynamics (MD) simulations were used to simulate the thiol-ene crosslinking reaction and establish a method for predicting thiol-ene reaction efficiency. Lastly, the feasibility of this hydrogel system for in vitro modeling was confirmed via assessment of metabolic activity of encapsulated primary human meniscal cells.

bioengineering↗

bioRxiv2026

Competing forms of protein-protein association and DNA binding exhibited by BrxC from the BREX phage restriction system

Bacteriophage exclusion (BREX) defense systems restrict phage infection via inhibition of phage DNA replication, while also modifying and protecting the bacterial genome. Type I BREX systems encode six conserved proteins, including a site-specific DNA methyltransferase. Host methylation requires a subset of BREX proteins, whereas phage restriction generally requires them all, suggesting that distinct but overlapping complexes mediate these activities. Full details of the mechanism and regulation of BREX remains to be understood. Here, we characterize the behavior and structures of the conserved BrxC AAA+ ATPase protein. BrxC forms multiple competing assemblages - various self-associating multimers, as well as a complex with BrxB-PglZ - that can be uncoupled via distinct point mutations, leading to differing effects on host methylation versus phage restriction. BrxCs self-association, as well as its ability to bind DNA, is regulated by ATP binding and hydrolysis; BrxA and BrxB appear to also regulate those behaviors. These collective results suggest that BrxC may play a key role in controlling the two activities of BREX, with BrxB, BrxC and PglZ forming a core complex, and the equilibrium among competing assemblies containing those proteins modulating the balance between idling and activated restrictive states.

biochemistry↗

bioRxiv2025

Glycation enhances protein association with lipid bilayer membranes

Glycation is a non-enzymatic post-translational modification that leads to the formation of advanced glycation end-products (AGEs), which accumulate in the blood-stream under chronic hyperglycemia and are implicated in diabetes-related pathologies. While glycated proteins such as albumin or hemoglobin are widely used as biomarkers for glycemic control, the structural and chemical changes induced by glycation may also alter their interactions with lipid interfaces, including cellular membranes and lipoproteins, potentially affecting their biological distribution and diagnostic detectability. In this study, we investigated how glycation influences the interaction of bovine serum albumin (BSA) with supported lipid bilayers (SLBs) of different compositions, used as model systems to replicate the diversity of membrane surface charges and fluidity. Using neutron reflectometry (NR), we compared the membrane association of BSA and a chemically-enhanced glycated form of BSA (gBSA), focusing on nanostructural changes at the bilayer interface. Our results showed negligible interaction of either proteins with zwitterionic or cationic membranes. In contrast, both BSA and gBSA exhibited significant binding to negatively charged bilayers, with glycation significantly amplifying this interaction. Quantitatively, the membrane-associated protein volume fraction increased from 0.11 (BSA) to 0.17 (gBSA), suggesting that glycation modifies the proteins surface properties in ways that promote stronger lipid interactions with negatively charged membranes. These findings suggest that glycation not only affects protein structure but also modulates protein-membrane affinity in a lipid-dependent manner. This has important implications for the bioavailability and behavior of glycated albumin in the bloodstream, potentially influencing the accuracy of clinical assays and contributing to membrane-related pathophysiology in diabetes. Our work highlights the need for a deeper understanding of glycation-induced changes in protein-lipid interactions and their consequences for biomarker reliability and disease mechanisms. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/685514v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@150e71aorg.highwire.dtl.DTLVardef@749b35org.highwire.dtl.DTLVardef@179f468org.highwire.dtl.DTLVardef@19cfe8e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

High-throughput discovery of a dearomative cycloaddition enables dual photochemical-photophysical perturbative probing of protein function

Proteins exist in multiple conformations or states, often associated with different functional capacities. The ability to selectively identify and study these states is crucial for understanding the dynamic nature of proteins and their roles in cellular processes, yet can be currently limited by the artefacts of existing molecular labels and the lack of strategies to exploit them in diverse ways. Whilst i) methods for the photochemical perturbation of proteins and ii) photophysical protein probes and sensors are both known powerful tools, simultaneous methods for site- and context-specific photochemical modification of a protein side chain with concomitant modulation of photophysical properties would allow interrogation of protein function via diverse modes (potentially reporting simultaneously on structure and dynamics of ground- and reactive-state properties). Due to their mechanistic complexity, rational approaches for the design of suitable photochemical strategies can be difficult and non-intuitive. Here, we describe a high-throughput experimentation (HTE) strategy designed to allow the photochemical modification of a genetically-encoded, minimally disruptive ( zero-size), photophysically-active - yet typically unreactive and biologically-inert - unnatural amino acid (uAA) residue in proteins. The discovery of a novel dearomative, formal [4+3] photocycloaddition of imidazopyrimidine reagents which proceeds via photochemically generated C* intermediates with polyaromatic substrates enabled chemoselective application to the normally unreactive Trp-mimetic residue, 2-naphthylalanine (Npa). Npas site-selective installation allows dual photochemical and photophysical dearomative perturbation benignly and efficiently in proteins. Replacement of Trp in the archetypal apoptotic biosensor protein Annexin A5 (AnxV) enabled dual photochemical-photophysical determination of switched, conformationally-determined reactive states induced by Ca2+-binding, without any apparent functional perturbation of its in vitro or cellular recognition of phospholipids, indicating an ordered annexin mechanism. This ready and benign unification of photochemistry and photophysics suggests a general approach for using high-throughput light-mediated experimentation in artefact-free chemical biology to capture different functional states of proteins and to interrogate those states using combined photochemical-photophysical methods. HighlightsO_LIDevelopment of a general, high-throughput experimentation (HTE) approach enabled identification of an unprecedented photochemical reaction with potential for editing amino acid side chains within proteins. C_LIO_LIGenetic incorporation of 2-naphthylalanine, a minimally-disruptive ( zero-size) Trp mimic, enabled photochemical side chain editing with concomitant modulation of its distinctive photophysical properties in proteins. C_LIO_LIA naphthalene-tagged variant of the apoptotic biomarker protein AnxV enabled dual photochemical-photophysical exploration of its dynamic conformational states induced by Ca2+-binding whilst fully maintaining its functional capacity for in vitro or cellular recognition of phospholipids. C_LI

biochemistry↗

bioRxiv2025

Intravenous Administration of Serotonergic Psychedelics Produce Short-lasting Changes in Sleep-Wake Behavior and High Gamma Functional Connectivity in Rats

Background and PurposeGiven the increase in recreational psychedelic use and ongoing efforts to explore psychedelics as therapeutic agents for mental health disorders, there is an urgent need to understand the effect of psychedelics such as psilocybin and N,N-dimethyltryptamine (DMT) on sleep-wake states, which share a bidirectional relationship with mental health. Here, we investigated the effects of intravenous psilocybin and DMT on sleep-wake states and EEG spectral power and functional connectivity in rats. Experimental ApproachSprague Dawley rats (n=25, 13 male) were surgically instrumented to record high-density EEG (27 electrodes) and EMG during 12-h light and 12-h dark cycle after intravenous psilocybin (2.5 mg/kg, 10 mg/kg), DMT (3.75 mg/kg, 7.5 mg/kg) or 0.9% saline. The EEG/EMG data were scored in 4-second epochs into wake, slow-wave sleep (SWS), and rapid eye movement (REM) sleep. EEG spectral power and corticocortical coherence, a surrogate for functional connectivity, were computed in 12-second epochs. Key ResultsPsilocybin and DMT delayed the onset of SWS and REM sleep, and caused a short-lasting increase in wakefulness and decrease in SWS. Psilocybin also produced a 1) decrease in REM sleep, 2) decrease in theta power and coherence and increase in high gamma power and coherence during wake and SWS, and 3) increase in high gamma coherence during REM sleep. DMT increased gamma coherence only during wakefulness. Conclusions and ImplicationsSerotonergic psychedelics have minimal effects on sleep-wake states. The enhanced high gamma functional connectivity suggests that the psychedelic-induced changes in EEG/neural dynamics can occur independent of the arousal states.

neuroscience↗

bioRxiv2025

APOE Tumor-Associated Macrophages and CD4-DOCK4 T Cells Reveal Distinct Microenvironmental Features in HER2-Low and HER2-0 Hormone Receptor-Positive Breast Cancer

Novel anti-HER2 antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), have shown efficacy in tumors with varying HER2 expression, including HER2-low and even tumors with minimal HER2 presence. This has sparked interest in the biology underlying the HER2 expression spectrum. Using molecular and multiplexed imaging, we revealed distinct immune and stromal features in treatment-naive, hormone receptor-positive (HR+) HER2-low versus HER2-0 tumors. HER2-0 tumors exhibit inflammatory and tissue remodeling gene signatures, with enrichment of APOE tumor-associated macrophages (TAMs) and DOCK4 CD4 T cells. In contrast, HER2-low tumors are more immunosuppressed, with elevated cell cycle, metabolic, and estrogen signaling pathways, suggesting increased proliferative activity. These findings underscore key biological differences between HR+ HER2-low and HER2-0 breast cancers, and may inform more tailored therapeutic strategies. Statement of significanceThis study revealed the distinct biological profiles of HR+ HER2-low and HER2-0 breast tumors. HER2-0 tumors exhibit inflammatory and tissue remodeling signatures, whereas HER2-low tumors have elevated cell cycle, metabolic, and estrogen signaling. These insights may help refine therapeutic approaches to improve outcomes for breast cancer patients.

cancer biology↗

bioRxiv2025

EssSubgraph improves performance and generalizability of mammalian essential gene prediction with large networks

Predicting essential genes is important for understanding the minimal genetic requirements of organisms, identifying disease-associated genes, and discovering potential drug targets. Wet-lab experiments for identifying essential genes are time-consuming and labor-intensive. Although various machine learning methods have been developed for essential gene prediction, both systematic testing with large collections of gene knockout data and rigorous benchmarking for efficient methods are very limited to date. Furthermore, current graph-based approaches require learning the entire gene interaction networks, leading to high computational costs, especially for large-scale networks. To address these issues, we propose EssSubgraph, an inductive representation learning method that integrates graph-structured network data with omics features for training graph neural networks. We used comprehensive lists of human essential genes distilled from the latest collection of knockout datasets for benchmarking. When applied to essential gene prediction with multiple types of biological networks, EssSubgraph achieved superior performance compared to existing graph-based and other models. The performance is more stable than other methods with respect to network structure and gene feature perturbations. Because of its inductive nature, EssSubgraph also enables predicting gene functions using dynamical networks with unseen nodes and it is scalable with respect to network sizes. Finally, EssSubgraph has better performance in cross-species essential gene prediction compared to other methods. Our results show that EssSubgraph effectively combines networks and omics data for accurate essential gene identification while maintaining computational efficiency. The source code and datasets used in this study are freely available at https://github.com/wenmm/EssSubgraph.

bioinformatics↗

bioRxiv2025

Spatiotemporal distribution and species diversity of pathogenic Vibrios in estuarine recreational waters of southeast Louisiana

Vibrio bacteria occur naturally in brackish water and can cause illnesses through recreational water exposure. Vibrio infections have shown a notable increase in recent years worldwide. In this study, bacterial culture and molecular methods were used to assess the prevalence and diversity of Vibrio species in the estuary of Lake Pontchartrain, the second largest inland brackish body in the United States. Water samples (n= 101) were collected from 9 recreational sites from November 2023 to November 2024. During the summer months (June, July, and August), the average Vibrio species. concentration was 5.2 x 104 colony-forming unit (CFU)/L. While in the winter months (December, January, and February), the average Vibrio spp. concentration was 3.2 x 103 CFU/L. Likewise, the temperature differed between summer and winter, with the average water temperatures being 30.39 {degrees}C and 14.45 {degrees}C, respectively. Linear modelling showed water temperature and salinity were found to be significant (p < 0.05) predictors of Vibrio concentrations from both culture methods and quantitative PCR, while precipitations were only significant for bacterial culture. The toxR genes of Vibrio cholerae, Vibrio vulnificus, and Vibrio parahaemolyticus persisted throughout the year, and 14.8% (n=9) of sequenced samples were identified as the O139 serotype of V. cholerae. Bacterial isolate sequencing revealed more than 100 Vibrio species in the lake with V. cholerae, V. vulnificus, and V. mimicus making up the largest proportion of the community. Continuous environmental monitoring of Vibrio is warranted in informing public health preparedness and expanding our understanding of the ecology of this pathogen. ImportanceGlobally, the diverse bacterial genus Vibrio is an important group of pathogens in coastal water environments. These bacteria are responsible for waterborne and seafood-borne illnesses as well as skin infections from recreational activities. Despite the rising incidence of Vibrio infections, routine monitoring of Vibrio species (spp.) in the environment remains limited. This gap hinders our understanding of their distribution, especially in estuarine areas, and potential public health risks linked to recreational activities. This study employed multiple techniques including bacterial culture, quantitative PCR, and genome sequencing to assess the prevalence, distribution, and diversity of Vibrios in the estuary. This study shows that Vibrio cholerae were prevalent in recreational water of a non-endemic region. The findings underscore the need for regular monitoring of Vibrio levels in recreational water and educating the public on the risks.

microbiology↗

bioRxiv2025

Generation of knock-in Cre and FlpO mouse lines for precise targeting of striatal projection neurons and dopaminergic neurons

The basal ganglia and midbrain dopaminergic systems are critical for motor control, reward processing, and reinforcement learning, with dysfunction in these systems implicated in numerous neurodegenerative and neuropsychiatric disorders. To enable precise genetic targeting of key neuronal populations, we generated and characterized five knock-in mouse lines: Drd1-Cre, Adora2a-Cre, Drd1-FlpO, Adora2a-FlpO, and DAT-FlpO. These lines allow for Cre-or FlpO-mediated recombination in dopamine D1 receptor-expressing spiny projection neurons (SPNs), adenosine A2a receptor-expressing SPNs, and dopamine transporter (DAT)-expressing neurons in the midbrain. Histological analyses confirmed recombinase activity in expected brain regions, and whole-cell electrophysiological recordings validated the intrinsic excitability profiles of each neuronal subpopulation. These tools provide high specificity and reliability for studying basal ganglia circuitry and dopaminergic neurons. By enabling targeted manipulations, these openly available knock-in lines will advance research into the neural mechanisms underlying motor control, reward, and neuropsychiatric diseases.

neuroscience↗

bioRxiv2025

RBP47 family members are negative regulators of heat stress tolerance in Arabidopsis thaliana

Stress granules (SGs) are liquid-liquid phase-separated condensates that sequester RNA, proteins, and metabolites to modulate cellular physiology under stress. In Arabidopsis, the RNA-binding protein RBP47b is a canonical SG marker, yet its functional contribution to thermotolerance remains unresolved. Here, we combined mTurboID proximity labeling with multi-omics profiling to define the RBP47b interactome and its physiological impact. mTurboID identified a stress-specific enrichment of 40S ribosomal subunits within RBP47b SGs, implicating these condensates in translational control. Surprisingly, quadruple mutant plants lacking all four RBP47 paralogues (rbp47abcc') displayed enhanced survival, attenuated growth delay, and faster recovery of photosynthetic efficiency after severe heat stress. Integrated transcriptome, proteome, and metabolome analyses revealed that this gain of thermotolerance is associated with (i) accelerated re-initiation of translation, (ii) constitutively elevated jasmonate and oxylipin pools, and (iii) reduced ROS accumulation during heat and recovery. We conclude that the RBP47 family acts as a negative regulator of heat tolerance by sequestering 40S subunits and limiting translational restart; loss of these SG scaffolds pre-primes jasmonate-dependent detoxification pathways and expedites proteome rebuilding, thereby conferring superior thermotolerance.

plant biology↗

bioRxiv2025

PglZ from Type I BREX phage defence systems is a metal-dependent nuclease that forms a sub-complex with BrxB

BREX (Bacteriophage Exclusion) systems, identified through shared identity with Pgl (Phage Growth Limitation) systems, are a widespread, highly diverse group of phage defence systems found throughout bacteria and archaea. The varied BREX Types harbour multiple protein subunits (between four and eight) and all encode a conserved putative phosphatase (PglZ aka BrxZ) and an equally conserved, putative ATPase (BrxC). Almost all BREX systems also contain a site-specific methyltransferase (PglX aka BrxX). Despite having determined the structure and fundamental biophysical and biochemical behaviours for the PglX methyltransferase, the BrxL effector, the BrxA DNA-binding protein and the BrxR transcriptional regulator, the mechanism by which BREX impedes phage replication remains largely undetermined. In this study, we identify a stable BREX sub-complex of PglZ:BrxB, validate the structure and dynamic behaviour of that sub-complex, and assess the biochemical activity of PglZ, revealing it to be a metal-dependent nuclease. PglZ can cleave cyclic oligonucleotides, linear oligonucleotides, plasmid DNA and both non-modified and modified linear phage genomes. PglZ nuclease activity has no obvious role in BREX-dependent methylation, but does contribute to BREX phage defence. BrxB binding does not impact PglZ nuclease activity. These data contribute to our growing understanding of the BREX phage defence mechanism.

biochemistry↗

bioRxiv2025

Deep Learning-Powered Colloidal Digital SERS for Precise Monitoring of Cell Culture Media

Maintaining consistent quality in biopharmaceutical manufacturing is essential for producing high-quality complex biologics. Yet, current process analytical technologies (PAT) struggle to achieve rapid and highly accurate monitoring of small molecule critical process parameters and critical quality attributes. While Raman spectroscopy holds great promise as a highly sensitive and specific bioanalytical tool for PAT applications, its conventional implementation, surface-enhanced Raman spectroscopy (SERS), is constrained by considerable temporal and spatial intensity fluctuations, limiting the achievable reproducibility and reliability. Herein, we introduce a deep learning-powered colloidal digital SERS platform to address these limitations. Rather than addressing the intensity fluctuations, the approach leverages their very stochastic nature, arising from highly dynamic analyte-nanoparticle interactions. By converting the temporally fluctuating SERS intensities into digital binary "ON/OFF" signals using a predefined intensity threshold by analyzing the characteristic SERS peak, this approach enables digital visualization of single-molecule events and significantly reduces false positives and background interferences. By further integrating colloidal digital SERS with deep learning, the applicability of this platform is significantly expanded and enables detection of a broad range of analytes, unlimited by the lack of characteristic SERS peaks for certain analytes. We further implement this approach for studying AMBIC 1.1, a chemically-defined, serum-free complete media for mammalian cell culture. The obtained highly accurate and reproducible results demonstrate the unique capabilities of this platform for rapid and precise cell culture media monitoring, paving the way for its widespread adoption and scaling up as a new PAT tool in biopharmaceutical manufacturing and biomedical diagnostics.

biophysics↗

bioRxiv2025

Human milk oligosaccharide metabolism by Clostridium species suppresses inflammation and pathogen growth

Gut microbiome development is strongly impacted by breastmilk and human milk oligosaccharides (HMOs), with short- and long-term health implications. HMO metabolism is best characterised within bifidobacteria, but the full range of other HMO-utilising species remains unknown. This study examined HMO-utilising bacteria that colonise preterm infants (born <32 weeks gestation), their role in microbiome modulation, and their effects on intestinal barrier function. We found that infant-derived Clostridium perfringens, and three other Clostridium species, metabolise HMOs, producing short chain fatty acids, tryptophan catabolites, and other metabolites known to improve host health. C. perfringens inhibited pathobiont growth and supressed inflammation in preterm-derived intestinal organoids. These findings suggest a previously unrecognised role for C. perfringens, specifically those lacking the perfringolysin O gene, in promoting healthy gut development during infancy.

microbiology↗

bioRxiv2024

An estrogen receptor signaling transcriptional program linked to immune evasion in human hormone receptor-positive breast cancer

T cells are generally sparse in hormone receptor-positive (HR+) breast cancer, potentially due to limited antigen presentation, but the driving mechanisms of low T cell abundance remains unclear. Therefore, we defined and investigated programs ( gene modules), related to estrogen receptor signaling (ERS) and immune signaling using bulk and single-cell transcriptome and multiplexed immunofluorescence of breast cancer tissues from multiple clinical sources and human cell lines. The ERS gene module, dominantly expressed in cancer cells, was negatively associated with immune-related gene modules TNF/NF-{kappa}B signaling and type-I interferon (IFN-I) response, which were expressed in distinct stromal and immune cell types, but also, in part, expressed and preserved as a cancer cell-intrinsic mechanisms. Spatial analysis revealed that ERS strongly correlated with reduced T cell infiltration, potentially due to its association with suppression of TNF/NF-{kappa}B-induced angiogenesis and IFN-I-induced HLA expression in macrophages. Preoperative endocrine therapy in ER+/HER2-breast cancer patients produced better responses in ERS-high patients, with TNF/NF-{kappa}B expression associated with reduced ERS. Targeting these pathways may enhance T cell infiltration in HR+ breast cancer patients. Statement of SignificanceThis study elucidates the immunosuppressive role of ER signaling in breast cancer, highlighting a complex interplay between cancer, stromal, and immune cells and reveals potential approaches to enhance immunogenicity in HR+ breast cancer. These findings offer crucial insights into immune evasion in breast cancer and identify strategies to enhance T cell abundance.

cancer biology↗