Biology subjects

Rosen, M. J.

Publications and source records attributed to Rosen, M. J..

10 recordsLinked to original sources

bioRxiv2026

Single-cell immune repertoire atlas maps coordinated circulating adaptive immune states in inflammatory bowel disease

Single-cell studies have defined immune states in inflammatory bowel disease (IBD), but how adaptive receptor histories organize circulating immunity remains unclear. We generated a single-cell transcriptomic atlas of peripheral blood from 249 participants with Crohn's disease, ulcerative colitis, or non-IBD control status, including 182 with productive TCR and BCR recovery. Expanded TCR clonotypes marked inflammatory-memory and cytotoxic states, while distinct but similar paired TCRs shared inflammatory programs across participants. BCR lineage maturation linked IgA-associated mucosal and plasma B cell programs to somatic mutation and class switching, distinguishing maturation-associated biology from clonal expansion. Helper, regulatory, and cytotoxic T-cell programs covaried with B-cell states, and inferred interactions nominated reciprocal antigen-presentation and helper pathways. Repertoire-based machine learning distinguished diagnosis, inflammation, and contemporaneous six-month treatment-response status. Together, this atlas connects receptor architecture to coordinated systemic immune remodeling, establishes a foundation for repertoire-informed patient stratification, and prioritizes candidate mechanisms of IBD pathogenesis.

immunology↗

bioRxiv2026

Intelligible distracting speech disrupts early auditory attention

Intelligible speech disrupts selective auditory attention more than an unintelligible stream. However, low-level acoustic features of intelligible speech are relatively similar to target speech, confounding results. While controlling acoustic similarity and limiting energetic masking, we examined how masker intelligibility affects behavior and electroencephalography (EEG). Normal hearing listeners detected color words within a target stream of randomly timed words while ignoring an ongoing masker. Maskers were either spoken by the same or a different talker and comprised either isochronous sequences of intelligible words or temporally scrambled versions. Scrambled maskers either lacked broadband energy changes over time (Experiment 1) or were amplitude modulated to have the same energy profiles as intelligible, isochronous maskers (Experiment 2). In both experiments, scrambled maskers yielded better performance than intelligible maskers. For intelligible maskers, performance was better for different compared to identical talkers. EEG responses paralleled behavior: target-evoked onset responses were larger for scrambled than for intelligible maskers, particularly for identical talkers. Later target recognition responses were larger for color than other target words but unaffected by masker type or talker. Even when low-level acoustic features were carefully matched, intelligible maskers impaired auditory attention and reduced target-evoked neural responses more than scrambled maskers, implicating early sensory filtering.

neuroscience↗

bioRxiv2026

FOXP3-engineered regulatory T cells restore intestinal barrier integrity in Crohn's disease enteroids via PDGF-AA

Epithelial regeneration and barrier integrity are impaired in inflammatory bowel diseases, including Crohns disease (CD), yet current therapies largely target immune inflammation without directly promoting mucosal repair. While regulatory T cells are classically immunomodulatory, their capacity to directly support human intestinal stem cells (ISCs) and barrier function remains unclear. In this study, we tested the hypothesis that FOXP3-expressing regulatory T cells--engineered CD4LVFOXP3 and thymic-derived Treg (tTreg)--directly support human ISC maintenance and restore epithelial barrier function independent of their immunomodulatory function. Using CD patient ISCs-derived enteroids that display disease-associated damage, we established co-culture with FOXP3-engineered Treg cell-CD4LVFOXP3 or thymic-derived Treg (tTreg). The presence of either CD4LVFOXP3 or tTreg cells enhanced enteroid growth, improved epithelial barrier function, and restored apical-basal polarity of ISCs, indicating reparative capacity. Conversely, activated conventional CD4+ T cells reduced barrier function and abrogated apical-basal polarity. Integrating secretome profiling with ligand add-back and receptor or ligand blockade, we identify the PDGF-AA-PDGFR axis as a key regulator of Treg-mediated intestinal epithelial barrier integrity, but dispensable for Treg suppressive capacity. Collectively, our data delineate a direct, human tissue-intrinsic role of FOXP3-driven Treg in the interaction with ISCs via PDGF-AA-PDGFR, enhancing epithelial barrier function and positioning CD4LVFOXP3 as a treatment approach coupling immunoregulation with epithelial repair. One Sentence SummaryRegulatory T cells improve the intestinal epithelial barrier function, primarily, through the PDGF-AA-PDGFR axis

immunology↗

bioRxiv2025

Developmental and Stress-Induced Effects on 5-HT3R-Expressing Interneurons within Auditory Cortex

Early life stress (ELS) is a well-known predictor of neuropsychiatric disease and contributes to the development of sensory processing deficits that persist throughout life. Organisms are particularly susceptible to the deleterious effects of stress during critical periods, when neuroplasticity is heightened, and initial representations of the sensory environment are mapped to cortex. When ELS is induced during the auditory cortical (ACx) critical period, it impairs both neural and behavioral responses to a variety of auditory stimuli that rely on temporal processing. Mechanisms by which ELS may alter critical period plasticity are of particular interest in understanding ELS-related pathology, including the 5-HT3R interneuron system, which has been implicated in regulating neural activity during critical periods. Here we examined two principal subpopulations of interneurons in primary ACx: VIP and NDNF cells, which account for a majority of cortical neurons expressing 5-HT3R. The expression of the Htr3a gene during normal development and under ELS conditions was quantified using multiplex fluorescent in situ hybridization. We show that densities of cells expressing NDNF and VIP decrease following ear opening and across the ACx critical period, and that ELS results in the maintenance of elevated cell densities compared to age-matched controls. Further, Htr3a in VIP neurons is developmentally upregulated, and its expression is further increased by ELS beyond normal physiologic levels. Stress-induced shifts in these serotonergic interneurons may contribute to deficits that arise in auditory cortical and perceptual responses via effects on local cortical circuitry.

neuroscience↗

bioRxiv2024

Characterizing Behavioral Effects of Early-Life Stress in an Animal Model of Auditory Processing

Animal models provide significant insight into the development of typical and disordered sensory processing. Such models have been established to take advantage of physical and behavioral characteristics of specific species. For example, the Mongolian gerbil is a well-established model for auditory processing, with a hearing range similar in frequency to that of humans and an easily accessible cochlea. Recently, early-life stress (ELS) has been shown to affect sensory processing in auditory, visual, and somatosensory neural regions. To understand the functional impact of ELS, it is necessary to evaluate the susceptibility of sensory perceptual abilities to this early perturbation. Yet measuring sensory perception - e.g., using operant conditioning - often concurrently involves animal behavioral elements such as attention, memory, learning, and emotion. All of these elements are well-known to be impacted by ELS, and may affect behavioral measurements in ways that could be misconstrued as sensory deficits. Thus, it is critical to characterize which behavioral elements are affected by ELS in any sensory model. Here we induced ELS during a developmental time window for maturation of the auditory cortex in Mongolian gerbils. We conducted behavioral measures in juveniles, a developmental age when ELS is known to impair the auditory pathway. ELS had no effect on overall activity but reduced anxiety-related behavior, impaired recognition memory, and improved spatial memory, with some sex-specific effects. These effects may influence the ability of gerbils to learn and retain operant training, particularly if anxiety-provoking reinforcement is used.

animal behavior and cognition↗

bioRxiv2024

Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis

Background & AimsUlcerative colitis (UC) is associated with epithelial metabolic derangements which exacerbate gut inflammation. Patient-derived organoids recapitulate complexities of the parent tissue in health and disease; however, whether colon organoids (colonoids) model metabolic impairments in the pediatric UC epithelium is unclear. This study determined the functional metabolic differences in the colon epithelia using epithelial colonoids from pediatric patients. MethodsWe developed biopsy-derived colonoids from pediatric patients with endoscopically active UC, inactive UC, and those without endoscopic or histologic evidence of colon inflammation (non-IBD controls). We extensively interrogated metabolic dysregulation through extracellular flux analyses and tested potential therapies that recapitulate or ameliorate such metabolic dysfunction. ResultsEpithelial colonoids from active UC patients exhibit elevated oxygen consumption and proton leak supported by enhanced glycolytic capacity and dysregulated lipid metabolism. The hypermetabolic features in active UC colonoids were associated with increased cellular stress and chemokine secretion, specifically during differentiation. Transcriptomic and pathway analyses indicated a role for PPAR- in lipid-induced hypermetabolism in active UC colonoids, which was validated by PPAR- activation in non-IBD colonoids. Accordingly, limiting neutral lipid accumulation in active UC colonoids through pharmacological inhibition of PPAR- induced a metabolic shift towards glucose consumption, suppressed hypermetabolism and chemokine secretion, and improved cellular stress markers. Control and inactive UC colonoids had similar metabolic and transcriptomic profiles. ConclusionsOur pediatric colonoids revealed significant lipid-related metabolic dysregulation in the pediatric UC epithelium that may be alleviated by PPAR- inhibition. This study supports the advancement of colonoids as a preclinical human model for testing epithelial-directed therapies against such metabolic dysfunction. What You Need to KnowO_ST_ABSBackground and ContextC_ST_ABSColon mucosa healing in pediatric UC requires reinstating normal epithelial function but a lack of human preclinical models of the diseased epithelium hinders the development of epithelial-directed interventions. New FindingsUsing colon biopsy-derived epithelial organoids, samples from pediatric patients with active UC show hyperactive metabolic function largely driven by enhanced lipid metabolism. Pharmacologic inhibition of lipid metabolism alleviates metabolic dysfunction, cellular stress, and chemokine production. LimitationsThough our epithelial colon organoids from active UC patients show targetable metabolic and molecular features from non-IBD controls, they were cultured under sterile conditions, which may not fully capture any potential real-time contributions of the complex inflammatory milieu typically present in the disease. Clinical Research RelevanceCurrent therapies for pediatric UC mainly target the immune system despite the need for epithelial healing to sustain remission. We identified a pharmacologic target that regulates epithelial metabolism and can be developed for epithelial-directed therapy in UC. Basic Research RelevancePediatric UC patient tissue adult stem cell-derived colon epithelial organoids retain disease-associated metabolic pathology and can serve as preclinical human models of disease. Excess reliance on lipids as an energy source leads to oxidative and inflammatory dysfunction in pediatric UC colon organoids. Preprint: This manuscript is currently on bioRxiv. doi: https://doi.org/10.1101/2024.08.22.609271 Lay Summary: Using patient tissue-derived colon epithelial organoids, the investigators identified epithelial metabolic dysfunction and inflammation in pediatric ulcerative colitis that can be alleviated by PPAR-a inhibition.

physiology↗

bioRxiv2023

Increased reliance on temporal coding when target sound is softer than the background

Everyday environments often contain multiple concurrent sound sources that fluctuate over time. Normally hearing listeners can benefit from high signal-to-noise ratios (SNRs) in energetic dips of temporally fluctuating background sound, a phenomenon called dip-listening. Specialized mechanisms of dip-listening exist across the entire auditory pathway. Both the instantaneous fluctuating and the long-term overall SNR shape dip-listening. An unresolved issue regarding cortical mechanisms of dip-listening is how target perception remains invariant to overall SNR, specifically, across different tone levels with an ongoing fluctuating masker. Equivalent target detection over both positive and negative overall SNRs (SNR invariance) is reliably achieved in highly-trained listeners. Dip-listening is correlated with the ability to resolve temporal fine structure, which involves temporally-varying spike patterns. Thus the current work tests the hypothesis that at negative SNRs, neuronal readout mechanisms need to increasingly rely on decoding strategies based on temporal spike patterns, as opposed to spike count. Recordings from chronically implanted electrode arrays in core auditory cortex of trained and awake Mongolian gerbils that are engaged in a tone detection task in 10 Hz amplitude-modulated background sound reveal that rate-based decoding is not SNR-invariant, whereas temporal coding is informative at both negative and positive SNRs.

neuroscience↗

bioRxiv2022

Oncogenic context shapes the fitness landscape of tumor suppression

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the features of this landscape remain poorly understood and cannot be revealed by human cancer genotyping alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. The resulting fitness landscape is rugged (the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context), shows no evidence of diminishing-returns epistasis within variants of the same oncogene, and is inconsistent with expectations of a simple linear signaling relationship among these three oncogenes. Our findings suggest that tumor suppressor effects are strongly context-specific, which limits the set of evolutionary paths that can be taken through the fitness landscape.

cancer biology↗

bioRxiv2022

Early-Life Stress Impairs Perception and Neural Encoding of Rapid Signals in the Auditory Pathway

In children, early ear infections are a risk factor for later speech perception deficits. This is likely because auditory deprivation during a developmental critical period (CP) induces long-lasting deficits in perception and ACx encoding of temporally-varying sounds. CPs also create susceptibility to early-life stress (ELS) in neural regions involved with cognition and anxiety. As CP mechanisms are shared by sensory cortices and higher neural regions, ACx and temporal encoding may also be susceptible to ELS. To examine the effects of ELS on temporal processing, we developed a model of ELS in the Mongolian gerbil, a well-established model for auditory processing. ELS induction impaired the behavioral detection of short gaps in sound, which are critical for speech perception. This was accompanied by reduced neural responses to gaps in ACx, the auditory periphery, and auditory brainstem. These ELS effects presumably degrade the fidelity of sensory representations available to higher regions, and could contribute to ELS-induced problems with cognition.

neuroscience↗

bioRxiv2020

Sprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33.

Dynamic regulation of intestinal cell differentiation is crucial for both homeostasis and the response to injury or inflammation. Sprouty2, an intracellular signaling regulator, controls pathways including PI3K and MAPKs that are implicated in differentiation and are dysregulated in inflammatory bowel disease. Here, we asked whether Sprouty2 controls secretory cell differentiation and the response to colitis. We report that colonic epithelial Sprouty2 deletion led to expanded goblet and tuft cell populations. Sprouty2 loss induced PI3K/Akt signaling, leading to GSK3{beta} inhibition and epithelial interleukin (IL)-33 expression. In vivo, this resulted in increased stromal IL-13+ cells. IL-13 in turn induced tuft and goblet cell expansion in vitro and in vivo. Sprouty2 was downregulated by inflammation; this appeared to be a protective response, as VillinCre;Sprouty2F/F mice were resistant to DSS colitis. In contrast, Sprouty2 was elevated in colons of inflammatory bowel disease patients, suggesting that this protective epithelial-stromal signaling mechanism is lost in disease.

physiology↗