Biology subjects

Dau, T.

Publications and source records attributed to Dau, T..

18 recordsLinked to original sources

bioRxiv2026

Perceptual sensitivity is explained by optimization for ecological tasks

When asked to discriminate between two stimuli that differ along some dimension, such as intensity, frequency, or orientation, humans exhibit a smallest stimulus difference, or threshold, below which discrimination becomes impossible. These limits on perceptual sensitivity have traditionally been explained by internal noise. Contemporary theories instead link perceptual sensitivity to efficient coding of the natural environment but have not been comprehensively tested. Here, we measured the psychoacoustic sensitivity of a computational model optimized for everyday sound localization and recognition tasks. We used linear classifiers operating on the model's learned representations to estimate 1632 thresholds spanning the perceptual dimensions of sound. These model-derived thresholds closely matched thresholds measured behaviorally in humans on the same test battery. The results show that many classical psychophysical phenomena emerge from representations optimized for natural behavior and suggest that discrimination thresholds are determined by linear separability in these optimized representations, rather than intrinsic neural noise.

neuroscience↗

bioRxiv2026

Fatigue-related changes in value-based decision-making during listening are associated with increased frontal cortical activation

Hearing aid users commonly report listening-related fatigue, which may contribute to disengagement from demanding listening situations and negative psychosocial outcomes. Hearing rehabilitation currently lacks strategies to mitigate listening fatigue, partly because fatigue build-up and its consequences are difficult to measure beyond self-report. This study investigated whether value-based listening decisions and associated frontal cortical activity are modulated by fatigue. Thirty hearing aid users completed a one-hour listening paradigm while cortical hemodynamic activity was measured using functional near-infrared spectroscopy (fNIRS). On each trial, participants decided whether to engage in listening or rest based on an offer defined by expected task difficulty and reward, and rated their momentary fatigue. Fatigue ratings increased over time, and unsuccessful listening trials were associated with larger subsequent increases in fatigue, suggesting that performance contributed to changes in self-reported fatigue. Listen-versus-rest decisions followed the expected effort-reward trade-off, with participants more likely to accept offers that provided higher rewards and lower listening demands. Over the course of the experiment, participants became less likely to accept listening offers; however, neither time on task nor subjective fatigue altered the weighting of reward and difficulty. In contrast, frontal cortical activation during evaluation of accepted offers increased over time for high-difficulty offers with low or medium rewards. Follow-up analyses indicated that frontal oxygenation and listening decisions were more strongly associated with time on task than with subjective fatigue ratings. Together, these findings suggest that behavioral and neural measures obtained before listening capture fatigue-related processes beyond self-report, providing a basis for identifying and potentially addressing fatigue in hearing rehabilitation.

neuroscience↗

bioRxiv2026

Transient protein phosphorylation promotes disease tolerance to sepsis

One of the enduring paradoxes of sepsis is that organs fail despite little evidence of irreversible tissue injury. Emerging evidence suggests that this state reflects a regulated metabolic shutdown within host tissues, yet whether such hypometabolism contributes to pathology or promotes survival remains unclear. This phenomenon resembles torpor, a physiological state of profound hypometabolism induced by environmental stress and mediated through reversible protein phosphorylation. Septic hypometabolism is identified here as a conserved tissue-specific metabolic adaptation which is characterized by transient activation of Glycogen Synthase Kinase (GSK)3{beta}. This activation reduced disease severity of bacterial sepsis without affecting the hosts pathogen burden, indicating that GSK3{beta} activity promotes disease tolerance to infection. Consistent with these findings, plasma signatures associated with GSK3{beta} inhibition correlated with worse clinical outcomes in patients with sepsis. Together, these results define septic hypometabolism as a torpor-like response and identify reversible phosphorylation as a key mechanism governing host adaptation to severe bacterial infection.

immunology↗

bioRxiv2025

Predicting spectro-temporal modulation detection thresholds with a functional auditory model

Spectro-temporal modulation (STM) sensitivity has been proposed as a sensitive marker of speech intelligibility in challenging listening conditions, yet the underlying auditory mechanisms involved in STM detection remain incompletely understood. The present study measured STM detection thresholds in young normal-hearing and older hearing-impaired listeners and evaluated whether the revised Computational Auditory Signal Processing and Perception model [CASP, Paulick et al. (2025). J.Acoust.Am.157(5), 3232-3244] can account for individual performance. Thresholds were obtained for six modulation detection conditions, defined by combinations of spectral (0, 1, 2 c/o) and temporal (4, 12 Hz) rates. To individualise CASP, outer and inner hair cell loss estimates were obtained from audiometric and Adaptive Categorical Loudness Scaling (ACALOS) data. The results showed systematically elevated thresholds in older hearing-impaired listeners as compared to the young normal-hearing group, particularly at higher spectral rates. The model simulations reproduced overall threshold patterns, but substantially underestimated group differences and inter-individual variability in the data. Moreover, the simulations showed limited sensitivity to estimates of outer and inner hair cell loss, supporting the idea that additional supra-threshold mechanisms contribute to STM deficits. While these findings demonstrate the potential of auditory models to predict STM performance, they also highlighting the need for refined representations of peripheral and central processing to account for individual STM detection thresholds.

neuroscience↗

bioRxiv2025

The microcephaly-associated protein YIPF5 differentially regulates ER-export

YIPF5 is a small ER-membrane protein implicated in ER-Golgi transport. Mutations in YIPF5 cause MEDS2 (microcephaly with simplified gyral pattern, epilepsy, and neonatal diabetes syndrome), a fatal disorder manifesting in early childhood. We demonstrate that YIPF5 is involved in ER export of a subset of proteins, including cargoes of the ER-export receptor SURF4, with which it directly interacts. In YIPF5 knockout cells, we observe a shift in the cell surface and secretome composition, marked by reduced neuronal adhesion molecules and increased secretion of ER chaperones influencing cell migration. YIPF5 depletion enhances cell migration in a wound-healing assay and alters SURF4 localization, causing elongated ERGIC53- and Rab1-positive tubules from COPII-labeled ER exit sites. Kinetic analysis suggests that YIPF5 negatively regulates SURF4-mediated ER export. In utero knockdown of Yipf5 in embryonic mouse brains induces premature neuronal migration and abnormal neuronal morphology. These findings suggest that YIPF5 and SURF4 coordinate ER export, and disruption may underlie cortical development defects leading to microcephaly.

cell biology↗

bioRxiv2024

A modiolar-pillar gradient in auditory-nerve dendritic length: a novel post-synaptic contribution to dynamic range?

Auditory-nerve fibers (ANFs) from a given cochlear region can vary in threshold sensitivity by up to 60 dB, corresponding to a 1000-fold difference in stimulus level, although each fiber innervates a single inner hair cell (IHC) via a single synapse. ANFs with high-thresholds also have low spontaneous rates (SRs) and synapse on the side of the IHC closer to the modiolus, whereas the low-threshold, high-SR fibers synapse on the side closer to the pillar cells. Prior biophysical work has identified modiolar-pillar differences in both pre- and post-synaptic properties, but a comprehensive explanation for the wide range of sensitivities remains elusive. Here, in guinea pigs, we used immunostaining for several neuronal markers, including Caspr, a key protein in nodes of Ranvier, to reveal a novel modiolar-pillar gradient in the location of the first ANF heminodes, presumed to be the site of the spike generator, just outside the sensory epithelium. Along the cochlea, from apex to base, the unmyelinated terminal dendrites of modiolar ANFs were 2 - 4 times longer than those of pillar ANFs. This modiolar-pillar gradient in dendritic length, coupled with the 2 - 4 fold smaller caliber of modiolar dendrites seen in prior single-fiber labeling studies, suggests there could be a large difference in the number of length constants between the synapse and the spike initiation zone for low- vs high-SR fibers. The resultant differences in attenuation of post-synaptic potentials propagating along these unmyelinated dendrites could be a key contributor to the observed range of threshold sensitivities among ANFs.

neuroscience↗

bioRxiv2024

The Computational Auditory Signal Processing and Perception Model (CASP): A Revised Version

This study introduces a revised version of the computational auditory signal processing and perception (CASP) model (Jepsen et al., 2008), which has undergone substantial updates and refinements aimed at enhancing its accuracy and usability across various applications. A primary motivation for the revision was the integration of a more realistic non-linear inner hair cell (IHC) model to address the limitations of its more simplistic predecessor. Demonstrating backwards compatibility, the revised model exhibited similar predictive power to previous CASP implementations across conditions of intensity discrimination, simultaneous and forward masking, and modulation detection, effectively accounting for data from normal-hearing listeners. Additionally, improved decision-making strategies and a streamlined model configuration further enhance the models usability and accessibility. Overall, the revised CASP offers a more accurate and intuitive framework for simulating auditory processing and perception across diverse conditions and tasks. The revised model may be a useful tool in studying the influence of the ears nonlinear response properties on internal representations, particularly concerning the effects of sensorineural hearing loss on auditory perception.

neuroscience↗

bioRxiv2024

Real-time control of a hearing instrument with EEG-based attention decoding

Enhancing speech perception in everyday noisy acoustic environments remains an outstanding challenge for hearing aids. Speech separation technology is improving rapidly, but hearing devices cannot fully exploit this advance without knowing which sound sources the user wants to hear. Even with high-quality source separation, the hearing aid must know which speech streams to enhance and which to suppress. Advances in EEG-based decoding of auditory attention raise the potential of neurosteering, in which a hearing instrument selectively enhances the sound sources that a hearing-impaired listener is focusing their attention on. Here, we present and discuss a real-time brain-computer interface (BCI) system that combines a stimulus-response model based on canonical correlation analysis (CCA) for real-time EEG attention decoding, coupled with a multi-microphone hardware platform enabling low-latency real-time speech separation through spatial beamforming. We provide an overview of the system and its various components, discuss prospects and limitations of the technology, and illustrate its application with case studies of listeners steering acoustic feedback of competing speech streams via real-time attention decoding. A software implementation code of the system is publicly available for further research and explorations.

neuroscience↗

bioRxiv2024

IER3IP1-mutations cause microcephaly by selective inhibition of ER-Golgi transport

Mutations in the IER3IP1 (Immediate Early Response-3 Interacting Protein 1) gene can give rise to MEDS1 (Microcephaly with Simplified Gyral Pattern, Epilepsy, and Permanent Neonatal Diabetes Syndrome-1), a severe condition leading to early childhood mortality. The small endoplasmic reticulum (ER)-membrane protein IER3IP1 plays a non-essential role in ER-Golgi transport. Here, we employed secretome and cell-surface proteomics to demonstrate that the absence of IER3IP1 or the presence of the pathogenic p.L78P mutation results in the retention of specific cell-surface receptors and secreted proteins crucial for neuronal migration within the ER. This phenomenon correlates with the distension of ER membranes and increased lysosomal activity. Notably, the trafficking of cargo receptor ERGIC53 and KDEL-receptor 2 is compromised, with the latter leading to the anomalous secretion of ER-localized chaperones. Our investigation extended to in-utero knock-down of Ier3ip1 in mouse embryo brains, revealing a morphological phenotype in newborn neurons. In summary, our findings provide insights into how the loss or mutation of a 10 kDa small ER-membrane protein can cause a fatal syndrome.

cell biology↗

bioRxiv2023

Automated workflow for BioID improves reproducibility and identification of protein-protein interactions

Proximity dependent biotinylation is an important method to study protein-protein interactions in cells, for which an expanding number of applications has been proposed. The laborious and time consuming sample processing has limited project sizes so far. Here, we introduce an automated workflow on a liquid handler to process up to 96 samples at a time. The automation does not only allow higher sample numbers to be processed in parallel, but also improves reproducibility and lowers the minimal sample input. Furthermore, we combined automated sample processing with shorter liquid chromatography gradients and data-independent acquisition to increase analysis throughput and enable reproducible protein quantitation across a large number of samples. We successfully applied this workflow to optimise the detection of proteasome substrates by proximity-dependent labelling.

biochemistry↗

bioRxiv2023

Impact of age versus hearing loss on amplitude modulation frequency selectivity and speech intelligibility

The perception of amplitude modulation (AM), characterized by a frequency-selective process in the modulation domain, is considered critical for speech intelligibility. Previous literature has provided evidence of an age-related decline in AM frequency selectivity. Additionally, a notable sharpening of AM tuning with hearing loss has been observed, which was proposed to be related to a perceptual advantage resulting from peripheral compression loss. This study explores whether such changes in AM tuning with age and hearing loss contribute to the speech intelligibility challenges that older listeners often face in noisy environments. Young (n=10, 22-28 years) and older (n=9, 57-77 years) listeners with normal hearing as well as older listeners with hearing impairment (n=9, 64-77 years) participated in the study. All had previously taken part in studies on AM tuning. Speech-reception thresholds (SRTs) were collected in conditions including stationary, fluctuating, and competing-speech maskers. The results revealed an age-related increase in SRTs, with an additional negative impact of hearing loss. Beyond age and audibility, a measure of AM tuning significantly contributed to explaining the variance in SRTs across listeners for specific maskers. These findings motivate further exploration of the relationship between AM frequency selectivity and speech intelligibility in noise.

neuroscience↗

bioRxiv2023

Disentangling the effects of hearing loss and age on amplitude modulation frequency selectivity

The processing and perception of amplitude modulation (AM) in the auditory system reflect a frequency-selective process, often described as a modulation filterbank. Previous studies on perceptual AM masking reported similar results for older listeners with hearing impairment (HI) and young listeners with normal hearing (NH), suggesting no effects of age or hearing loss on AM frequency selectivity. However, recent evidence has shown that age, independently of hearing loss, adversely affects AM frequency selectivity. Hence, this study aimed to disentangle the effects of hearing loss and age. A simultaneous AM masking paradigm was employed, utilizing a sinusoidal carrier at 2.8 kHz, narrow-band noise modulation maskers, and target modulation frequencies of 4, 16, 64, and 128 Hz. The results obtained from young (n=3, 24-30 years) and older (n=10, 63-77 years) HI listeners were compared to previously obtained data from young and older NH listeners. Notably, the HI listeners generally exhibited lower (unmasked) AM detection thresholds and greater AM frequency selectivity than their NH counterparts in both age groups. Overall, the results suggest that age negatively affects AM frequency selectivity for both NH and HI listeners, while hearing loss improves AM detection and AM selectivity, likely due to the loss of peripheral compression.

neuroscience↗

bioRxiv2022

ProteasomeID: quantitative mapping of proteasome interactomes and substrates for in vitro and in vivo studies

Proteasomes are essential molecular machines responsible for the degradation of proteins in eukaryotic cells. Altered proteasome activity has been linked to neurodegeneration, auto-immune disorders and cancer. Despite the relevance for human disease and drug development, no method currently exists to monitor proteasome composition and interactions in vivo in animal models. To fill this gap, we developed a strategy based on tagging of proteasomes with promiscuous biotin ligases and generated a new mouse model enabling the quantification of proteasome interactions by mass spectrometry. We show that biotin ligases can be incorporated in fully assembled proteasomes without negative impact on their activity. We demonstrate the utility of our method by identifying novel proteasome-interacting proteins, charting interactomes across mouse organs, and showing that proximity-labeling enables the identification of both endogenous and small molecule-induced proteasome substrates.

biochemistry↗

bioRxiv2020

Proteomics Using Protease Alternatives to Trypsin Benefits from Sequential Digestion with Trypsin

Trypsin is the most used enzyme in proteomics. Nevertheless, proteases with complementary cleavage specificity have been applied in special circumstances. In this work, we analyzed the characteristics of five protease alternatives to trypsin for protein identification and sequence coverage when applied to S. pombe whole cell lysates. The specificity of the protease heavily impacted on the number of proteins identified. Proteases with higher specificity let to the identification of more proteins than proteases with lower specificity. However, AspN, GluC, chymotrypsin and proteinase K largely benefited from being paired with trypsin in sequential digestion, as had been shown by us for elastase before. In the most extreme case, pre-digesting with trypsin improves the number of identified proteins for proteinase K by 731 %. Trypsin pre-digestion also improved the protein identifications of other proteases, AspN (+62 %), GluC (+80 %) and chymotrypsin (+21 %). Interestingly, the sequential digest with trypsin and AspN yielded even higher number of protein identifications than digesting with trypsin alone.

biochemistry↗

bioRxiv2019

Supra-threshold perception and neural representation of tones presented in noise in conditions of masking release

The neural representation and perceptual salience of tonal signals presented in different noise maskers were investigated. The properties of the maskers and signals were varied such that they produced different amounts of either monaural masking release, binaural masking release, or a combination of both. The signals were then presented at different levels above their corresponding masked thresholds and auditory evoked potentials (AEPs) were measured. It was found that, independent of the masking condition, the amplitude of the P2 component of the AEP was similar for the same stimulus levels above masked threshold, suggesting that both monaural and binaural effects of masking release were represented at the level of P2 generation. The perceptual salience of the signal was evaluated at equal levels above masked threshold using a rating task. In contrast to the electrophysiological findings, the subjective ratings of the perceptual signal salience were less consistent with the signal level above masked threshold and varied strongly across listeners and masking conditions. Overall, the results from the present study suggest that the P2 amplitude of the AEP represents an objective indicator of the audibility of a target signal in the presence of complex acoustic maskers.

neuroscience↗

bioRxiv2018

Sound source localization with varying amount of visual information in virtual reality

To achieve accurate spatial auditory perception, subjects typically require personal head-related transfer functions (HRTFs) and the freedom for head movements. Loudspeaker-based virtual sound environments allow for realism without individualized measurements. To study audio-visual perception in realistic environments, the combination of spatially tracked head mounted displays (HMDs), also known as virtual reality glasses, and virtual sound environments may be valuable. However, HMDs were recently shown to affect the subjects HRTFs and thus might influence sound localization performance. Furthermore, due to limitations of the reproduction of visual information on the HMD, audio-visual perception might be influenced. Here, a sound localization experiment was conducted both with and without an HMD and with a varying amount of visual information provided to the subjects. Furthermore, interaural time and level difference errors (ITDs and ILDs) as well as spectral perturbations induced by the HMD were analyzed and compared to the perceptual localization data. The results showed a reduction of the localization accuracy when the subjects were wearing an HMD and when they were blindfolded. The HMD-induced error in azimuth localization was found to be larger in the left than in the right hemisphere. Thus, the errors in ITD and ILD can only partly account for the perceptual differences. When visual information of the limited set of source locations was provided, the localization error induced by the HMD was found to be negligible. Presenting visual information of hand-location, room dimensions, source locations and pointing feedback on the HMD revealed similar effects as previously shown in real environments.

neuroscience↗

bioRxiv2018

Sequential digestion with Trypsin and Elastase in cross-linking/mass spectrometry

Cross-linking/mass spectrometry has become an important approach for studying protein structures and protein-protein interactions. The amino acid composition of some protein regions impedes the detection of cross-linked residues, although it would yield invaluable information for protein modelling. Here, we report on a sequential digestion strategy with trypsin and elastase to penetrate regions with a low density of trypsin cleavage sites. We exploited intrinsic substrate recognition properties of elastase to specifically target larger tryptic peptides. Our application of this protocol to the TAF4-12 complex allowed us to identify cross-links in previously inaccessible regions.

biochemistry↗

bioRxiv2018

An integrated workflow for cross-linking/mass spectrometry

We present a concise workflow to enhance the mass spectrometric detection of cross-linked peptides by introducing sequential digestion and the cross-link identification software Xi. Sequential digestion enhances peptide detection by shortening long tryptic peptides while avoiding over-digestion. We demonstrate our simple 12-fraction protocol for cross-linked multi-protein complexes and cell lysates, quantitative analysis, and high-density cross-linking, without requiring specific cross-linker features. This overall approach reveals dynamic protein-protein interaction sites, which are accessible, have fundamental functional relevance and are therefore ideally suited for the development of small molecule inhibitors.

biochemistry↗