Biology subjects

Scherer, J.

Publications and source records attributed to Scherer, J..

11 recordsLinked to original sources

bioRxiv2026

A perturbation atlas of mouse neural organoids resolves macroglial reactivity and nominates drivers of degeneration

Understanding neuro-glial roles in homeostasis and disease requires scalable central nervous system (CNS) models, particularly as macroglia like astrocytes and Muller glia remain challenging to study in slow-developing human systems. Here, we generate and map the cellular diversity of mouse neural organoids spanning multiple brain regions and the retina. Benchmarking transcriptomic maturation against in vivo references captures postnatal neuro-macroglial states within a month. We show that macroglia are highly responsive to inflammatory cues and adopt specific transcriptomic states also found in vivo. Through a single-cell perturbation screen targeting 13 Muller-glia-specific pathways, we map how certain inflammatory cytokines drive degeneration-like stress programs in photoreceptors and distinct reactive states in Muller glia, including an Oncostatin M-driven chaperone-associated state. Mechanistically, we identify gp130-STAT3 signaling as a targetable driver of macroglial reactivity and photoreceptor distress. Together, these single-cell atlases provide a foundation for dissecting cellular crosstalk and neuro-glial pathology in the mature CNS.

neuroscience↗

bioRxiv2026

Constitutive and tissue-specific target site preferences of the maize Mutator transposon

Transposable elements insert non-randomly into host genomes, generating mutations whose consequences depend on the tissue and developmental stage in which transposition occurs. We analyzed 3.2 million de novo Mutator (Mu) insertions across maize leaf, root, pollen, and endosperm to map target site preferences and their tissue specificity at fine-scale resolution. Insertions clustered into 29,408 genomic hotspots near gene 5' ends, collectively capturing 85% of events while covering just 1.9% of the genome. The vast majority of hotspots were consistently targeted across tissues, indicating that Mu insertion-site preference is largely constitutive rather than tissue-regulated. A minority ([~]5%) showed significant tissue-associated variation in Mu activity; this variation was correlated with tissue-specific gene expression, but the relationship was imperfect: some tissue-associated hotspots overlapped broadly expressed genes, while other constitutively active hotspots overlapped genes with tissue-specific expression. These discrepancies indicate that gene expression alone is insufficient to predict Mu insertion-site preference, pointing to additional genomic or chromatin determinants. Together, our results provide a genome-wide, locus-level map of Mu targeting and a quantitative framework for understanding how developmental and genomic context shapes transposon target site preference.

plant biology↗

bioRxiv2026

A distributive germline restricts the spread of new mutations

Genetic bottlenecks in the germline can amplify the impact of mutations, increasing the likelihood that new mutations are transmitted to multiple offspring. Here, we evaluate the timing and consequences of bottlenecks leading to maize pollen. By tracking transposon-induced mutations across tissues, we find that pollen derives from multiple early embryonic cell lineages, maintained by radial symmetries throughout development. In controlled crosses, offspring from bulk pollen or apical branches rarely share mutations, whereas lateral branches sample fewer lineages and produce offspring with a 6.2-fold increase in mutation sharing. Thus, the persistence of multiple, early-diverged cell lineages into the germline reduces mutation recurrence without altering the underlying mutation rate. Similar principles may apply in animals, where diverse mechanisms ensure that multiple cell lineages contribute to the germline.

genetics↗

bioRxiv2025

Embodied Navigation: whole-body movement drives path integration in large-scale free-walking virtual reality

Human navigation relies on combining body cues (vestibular and proprioceptive signals) with visual cues such as optic flow. The weighting and integration of these signals during the continuous tracking of walked distances and angles, known as path integration, remain poorly understood. Previous path integration studies have been limited to small spaces (< 150 m2) and the influence of complex environments on cue weighting of body and vision cues is still unclear. Here, we conducted the largest-environment free-walking virtual reality navigation study to date in a 45 x 25 m facility (1, 215 m2) using triangle completion tasks in naturalistic environments. We systematically manipulated sensory input across three conditions: natural active walking (full sensory integration), active joystick control (visual cues only), and blindfolded active walking (body cues only). Participants navigated through both sparse fallow land without trees and more complex forest environments with 400 trees. We embedded performance data in a Bayesian cue combination model to analyse the underlying combination mechanism. Our results provide evidence that most participants substantially favour body cues over visual cues in a non-Bayesian combination process, with considerable inter-individual variance in cue dominance strength and side biases. While transitioning from fallow land to forests reduced directional variance, weighting of body and visual information remained constant. These findings advance our understanding of human spatial navigation by demonstrating that body-based cues dominate path integration even in visually rich, large-scale environments, challenging assumptions about optimal Bayesian cue integration in human navigation.

neuroscience↗

bioRxiv2025

Uncovering persistent biases in human path integration by separating left and right trials

Navigation ability strongly varies between humans. Careful analysis of errors occurring in navigation, or indeed any cognitive process, offers insight into the underlying mechanisms at different levels. While analyses at the individual level allow nuanced identification of error persistences across conditions and time, the population level facilitates generalisation but precludes conclusions about lower-level phenomena. Regarding the critical navigation mechanism of path integration - the continuous tracking of navigated paths for self-localisation - previous studies have focused on populationlevel analyses, revealing systematic errors in estimating the travelled angles and distances. However, at the individual level, there are indications that people also possess left or right biases that are classically overlooked when pooling left and right trials. Therefore, we carefully investigate individual path integration errors in (1) a re-analysis of data from several influential human navigation studies, and (2) our own virtual reality path integration experiment. For both, we confirm time-persistent individual side biases, but find no evidence for consistent errors at the population level, suggesting that important aspects in human navigation performance might be overlooked by averaging across sides.

animal behavior and cognition↗

bioRxiv2025

Integrating Human Genetics and Protective Genome Editing to Enable ADGRE2-Directed AML Therapy

Acute myeloid leukemia (AML) remains a major therapeutic challenge due to extensive disease heterogeneity and lack of cancer-specific antigens. ADGRE2 has emerged as a promising AML target with broad expression in AML patient blast and leukemic stem cell-enriched populations. However, comparable expression in healthy hematopoietic stem and progenitor cells (HSPCs) and myeloid lineages suggests a high susceptibility to on-target, off-tumor myelotoxicity with ADGRE2-targeted therapies. Guided by human genetics data identifying loss-of-function variants, we evaluated whether ADGRE2 is dispensable in hematopoietic stem cells as a protective approach for transplant-based shielding from ADGRE2-directed therapies. Using CRISPR-Cas9 and adenine base editors, we achieved high-efficiency ADGRE2 knockout (>94%) in HSPCs with corresponding protein loss without impairing cell viability, differentiation, and cytokine release in vitro, or long-term engraftment, multilineage differentiation, and persistence of gene editing in mouse xenografts. We also developed novel ADGRE2-specific chimeric antigen receptor (CAR) T cells that demonstrated potent cytotoxicity against AML cells, even at low antigen levels. Together, these findings establish ADGRE2 as a compelling AML target and provide a framework for hematopoietic stem cell transplant with protective gene editing to enable ADGRE2-directed immunotherapies while minimizing myelotoxicity.

cancer biology↗

bioRxiv2025

Mobile Eye Tracking in the Real World: Best Practices

As research on human behavior, such as spatial navigation, increasingly adopts naturalistic settings, establishing best practices for such experiments becomes essential. While virtual reality (VR) offers a bridge between laboratory control and real-world complexity, it does not fully capture the experiential richness of real-world environments. Here, we present a demonstration of a mobile eye-tracking study conducted in a large-scale, outdoor urban environment, featuring unconstrained, long-duration free exploration and outside-pointing tasks. Using the city of Limassol, Cyprus as our testbed, we showcase the feasibility of collecting high-quality mobile eye-tracking, head orientation, and GPS data "in the wild," capturing a wide range of natural behavior with minimal experimental constraints. Based on this experience, we provide a set of best practices tailored to the logistical and methodological challenges posed by complex, real-world urban settings, challenges unlikely to arise in traditional indoor or highly controlled environments. While these recommendations have general relevance, we exemplify them in the context of spatial navigation research. By establishing methodological standards for studies at this scale, we aim to encourage and inform future research into naturalistic human behavior outside the laboratory.

neuroscience↗

bioRxiv2025

High-throughput histopathology for complex in vitro models

Human complex in vitro models (CIVMs) have demonstrated remarkable potential to study tissue development, physiology and disease at high-throughput. To effectively employ these miniaturized systems in translational preclinical research, their in-depth benchmarking is pivotal. Histology has been the core of tissue characterization for centuries and the foundation of spatial phenotyping. However, standard histology workflows are inherently low-throughput and centered on large tissue pieces. This does not match the high sample volumes and small sample sizes in CIVM research. Here, we introduce a holistic histo-workflow, utilizing 3D-printed histomolds that facilitate co-planar embedding of CIVMs at high-throughput, resulting in up to 48 samples in one section. We developed a variety of model-specific histomold designs that enable spatially controlled histological sectioning and downstream analyses. We describe these workflows, including mold generation, highplex staining and image analysis, and exemplify their application to histological analyses of various CIVMs. Altogether, the histomolds introduced here afford opportunities for CIVM processing and analysis, while significantly reducing labor and reagent resources, thereby democratizing high-throughput CIVM in histopathology.

pathology↗

bioRxiv2025

Ultra-deep sequencing of somatic mutations induced by a maize transposon

Cells accumulate mutations throughout development, contributing to cancer, aging, and evolution. Quantitative data on the abundance of de novo mutations within plants or animals are limited, as new mutations are often rare within a tissue and fall below the limits of current sequencing depths and error rates. Here, we show that mutations induced by the maize Mutator (Mu) transposon can be reliably quantified down to a detection limit of 1 part in 16,000. We measured the abundance of millions of de novo Mu insertions across four tissue types. Within a tissue, the distribution of de novo Mu allele frequencies was highly reproducible between plants, showing that, despite the stochastic nature of mutation, repeated statistical patterns of mutation abundance emerge. In contrast, there were significant differences in the allele frequency distribution between tissues. At the extremes, root was dominated by a small number of highly abundant de novo insertions, while endosperm was characterized by thousands of insertions at low allele frequencies. Finally, we used the measured pollen allele frequencies to reinterpret a classic genetic experiment, showing that evidence for late Mu activity in pollen are better explained by cell division statistics. These results provide insight into the complexity of mutation accumulation in multicellular organisms and a system to interrogate the factors that shape mutation abundance. SignificanceNew mutations provide the raw material for evolution and contribute to cancer, aging, and genetic diseases. It has been challenging to follow the origin and spread of new mutations because they can be exceptionally rare and difficult to detect. By focusing on a class of mutation that can be detected more readily - Mu transposon insertions - we followed the abundance of new mutations in multiple maize tissues. We find that the Mu has broad activity across tissues, but with significant tissue-specific differences in how abundant individual new mutations become. Most mutations were below the detection limit available for other classes of mutation. These results provide a glimpse into the complexity of mutation within multicellular organisms.

plant biology↗

bioRxiv2023

Not seeing the forest for the trees: Combination of path integration and landmark cues in human virtual navigation

IntroductionIn order to successfully move from place to place, our brain often combines sensory inputs from various sources by dynamically weighting spatial cues according to their reliability and relevance for a given task. Two of the most important cues in navigation are the spatial arrangement of landmarks in the environment, and the continuous path integration of travelled distances and changes in direction. Several studies have shown that Bayesian integration of cues provides a good explanation for navigation in environments dominated by small numbers of easily identifiable landmarks. However, it remains largely unclear how cues are combined in more complex environments. MethodsTo investigate how humans process and combine landmarks and path integration in complex environments, we conducted a series of triangle completion experiments in virtual reality, in which we varied the number of landmarks from an open steppe to a dense forest, thus going beyond the spatially simple environments that have been studied in the past. We analysed spatial behaviour at both the population and individual level with linear regression models and developed a computational model, based on maximum likelihood estimation (MLE), to infer the underlying combination of cues. ResultsOverall homing performance was optimal in an environment containing three landmarks arranged around the goal location. With more than three landmarks, individual differences between participants in the use of cues are striking. For some, the addition of landmarks does not worsen their performance, whereas for others it seems to impair their use of landmark information. DiscussionIt appears that navigation success in complex environments depends on the ability to identify the correct clearing around the goal location, suggesting that some participants may not be able to see the forest for the trees.

neuroscience↗

bioRxiv2019

A Kinesin-3 Recruitment Complex Facilitates Axonal Sorting of Enveloped Alpha Herpesvirus Capsids

Axonal sorting, the controlled passage of specific cargoes from the cell soma into the axon compartment, is critical for establishing and maintaining the polarity of mature neurons. To delineate axonal sorting events, we took advantage of two neuroinvasive alpha-herpesviruses. Human herpes simplex virus 1 (HSV-1) and pseudorabies virus of swine (PRV; suid herpesvirus 1) have evolved as robust cargo of axonal sorting and transport mechanisms. For efficient axonal sorting and subsequent egress from axons and presynaptic termini, progeny capsids depend on three viral membrane proteins (Us7 (gI), Us8 (gE), and Us9), which engage axon-directed kinesin motors. We present evidence that Us7-9 of the veterinary pathogen pseudorabies virus (PRV) form a tripartite complex to recruit Kif1a, a kinesin-3 motor. Based on multi-channel super-resolution and live TIRF microscopy, complex formation and motor recruitment occurs at the trans-Golgi network. Subsequently, progeny virus particles enter axons as enveloped capsids in a transport vesicle. Artificial recruitment of Kif1a using a drug-inducible heterodimerization system was sufficient to rescue axonal sorting and anterograde spread of PRV mutants devoid of Us7-9. Importantly, biophysical evidence suggests that Us9 is able to increase the velocity of Kif1a, a previously undescribed phenomenon. In addition to elucidating mechanisms governing axonal sorting, our results provide further insight into the composition of neuronal transport systems used by alpha-herpesviruses, which will be critical for both inhibiting the spread of infection and the safety of herpesvirus-based oncolytic therapies.\n\nAuthor SummaryAlpha-herpesviruses represent a group of large, enveloped DNA viruses that are capable to establish a quiescent (also called latent) but reactivatable form of infection in the peripheral nervous system of their hosts. Following reactivation of latent genomes, virus progeny are formed in the soma of neuronal cells and depend on sorting into the axon for anterograde spread of infection to mucosal sites and potentially new host. We studied two alpha-herpesviruses (the veterinary pathogen pseudorabies virus (PRV) and human herpes simplex virus 1 (HSV-1)) and found viral membrane proteins Us7, Us8, and Us9 to form a complex, which is able to recruit kinsin-3 motors. Motor recruitment facilitates axonal sorting and subsequent transport to distal egress sites. Complex formation occurs at the trans-Golgi network and mediates efficiency of axonal sorting and motility characteristics of egressing capsids. We also used an artificial kinesin-3 recruitment system, which allows controlled induction of axonal sorting and transport for virus mutants lacking Us7, Us8, and Us9. Overall, these data contribute to our understanding of anterograde alpha-herpesvirus spread and kinesin-mediated sorting of vesicular axonal cargoes.

microbiology↗