Biology subjects

Steinhauser, M.

Publications and source records attributed to Steinhauser, M..

6 recordsLinked to original sources

bioRxiv2025

TGF-β Coordinates Alanine Synthesis and Import for Myofibroblast Differentiation in Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease marked by aberrant fibroblast-to-myofibroblast differentiation, a process that requires metabolic reprogramming. We identify alanine as a critical metabolite that confers metabolic flexibility to support differentiation. TGF-{beta} increases alanine by activating both its synthesis and import in normal and IPF lung fibroblasts. Alanine is synthesized primarily by GPT2, which is regulated by a glutamine-glutamate--ketoglutarate axis. Inhibiting GPT2 depletes alanine and suppresses TGF-{beta}-induced expression of -SMA and COL1A1, an effect reversed by alanine supplementation. We also identify SLC38A2 as a key transporter of both alanine and glutamine that is upregulated by TGF-{beta} and alanine deprivation. Together, SLC38A2 and GPT2 activities converge to maintain intracellular alanine levels to support myofibroblast differentiation. Mechanistically, alanine deficiency suppresses glycolysis and depletes tricarboxylic acid cycle intermediates, while supplementation provides carbon and nitrogen for intracellular glutamate and proline biosynthesis, particularly in the absence of glutamine. Combined inhibition of GPT2 and SLC38A2 suppresses fibrogenic responses in fibroblasts and in human precision-cut lung slices, highlighting a potential therapeutic strategy for fibrotic lung disease.

cell biology↗

bioRxiv2025

Targeting NEDD9-SH3 with a Covalent Peptide Controls Endothelial Phenotype

Src homology 3 (SH3) proteins regulate numerous fibroproliferative pathophenotypes including pulmonary arterial hypertension (PAH) but are challenging to target therapeutically. We innovated a peptidomimetic that occupies the canonical focal adhesion kinase (FAK) binding site on the SH3 domain of the neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) protein, a pro-PAH regulator. Peptidomimetic derivatization with a bromoacetamide group alkylated a NEDD9 cysteine positioned uniquely among SH3 domains (Cys18), which stabilized the RT loop, prevented FAK binding, and inhibited human pulmonary artery endothelial cell (HPAEC) migration. When linked to a thalidomide moiety, the peptide showed degrader activity of NEDD9 protein and, therefore, we next investigated therapeutic application of NEDD9 inhibition. In HPAECs, si-NEDD9 downregulated sulfatase-1, which increased podosome rosette formation and cell migration via 6-O-desulfation of glycocalyx-forming heparan sulfate proteoglycans, and reversed vascular remodeling and PAH in vivo. Whereas sulfatase-1 overexpression decreased pulmonary endothelial podosome formation, cell migration, and tube formation and increased collagen III synthesis, sulfatase-1 knockdown prevented fibroproliferative remodeling and pulmonary hypertension in PAH in vivo. These data leverage cysteinyl thiol reactivity to establish an SH3 domain-targeting structure-validated covalent peptide and identify two convergent mechanisms through NEDD9 that control endothelial phenotype, including reverse remodeling via sulfatase-1 transcriptional control. Overall, this study advances an SH3-specific therapeutic approach with relevance to PAH and other fibroproliferative pathophenotypes.

molecular biology↗

bioRxiv2023

Exceptional longevity of mammalian ovarian and oocyte macromolecules throughout the reproductive lifespan

The mechanisms contributing to age-related deterioration of the female reproductive system are complex, however aberrant protein homeostasis is a major contributor. We elucidated exceptionally stable proteins, structures, and macromolecules that persist in mammalian ovaries and gametes across the reproductive lifespan. Ovaries exhibit localized structural and cell-type specific enrichment of stable macromolecules in both the follicular and extrafollicular environments. Moreover, ovaries and oocytes both harbor a panel of exceptionally long-lived proteins, including cytoskeletal, mitochondrial, and oocyte-derived proteins. The exceptional persistence of these long-lived molecules suggest a critical role in lifelong maintenance and age-dependent deterioration of reproductive tissues. One sentence summaryExceptionally long-lived macromolecules in mammalian ovaries and oocytes as pillars for lifelong reproductive health span.

physiology↗

bioRxiv2020

Adaptive rescheduling of error monitoring in multitasking

The concurrent execution of temporally overlapping tasks leads to considerable interference between the subtasks. This also impairs control processes associated with the detection of performance errors. In the present study, we investigated how the human brain adapts to this interference between task representations in such multitasking scenarios. In Experiment 1, participants worked on a dual-tasking paradigm with partially overlapping execution of two tasks (T1 and T2), while we recorded error-related scalp potentials. The error positivity (Pe), a correlate of higher-level error evaluation, was reduced after T1 errors but occurred after a correct T2-response instead. MVPA-based and regression-based single-trial analysis revealed that the immediate Pe and deferred Pe are negatively correlated, suggesting a trial-wise trade-off between immediate and postponed error processing. Experiment 2 confirmed this finding and additionally showed that this result is not due to credit-assignment errors in which a T1 error is falsely attributed to T2. For the first time reporting a Pe that is temporally detached from its eliciting error event by a considerable amount of time, this study illustrates how reliable error detection in dual-tasking is maintained by a mechanism that adaptively schedules error processing, thus demonstrating a remarkable flexibility of the human brain when adapting to multitasking situations. Significance StatementMultitasking situations are associated with impaired performance, as the brain needs to allocate resources to more than one task at a time. This also makes it more difficult to detect ones own performance errors in such complex scenarios. In two experiments, we recorded error-related electroencephalographic (EEG) activity and found that the commonly assumed fixed temporal succession of control processes in error monitoring can be strategically interrupted. Individual processes of error detection can be temporally rescheduled to after completion of competing tasks. This reduces interference between the neural task representations and supports a more efficient execution of concurrent tasks in multitasking.

neuroscience↗

bioRxiv2019

Cognitive modelling reveals distinct electrophysiological markers of decision confidence and error monitoring

Is confidence in perceptual decisions generated by the same brain processes as decision itself, or does confidence require metacognitive processes following up on the decision? In a masked orientation task with varying stimulus-onset-asynchrony, we used EEG and cognitive modelling to trace the timing of the neural correlates of confidence. Confidence as reported by observers increased with stimulus-onset-asynchrony in correct and to a lesser degree in incorrect trials, a pattern incompatible with established models of confidence. Electrophysiological activity in two different time periods was associated with confidence, namely, 350 - 500 ms after stimulus onset and 250 - 350 ms after the response. Cognitive modelling revealed that only the activity following on the stimulus exhibited the same statistical regularities as confidence, while the statistical pattern of the activity following the response was not compatible with confidence. It is argued that electrophysiological markers of decision confidence and error awareness are at least in parts distinct.

neuroscience↗

bioRxiv2018

Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap-/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis: transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap-/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improved Yap-deficiency phenotypes, indicating functional importance of glucose-fuelled nucleotide biosynthesis. Yap-regulated Glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signalling in metabolic homeostasis.

developmental biology↗