Biology subjects

Schulte, A.

Publications and source records attributed to Schulte, A..

9 recordsLinked to original sources

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

Tumor-derived FXII engages the intrinsic coagulation cascade to support breast cancer liver metastasis.

Metastasis is the leading cause of death in breast cancer, yet the mechanisms controlling organotropism are not well defined. Coagulation has emerged as a biologically relevant contributor to metastatic progression, but mechanisms linking pro-thrombotic phenotypes to organ-specific metastasis remain unresolved, significantly hindering the development of novel treatments. Here, a serial transplantation approach was used to enrich for liver organotropism from a spontaneous mouse mammary tumor model with occasional liver and lymph node metastasis. Comparative transcriptomics between the enriched liver and lymph node metastases revealed strong upregulation of coagulation in liver metastases, due in part to loss of repression of FXII with knockout of the E2F5 transcription factor. In vitro clotting assays demonstrated that tumor-derived FXII was sufficient to induce fibrin(ogen) clot formation. Moreover, liver metastatic cells exhibit elevated lipid peroxide levels and impaired lipid droplet formation associated with a pro-coagulant phenotype. Inhibition of coagulation with low molecular weight heparin reduced the presence of circulating tumor cells and suppressed liver metastasis in the mouse model. Human electronic health record data supported the translational relevance of these findings. Together, these data reveal a new mouse model where loss of E2F5 has resulted in tumors with elevated expression of FXII that have a propensity for liver metastasis and illustrates that anti-coagulation dramatically reduces the liver-specific metastasis in breast cancer. HighlightsE2F5 conditional knockout model develops breast tumors with liver tropism Liver metastasis hijacks the intrinsic coagulation cascade mediated by tumor-derived FXII Liver metastatic cells displayed lipid metabolic alterations that contributed to a pro-coagulant phenotype Low molecular weight heparin blocks liver metastasis and significantly reduces circulating tumor cells

cancer biology↗

bioRxiv2026

Villin-SNAP25 interaction regulates insulin secretion downstream of ICA512 signaling

Pancreatic islet {beta}-cells step-up insulin production and secretion in response to the elevation of blood glucose levels. ICA512/PTPRN is a transmembrane cargo of the insulin secretory granules (SGs). Upon SG exocytosis, its Ca2+/calpain mediated cleavage at the plasma membrane generates an ICA512-cleaved cytosolic fragment (ICA512-CCF) which as a decoy phosphatase prolongs phospho-STAT5/3 activities, thereby enhancing the transcription of mRNAs for SG cargoes, including insulin and its own, to replenish SG stores. In addition, ICA512 positively regulates the expression of F-actin modifier villin. Villin, in turn, modulates the size of actin cages surrounding cortical SGs, hence regulating SG mobility and exocytosis. Here we show that villin controls the number of SG docking sites for exocytosis by directly interacting at low glucose with the t-SNARE SNAP-25, thus restricting in this condition SG access to fusion sites and insulin release. Replacement of ICA512-CCF N-terminal ubiquitin-acceptor lysine 609 (K609) with valine (V) stabilized ICA512-CCF in insulinoma cells and homozygous ICA512K609V mice and enhanced the levels of phospho-STAT5/3 and villin. In ICA512K609V female mice these molecular traits correlated with reduced body weight, improved insulin sensitivity, reduced basal insulin secretion and onset time for glucose stimulated insulin secretion. Taken together, these data demonstrates that SG exocytosis induced ICA512 retrograde signaling acts in concert with the novel SNARE complex regulator villin to plastically adapt {beta}-cell actin cytoskeleton and access to SG docking sites for optimal control of insulin secretion in response to variations in extracellular glucose levels. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/699220v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@37d835org.highwire.dtl.DTLVardef@5389f1org.highwire.dtl.DTLVardef@855d98org.highwire.dtl.DTLVardef@1c3c639_HPS_FORMAT_FIGEXP M_FIG Graphical abstract Model of ICA512 and STAT3/5-dependent regulation of -cell function. At basal conditions, villin limits secretory granule (SG) docking by interacting with SNAP-25, restricting insulin release (1). Increased metabolic load triggers hyperglycemia-induced ICA512 processing and growth factor-mediated STAT3/5 phosphorylation (2-4), enhancing ISG mRNAs, granule biogenesis, and villin expression (5,6). Villin modulates SNARE protein availability, controlling SG docking and secretion. Together, ICA512 retrograde signaling and villin-mediated SNARE regulation dynamically remodel the -cell actin cytoskeleton, adjusting SG docking site access to ensure appropriate insulin secretion in response to fluctuating glucose levels. C_FIG

cell biology↗

bioRxiv2024

Transcriptional Regulation of Mammary Alveolar Proliferation and Differentiation during Early Pregnancy

The E2F transcription factors are well-established cell cycle regulators, but their roles in coordinating proliferation and differentiation remain poorly understood. Here, we investigated the function of E2F5 during mammary gland development using a mammary epithelial-specific conditional knockout model. We found that E2F5 expression and chromatin binding increase during early pregnancy, coinciding with the critical window of alveolar development. Loss of E2F5 resulted in delayed alveolar expansion during early pregnancy, characterized by reduced side branching and smaller alveolar structures during early pregnancy. Mechanistically, E2F5 deletion led to reduced expression of canonical E2F target genes involved in cell cycle progression. Surprisingly, E2F5 loss also caused enrichment of luminal progenitor populations at the expense of differentiated alveolar cells, with chromatin profiling revealing substantial depletion of the repressive H3K27me3 mark at luminal progenitor-associated genes. These findings suggest that E2F5 promotes differentiation of luminal progenitors into proliferative alveolar precursors during early pregnancy. We propose that E2F5 coordinates both proliferation and differentiation by driving progenitor cells to differentiate into mature luminal cells. The dual function of E2F5 in mammary development distinguishes it from classical cell cycle regulators and positions it as a critical coordinator of the developmental transitions required for lactation.

developmental biology↗

bioRxiv2023

Human dorsal root ganglia after plexus injury: either preservation or loss of the multicellular unit

ObjectivePlexus injury results in lifelong suffering of flaccid paralysis, sensory loss, and intractable pain. For this clinical problem, regenerative medicine concepts, such as cell replacement for restoring dorsal root ganglion (DRG) function, set high expectations. However, it is completely unclear which DRG cell types are affected by plexus injury. MethodsWe investigated the cellular composition of human DRG in a clinically characterized cohort of patients with plexus injury. Avulsed DRG of 13 patients were collected during reconstructive nerve surgery. Then, we analyzed the cellular composition of the DRG with a human-adapted objective deep learning-based analysis of large-scale microscopy images. ResultsSurprisingly, in about half of the patients, the injury-affected DRG no longer contained DRG cells. The complete entity of neurons, satellite glial cells, and microglia was lost and replaced by mesodermal/connective tissue. In the other half of patients, the cellular entity of the DRG was well preserved. We found no loss of neurons, no gliosis, and macrophages close to single sensory neuron/satellite glial cell entities. Patients with neuronal preservation had less pain than patients with neuronal loss. InterpretationThe findings classify plexus injury patients in two categories: type I (neuronal preservation) and type II (neuronal loss). We call for early, post-accidental interventions to protect the entire DRG and improved MRI diagnostics to detect neuronal loss. Regenerative medicine to restore DRG function will need at least two translational directions: reafferentation of existing DRG units for type I injuries; or replacement of the entire DRG structure for type II patients.

neuroscience↗

bioRxiv2022

Identification of a unique transcriptomic signature associated with islet amyloidosis

AimsThis cross-sectional study aims to identify potential transcriptomic changes conveyed by presence of amyloid deposits in islets from pancreatic tissue obtained from metabolically profiled living donors. MethodsAfter establishing Thioflavin S as the most sensitive approach to detect islet amyloid plaques, we utilized RNA sequencing data obtained from laser capture microdissected islets to define transcriptomic effects of this pathological entity. The RNA sequencing data was used to identify differentially expressed genes by linear modeling. Further analyses included functional enrichment analysis of KEGG and Hallmark gene sets as well as a weighted gene correlation network analysis. ResultsEleven differentially expressed genes were identified in islets affected by amyloidosis. Enrichment analyses pointed to signatures related to protein aggregation diseases, energy metabolism and inflammatory response. A gene co-expression module was identified that correlated to islet amyloidosis. ConclusionAlthough the influence of underlying Type 2 diabetes could not be entirely excluded, this study presents a valuable insight into the biology of islet amyloidosis, particularly providing hints into the potential relationship between islet amyloid deposition and structural and functional proteins involved in insulin secretion. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIIslet amyloidosis is the only histological marker of Type 2 diabetes in the pancreas C_LIO_LIIndividuals not suffering from Type 2 diabetes can also be affected by islet amyloidosis C_LIO_LIThe clinicopathological significance of this phenomenon is still unclear C_LI What is the key question?O_LIDoes the islet transcriptome of individuals with islet amyloidosis provide explanations for the onset of this phenomenon and its pathophysiological value? C_LI What are the new findings?O_LIIslet transcriptomes of affected subjects exhibit only limited transcriptomic differences compared to unaffected ones. C_LIO_LIStructural and functional proteins involved in insulin secretion machinery may be involved in the pathophysiological sequence of amyloid formation C_LI

systems biology↗

bioRxiv2020

Multi-omics profiling of living human pancreatic islet donors reveals heterogeneous beta cell trajectories toward type 2 diabetes

Existing studies do not sufficiently describe the molecular changes of pancreatic islet beta cells leading to their deficient insulin secretion in type 2 diabetes (T2D). Here we address this deficiency with a comprehensive multi-omics analysis of metabolically profiled pancreatectomized living human donors stratified along the glycemic continuum from normoglycemia to T2D. Islet pools isolated from surgical samples by laser-capture microdissection had remarkably heterogeneous transcriptomic and proteomic profiles in diabetics, but not in non-diabetic controls. Transcriptomics analysis of this unique cohort revealed islet genes already dysregulated in prediabetic individuals with impaired glucose tolerance. Our findings demonstrate a progressive but disharmonic remodeling of mature beta cells, challenging current hypotheses of linear trajectories toward precursor or trans-differentiation stages in T2D. Further, integration of islet transcriptomics and pre-operative blood plasma lipidomics data enabled us to define the relative importance of gene co-expression modules and lipids positively or negatively associated with HbA1c levels, pointing to potential prognostic markers.

bioinformatics↗

bioRxiv2020

Vibrio campbellii chitoporin: thermostability study and implications for the development of therapeutic agents against Vibrio infections

Vibrio campbellii (formerly Vibrio harveyi) is a bacterial pathogen that causes vibriosis, which devastates fisheries and aquaculture worldwide. V. campbellii expresses chitinolytic enzymes and chitin binding/transport proteins, which serve as excellent targets for antimicrobial agent development. We previously characterized VhChiP, a chitooligosaccharide-specific porin from the outer membrane of V. campbellii BAA-1116. This study employed far-UV circular dichroism and tryptophan fluorescence spectroscopy, together with single channel electrophysiology to demonstrate that the strong binding of chitoligosaccharides enhanced thermal stability of VhChiP. The alanine substitution of Trp136 at the center of the affinity sites caused a marked decrease in the binding affinity and decreased the thermal stability of VhChiP. Tryptophan fluorescence titrations over a range of temperatures showed greater free-energy changes on ligand binding ({Delta}G{degrees}binding) with increasing chain length of the chitooligosaccharides. Our findings suggest the possibility of designing stable channel-blockers, using sugar-based analogs that serve as antimicrobial agents, active against Vibrio infection.

biochemistry↗

bioRxiv2020

Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion

Genome-wide association studies have identified thousands of genetic variants associated with type 2 diabetes (T2D) risk. Using chromatin conformation capture we show that an enhancer cluster in the STARD10 T2D locus forms a defined 3D chromatin domain. A 4.1 Kb region within this region, carrying five disease-associated variants, physically interacts with CTCF-binding regions and with an enhancer possessing strong transcriptional activity. Analysis of human islet 3D chromatin interaction maps identifies FCHSD2 gene as an additional target of the enhancer cluster. CRISPR-Cas9-mediated deletion of the variant region, or of an associated enhancer, in human pancreatic beta cells impaired glucose-stimulated insulin secretion. Expression of both STARD10 and FCHSD2, but not ARAP1, was reduced in cells harboring CRISPR deletions, and expression of STARD10 and FCHSD2 was associated with the possession of variant alleles in human islets. Finally, CRISPR-Cas9-mediated loss of STARD10 or FCHSD2 impaired regulated insulin secretion. Thus, multiple genes at the STARD10 locus influence {beta} cell function.

cell biology↗