Biology subjects

Fink, S.

Publications and source records attributed to Fink, S..

6 recordsLinked to original sources

bioRxiv2026

Extended high frequency hearing influences cortical response amplitudes to speech

Since young adults hear sounds up to 20 kHz, the loss of extended high-frequency hearing (EHF; above 8 kHz) is a hallmark of age-related hearing loss, often progressing from early lifetime. However, this deficit frequently goes undetected because routine clinical hearing tests and most hearing aids are currently limited mostly up to 8 kHz. EHF hearing has been linked to deficits in speech perception in noise and to self-reported hearing. However, it remains elusive how EHF hearing influences speech intelligibility. Here we recorded neuromagnetic brain responses using magnetoencephalography (MEG) within a frequency-tagging speech paradigm designed to probe hierarchical levels of attention and memory-dependent speech processing and recognition. Auditory evoked cortical magnetic field (AEF) responses were significantly reduced in both left and right brain hemispheres in individuals with impaired EHF hearing compared to those subjects with rather preserved EHF hearing. A gradual reinforcement of left-hemispheric AEF seen over age was not observed in young adults (19-29 y) with preserved EHF hearing. This was linked to stronger auditory brainstem responses (ABR), reflecting better neural synchronized auditory responses at stimulus onset. The reinforced left hemispheric dominance in young adults with impaired EHF hearing, in contrast, was linked to lower ABRs. Our findings suggest that sound energy above 8 kHz contributes through its impact on stimulus-onset synchrony to phase locking of oscillations in the auditory cortex to intelligible speech. Together, the results highlight the need to reconsider the neglect of EHF hearing in both audiological assessment and hearing aid design. SignificanceWe show here that deficits in extended high-frequency (EHF) hearing, up to now neglected in routine clinical audiometry and hearing aid technology, lead to reduced cortical evoked auditory field (AEF) response amplitudes to attended and unattended speech, even at a young age. A gradual increase in reinforced left-hemispheric AEF responses during attended speech does not occur in young people with good EHF hearing; this is linked to better synchronization of neural responses at the onset of sound. This suggests a crucial role of sounds containing energy above 8kHz in minimizing the need for cognitive resources during active listening. Collectively, our results challenge current clinical practices and underscore the need to incorporate EHF hearing into audiological assessment and hearing aid design.

neuroscience↗

bioRxiv2025

Clinical development of gene edited tacrolimus-resistant Treg (FKBP12KO-Treg) to enable simultaneous immunosuppression and support of immune regulation

Background: Unwanted immune responses play a central role in the pathogenesis of solid organ allograft rejection. These are managed by life-long immunosuppression with considerable burden for the patient and society. Adoptive therapy with regulatory T-cells (Treg) is a promising approach to restore sustainable immune balance and avoid long-term adverse effects of immunosuppression. While Treg effectively inhibit activation of unwanted immune responses, they are less effective in controlling pre-existing/activated memory effector T-cells (Teff). Thus, co-administration of Treg with immunosuppressants is required to achieve a sustainable organ acceptance. Calcineurin inhibitors (CNI) are powerful in controlling de novo generated and preformed Teff. However, CNI also dampen Treg immunoregulatory function. Thus, we hypothesize improved results of adoptive Treg therapy in immunosuppressed patients applying tacrolimus-resistant Treg. Methods: While retaining CNI modulation of Teff with tacrolimus, we knocked-out FKBP12 in Treg (FKBP12KO-Treg) by gene-editing using ribonucleoprotein-based CRISPR/Cas9 technology to generate tacrolimus-resistant Treg and characterised them using flow cytometry, functional assays and in-depth phenotyping. Results: This detailed in vitro analysis showed FKBP12KO-Treg were comparable to non-gene edited Treg and impervious to tacrolimus while maintaining immunoregulatory function and sensitivity to alternative CNIs raising no safety concerns. Furthermore, we aligned our methodology to achieve GMP compliance laying the basis for a manufacturing license in preparation of a clinical trial. Conclusion: Based on the presented preclinical dataset implying safety and efficacy of FKBP12KO-Treg, we are now seeking to undertake a proof-of-concept clinical trial to evaluate the co-administrationof FKBP12KO-Treg and tacrolimus to enhance the management of living donor kidney transplant recipients.

immunology↗

bioRxiv2025

Glomerulus-specific inhomogeneity of the basal activity map in the olfactory bulb supports olfactory-driven behavior

Glomeruli are signal-processing units of the olfactory bulb (OB), playing a key role in many OB computations, including contrast enhancement, gain control, and odorant-selective habituation. In awake mice, we uncover an extremely stable inhomogeneous map of basal glomerulus-specific activity as a background against which olfactory signal processing is performed. This activity is strongly driven by (i) centrifugal cholinergic projections, (ii) endogenous, and (iii) airflow-evoked spiking of olfactory sensory neurons and, to a small extent, (iv) by the odor environment. Importantly, early olfactory impairment in a mouse model of Alzheimers disease is parallelled by the loss of glomerular map inhomogeneity and diminished cholinergic innervation. These results reveal an important layer in the signal-processing network of the OB, likely acting by increasing the variance in and dynamic range of the system via glomerulus-specific functional inhomogeneity. TeaserA new layer in the signal-processing network of the olfactory bulb supports olfactory-driven behavior.

neuroscience↗

bioRxiv2025

Combinatorial effects of multiple genes contribute to beneficial aneuploidy phenotypes

Aneuploidy is one of the most common adaptive mechanisms to environmental selection in cells, yet its advantages over other genomic alterations remain unclear. We used budding yeast to determine if beneficial aneuploidy phenotypes are driven primarily by combinatorial expression changes of multiple genes. To determine the impact of complex aneuploidy on cellular fitness and drug resistance, we generated yeast collections with nearly every combination of two chromosome gains or losses. Additionally, we genetically dissected aneuploid chromosomes using partial deletions to identify chromosomal regions contributing to aneuploidy-driven drug resistance. Strong resistance phenotypes consistently came from combinations of chromosomes or chromosomal regions, with up to five regions on a chromosome contributing to resistance to a single drug. Gene ontology terms had limited predictive power in identifying the genes contributing to resistance phenotypes, as the combinatorial effects from different aneuploid regions act through multiple resistance pathways. The strongest phenotypes came from synergistic effects between copy number changes of different chromosomes or chromosomal regions, demonstrating how subtle gene expression changes of many genes combine to greatly impact cell survival.

genetics↗

bioRxiv2024

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other {beta}-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for {gamma}-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics of sickle cell disease and other {beta}-hemoglobinopathies. Key PointsO_LIEstablished a robust HbF luciferase reporter cell line to monitor endogenous {gamma}-globin expression for a chemogenomic screen of compounds for the treatment of sickle cell disease. C_LIO_LILead hit compounds were mechanistically confirmed for their ability to decrease expression of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/601536v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@7f86f6org.highwire.dtl.DTLVardef@75b613org.highwire.dtl.DTLVardef@49fc9org.highwire.dtl.DTLVardef@196472e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Lithic bacterial communities: ecological aspects focusing on Tintenstrich communities

Tintenstrich communities (TC) are mainly composed by Cyanobacteria developing on the rock substrate and forming physical structures strictly connected to the rock itself. Endolithic and epilithic bacterial communities are important because they contribute to nutrients release within run-off waters flowing on the rock surface. Despite them being ubiquitous, little information about their ecology and main characteristics is available. In this paper, we characterized the bacterial communities of rock surfaces of TC in Switzerland through Illumina sequencing and investigated their bacterial community composition on two substrate types (silicious and limestone rocks) through multivariate models. Our results show that Cyanobacteria and Proteobacteria are the predominant phyla in this environment. Bacterial alpha diversity was higher on limestone than on siliceous rock, and beta diversity of siliceous rock varied with changes in rock surface structure. Here we provide novel insights into the bacterial community composition of TC, their differences from other lithic communities, and the effects of the rock substrate and structure.

microbiology↗