Biology subjects

Rosen, S.

Publications and source records attributed to Rosen, S..

10 recordsLinked to original sources

bioRxiv2025

Multi-omic integration reveals dynamic changes in human placental metabolism across gestation

ObjectivesMetabolic demands of the developing conceptus are highly dynamic during pregnancy. While placental metabolism has been well described at term and in cell lines, changes in the placental metabolome during development remains understudied. We investigated the placental metabolome, metabolite trajectories, and altered pathways across trimesters in normal human pregnancy by integrating metabolomic and transcriptomic data. MethodsTargeted aqueous metabolomic profiling of 372 metabolites was conducted on placental biopsies from samples collected in the first (n=12), second (n=13), and third (n=11) trimesters of normal pregnancy using liquid chromatography-tandem mass spectrometry. Robust linear models identified differentially abundant metabolites across trimesters in models adjusted for fetal sex and total protein. We conducted pathway analysis using a human metabolic reconstruction. To further aid in biological interpretation, we leveraged publicly available transcriptomics data to conduct pathway-level multi-omic integration throughout gestation. ResultsSamples clustered by trimester in principal component analysis and we identified 5 metabolite trajectories. Out of 193 detectable metabolites, 149 (77%) differed by trimester (FDR<0.05). Using pathway-level multi-omic integration, pathways involved in extracellular transport, and pyruvate, amino acid, NAD, and membrane lipid metabolism are up-regulated in the second trimester compared to the first. In the late third trimester, pathways involved in amino acid metabolism, redox balance, mitochondrial transport, and biomolecule synthesis were down-regulated compared to second trimester. ConclusionsPlacental metabolite abundances change substantially across gestation and integration with metabolic gene expression provides insight into dynamic metabolic function during pregnancy. Observed pathway-level changes potentially reflect the metabolic response to invading maternal circulation in the first-to-second trimester transition, as well as changing maternal and fetal metabolic requirements. Differences observed at term may reflect placental senescence and preparation for parturition. These data can inform other molecular analyses of the placenta by providing enhanced resolution of metabolic changes across pregnancy.

systems biology↗

bioRxiv2025

Visual contributions to the perception of speech in noise

Investigations of the role of audiovisual integration in speech-in-noise perception have largely focused on the benefits provided by lipreading cues. Nonetheless, audiovisual temporal coherence can offer a complementary advantage in auditory selective attention tasks. We developed an audiovisual speech-in-noise test to assess the benefit of visually conveyed phonetic information and visual contributions to auditory streaming. The test was a video version of the Childrens Coordinate Response Measure with a noun as the second keyword (vCCRMn). The vCCRMn allowed us to measure speech reception thresholds in the presence of two competing talkers under three visual conditions: a full naturalistic video (AV), a video which was interrupted during the target word presentation (Inter), thus, providing no lipreading cues, and a static image of a talker with audio only (A). In each case, the video/image could display either the target talker, or one of the two competing maskers. We assessed speech reception thresholds in each visual condition in 37 young ([≤] 35 years old) normal-hearing participants. Lipreading ability was independently assessed with the Test of Adult Speechreading (TAS). Results showed that both target-coherent AV and Inter visual conditions offer participants a listening benefit over the static image audio-only condition, with the full AV target-coherent condition providing the most benefit. Lipreading ability correlated with the audiovisual benefit shown in the full AV target-coherent condition, but not the benefit in the Inter target-coherent condition. Together our results are consistent with visual information providing independent benefits to listening, through lip reading and enhanced auditory streaming.

neuroscience↗

bioRxiv2025

Single nucleus multiomic atlas of human dorsal root ganglia reveals the contribution of non-neuronal cell types to pain

Sensory neurons residing in dorsal root ganglia (DRG) transmit sensory information such as pain, itch, touch, pressure and bodily position to the central nervous system. The activity of sensory neurons is regulated by non-neuronal cell types in the DRG, including satellite glial cells (SGCs), immune cells and fibroblasts. Dysregulated gene expression in DRG cells contributes to sensory nervous system disorders such as chronic pain. Understanding the genetic underpinnings of these conditions requires dissecting transcriptional regulation in human tissue. In this study, we profiled transcriptomic and chromatin accessibility landscapes from postmortem human DRG (hDRG) samples at single-nucleus level. We demonstrate that sequencing depth significantly impacts downstream analysis, with deeper sequencing yielding more detected cells and features, improved data integration, refined clustering and annotation, and more accurate scientific interpretations. We identified nine major cell types, defined their molecular signatures, and mapped cis-regulatory landscapes. Integration of gene expression with chromatin accessibility enabled peak-gene association and transcriptional network analyses, revealing transcription factors, their target genes, regulatory elements and potential partners that cooperatively drive cell-type-specific gene expression programs. This integrative approach identified cell types, genes, and cis-regulatory regions potentially driving pain conditions. Our unbiased genome-wide analysis not only recovered known pain-related genes but also highlighted novel candidate genes and regulatory regions implicated in pain mechanisms. Importantly, our results demonstrate that non-neuronal cells, including endothelial cells, fibroblasts, macrophages, and SGCs, play critical roles in pain pathogenesis and should be investigated as therapeutic targets. One Sentence SummaryOur work provides a comprehensive single-nucleus multi-omic atlas of human dorsal root ganglia, uncovering novel cell-type-specific regulatory mechanisms and candidate therapeutic targets for pain, thereby directly advancing translational insights into human sensory disorders and chronic pain pathogenesis.

neuroscience↗

bioRxiv2025

Rapid FFR: A rapid method for obtaining Frequency Following Responses

ObjectivesFrequency-Following Responses (FFRs) are typically recorded using stimuli of 40-250 ms in duration separated by silent intervals. Because robust FFRs require averaging across approximately 3000 stimulus repetitions, conventional acquisition is time-intensive. We introduce the Rapid FFR, a technique that minimises recording time by presenting the stimulus continuously (i.e., without inter-stimulus intervals) and by averaging across individual response cycles. This study aimed to: (a) compare Rapid and Conventional FFR performance under time-matched conditions; (b) assess test-retest reliability of both methods, and (c) examine potential neural adaptation during extended Rapid FFR recordings. DesignAll participants (37 in total) were young adults with clinically normal hearing. In Experiment 1, FFRs were elicited from 16 listeners using a 128 Hz sawtooth wave presented in two ways: (1) continuously over approximately 1 minute in each polarity for the Rapid FFR and (2) as discrete tone bursts (1500 trials per polarity) for the standard FFR. Signal-to-Noise ratios (SNRs), response amplitudes, and test-retest reliability were compared across techniques. In Experiment 2, the Rapid FFR was recorded continuously from 21 listeners for nearly nine minutes to assess potential adaptation over time. ResultsThe Rapid FFR produced significantly higher SNRs than the standard FFR, reflecting improved recording efficiency. Both techniques captured inter-individual differences reliably, with comparable frequency-domain response patterns across participants. In particular, measures derived from the Rapid FFR showed strong agreement with those from the standard FFR for lower harmonics (F0-H3). Higher harmonics (H4-H7) exhibited greater variability but remained consistent between techniques. In the prolonged recording condition, FFR amplitudes remained stable over time, with no significant decline across the nine minute recording. This indicates that continuous stimulation did not result in measurable neural adaptation or response fatigue. ConclusionsThe Rapid FFR offers a time-efficient alternative to standard protocols, preserving signal fidelity and reliability while enabling shorter acquisition times. These findings suggest that the Rapid FFR is well-suited for use in populations where long recordings are challenging (e.g., in infants and the clinic) and can facilitate more extensive experimental designs within a single session. The method holds promise for advancing both research and clinical applications of the FFR. Future studies should explore its use across a broader range of sounds (in particular, dynamically varying ones) and listener groups.

neuroscience↗

bioRxiv2024

Prosocial reward relates to speech reception thresholds and age relates to subjective ratings of speech perception in noise

I.Motivation plays an important role in a listeners effort when in noisy environments. However, there remain gaps in the previous literature pertaining to the social psychological factors underlying motivation and listening effort. To fill these gaps, this study explored how prosociality and social reward relate to speech perception in noise (SPiN) in a group of normal hearing English speakers (n = 136; mean age: 29.6, age range: 18-68). We investigated SPiN performance and subjective listening experiences across different speech masking conditions: 1-speaker, 2-speaker, and speech-spectrum shaped noise (SSN), along with a working memory task, and questionnaires pertaining to social orientation. Results indicated a robust effect of different maskers, and that individuals who rated themselves higher in prosocial traits performed better in the masker that yielded the highest threshold out of the three conditions, the 2-speaker condition. Additionally, subjective ratings of listening effort particularly in the 1-speaker condition related to age, where older participants reported greater effort. These findings highlight prosociality and age as important social psychological factors influencing SPiN performance and listening effort, respectively, particularly in complex listening scenarios.

neuroscience↗

bioRxiv2024

Endothelin B receptor inhibition rescues aging-dependent neuronal regenerative decline

Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using single cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron soma residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex-vivo in DRG explant cultures improves axon growth in both adult and aged conditions. In vivo, treatment with the FDA-approved compound, Bosentan, improves axon regeneration and reverses the age-dependent decrease in axonal regenerative capacity. Single-nuclei RNA sequencing and electron microscopy analyses reveal a decreased abundance of SGCs in aged mice compared to adult mice. Additionally, the decreased expression of connexin 43 (Cx43) in SGCs in aged mice after nerve injury is partially rescued by Bosentan treatment. These results reveal that inhibiting ETBR function enhances axon regeneration and rescues the age-dependent decrease in axonal regenerative capacity, providing a potential avenue for future therapies. One Sentence SummaryInhibition of endothelin signaling improves nerve regeneration after central and peripheral injuries and counters age-related regenerative decline.

neuroscience↗

bioRxiv2024

Effects of childhood hearing loss on the subcortical and cortical representation of speech

Little is known about the effects of childhood mild-to-moderate sensorineural hearing loss (MM HL) on the function of the auditory pathway. We aimed to examine the effect of childhood MM HL and the benefit of frequency-specific amplification on both subcortical and cortical auditory processing, and to relate it to speech-perceptual abilities. We recorded subcortical and cortical responses to speech syllables in nineteen children with congenital MM HL (unamplified and amplified), and sixteen children with typical hearing (unamplified sounds only). Speech perception was measured behaviourally. Congenital HL led to smaller subcortical and cortical responses to unamplified speech sounds. There was a significant benefit of amplification on subcortical and early, but not late, cortical responses, with some effects differing across age. No relationship was found between the neural and behavioural measures. Childhood MM HL affects both subcortical and cortical processing of speech. Amplification mostly benefits subcortical processing of speech in younger children. Childhood HL leads to functional changes in the processing of sounds, with amplification differentially affecting subcortical and cortical levels of the auditory pathway.

physiology↗

bioRxiv2021

Single-cell RNA transcriptome analysis reveals CXCL16/CXCR6 as maintenance factors for CNS tissue resident T cells that drive synapse elimination during viral recovery

BackgroundEmerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS resident memory T (TRM) cells activate microglia, limiting synapse recovery and inducing spatial learning defects in WNV-recovered mice. The signals involved in T cell-microglia interactions are unknown. MethodsHere, we examined the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation, genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. ResultsProfiling of host transcriptome at 25 days post-infection revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in TRM cell biology, was identified as critically regulating CXCR6 expressing CD8+ TRM cell numbers within the WNV-recovered forebrain. We demonstrate that CXCL16 is highly expressed by all myeloid cells, and its unique receptor, CXCR6, is highly expressed on all CD8+ T cells. Using genetic and pharmacological approaches, we demonstrate that CXCL16/CXCR6 is required not only for the maintenance of WNV-specific, CD8 TRM cells in the post-infectious CNS, but also contributes to their expression of TRM cell markers. Moreover, CXCR6+CD8+ T cells are required for glial activation and ongoing synapse elimination. ConclusionsWe provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD8+ T cells that maintains forebrain TRM cells, microglial and astrocyte activation, and ongoing synapse elimination in virally recovered animals. We also show that therapeutic targeting of CXCL16 during recovery may reduce CNS CD8+ TRM cells.

immunology↗

bioRxiv2021

Reward enhances online participants' engagement with a demanding auditory task

Online recruitment platforms are increasingly utilized for experimental research. Crowdsourcing is associated with numerous benefits but also notable constraints, including lack of control over participants environment and engagement. In the context of auditory experiments, these limitations may be particularly detrimental to threshold-based tasks that require effortful listening. Here, we ask whether incorporating a performance-based monetary bonus will improve speech reception performance of online participants. In two experiments, participants performed an adaptive matrix-type speech-in-noise task (where listeners select two key words out of closed sets). In Experiment 1, our results revealed worse performance in online (N = 49) compared with in-lab (N = 81) groups. Specifically, relative to the in-lab cohort, significantly fewer participants in the online group achieved very low (< -17dB) thresholds. In Experiment 2 (N = 200), we show that a monetary reward improved listeners threshold to levels similar to those observed in the lab setting. Overall the results suggest that providing a small performance-based bonus increases participants task-engagement, facilitating a more accurate estimation of auditory ability under challenging listening conditions.

neuroscience↗

bioRxiv2020

Role of Diversity-Generating Retroelements for Regulatory Pathway Tuning in Cyanobacteria

BackgroundCyanobacteria maintain extensive repertoires of regulatory genes that are vital for adaptation to environmental stress. Some cyanobacterial genomes have been noted to encode diversity-generating retroelements (DGRs), which promote protein hypervariation through localized retrohoming and codon rewriting in target genes. Past research has shown DGRs to mainly diversify proteins involved in cell-cell attachment or viral-host attachment within viral, bacterial, and archaeal lineages. However, these elements may be critical in driving variation for proteins involved in other core cellular processes. ResultsMembers of 31 cyanobacterial genera encode at least one DGR, and together, their retroelements form a monophyletic clade of closely-related reverse transcriptases. This class of retroelements diversifies target proteins with unique domain architectures: modular ligand-binding domains often paired with a second domain that is linked to signal response or regulation. Comparative analysis indicates recent intragenomic duplication of DGR targets as paralogs, but also apparent intergenomic exchange of DGR components. The prevalence of DGRs and the paralogs of their targets is disproportionately high among colonial and filamentous strains of cyanobacteria. ConclusionWe find that colonial and filamentous cyanobacteria have recruited DGRs to optimize a ligand-binding module for apparent function in signal response or regulation. These represent a unique class of hypervariable proteins, which might offer cyanobacteria a form of plasticity to adapt to environmental stress. This analysis supports the hypothesis that DGR-driven mutation modulates signaling and regulatory networks in cyanobacteria, suggestive of a new framework for the utility of localized genetic hypervariation.

microbiology↗