Biology subjects

Eriksson, J.

Publications and source records attributed to Eriksson, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Apical-Out Ileal Organoids: A Versatile Platform for Probing Gut-Nanomaterial Interactions

The human ileal epithelium forms a critical interface governing interactions with luminal microorganisms and nanomaterials, yet physiologically relevant in vitro models with accessible apical surfaces remain limited. Here, human apical-out ileoids derived from healthy ileal biopsies are established as a platform that recapitulates the architecture and complexity of the native ileal epithelium. Assessment of donor- and passage-dependent variability identifies a representative ileoid line and a robust culture window. Integrated proteomic, imaging, ultrastructural, and functional analyses demonstrate preservation of key epithelial features, including brush-border organization, barrier integrity, absorptive capacity, and multiple endocytic pathways. Intact ileoids internalize nanoparticles of distinct surface charge, including empty lipid nanoparticles compositionally matched to approved mRNA vaccine formulations, establishing that uptake can be quantified across an unperturbed apical surface. This uptake is restrained by a retained mucin-rich glycocalyx. Cleavage of surface-attached mucins selectively enhances uptake of negatively charged nanoparticles, leaving near-neutral and positively charged nanoparticles unchanged, and increasing entry of Salmonella bacteria. These findings reveal the glycocalyx as a charge-selective regulator of epithelial uptake. In conclusion, our study provides a foundation for nanoparticle-epithelium investigations using human apical-out ileoids, and a versatile, translationally relevant platform for nanomedicine delivery, host-microbe interactions, and epithelial transport.

cell biology↗

bioRxiv2026

Prenatal exposure to PFAS and multimodal structural brain development across childhood

BackgroundPer- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental pollutants that are posited to be neurotoxic to the developing brain; however, the impact of prenatal exposure to PFAS -- particularly to newer, short-chain PFAS -- on brain development across childhood is unclear. MethodsConcentrations of 9 PFAS were quantified in cord blood plasma of 459 infants who later participated in structural and diffusion magnetic resonance imaging (MRI) at ages 4.5, 6, 7.5, and 10.5 years, providing estimates of regional cortical thickness and surface area, subcortical volumes, and fractional anisotropy (FA) of key white matter tracts. Longitudinal mixed effect models estimated associations of PFAS with age 4.5 brain metrics and their developmental trajectories across childhood. ResultsHigher concentrations of long-chain PFAS (PFNA, PFHxS, PFDA) in cord blood were associated with lower surface area of the right paracentral lobule at age 4.5. PFHpA was associated with faster surface area growth in the left rostral anterior cingulate and slower growth in the right caudal middle frontal gyrus from 4.5 to 10.5 years. The short-chain compound PFBS was linked with greater FA in 17 of 27 white matter tracts at 4.5 years; those associations attenuated with age. Finally, PFOA was associated with lower FA in 6 tracts at 4.5 years. ConclusionsPrenatal exposure to PFAS was associated with altered development of frontal and paracentral regions and of white matter microstructure. These findings highlight the need for further research examining the long-term effects of prenatal exposure to PFAS on childrens neurodevelopment.

neuroscience↗

bioRxiv2026

Developing a multi-modal neuroimaging-based BrainAge model across childhood

BrainAge models hold promise as a clinical biomarker for developmental brain health, especially in childhood when there is the potential for early intervention. To distinguish between normative developmental variance and pathological divergence, BrainAge models should reflect the dynamic and diverse neurodevelopmental processes that occur in distinct developmental windows across childhood. We utilized multi-modal neuroimaging data from three pediatric cohorts covering ages 4 to 13 years (n = 1005, 2126 scans), split into Train and Test datasets. Twelve sex-stratified BrainAge models were built stratified by type and different combinations of neuroimaging features. Model types were "Full-Span" models covering the full age range, and "Phase-Specific" models split into early- and late-childhood. We first compared BrainAge estimates in the Test dataset amongst our candidate models, then benchmarked the best-performing model against published pre-trained models and DNA-based biological age measures. Our findings show that a BrainAge model that was phase-specific and consisted of both structural and functional features (cortical thickness, subcortical volumes, and functional network integration measures) showed good prediction of age and best distinguished between healthy and symptomatic subgroups. We present a proof-of-concept for developmental models supporting building BrainAge models of higher temporal resolution that align to different childhood developmental phases.

neuroscience↗

bioRxiv2026

Predicting Pre-treatment Resistance or Post-treatment Effect? A Systematic Benchmarking of Single-Cell Drug Response Models

Intratumoral heterogeneity drives variable drug responses in cancer. Single-cell RNA sequencing (scRNA-seq) enables characterization of such heterogeneity and prediction of drug response at single-cell resolution. Accordingly, various computational models have been developed to infer drug response from scRNA-seq data. However, their performance, robustness, and generalizability across different biological contexts remain insufficiently evaluated. To address this gap, we benchmarked representative single-cell drug response prediction models using 26 curated datasets comprising over 760,000 cells across 12 cancer types and 21 therapeutic agents. We constructed balanced and imbalanced scenarios to reflect realistic drug-response label distributions. To address the lack of ground-truth labels in conventional scRNA-seq datasets, we incorporated lineage-tracing data with experimentally validated drug-response annotations, enabling evaluation in a clinically relevant pre-treatment prediction setting. Our results show that prediction performance was markedly higher in cell lines than in tissue samples. Under imbalanced conditions, most methods exhibited sharp performance declines, whereas scDEAL demonstrated the highest robustness. Independent validation using an in-house pancreatic ductal adenocarcinoma dataset further confirmed scDEALs robustness and ability to capture biologically meaningful state transitions. Label-substitution experiment revealed that this robustness was partially driven by the models specific training-label construction. However, benchmarking with lineage-tracing data revealed a fundamental limitation: most models capture drug-induced transcriptional changes but struggled to predict intrinsic resistance before treatment. In summary, our study defines the performance boundaries of current approaches and highlights their limitations in addressing intratumoral heterogeneity, class imbalance, and intrinsic resistance prediction, emphasizing the need for the next-generation single-cell drug response models with stronger clinical relevance.

bioinformatics↗

bioRxiv2026

Dual Screen for Gut Metabolites Suppressing Enterobacterial Growth and Invasiveness Reveals Structure - Activity Relationships among Anti-Infective Indoles

The antibiotic resistance crisis makes characterization of new anti-infective molecules a pressing matter. Molecules that suppress bacterial growth and survival, virulence, or the combination of these traits, all warrant further exploration. Naturally occurring microbe-host ecosystems, such as the human gut, provide incompletely tapped resources in this regard. We developed a flexible platform to parallelly assess how gut metabolites affect the growth and epithelial cell invasion capacity of the enteropathogens Salmonella enterica Typhimurium (Salmonella) and Shigella flexneri. By screening a gut metabolite library, the assays identified multiple anti-infective compound classes and extended previously reported antibacterial activities for e.g. medium chain fatty acids, bile acids, purine nucleotides, and indole. Importantly, a targeted follow-up screen combined with chemical biology iterations showed how the anti-infective activity of indole is impacted by its derivatization. Specifically, a methyl group at either of the carbons of the indole scaffold potentiated the suppressive effect on type-III-secretion-system-mediated virulence, flagellar motility (for Salmonella), and growth, in a concentration-dependent manner. By contrast, N1-methylation markedly attenuated the activity of indole and its C-derivatized versions. The study, hence, offers assays for dual growth and virulence analysis of invasive enterobacteria exposed to anti-infective candidate molecules, and informs on structure-activity relationships among indole metabolites.

microbiology↗

bioRxiv2025

Proteome profiling reveals HES1-driven mitotic catastrophe in ovarian serous carcinoma

Ovarian high-grade serous cancer (HGSC) is an aggressive subtype of epithelial ovarian cancer. Here, we identify BX-912, a phosphoinositide-dependent kinase 1 (PDPK1) inhibitor, as a promising therapeutic agent for HGSC. BX-912 suppressed HGSC growth as a single agent and synergized with olaparib independently of BRCA status. Unexpectedly, BX-912 treatment induced multinucleation, a phenotype not observed with other PDPK1 inhibitors. Proteome Integral Solubility Alteration (PISA) profiling revealed the transcription factor HES1 as a functional target of BX-912. Structural modeling showed that BX-912 binds the Orange domain of HES1, while its WRPW motif mediates interactions with protein partners, including the AP2 endocytic protein complex, coordinating their nuclear accumulation that leads to a mitotic catastrophe. Furthermore, cell cycle analyses showed that BX-912 combined with olaparib synergistically enhanced DNA damage and G2-M arrest. Our study demonstrates the value of proteomics for revealing hidden drug activities. It also identifies potential inhibition strategies for HES1, which is commonly overexpressed in HGSC. Additionally, this study proposes a novel strategy of targeting consecutive cell cycle phases to enhance treatment efficacy in HGSC.

cancer biology↗

bioRxiv2025

Matrix-M(R) adjuvant triggers inflammasome activation and enables antigen cross-presentation through induction of lysosomal membrane permeabilization

Matrix-M(R) adjuvant, containing saponins, delivers a potent adjuvant effect and good safety profile. Given that Matrix-M is composed of Matrix-A and Matrix-C particles, comprising different saponin fractions, understanding their distinct roles can provide deeper insight into the mechanism of action of Matrix-M and guide future applications. Here, we demonstrate that antigen and Matrix-M, Matrix-A, or Matrix-C colocalize in lysosomes following uptake by bone marrow-derived dendritic cells. Matrix-M, Matrix-A, and Matrix-C induce lysosomal membrane permeabilization (LMP), but Matrix-C shows the highest LMP potential. LMP is required for interleukin (IL)-1{beta} and IL-18 secretion in vitro. In vivo, a robust adjuvant effect of Matrix-M, Matrix-A, and Matrix-C is observed, both in the presence and absence of the NLRP3 inflammasome. LMP induced by Matrix-M, as well as Matrix-A and Matrix-C, also enables antigen cross-presentation. Thus, Matrix-induced LMP explains the capability of Matrix-M- adjuvanted protein vaccines to induce CD8+ T-cell responses.

immunology↗

bioRxiv2025

Human jejunal enteroids for studies of epithelial drug transport and metabolism

Intestinal enteroids are stem cell-based "mini-guts" that mimic many aspects of the corresponding epithelial barrier in vivo. Here, we established and characterized differentiated apical-out (AO) and basal-out (BO) jejunal enteroids in suspension and followed their differentiation by quantitative global proteomics and different microscopic techniques. The barrier integrity and function and subcellular location of nutrient and clinically important drug transporters were investigated in the matured enteroids using live-cell microscopy. The presystemic metabolism of two drugs by CYP3A4 was determined and the results were used to predict the pharmacokinetics after oral administration by a PBPK population model. The differentiated AO enteroids displayed a protein profile that overlapped both qualitatively and quantitatively with that of freshly isolated jejunal enterocytes and tissue. They exhibited a morphology that recapitulates the mature villus enterocyte in vivo, formed an intact barrier with a well-developed glycocalyx and are impermeable to the hydrophilic low molecular weight compound lucifer yellow and transported a medium chain fatty acid derivative by FATP4 into lipid deposits. The clinically important ABC-transporters Pgp and BCRP were expressed at near in vivo levels, had the correct subcellular localization and effluxed their substrates. Terfenadine and midazolam were metabolized by CYP3A4 and the results were used to predict the clinical pharmacokinetics of the drugs after oral administration with good accuracy. We conclude that suspended 3D AO enteroids provide a physiologically relevant model for studies of intestinal function that offers convenient access to the apical surface and is easy to dispense in multi-wells formats for large scale experimentation.

cell biology↗

bioRxiv2025

Subliminal risk influences subjective value in the ventromedial prefrontal cortex

The relationship between conscious awareness and decisions has been heavily debated. Here we investigated whether subliminal probabilities are integrated with conscious rewards to form subjective value (SV) representations in the anterior ventral striatum (aVS) and ventromedial prefrontal cortex (vmPFC). Participants played an incentivized competitive game with risky choice to accumulate points across trials in a behavioral and fMRI experiment. The game was a modified attentional-blink paradigm that rendered a probability cue unseen (indicating a 100% or 0% chance to win a risky reward). Following the probability cue, participants chose between a safe (1 point with certainty) or risky option (>1 or 0 points depending on probability cue). The risky reward was either 2 or 5 points, varying across trials. In some trials the probability cue was absent (replaced by a random distractor) and the probability to win the risky reward was 50%. When probability cues were unseen, they did not influence choice, as value-maximizing choice (d) was not greater than chance, but they did influence reaction time in both experiments. Consistent with SV integration, the BOLD signal in aVS and vmPFC was higher for both conscious rewards (high > low) and subliminal probabilities (high > low) and could not be explained by subliminal salience (cue present > absent). Moreover, multivariate pattern similarity between conscious rewards and subliminal probabilities in vmPFC suggest integration into an abstract value representation. Additionally, we found brain-wide subliminal probability and salience effects. Taken together, these results suggest that conscious awareness is not necessary for probability to be integrated with conscious rewards to form an abstract "common currency" SV representation in vmPFC. Additionally, brain-wide subliminal probability and salience effects suggests information can have "global access" without conscious awareness.

neuroscience↗

bioRxiv2025

A human induced pluripotent stem cell toolbox for studying sex chromosome effects

Sex chromosomes shape male (XY) - female (XX) differences in development and disease. These differences can be modelled in vitro by comparing XY and XX human induced pluripotent stem cells (hiPSCs). However, in this system, inter-individual autosomal variation and unstable X-dosage compensation can confound identification of sex chromosomal effects. Here, we utilise sex chromosome loss in XXY fibroblasts to generate XX and XY hiPSCs that are autosomally isogenic and exhibit stable X-dosage compensation. We also create X-monosomic (XO) hiPSCs, to investigate X-Y dosage effects. Using these autosomally isogenic lines, we examine sex differences in pluripotent stem cell expression. Transcriptional differences between XX and XY hiPSCs are surprisingly modest. However, X-haploinsufficiency induces transcriptional deregulation predominantly affecting autosomes. This effect is mediated by Y-genes with broad housekeeping functions that have X-homologues escaping X-inactivation. Our isogenic hiPSC lines provide a resource for exploring sex chromosome effects on development and disease in vitro.

genetics↗

bioRxiv2024

Uncovering pre-sensitizing agents to FLT3 inhibitors in acute myeloid leukemia with ReSisTrace lineage tracing

While FLT3 inhibitors have significantly improved the treatment of aggressive FLT3-mutated acute myeloid leukemia (AML), the emergence of resistance remains as a major challenge. Here, we applied our recently developed single-cell lineage-tracing method ReSisTrace to identify cells that are pre-resistant or pre-sensitive to FLT3 inhibitors midostaurin and quizartinib in FLT3-ITD-positive AML. By comparing the gene expression profiles of these cells, we unraveled the transcriptional pre-resistance signatures, including G1 to S phase transition 1 (GSPT1) gene. Targeting GSPT1 with the small molecule CC-90009 exhibited strong synergistic effect when combined with FLT3 inhibitors in the FLT3-ITD-mutated MOLM-13 and MV4-11 cell lines and primary AML patient samples. Further, we identified novel compounds that induced transcriptomic changes opposite to the pre-resistance signatures, thereby driving cells to FLT3 inhibitor-sensitive states. Vistusertib (mTOR inhibitor), linsitinib (IGF1R and insulin receptor inhibitor), and meisoindigo (IGF1R and Src family kinase inhibitor), all inhibiting pathways parallel to or downstream of oncogenic FLT3 signaling, were predicted and validated to pre-sensitize the FLT3-ITD-mutated cell lines and primary cells to FLT3 inhibitors. Collectively, these findings demonstrate the validity of our lineage-tracing method in unveiling pre-existing transcriptional features of treatment vulnerability in hematological cancers, and elucidate novel strategies for enhancing FLT3 inhibitor treatment efficacy in FLT3-ITD-positive AML by preventing the emergence of treatment resistance.

cancer biology↗

bioRxiv2024

Maturation of Human Intestinal Epithelial Cell Layers Fortifies the Apical Surface against Salmonella Attack

The active invasion of intestinal epithelial cells (IECs) represents a key event in the infection cycle of many gut pathogens. Studies of how Salmonella enterica Typhimurium (S.Tm) bacteria enter transformed cell lines have shaped the paradigm for swift type-three-secretion-system-1 (TTSS-1)-driven IEC invasion, fueled by expansive membrane ruffles. However, comparative studies suggest that non-transformed IECs in the intact gut context comprise a much more challenging target for the attack. The molecular and cellular features that explain these discrepancies remain undefined. By live-cell imaging in human enteroid-and colonoid-derived IEC layers, we demonstrate that the maturation state of gut epithelia dramatically impacts permissiveness to S.Tm invasion. IEC layers kept under immature progenitor-cell-promoting conditions are permissive to the bacterial invasion, whereas maturation towards an enterocyte/colonocyte fate reduces the frequency of S.Tm-induced epithelial entry structures, and lowers the invasion efficiency by up to tenfold. This phenotypic shift during IEC maturation couples to an altered expression of actin regulatory proteins implicated in the invasion process, and an increased dependence on the S.Tm TTSS-1 effector SipA for successful entry. In addition, IEC maturation involves upregulation of cell surface mucins, e.g. MUC13, and shifts in glycocalyx composition, as revealed by multiple lectin stainings. Enzymatic treatment of the apical surface with the StcE mucinase converts maturing IEC layers back to the S.Tm-invasion-permissive state of their immature counterparts. Taken together, these results showcase how the maturation state of human IECs dictates the susceptibility to invasion by a prototype enterobacterium.

cell biology↗

bioRxiv2024

Determinants of the Divergent Salmonella and Shigella Epithelial Colonization Strategies Resolved in Human Enteroids and Colonoids

Despite close relatedness, the major enteropathogens Salmonella and Shigella differ in infectious dose, pathogenesis, and disease kinetics. The prototype strains Salmonella enterica serovar Typhimurium (Salmonella) and Shigella flexneri (Shigella) use Type-3-secretion-systems (T3SSs) to colonize intestinal epithelial cells (IECs), but have evolved partially unique sets of T3SS effectors and accessory virulence factors. A synthesis of how these differences impact the temporal progression of infection in non-transformed human epithelia is missing. Here, we followed Salmonella and Shigella infections of human enteroids and colonoids by time-lapse imaging to pinpoint virulence factor modules that shape the divergent epithelial colonization strategies. By an apical targeting module that integrates flagella and the SPI-4-encoded adhesin system with T3SS, Salmonella accomplishes appreciable numbers of apical invasion events, promptly terminated by IEC death, and thus fostering a polyclonal iterative epithelial colonization strategy. The lack of a corresponding module in Shigella makes this pathogen reliant on external factors such as preexisting damage for rare apical access to the intraepithelial environment. However, Shigella compensates for this ineptness by an intraepithelial expansion module, where tight coupling of OspC3-dependent temporal delay of cell death and IcsA-mediated lateral spread enables intraepithelial Shigella to outrun the IEC death response, fostering an essentially monoclonal colonization strategy.

microbiology↗

bioRxiv2023

Histopathology-assisted proteogenomics provides foundations for stratification of melanoma metastases

Here we describe the histopathology-driven proteogenomic landscape of 142 treatment-naive metastatic melanoma samples. We identified five proteomic subtypes that integrate the immune and stroma microenvironment components, and associate with clinical and histopathological parameters, providing foundations for an in-depth molecular classification of melanoma. Our study shows that BRAF V600 mutated melanomas display heterogeneous biology, where the presence of an oncogene-induced senescence-like phenotype improves patient survival. Therefore, we propose a mortality-risk-based stratification, which may contribute to a more personalized approach to patient treatment. We also found a strong association between tumor microenvironment composition, disease progression, and patient outcome supported by single-cell omic signatures that point to straightforward histopathological connective tissue-to-tumor ratio assessment for better informed medical decisions. A melanoma-associated signature of single amino acid variants (SAAV) responsible for remodeling the extracellular matrix was uncovered together with SAAV-derived neoantigen candidates as targets of anti-tumor immune responses. Overall, this study offers comprehensive stratifications of melanoma metastases that may help develop tailored strategies for diagnosing and treating the disease.

cancer biology↗

bioRxiv2023

A Two-Step Activation Mechanism Enables Mast Cells to Differentiate their Response between Extracellular and Invasive Enterobacterial Infection

Mast cells (MCs) localize to mucosal tissues and contribute to innate immune defenses against infection. How MCs sense, differentiate between, and respond to bacterial pathogens remains a topic of ongoing debate. Using the prototype enteropathogen Salmonella Typhimurium (S.Tm) and other closely related enterobacteria, we here demonstrate that MCs can regulate their cytokine secretion response to distinguish between extracellular and invasive bacterial infection. Tissue-invasive S.Tm and MCs colocalize in the Salmonella-infected mouse gut. Toll-like Receptor 4 (TLR4) sensing of extracellular S.Tm, or pure LPS, causes a slow and modest induction of MC cytokine transcripts and proteins, including IL-6, IL-13, and TNF. By contrast, type-III-secretion-system-1 (TTSS-1)-dependent S.Tm invasion of both mouse and human MCs triggers rapid and potent inflammatory gene expression and >100-fold elevated cytokine secretion. The S.Tm TTSS-1 effectors SopB, SopE, and SopE2 here elicit a second activation signal, including Akt phosphorylation downstream of effector translocation, which combines with TLR activation to promote the full-blown MC response. Supernatants from S.Tm-infected MCs boost macrophage survival and maturation from bone-marrow progenitors. Taken together, this study shows that MCs can differentiate between extracellular and host-cell invasive enterobacteria via a two-step activation mechanism and tune their inflammatory output accordingly.

immunology↗

bioRxiv2022

High-efficiency transfection of Acanthamoeba castellanii using a cationic polymer

The free-living amoeba Acanthamoeba castellanii is an ecologically, clinically, and evolutionarily important microorganism. A. castellanii amoebae are directly pathogenic to humans and serve as reservoirs for bacterial pathogens (e.g., Legionella pneumophila) but also regulate the proliferation of other microorganisms in the soil. Despite their importance, no reliable genetic system has been developed, hampering the use of A. castellanii and related species as model organisms. Transfecting A. castellanii with plasmids is possible with commercial kits, but it is expensive, inefficient, and vulnerable to product discontinuation. In this contribution, we present a method for efficient transfection of A. castellanii with readily available and inexpensive polyethylenimines. We systematically explore the methods parameters, obtaining up to 100-fold higher efficiency than currently used protocols. The method presented here provides a robust step towards a complete genetic toolbox for A. castellanii, hence expanding its use as a model organism.

microbiology↗

bioRxiv2022

Tracing back primed resistance in cancer via sister cells

Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance. We applied ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells. The pre-resistant phenotypes were defined by cell cycle and proteostatic features, reflecting the traits enriched in the upcoming subclonal selection. Furthermore, DNA repair deficiency rendered cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leveraged the pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.

cancer biology↗

bioRxiv2022

Bimodal pilot study on inner speech decoding reveals the potential of combining EEG and fMRI

The recognition of inner speech, which could give a voice to patients that have no ability to speak or move, is a challenge for brain-computer interfaces (BCIs). A shortcoming of the available datasets is that they do not combine modalities to increase the performance of inner speech recognition. Multimodal datasets of brain data enable the fusion of neuroimaging modalities with complimentary properties, such as the high spatial resolution of functional magnetic resonance imaging (fMRI) and the temporal resolution of electroencephalography (EEG), and therefore are promising for decoding inner speech. This paper presents the first publicly available bimodal dataset containing EEG and fMRI data acquired nonsimultaneously during inner-speech production. Data were obtained from four healthy, right-handed participants during an inner-speech task with words in either a social or numerical category. Each of the 8-word stimuli were assessed with 40 trials, resulting in 320 trials in each modality for each participant. The aim of this work is to provide a publicly available bimodal dataset on inner speech, contributing towards speech prostheses.

neuroscience↗