Biology subjects

Heuer, H.

Publications and source records attributed to Heuer, H..

17 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2026

Natural variation in soybean perception of bacterial quorum-sensing signals shapes primed defense

Plants perceive N-acyl homoserine lactones (AHLs), the quorum-sensing signals of rhizobacteria, and can translate them into a primed state of enhanced inducible immunity. Whether this perception-to-defense translation varies heritably among genotypes is largely unknown. Using soybean (Glycine max) responses to N-3-oxo-tetradecanoyl-L-homoserine lactone (oxo-C14-HSL), with root invasion by the nematode Pratylenchus penetrans as a quantitative challenge revealing the primed state, we tested whether AHL-triggered priming is genotype-dependent. Priming with the oxo-C14-HSL-producing rhizobacterium Ensifer meliloti ExpR+ potentiated defense in the responsive cultivar Primus, reducing nematode invasion (P < 0.001), but not in the weakly responsive Sigalia (P = 0.082). The purified molecule reproduced this contrast, localizing the difference to signal transduction within the plant rather than bacterial colonization. Correspondingly, the phytoalexin glyceollin accumulated in a priming- and challenge-dependent manner in Primus but not Sigalia, the formal signature of priming. Across a Sigalia x Primus recombinant inbred line population and an independent diversity panel, responsiveness was heritable, continuously distributed, and transgressive. Two genome-wide association studies and a cross-population meta-analysis converged on a well-calibrated null, indicating a polygenic or strongly environment-dependent architecture rather than a common-variant, large-effect-size model. Translating a bacterial signal into primed defense is thus a quantitatively varying plant trait.

microbiology↗

bioRxiv2026

Assembly of plant holobionts is governed by nematode communities and their associated microbiota, conditioned by preceding plants

Plants form holobionts by associating with diverse microbiota. Self-organization gives rise to emergent properties of the holobiont, such as increased resistance to pathogens. However, the local factors contributing to the self-organization are not well understood. We hypothesized that nematode communities and their associated microbiota govern the rhizobiome of the model plant holobiont tomato in terms of its suppression of root invasion by the parasite Meloidogyne hapla, and that the soil legacy influences the suppressive potential mediated by these biota. In pot experiments, a resistant tomato holobiont was favored by assembly in the presence of a nematode community conditioned by tomato plants, compared to oilseed rape or fallow soil. Nematode communities conditioned by tagetes could enhance resistance even better than tomato. Microbiota from crushed tomato-conditioned nematode communities increased resistance of the tomato holobiont, compared to microbiota of nematode communities conditioned by maize, or heat-inactivated microbiota. The 0.2 {micro}m-filtered microbiota from crushed nematodes had the same effect, suggesting a role of nematode-associated bacteriophages in holobiont assembly. The results indicate that soil nematodes and their associated microbiota play a role in the local organization and stabilization of plant holobionts. They can influence the resistance of plants that subsequently grow in the same soil. From an applied perspective, crop rotation schemes that alter nematode-microbiota communities could be harnessed to engineer crop holobionts. SUMMARY STATEMENTDepending on plant-specific soil legacies, nematode communities and their associated phages govern holobiont assembly leading to increased resistance against pathogen invasion.

ecology↗

bioRxiv2025

Distinct Effects of Aging and Klotho Deletion on the Choroid Plexus

Klotho (Kl) is an anti-aging protein primarily produced in the kidney and the choroid plexus (CP, where it regulates cerebrospinal fluid composition and exerts neuroprotective effects. Here, we investigated the age-dependent consequences of a CP-specific Kl deletion on CP structure and function using mice lacking KL exclusively in CP epithelial cells (Kl{Delta}CP). In control mice, aging markedly disrupted CP architecture and cilia organization both in the lateral (LV-CP) and fourth ventricle (FV-CP). While CP-specific Kl deletion alone caused no major structural changes it induced region- and age-dependent calcification: FV-CP calcification increased in both aged and young Kl{Delta}CP mice, whereas LV-CP calcification emerged only in older Kl{Delta}CP mice. Proteomic analysis of the CP and hippocampus revealed mild molecular alterations, suggesting compensatory mechanisms that preserve structural and functional stability despite calcium dysregulation. Consistently, Kl{Delta}CP mice exhibited no significant behavioral or cognitive deficits. Overall, Kl deficiency sensitizes the CP to age-related calcification prior to overt structural decline, revealing a region-specific and functional link between Klotho, calcium imbalance, and brain aging.

neuroscience↗

bioRxiv2024

Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia

INTRODUCTIONSex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD). METHODSParticipants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). RESULTSWhile sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants. DISCUSSIONIn genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.

neuroscience↗

bioRxiv2024

msiFlow: Automated Workflows for Reproducible and Scalable Multimodal Mass Spectrometry Imaging and Immunofluorescence Microscopy Data Processing and Analysis

Multimodal imaging by matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI MSI) and immunofluorescence microscopy holds great potential for understanding pathological mechanisms by mapping molecular signatures from the tissue microenvironment to specific cell populations. However, existing open-source software solutions for analysis of MALDI MSI data are incomplete, require programming skills and contain laborious manual steps, hindering broadly applicable, reproducible, and high-throughput analysis to generate impactful biological discoveries across interdisciplinary research fields. Here we present msiFlow, an accessible open-source, platform-independent and vendor-neutral software for end-to-end, high-throughput, transparent and reproducible analysis of multimodal imaging data. msiFlow integrates all necessary steps from import and pre-processing of raw MALDI MSI data to visual analysis output, as well as registration, along with state-of-the-art and newly developed algorithms, into automated workflows. Using msiFlow, we unravel the molecular heterogeneity of leukocytes in infected tissues by spatial regulation of ether-linked phospholipids containing arachidonic acid. We anticipate that msiFlow will facilitate the broad applicability of MSI in the emerging field of multimodal imaging to uncover context-dependent cellular regulations in disease states.

bioinformatics↗

bioRxiv2024

Perceived multisensory common cause relations shape the ventriloquism effect but only marginally the trial-wise aftereffect

Combining multisensory cues is fundamental for perception and action, and reflected by two frequently-studied phenomena: multisensory integration and sensory recalibration. In the context of audio-visual spatial signals, these are exemplified by the ventriloquism effect and its aftereffect. The ventriloquism effect occurs when the perceived location of a sound is biased by a concurrent visual stimulus, while the aftereffect manifests as a recalibration of sound localization after exposure to spatially discrepant stimuli. The relationship between these processes--whether recalibration is a direct consequence of integration or operates independently--remains debated. This study investigates the role of causal inference in these processes by examining whether trial-wise judgments of audio-visual stimuli as originating from a common cause influence both the ventriloquism effect and the immediate aftereffect. Using a spatial paradigm, participants made explicit judgments about the common cause of stimulus pairs, and their influence on both perceptual biases was assessed. Our results indicate that while multisensory integration is contingent on common cause judgments, the immediate recalibration effect is not. This suggests that recalibration can occur independently of the perceived commonality of the multisensory stimuli, challenging the notion that recalibration is solely a byproduct of integration.

neuroscience↗

bioRxiv2023

Post-ischemic triiodothyronine treatment improves stroke outcome by stabilizing the blood-brain barrier

Thyroid hormones control a variety of processes in the central nervous system and influence its response to different stimuli, such as ischemic stroke. Post-stroke administration of triiodothyronine (T3) has been reported to substantially improve outcomes, but the optimal dosage and time window remain elusive. To this end we investigated the consequences of T3 treatment in an experimental model of ischemic stroke in mice. Our research demonstrated a dose-dependent protective effect of T3 by reducing infarct volumes, with the optimal T3 dosage identified as 25 {micro}g/kg. In addition, we observed a time-dependent effectiveness that was most pronounced when T3 was administered 1 h after transient middle cerebral artery occlusion, with a gradual reduction in efficacy at 4.5 h, and no reduction in infarct volumes when T3 was injected with an 8 h delay. This protective effect persisted for 72 h post-tMCAO, and had accelerated the recovery of motor function by day 3. In-depth investigations further revealed stabilization of the blood-brain barrier, indicated by reduced extravasation of Evans Blue and diminished aquaporin-4 expression, with reduced inflammation and less cell death as underlying reasons. Our findings suggest that thyroid hormones may be a promising intervention for clinical stroke.

neuroscience↗

bioRxiv2023

The highly and perpetually upregulated thyroglobulin gene is a hallmark of functional thyrocytes

Abnormalities are indispensable for studying normal biological processes and mechanisms. In the present work, we draw attention to the remarkable phenomenon of a perpetually and robustly upregulated gene, the thyroglobulin gene (Tg). The gene is expressed in the thyroid gland and, as it has been recently demonstrated, forms so-called transcription loops, easily observable by light microscopy. Using this feature, we show that Tg is expressed at a high level from the moment a thyroid cell acquires its identity and both alleles remain highly active over the entire life of the cell, i.e. for months or years depending on the species. We demonstrate that this high upregulation is characteristic of thyroglobulin genes in all major vertebrate groups. We provide evidence that Tg is not influenced by the thyroid hormone status, does not oscillate round the clock and is expressed during both the exocrine and endocrine phases of thyrocyte activity. We conclude that the thyroglobulin gene represents a valuable model to study the maintenance of a high transcriptional upregulation. SUMMARY STATEMENTThe thyroglobulin gene is highly and permanently expressed in thyrocytes of all vertebrates, at any condition and round the clock, offering a unique model to study mechanisms of high upregulation maintenance and chromatin dynamics

cell biology↗

bioRxiv2023

Stimulus specific and configurational features of multiple visual stimuli shape multisensory binding

Studies on multisensory perception often focus on simplistic conditions in which one single stimulus is presented per modality. Yet, in everyday life we usually encounter multiple signals per modality. To understand how multiple signals within and across the senses are combined we extended the classical audio-visual spatial ventriloquism paradigm to combine two visual stimuli with one sound. The individual visual stimuli presented in the same trial differed in their relative timing and spatial offsets to the sound, allowing us to contrast their individual and combined influence on sound localization judgements. We find that the ventriloquism bias is not dominated by a single visual stimulus but rather is shaped by the collective multisensory evidence. In particular, the contribution of an individual visual stimulus to the ventriloquism bias depends not only on its own relative spatio-temporal alignment to the sound but also the spatio-temporal alignment of the other visual stimulus. We propose that this pattern of multi-stimulus multisensory integration reflects the evolution of evidence for sensory causal relations during individual trials, calling for the need to extend established models of multisensory causal inference to more naturalistic conditions. Our data also suggest that this pattern of multisensory interactions extends to the ventriloquism aftereffect, a bias in sound localization observed in unisensory judgements following a multisensory stimulus.

neuroscience↗

bioRxiv2023

Different time scales of common-cause evidence shape multisensory integration, recalibration and motor adaptation

Perception engages the processes of integration, recalibration and sometimes motor adaptation to deal with discrepant multisensory stimuli. These processes supposedly deal with sensory discrepancies on different time scales, with integration reducing immediate ones and recalibration and motor adaptation reflecting the cumulative influence of their recent history. Importantly, whether discrepant signals are bound during perception is guided by the brains inference of whether they originate from a common cause. When combined, these two notions lead to the hypothesis that the different time scales on which integration and recalibration (or motor adaptation) operate are associated with different time scales of evidence of a common cause underlying two signals. We tested this prediction in a well-established visuo-motor paradigm, in which human participants performed visually guided hand movements. The kinematic correlation between hand and cursor movements indicates their common origin, allowing us to manipulate the common-cause evidence by this correlation between visual and proprioceptive signals. Specifically, we dissociated hand and cursor signals during individual movements while preserving their correlation across movement endpoints. Following our hypothesis, this manipulation reduced integration compared to a condition in which visual and proprioceptive signals were perfectly correlated. In contrast, recalibration and motor adaption were not affected. This supports the notion that multisensory integration and recalibration are guided by common-cause evidence but deal with sensory discrepancies on different time scales: while integration is prompted by local common-cause evidence and reduces immediate discrepancies instantaneously, recalibration and motor adaptation are prompted by global common-cause evidence and reduce persistent discrepancies.

neuroscience↗

bioRxiv2022

Triac treatment prevents neurodevelopmental and locomotor impairments in Mct8/Oatp1c1 double knockout mice.

BackgroundPatients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to an insufficient TH transport and action in the CNS. As a therapeutic strategy, application of Triac (3, 5, 3-triiodothyroacetic acid) and Ditpa (3, 5 -diiodo-thyropropionic acid) have been proposed as both thyromimetic compounds are not dependent on MCT8 for cellular entry. Here, we tested and directly compared the thyromimetic actions of Triac versus Ditpa in Mct8/Oatp1c1 double knockout mice (Dko), a mouse model for human MCT8 deficiency. MethodsNewborn Dko mice were daily injected during the first three postnatal weeks with either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) and compared with Wt and Dko mice receiving saline injections. A second cohort of Dko mice was daily injected with Triac (400 ng/g) only between postnatal week 3 and 6. Thyromimetic effects in the CNS and peripheral tissues were monitored at different postnatal time points by immunofluorescence stainings for neural marker proteins, in situ hybridization and quantitative real time PCR. Locomotor performance was assessed in rotarod and hanging wire test. Acute brain slices of Triac treated Dko mice and their respective controls were used for electrophysiological recordings. ResultsOnly Dko mice injected with Triac (400 ng/g) during the first three postnatal weeks showed normalized myelination, differentiation of cortical GABAergic interneurons as well as locomotor performance. Electrophysiological recordings revealed an increased frequencies of cortical spontaneous miniature inhibitory postsynaptic currents in Dko mice and a normalization of this parameter in Triac treated Dko mice. In comparison, treatment of Dko mice with Ditpa at 4000 ng/g during the first three postnatal weeks resulted in normal myelination and cerebellar development but was less effective in restoring neuronal parameters and locomotor function. Finally, Triac was more potent than Ditpa in suppressing Trh and Tshb expression, respectively, and exerts stronger thyromimetic effects in liver and kidneys. ConclusionsIn newborn Dko deficient mice, Triac is highly effective and more efficient than Ditpa in promoting CNS maturation and function. Yet, Triac treatment needs to be initiated directly after birth to achieve the most beneficial effects.

neuroscience↗

bioRxiv2022

The history of multisensory discrepancies affects the ventriloquism effect and the immediate aftereffect differentially.

Multisensory integration and recalibration are two processes by which perception deals with discrepant signals. Both are often studied in the spatial ventriloquism paradigm. There, integration is probed by the presentation of discrepant audio-visual stimuli, while recalibration manifests as an aftereffect in subsequent unisensory judgements. Both biases are typically quantified against the degree of audio-visual discrepancy, reflecting the possibility that both may arise from common underlying multisensory principles. We tested a specific prediction of this: that both processes should also scale similarly with the history of multisensory discrepancies experienced in previous trials. Analysing data from ten experiments we confirmed the expected dependency of each bias on the immediately presented discrepancy. And in line with the aftereffect being a cumulative process, this scaled with the discrepancies presented in multiple preceding audio-visual trials. However, the ventriloquism bias did not depend on the history of multisensory discrepancies and also did not depend on the aftereffect biases in previous trials - making these two multisensory processes experimentally dissociable. These findings support the notion that the ventriloquism bias and the aftereffect reflect distinct functions, with integration maintaining a stable percept by reducing immediate sensory discrepancies and recalibration maintaining an accurate percept by accounting for consistent discrepancies.

neuroscience↗

bioRxiv2021

Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency

The solute carrier monocarboxylate transporter 8 (MCT8) transports the thyroid hormones thyroxine and tri-iodothyronine (T3) across cell membranes. MCT8 gene deficiency, termed Allan-Herndon-Dudley syndrome, is an important cause of X-linked intellectual and motor disability. As no treatment of the neurological symptoms is available yet, we tested a gene replacement therapy in Mct8- and Oatp1c1-deficient mice as a well-established model of the disease. Here, we report that targeting brain endothelial cells for Mct8 expression by intravenously injecting the vector AAV-BR1-Mct8 increased T3 levels in the brain and ameliorated morphological and functional parameters associated with the disease. Importantly, the therapy resulted in a long-lasting improvement in motor coordination. Thus, the data support the concept that MCT8 mediates the transport of thyroid hormones into the brain and indicate that a readily accessible vascular target can help overcome the consequences of the severe disability associated with MCT8 deficiency.

neuroscience↗

bioRxiv2021

AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in an AHDS mouse model

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8-/y;Oatp1c1-/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T3-brain content and T3-related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.

neuroscience↗

bioRxiv2021

Visuo-proprioceptive integration and recalibration with multiple visual stimuli

To organize the plethora of sensory signals from our environment into a coherent percept, our brain relies on the processes of multisensory integration and sensory recalibration. We here asked how visuo-proprioceptive integration and recalibration are shaped by the presence of more than one potentially relevant visual stimulus, hence paving the way to studying multisensory perception under more naturalistic settings with multiple signals per sensory modality. By manipulating the spatio-temporal correspondence between the hand position and two visual stimuli during a cursor-control task, we contrasted two alternative accounts: that only the temporally more proximal signal enters integration and recalibration similar to a winner-takes-all process, or that the influences of both visual signals superpose. Our results show that integration - and likely also recalibration - are shaped by the superposed contributions of multiple stimuli rather than by only individual ones.

neuroscience↗

bioRxiv2019

Function of TRIP6 in brain-specific ciliogenesis

TRIP6, a member of the zyxin-family of LIM domain proteins, is a focal adhesion component. trip6 deletion in the mouse revealed, unexpectedly, in view of its ubiquitous expression, a function in the brain: ependymal and choroid plexus epithelial cells were poorly developed, carrying fewer and shorter cilia, and the mice developed hydrocephalus. TRIP6 disruption, via RNAi or inhibition of its homodimerization, in a choroid plexus epithelial cell line, confirmed its function in ciliogenesis. Zyxin-family members carry numerous protein interaction domains. In common with assembly of other multiprotein complexes, ciliogenesis may be facilitated by molecular assembly factors. Super-resolution microscopy demonstrated TRIP6 localization at the pericentriolar material and along the ciliary axoneme. The requirement for homodimerization which doubles its interaction sites, its punctate localization along the axoneme, and its co-localization with other cilia components suggest a scaffold/co-transporter function for TRIP6 in cilia. This is the first discovery of a protein assembly factor essential for mammalian ciliogenesis.

cell biology↗