Biology subjects

Buchholz, S.

Publications and source records attributed to Buchholz, S..

9 recordsLinked to original sources

bioRxiv2025

The S. aureus serine protease-like protein B (SplB) is a potent allergen causing eosinophilic airway inflammation in mice

Background: Asthma is associated with Staphylococcus aureus colonization. Two hypotheses were proposed to explain this phenomenon: (1) the allergic environment in asthma favors S. aureus colonization and (2) S. aureus colonization creates a pro-allergic environment. Since several S. aureus virulence factors, such as the serine protease-like protein (Spl) B, elicit a type 2 biased immune response, we asked whether the pathogen itself can cause asthma. Objective: Test the ability of recombinant SplB of S. aureus to sensitize mice and induce allergic airway inflammation (AAI). Methods: Mice were treated with repeated intratracheal inoculations of either catalytically active SplB or an inactive mutant. AAI was assessed by evaluating airway hypersensitivity, immune cell infiltration, cytokines, mucus production, fibrosis, and specific serum IgE. We compared the outcome between wild-type and gene-deficient C57BL/6J mice, including recombination-activating gene knockout mice (Rag2-/-), interleukin-33 knockout mice (Il33 -/-), and protease-activated receptor 2 knockout mice (F2rl1-/-). Results: Intratracheal exposure to SplB sensitized the mice and caused eosinophilic airway inflammation and hyperresponsiveness. The development of asthma required both the proteolytic activity of SplB and a functional adaptive immune system. The soluble protease sensor IL-33 was necessary for eosinophil tissue invasion, whereas the membrane-bound protease sensor PAR2 was not. Conclusion: The serine protease SplB of S. aureus is a potent allergen. Based on this finding we propose a third mechanism to explain the relationship between S. aureus colonization and asthma: S. aureus can release allergens, such as SplB, that sensitize individuals and lead to the development of asthma.

immunology↗

bioRxiv2025

Neurophysiological Sensitivity to Envelope and Pulse Timing Interaural Time Differences in Cochlear Implanted Rats with Different Hearing Experiences

Cochlear implants (CIs) have successfully restored hearing in more than one million patients with severe to profound hearing loss worldwide. While CIs effectively restore speech perception in quiet environments, sound localization remains challenging for bilateral CI users, particularly their ability to utilize interaural time differences (ITDs). The majority of clinical CI processors use a coding strategy that encodes ITD information only in the envelope of electrical pulse trains rather than their pulse timing, which may contribute to the poorer spatial hearing perception of CI users. We recently demonstrated in a behavioral study on early deafened, bilaterally CI-implanted rats that pulse timing ITDs completely dominate ITD perception, while sensitivity to envelope ITDs is almost negligible in comparison. Building on this, we here investigated the neurophysiological sensitivity of the inferior colliculus (IC) to envelope and pulse timing ITDs at two different pulse rates (900 and 4500 pulses/s) and three different stimulation modulations (5, 20 and 100 Hz) in CI rats with different hearing experiences. Our results indicate that IC neurons exhibit far greater sensitivity to pulse timing ITD than envelope ITD independent of pulse rate, modulation rate or hearing experience. These findings suggest that to improve binaural hearing outcome in bilateral CI users, clinical stimulation strategies should provide informative pulse timing ITDs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/675523v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1874d3borg.highwire.dtl.DTLVardef@1df79feorg.highwire.dtl.DTLVardef@c244e5org.highwire.dtl.DTLVardef@39220f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Interactions of Interaural Time and Level Differences in Spatial Hearing with Cochlear Implants

Normally hearing humans can localize sound sources quite accurately, with minimum audible angles as small as 1{degrees}. To achieve this, our auditory pathways combine information from multiple acoustic cues, including interaural time and interaural level differences (ITDs and ILDs). Patients relying on cochlear implants (CIs) to hear the world cannot match normal performance. These deficits are most pronounced in patients with little or no hearing experience early in life, and they appear to result from an impaired sensitivity to ITDs, but not to ILDs. However, little is known about how ITD and ILD sensitivities develop and interact in an early deafened auditory system shortly after CI implantation. We fitted neonatally deafened rats with bilateral CIs, and, providing informative ITDs and ILDs from stimulation onset, trained them to lateralize CI stimuli. These animals were exquisitely sensitive to both ILDs and ITDs of CI stimulus pulses, and combined information from both cues in a weighted sum. Importantly, ITDs are weighted heavily in our CI rats, such that only very modest ITDs pointing in one direction can confound quite large ILDs pointing in the opposite direction. This underlines the importance of informative ITDs for maximizing the potential for spatial hearing with CI devices. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=181 SRC="FIGDIR/small/635454v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@15ee6e2org.highwire.dtl.DTLVardef@1881bd4org.highwire.dtl.DTLVardef@db17c7org.highwire.dtl.DTLVardef@1f62f2f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Interaural level difference sensitivity in neonatally deafened rats fitted with bilateral cochlear implants

Bilateral cochlear implant (CI) patients exhibit significant limitations in spatial hearing. Their ability to process interaural time differences (ITDs) is often impaired, while their ability to process interaural level differences (ILDs) remains comparatively good. Clinical studies aiming to identify the causes of these limitations are often plagued by confounds and ethical limitations. Recent behavioral work suggests that rats may be a good animal model for studying binaural hearing under neuroprosthetic stimulation, as rats develop excellent ITD sensitivity when provided with suitable CI stimulation. However, their ability to use ILDs has not yet been characterized. Objective of this study is to address this knowledge gap. Neontally deafened rats were bilaterally fitted with CIs, and trained to lateralize binaural stimuli according to ILD. Their behavioral ILD thresholds were measured at pulse rates from 50 to 2400 pps. CI rats exhibited high sensitivity to ILDs with thresholds of a few dB at all tested pulse rates. We conclude that early deafened rats develop good sensitivity, not only to ITDs but also to ILDs, if provided with appropriate CI stimulation. Their generally good performance, in line with expectations from other mammalian species, validates rats as an excellent model for research on binaural auditory prostheses.

neuroscience↗

bioRxiv2024

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity

Tau pathology is a major hallmark of Alzheimers disease (AD) and related diseases, called tauopathies. While Tau is normally enriched in axons, somatodendritic missorting of the microtubule-associated protein is a key event in early disease development. Tau missorting promotes synaptic loss and neuronal dysfunction but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. Interestingly, the disease-associated Tau brain isoforms show different axodendritic distribution, but the distinct role of these isoforms in health and disease largely unknown. Here, we aimed to identify domains or motifs of Tau and cellular binding partners that are required for efficient axonal Tau sorting, and we studied the differences of the isoform-specific Tau interactome. By using human MAPT-KO induced pluripotent stem cell (iPSC)-derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncated or phosphorylation-mutant Tau constructs, and we used TurboID-based proximity labelling and proteomics to identify sorting- and isoform-specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N-terminal tail, the C-terminal repeat domains, and the general microtubule affinity of Tau. In contrast, the presence of the proline-rich region 2 (PRR2) was necessary for successful sorting. Our interactome data revealed peroxisomal accumulation of the Tau N-terminal half, while axonal Tau interacted with the PP2A activator HSP110. When we compared the interactome of 0N3R- and 0N4R-Tau, we observed specific interactions of 0N4R-Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, such as members of the CDC42 pathway and the RAB11 proteins, while 0N3R-Tau bound to MAP4 and other cytoskeletal elements. In sum, our study postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity, and unravels a potential isoform-specific role in synaptic function and AD-related dysfunction.

neuroscience↗

bioRxiv2023

Is Inappropriate Pulse Timing Responsible for Poor Binaural Hearing with Cochlear Implants?

Cochlear implants (CIs) have restored enough of a sense of hearing to around one million severely hearing impaired patients to enable speech understanding in quiet. However, several aspects of hearing with CIs remain very poor. This includes a severely limited ability of CI patients to make use of interaural time difference (ITD) cues for spatial hearing and noise reduction. A major cause for this poor ITD sensitivity could be that current clinical devices fail to deliver ITD information in a manner that is accessible to the auditory pathway. CI processors measure the envelopes of incoming sounds and then stimulate the auditory nerve with electrical pulse trains which are amplitude modulated to reflect incoming sound envelopes. The timing of the pulses generated by the devices is largely or entirely independent of the incoming sounds. Consequently, bilateral CIs (biCIs) provide veridical envelope (ENV) ITDs but largely or entirely replace the "fine structure" ITDs that naturally occur in sounds with completely arbitrary electrical pulse timing (PT) ITDs. To assess the extent to which this matters, we devised experiments that measured the sensitivity of deafened rats to precisely and independently controlled PT and ENV ITDs for a variety of different CI pulse rates and envelope shapes. We observed that PT ITDs completely dominate ITD perception, while the sensitivity to ENV ITDs was almost negligible in comparison. This strongly suggests that the confusing yet powerful PT ITDs that contemporary clinical devices deliver to biCI patients may be a major cause of poor binaural hearing outcomes with biCIs. Significance StatementCIs deliver spectro-temporal envelopes, including speech formants, to severely deaf patients, but they do little to cater to the brains ability to process temporal sound features with sub-millisecond precision. CIs "sample" sound envelope signals rapidly and accurately, and thus provide information which should make it possible in principle for CI listeners to detect envelope ITDs in a similar way to normal listeners. However, here we demonstrate through behavioral experiments on CI implanted rats trained to detect sub-millisecond ITDs that pulse timing ITDs completely dominate binaural hearing. This provides the strongest confirmation to date that the arbitrary pulse timing widely used in current clinical CIs is a critical obstacle to good binaural hearing through prosthetic devices.

neuroscience↗

bioRxiv2022

Interaural time difference sensitivity under binaural cochlear implant stimulation even at high pulse rates up to 900 pps

BackgroundSpatial hearing remains one of the major challenges for bilateral cochlear implant (biCI) users, and early deaf patients in particular are often completely insensitive to interaural time differences (ITDs) delivered through biCIs. One popular hypothesis is that this may be due to a lack of early binaural experience. However, we have recently shown that neonatally deafened rats fitted with biCIs in adulthood quickly learn to discriminate ITDs as well as their normal hearing litter mates, and perform an order of magnitude better than human biCI users. MethodsOur unique behaving biCI rat model allows us to investigate other possible limiting factors of prosthetic binaural hearing, such as the effect of stimulus pulse rate and envelope shape. Previous work has indicated that ITD sensitivity may decline substantially at the high pulse rates often used in clinical practice. We therefore measured behavioral ITD thresholds in neonatally deafened, adult implanted biCI rats to pulse trains of 50, 300, 900 and 1800 pulses per second (pps), with either rectangular or Hanning window envelopes. ResultsOur rats exhibited very high sensitivity to ITDs at pulse rates up to 900 pps for both envelope shapes, similar to those in common clinical use. However, ITD sensitivity declined to near zero at 1800 pps, for both Hanning and rectangular windowed pulse trains. ConclusionsCurrent clinical cochlear implant (CI) processors are often set to pulse rates [≥]900 pps, but ITD sensitivity in human CI listeners has been reported to decline sharply above [~]300 pps. Our results suggest that the relatively poor ITD sensitivity seen at >300 pps in human CI users may not reflect the hard upper limit of biCI ITD performance in the mammalian auditory pathway. Perhaps with training or better CI strategies good binaural hearing may be achievable at pulse rates high enough to allow good sampling of speech envelopes while delivering usable ITDs.

neuroscience↗

bioRxiv2020

Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during periods of clinical latency

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profiled rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identified IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lacked membranous IL6 receptor expression and mechanistic dissection revealed IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals was found to be niche-dependent as bone marrow stromal and endosteal cells down-regulated gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation rendered cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we found PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

cancer biology↗

bioRxiv2019

A multidimensional framework for measuring biotic novelty: How novel is a community?

Anthropogenic changes in climate, land use and disturbance regimes, as well as introductions of non-native species can lead to the transformation of many ecosystems. The resulting novel ecosystems are usually characterized by species assemblages that have not occurred previously in a given area. Quantifying the ecological novelty of communities (i.e. biotic novelty) would enhance the understanding of environmental change. However, quantification remains challenging since current novelty metrics, such as the number and/or proportion of non-native species in a community, fall short of considering both functional and evolutionary aspects of biotic novelty. Here, we propose the Biotic Novelty Index (BNI), an intuitive and flexible multidimensional measure that combines (1) functional differences between native and non-native introduced species with (2) temporal dynamics of species introductions. We show that the BNI is an additive partition of Raos quadratic entropy, capturing the novel interaction component of the communitys functional diversity. Simulations show that the index varies predictably with the relative amount of functional novelty added by recently arrived species, and they illustrate the need to provide an additional standardized version of the index. We present a detailed R-code and two applications of the BNI by (1) measuring changes of biotic novelty of dry grassland plant communities along an urbanization gradient in a metropolitan region and (2) determining the biotic novelty of plant species assemblages at a national scale. Results illustrate the applicability of the index across scales and its flexibility in the use of data of different quality. Both case studies revealed strong connections between biotic novelty and increasing urbanization, a measure of abiotic novelty. We conclude that the BNI framework may help in building a basis for a better understanding of the ecological and evolutionary consequences of global change.

ecology↗