Biology subjects

Neumann, A.

Publications and source records attributed to Neumann, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Transcriptome-wide analysis of alternative splicing in women with fibromyalgia highlights GNLY as an immune candidate

Background Fibromyalgia syndrome (FMS) affects 1 to 2 percent of the general population, with higher prevalence estimates in women. Recent evidence supports peripheral immune involvement in disease pathophysiology. Alternative splicing (AS) regulates immune cell function independently of transcript abundance and carries disease-relevant signal in related autoimmune conditions. No study has performed transcriptome-wide differential AS analysis directly in RNA-sequencing data from individuals with FMS. Methods We performed a secondary analysis of GSE221921, restricted to female participants (n = 91 FMS, n = 41 controls). Peripheral immune cell composition was estimated with ABIS, a deconvolution method specifically trained on peripheral blood mononuclear cell signatures. Differential AS was analysed with LeafCutter incorporating cell composition principal components as covariates. Differential gene expression was performed with DESeq2 under the same adjustment framework. Results FMS samples showed lower ABIS-inferred conventional monocyte estimates (Cliff's {delta} = -0.38, FDR = 0.008) and higher memory B-cell estimates (Cliff's {delta} = +0.32, FDR = 0.030). Composition-adjusted LeafCutter analysis identified 14 significant intron clusters, of which 9 were retained for biological interpretation. GNLY (granulysin) was the primary candidate, with a composition-adjusted 5' junction usage shift illustrated by pooled Sashimi visualisation. Composition adjustment substantially reduced significant differentially expressed genes from 10,803 to 3,186 (baseMean [≥] 10). Conclusions This first transcriptome-wide differential AS analysis in FMS identifies GNLY, encoding the cytolytic lymphocyte effector granulysin, as a splicing-specific candidate for functional follow-up. AS captures FMS-associated signal not detectable by gene-level expression analysis, and composition adjustment substantially altered the differential expression landscape.

genomics↗

bioRxiv2026

Neonatal Muscle Tone Predicts Cerebellar Morphology Later in Development Without Mediating Autistic Traits

Background: Infant muscle tone reflects early central nervous system integrity and has been associated with later motor and cognitive development, including autism traits. The cerebellum regulates both motor control and higher-order socio-cognitive functions and has been repeatedly implicated in autism, but its role in linking infant muscle tone to adolescent autistic traits has not previously been studied in a large, prospective population cohort. Methods: We used data from the prospective Generation R Study. Infant muscle tone (hypotonia and hypertonia) was assessed via Prechtl examination, and third-trimester fetal transcerebellar diameter was measured using ultrasound n=6,842). Cerebellar morphology at ages 6, 10, and 14 years (n=4,861) was measured using structural MRI. Linear mixed-effects models tested associations between infant muscle tone and 35 anatomical and 10 functional cerebellar regions. Causal mediation models tested whether cerebellar volume mediated associations between infant muscle tone and adolescent autistic traits at age 14 (Social Responsiveness Scale). Results: Hypotonia predicted larger vermis IX volumes across childhood (beta=0.037, pFDR =0.043). Hypertonia showed an age-dependent association with left lateral lobule IX (beta=-0.0027, pFDR =0.041), with differences diminishing with age. Third-trimester transcerebellar diameter did not predict postnatal muscle tone. Given its significant main effect, vermis IX volume was tested as a mediator, but did not mediate the pathway to adolescent autistic traits. However, infant hypotonia showed a small direct association with elevated autistic traits at age 14, specific to girls (beta=0.0255, p=0.020). Conclusions: Infant muscle tone is associated with localized differences in cerebellar volumes. These associations are specific to vermal and left hemispheric lobule IX, a region commonly implicated in spinocerebellar postural control, axial stability, and higher-order sensorimotor integration. Furthermore, infant muscle tone was not predicted by prenatal cerebellar diameter, and cerebellar volumes did not mediate the association between infant hypotonia and adolescent autistic traits in our study. Future research should further investigate these findings in clinical populations, integrating longitudinal whole-brain, multi-modal imaging to clarify the association between infant muscle tone, the cerebellar functioning, and autistic traits.

neuroscience↗

bioRxiv2026

The prenatal exposome and genome in predictive modelling of DNA methylation

IntroductionFetal development represents a critical window during which genetic and environmental influences shape lifelong health. DNA methylation (DNAm) is a candidate underlying mechanism. While individual prenatal exposures have been related to DNAm, no studies have investigated the broader prenatal exposome, nor incorporated genetics with the exposome. Here, we integrated the prenatal exposome and genetics as predictors of DNAm at birth. MethodsWe used data from the Dutch Generation R (n=2282) and English Avon Longitudinal Study of Parents and Children (ALSPAC; n=809) cohorts. We performed epigenome-wide elastic net regression, using Generation R for model development/internal validation and ALSPAC for external validation, to predict DNAm at each CpG site. We used three models: Model 1 included 42 prenatal exposures, Model 2 additionally included child sex, gestational age and birth weight, and Model 3 further included meQTLs. ResultsIn Model 1, the prenatal exposome explained on average 0.7% of DNAm variation across 347 validated CpGs (0.1% of tested CpGs). This increased to 40,044 CpGs (10.2%) with 1.3% of variation explained in Model 2, and 91,305 CpGs (23.2%) with 3.0% of variation explained in Model 3. In Model 1, prenatal smoking was the largest predictor, followed by delivery characteristics, among which meconium-stained amniotic fluid was a novel finding. In Model 3, typically both SNPs and multiple prenatal exposures were selected. DiscussionWe find that genomic associations with cord blood DNAm are stronger and more widespread than prenatal exposures, although typically, the prenatal exposome explains additional variation in DNAm beyond genetic influences.

genomics↗

bioRxiv2026

Planning in Nonhuman Primates Emerges from Structure Knowledge and is Distinct from Attention, Working Memory, Effort Control, and Learning

Forward planning involves mentally simulating future choices. Such mental simulation may constitute an independent cognitive operation, or it may be intricately linked to canonical cognitive operations supporting working memory of choice options, covert attentional information sampling, forming memory models of problem structure and effort control for pursuing future goals. Here, we test the relative independence of planning in non-human primates with an object-sequence planning task assessed together with an assay of simpler cognitive tasks. The sequence task unexpectedly masked objects at future serial positions probing NHPs to plan ahead serial future choices. We found that five of six subjects planned ahead 2-3 ordinal positions. Planning depth was predicted by knowledge of the serial structure but constituted a unique cognitive factor that was distinct from sequence memory, object memory, and learning efficacy. Similarly, planning was segregated from working memory capacity, attention, inhibitory control and effort control. These findings suggest that planning ahead constitutes a separate construct not reducible to other domain-general cognitive operations, and emerges in NHPs that successfully form an internal model of the problem structure.

animal behavior and cognition↗

bioRxiv2026

Structural assembly of the glycan-rich, chitin-reinforced adhesive of Hydra is coordinated by a lectin-like protein, HvAb1

Aquatic animals deploy adhesives, in numerous essential functions, and reversibility is a key adaptation. The molecular mechanisms of reversible wet adhesion remain poorly understood. Using a model organism, the freshwater cnidarian Hydra vulgaris, we dissect the mechanism of molecular assembly in a secreted adhesive and uncover a glycan and protein-based architecture organized by a lectin-like protein, Hydra vulgaris adhesive protein 1 (HvAb1). We identify HvAb1 as a nonredundant organizer of the adhesive matrix, being basal-disc specific and secreted. Knockdown of HvAb1 severely impaired attachment and disrupted footprint architecture in a mosaic pattern, with only HvAb1-positive regions of the adhesive footprint retaining their normal structure. The adhesive is wheat germ agglutinin (WGA)-reactive and contains a fibrillar chitin-based sub-network, synthesized by a basal-disc-specific chitin synthase. Applying exogeneous chitinase abolished both WGA staining and Hydra attachment, indicating that WGA-positive components perform essential roles in adhesion. Our results therefore describe a glycan-dominated matrix, organized via a lectin-like protein (HvAb1), which is reinforced by chitin and enables reversible adhesion underwater. This establishes Hydra as a tractable model to better understand the principles of reversible adhesion underwater and, potentially, inform future bioinspired, sustainable adhesives.

zoology↗

bioRxiv2026

Development of a microRNA clock for gestational age in the general population

IntroductionDNA methylation (DNAm) has shown promise as a biological marker of gestational age (GA). Here, we aimed to characterize how plasma circulating miRNAs - another epigenetic mechanism regulating gene expression - associate with GA at birth, and to construct a miRNA-based GA clock (miRClock-GA). MethodsWe leveraged 2083 umbilical cord plasma-derived circulating miRNAs from Generation R (N=1695). First, we performed linear regressions to identify miRNome-wide significant miRNAs associated with GA. Second, we applied elastic net regression to construct miRClock-GA. These steps were validated in Gen3G (N=213). Finally, we computed age acceleration (miRClock-AA) and evaluated association of miRClock-GA and miRClock-AA with child developmental outcomes up to 17 years of age, including comparisons with DNAmClocks. FindingsWe identified 123 miRNAs associated with GA, with miR-150-5p showing the strongest positive association ( B=0.244, SE=0.036, P=2.3e-11) and miR-373-3p the strongest negative association ( B=-0.255, SE=0.065, P=8.6e-5). MiRClock-GA correlated consistently with GA in Generation R train (rrange=0.62-0.72) and test sets (rrange=0.45-0.52) and in the independent validation cohort (rGen3G =0.33). Correlations between miRClock-GA and DNAmClocks were weak to moderate (rrange=0.28-0.42). MiRClock-AA explained significant variance in birthweight and childhood BMI beyond clinical GA. ConclusionsThis study reveals widespread associations between circulating miRNAs and GA, supports miRClock-GA as a consistent, well-performing biological marker of GA, with miRClock-AA predicting birthweight and childhood BMI beyond GA itself. Our findings provide a broader perspective on the potential utility of miRNAs as early markers of development. FundingE.U. Horizon Europe Research and Innovation Programme (FAMILY,No.101057529); European Research Council (TEMPO,No.101039672). Full funding in Acknowledgements. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSEpigenetic clocks have emerged as powerful tools for assessing individual differences in biological ageing. Existing epigenetic clocks are typically constructed using DNA methylation (DNAm) data and are developed to estimate whether an individuals epigenetic age deviates relative to their chronological age. In adults, higher predicted biological epigenetic age than chronological age (accelerated epigenetic ageing) is an established indicator of mortality risk and other age-related morbidities. MicroRNAs are another epigenetic mechanism associated with chronological age and age-related phenotypes across species such as C. elegans, mice, primates and humans. Recently, a plasma-derived, cell-free circulating miRNA clock was developed in a sample of older European adults, with accelerated miRNA age predicting biological age-related conditions such as frailty and multi-system blood biomarkers. However, miRNA-based estimations of biological gestational age at birth have not been previously done and their relationship to child health outcomes are unknown. Added value of this studyTo gain a broader perspective on the role of epigenetic markers in biological gestational age at birth and the potential utility of miRNAs as early markers of (altered) development, we leveraged cord blood plasma circulating miRNA data collected at birth in a large population-based cohort. First, we identified 123 miRNAs associated with gestational age. Second, we used this information to construct a miRNA-based epigenetic clock for gestational age (miRClock-GA) and validated this clock in an independent cohort. MiRClock-GA showed moderate correlations with both gestational age and existing DNAm-based gestational clocks. Third, we found that miRClock-GA correlated cross-sectionally with birthweight, as well as prospectively with several adaptive, behavioural, cognitive, and growth outcomes measured up to age 17y, after taking into account maternal influences such as maternal education level, smoking, pre-pregnancy BMI, and age. Accelerated ageing of miRClock-GA (miRClock-AA) explained variance in birthweight and childhood BMI beyond clinical GA, after accounting for maternal influences. Implications of all available evidenceOur study provides the first large-scale evidence that circulating miRNAs in cord blood plasma show widespread associations with gestational age at birth and can be used to derive a robust biological marker of GA (MiRClock-GA), which explains a substantial proportion of the variation in clinical GA. MiRClock-AA provides information beyond GA in some child outcomes, such as BMI. These findings extend adult research, supporting the potential of miRNAs as promising markers for early risk assessment and health monitoring in a developmental context.

genomics↗

bioRxiv2026

Cognitive engagement induces area-specific fingerprints of dopamine, acetylcholine, serotonin, glutamate and GABA in prefrontal cortex and striatum

Cholinergic, dopaminergic and serotonergic neuromodulation has pervasive effects on circuit functions in prefrontal cortex (PFC) and striatum and interact with glutamatergic and GABAergic transmission. But how these neurochemicals interact during cognitive engagement is largely unknown and inferred from studying few neuromodulators at a time. Here, we sampled the extracellular availabilities of five neurochemicals in the PFC and striatum of nonhuman primates and tested how they changed when subjects switched from rest to engage in a cognitive set shifting task using miniaturized probes for diffusion-based solid-phase microextraction. Cognitive engagement was best predicted by GABAergic and cholinergic changes in the PFC, and dopaminergic and cholinergic changes in the striatum. Glutamate co-modulated with acetylcholine across states in both the PFC and striatum, while serotonin changes in PFC and striatum correlated consistent with common external modulation. These findings document an area-specific multi-neuromodulatory fingerprint of an adaptive cognitive state in the fronto-striatal network of the nonhuman primate brain. TeaserEngaging in a cognitive task reshapes neurochemical profiles across the fronto-striatal network of the primate brain

neuroscience↗

bioRxiv2026

Inhibitory Control, Shifting, and Working Memory Updating Domains form Cognitive Phenotypes in Non-human Primates

Executive functions comprise at least four major subdomains: Inhibitory Control, Updating, Shifting, and Working Memory. Cognitive abilities in these subdomains are partially separable and partially unified in a common cognitive control factor in humans, but how these functions are organized in the nonhuman primate (NHP) is largely unknown. Here, we used a multi-task assessment approach and found that NHPs show within single sessions reliable cognitive markers of Inhibitory Control in an antisaccade task, (ii) Updating abilities in a multidimensional continuous updating task, (iii) Working Memory in a delayed matching task, and (iv) Shifting abilities in a feature-based rule learning task. First, we found that subjects performance fell into three separable cognitive phenotypes with unique strengths and weaknesses across cognitive subdomains. Second, beyond individual tasks cognitive metrics gave rise to four latent cognitive factors separating abilities for shifting/learning and working memory updating, and distinguishing abilities in inhibitory control of exogeneous versus endogenous interference. These results document four separable latent cognitive factors underlying executive control performance in this NHP sample, with inter-subject differences of these factors forming cognitive phenotypes.

animal behavior and cognition↗

bioRxiv2025

Two Distinct Attentional Priorities Guide Exploratory and Exploitative Gaze in Parallel

Gaze is directed to visual objects that are informative, reward-predictive, or novel. These gaze preferences may reflect the parallel influence of two separable attention systems: Exploratory attention prioritizing uncertainty and exploitative attention prioritizing learned information about reward. We tested this hypothesis in nonhuman primates learning feature-based attention to objects that had either previously learned reward associations or were novel. The reward history of features slowed down learning by attracting fixations of non-rewarded distractors that were previously targets. This reward history bias persisted in fixations used to choose objects even after choice accuracy stabilized. In contrast, fixational sampling that preceded a choice showed negligible history biases that were overcome quickly in favor of wider exploratory sampling. Quantifying the exploratory value object features with a Parallel Belief States model of attention confirmed that exploratory fixational sampling was unaffected by reward history, while exploitative fixations that committed to a decision showed persistent target history biases. These findings suggest that gaze is guided by two separable attentional priorities in parallel. Exploratory attention prioritizes uncertain items and instantiates information sampling, while exploitative attentional priority guides gaze to current and previously goal-relevant features.

animal behavior and cognition↗

bioRxiv2025

Streptococcus pyogenes nuclease A interferes with host complement functions

Bacterial pathogens deploy diverse virulence factors to subvert host immunity, yet the molecular details of these interactions often remain unresolved. Here, we investigate the structure and host interactome of the Streptococcus pyogenes nuclease A (SpnA). We characterized the structure and dynamics of SpnA using hydrogen-deuterium exchange mass spectrometry and single-particle electron cryo microscopy, yielding the first structural insights to this protein. This allowed us to identify an additional oligonucleotide-binding domain whose flexible structure may play an important function in the nucleolytic activity of SpnA. Affinity-pulldown mass spectrometry identified the complement system membrane attack complex C5b67 components as key interactors in human plasma. Cross-linking mass spectrometry combined with integrative modeling identified the direct binding interfaces between SpnA and C5b67. These interfaces are highly conserved among genetically diverse S. pyogenes strains. The interaction between SpnA and C5b67 is suggested to prevent the assembly of a functional membrane attack complex. Taken together, our findings uncover a novel function of SpnA in complement inhibition and identifies new potential targets to prevent and treat S. pyogenes infections.

microbiology↗

bioRxiv2025

Genome-wide analysis of social behaviour in context: a meta-regression approach across social domains, reporters and developmental stages

Social behaviour is a heritable, context-dependent trait that changes across social settings and development, influencing wellbeing and mental health. We present the first genome-wide meta-regression study of social behaviour from infancy to early adulthood, leveraging 491,246 repeat measures of low prosocial behaviour and peer/social difficulties in European-ancestry cohorts (Neff=121,777, Nind=73,321). We modelled heterogeneity in genetic effects across social domains, informants, and ages (2-29 years), capturing social context through genomic influences. Six loci were identified, including variation within CADM2 (p=2.51x10-9). The SNP-based heritability was modest (2-7%), and the genetic architecture of social behaviour multidimensional. Polygenic scores demonstrated predictability and accuracy in independent European-ancestry cohorts and, partially, in African-ancestry cohorts (Nind=16,305). Genetic correlations with later-life and mental health outcomes showed context-dependent patterns. Modelling predicted onsets of associations with social behaviour revealed distinct profiles, as observed for autism, ADHD, depression and schizophrenia, highlighting novel opportunities to genetically proxy developmental trajectories.

genomics↗

bioRxiv2025

Shedding of mitochondrial Voltage-Dependent Anion Channel-1 (VDAC1) Reflects COVID-19 Severity and Reveals Macrophage Dysfunction

COVID-19 severity correlates with lymphopenia and increased pro-inflammatory cytokines. However, the dysfunction of tissue macrophages in COVID-19 patients during the inflammatory cytokine storm has not been fully elucidated. Hospitalized COVID-19 patients were divided into three groups based on their symptomatic severity: exhibiting mild, moderate, or severe symptoms. Patients exhibited successively increased serum levels of mitochondrial voltage-dependent anion channel 1 (VDAC1) at days 0, 3, 7, 10, and 14, returning to those of non-infected subjects at day 28. Serum level of VDAC1 was positively correlated with COVID-19 severity and with increased white blood cell (WBC), neutrophil, lymphocyte, procalcitonin (PCT), and gamma-glutamyltransferase (GT) levels. Peripheral blood mononuclear cells (PBMCs) from hospitalized COVID-19 patients showed increased VDAC1 content concomitant with a reduced ATP content. Culture of monocytes, isolated from healthy individuals, and differentiated into polarized M1 macrophages, together with a cytokine mixture (IL-1{beta}, IFN-{gamma}, and TNF-), to mimic the inflammatory cytokine storm, for 24 h markedly increased VDAC1 and Monocyte chemoattractant protein-1 (MCP-1) release in culture medium. The presence of the cytokine mixture reduced the ATP content, cell viability, and the phagocytic capability of macrophages. Co-staining of VDAC1 and the plasma membrane marker Na+/K+-ATPase showed that cytokine-treatment mistargeted VDAC1 to the cell surface of macrophages. All these effects were prevented by VDAC1 inhibition using VBIT-4, VDAC1-specific antibody (VDAC1-ab), or metformin. Our findings indicate that increased VDAC1 expression and cell surface mistargeting in immune cells might be associated with cell dysfunction, potentially contributing to the severity of COVID-19 infection. The data also indicate serum VDAC1 as a biomarker of COVID-19 severity and the use of VDAC1 inhibitors as potential drug candidates restoring macrophages and PBMCs function in individuals severely affected by COVID-19.

pathology↗

bioRxiv2025

Assessing Attentiveness and Cognitive Engagement across Tasks using Video-based Action Understanding in Non-Human Primates

BackgroundDistractibility and attentiveness are cognitive states that are expressed through observable behavior. The effective use of behavior observed in videos to diagnose periods of distractibility and attentiveness is still not well understood. Video-based tools for classifying cognitive states from behavior have high potential to serve as versatile diagnostic indicators of maladaptive cognition. New methodWe describe an analysis pipeline that classifies cognitive states using a 2-camera set-up for video-based estimation of attentiveness and screen engagement in nonhuman primates performing cognitive tasks. The procedure reconstructs 3D poses from 2D labeled DeepLabCut videos, reconstructs the head/yaw orientation relative to a task screen, and arm/hand/wrist engagements with task objects, to segment behavior into an attentiveness and engagement score. ResultsPerformance of different cognitive tasks were robustly classified from video within a few frames, reaching >90% decoding accuracy with [≤]3min time segments. The analysis procedure allows setting subject-specific thresholds for segmenting subject specific movements for a time-resolved scoring of attentiveness and screen engagement. Comparison with existing methodsCurrent methods also extract poses and segment action units; however, they havent been combined into a framework that enables subject-adjusted thresholding for specific task contexts. This integration is needed for inferring cognitive state variables and differentiating performance across various tasks. ConclusionThe proposed method integrates video segmentation, scoring of attentiveness and screen engagement, and classification of task performance at high temporal resolution. This integrated framework provides a tool for assessing attention functions from video.

animal behavior and cognition↗

bioRxiv2025

Unified high-resolution immune cell fraction estimation in blood tissue from birth to old age

BackgroundBlood is composed of many different immune cell-types, whose proportions vary throughout life. If not accounted for, these variations can seriously cause confounding or hamper interpretation of DNAm-based biomarkers. Although cell-type deconvolution methods can address this challenge for cord and adult blood, there is currently no method that can be applied to blood tissue from other age groups, including infants and children. ResultsHere we construct and extensively validate a DNAm reference panel, called UniLIFE, for 19 immune cell-types, applicable to blood tissue of any age. We use UniLIFE to delineate the dynamics of immune-cell fractions from birth to old age, and to infer disease associated immune cell fraction variations in newborns, infants, children and adults. In a prospective longitudinal study of type-1 diabetes in infants and children, UniLIFE identifies differentially methylated positions that precede type-1 diabetes diagnosis and that map to diabetes related signaling pathways. In contrast to previous studies, we are able to validate these biomarker associations in an independent DNAm dataset comprising purified monocytes from monozygotic twins discordant for type-1 diabetes, but not in lymphocytes, highlighting the importance of epigenetic changes in the innate immune system in the development of type-1 diabetes. ConclusionsIn summary, we present a life course immune-cell estimator for blood tissue of any age to help improve the identification and interpretation of blood-based DNAm biomarkers for any age groups and specially for longitudinal studies that include infants and children. The UniLIFE DNAm reference panel and algorithms to estimate cell-type fractions and perform cell-type deconvolution are available from our EpiDISH Bioconductor R-package: https://bioconductor.org/packages/release/bioc/html/EpiDISH.html

bioinformatics↗

bioRxiv2024

Flexible Learning and Re-ordering of Context-dependent Object Sequences in Nonhuman Primates

Intelligent behavior involves mentally arranging learned information in novel ways and is particularly well developed in humans. While nonhuman primates (NHP) will learn to arrange new items in complex serial order and re-arrange neighboring items within that order, it has remained contentious whether they are capable to re-assign items more flexibly to non-adjacent positions. Such mental re-indexing is facilitated by inferring the latent temporal structure of experiences as opposed to learning serial chains of item-item associations. Here, we tested the ability for flexible mental re-indexing in rhesus macaques. Subjects learned to serially order five objects. A change of the background context indicated when the object order changed, probing the subjects to mentally re-arrange objects to non-adjacent positions of the learned serial structure. Subjects successfully used the context cue to pro-actively re-index items to new, non-adjacent positions. Mental re-indexing was more likely when the initial order had been learned at a higher level, improved with more experience of the re-indexing rule and correlated with working memory performance in a delayed match-to-sample task. These findings suggest that NHPs inferred the latent serial structure of experiences beyond a chaining of item-item associations and mentally re-arrange items within that structure. The pattern of results indicates that NHPs form non-spatial cognitive maps of their experiences, which is a hallmark for flexible mental operations in many serially ordered behaviors including communication, counting or foraging.

animal behavior and cognition↗

bioRxiv2024

What makes clocks tick? Characterizing developmental dynamics of adult epigenetic clock sites

DNA methylation (DNAm) at specific sites can be used to calculate epigenetic clocks, which in adulthood are used as indicators of age(ing). However, little is known about how these clock sites behave during development and what factors influence their variability in early life. This knowledge could be used to optimize healthy aging well before the onset of age-related conditions. Here, we leveraged results from two longitudinal population-based cohorts (N=5,019 samples from 2,348 individuals) to characterize trajectories of adult clock sites from birth to early adulthood. We find that clock sites (i) diverge widely in their developmental trajectories, often showing non-linear change over time; (ii) are substantially more likely than non-clock sites to vary between individuals already from birth, differences that are predictive of DNAm variation at later ages; and (iii) show enrichment for genetic and prenatal environmental exposures, supporting an early-origins perspective to epigenetic aging.

developmental biology↗

bioRxiv2024

Concerted neuron-astrocyte gene expression declines in aging and schizophrenia

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a striking relationship between peoples cortical neurons and cortical astrocytes. We used single-nucleus RNA-seq to analyze the prefrontal cortex of 191 human donors ages 22-97 years, including healthy individuals and persons with schizophrenia. Latent-factor analysis of these data revealed that in persons whose cortical neurons more strongly expressed genes for synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the Synaptic Neuron- and-Astrocyte Program (SNAP). In schizophrenia and aging - two conditions that involve declines in cognitive flexibility and plasticity 1,2 - cells had divested from SNAP: astrocytes, glutamatergic (excitatory) neurons, and GABAergic (inhibitory) neurons all reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy persons of similar age, may underlie many aspects of normal human interindividual differences and be an important point of convergence for multiple kinds of pathophysiology.

neuroscience↗

bioRxiv2023

PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation

The platelet-derived growth factor receptor (PDGFR) family of receptor tyrosine kinases allows cells to communicate with one another by binding to growth factors at the plasma membrane and activating intracellular signaling pathways to elicit responses such as migration, proliferation, survival and differentiation. The PDGFR family consists of two receptors, PDGFR and PDGFR{beta}, that dimerize to form PDGFR homodimers, PDGFR/{beta} heterodimers and PDGFR{beta} homodimers. Here, we overcame prior technical limitations in visualizing and purifying PDGFR/{beta} heterodimers by generating a cell line stably expressing C-terminal fusions of PDGFR and PDGFR{beta} with bimolecular fluorescence complementation fragments corresponding to the N-terminal and C-terminal regions of the Venus fluorescent protein, respectively. We found that these receptors heterodimerize relatively quickly in response to PDGF-BB ligand treatment, with a peak of receptor autophosphorylation following 5 minutes of ligand stimulation. Moreover, we demonstrated that PDGFR/{beta} heterodimers are rapidly internalized into early endosomes, particularly signaling endosomes, where they dwell for extended lengths of time. We showed that PDGFR/{beta} heterodimer activation does not induce downstream phosphorylation of ERK1/2 and significantly inhibits cell proliferation. Further, we characterized the PDGFR dimer-specific interactome and identified MYO1D as a novel protein that preferentially binds PDGFR/{beta} heterodimers. We demonstrated that knockdown of MYO1D leads to retention of PDGFR/{beta} heterodimers at the plasma membrane, resulting in increased phosphorylation of ERK1/2 and increased cell proliferation. Collectively, our findings impart valuable insight into the molecular mechanisms by which specificity is introduced downstream of PDGFR activation to differentially propagate signaling and generate distinct cellular responses. One-sentence summaryPDGFR/{beta} heterodimer binding to MYO1D contributes to rapid internalization of the dimerized receptors, thereby negatively affecting downstream ERK1/2 signaling and cellular proliferation.

cell biology↗