Biology subjects

Neubauer, S.

Publications and source records attributed to Neubauer, S..

6 recordsLinked to original sources

bioRxiv2026

Breathlessness catastrophising after COVID-19 involves both interoceptive and visceromotor connectivity

Persistent breathlessness is common after COVID-19, yet its severity typically correlates weakly with objective clinical measures. This discordance is often attributed to perceptual inference amplified by anxiety. Because breathing involves a closed perception-action loop, breathlessness may also reflect alterations in interoceptive and visceromotor pathways. We acquired 7-tesla resting-state functional MRI in 53 post-COVID patients with varying breathlessness and estimated functional connectivity across 18 pre-defined interoceptive and visceromotor regions. Linear regression identified two connections associated with breathlessness catastrophising: reduced dorsal periaqueductal grey-posterior insula (dPAG-PoI1) and increased basolateral amygdala-dorsal anterior cingulate (BLA-dACC) connectivity. The dPAG-PoI1 association was stronger in patients who had required mechanical ventilation, whereas the BLA-dACC association was attenuated at higher generalised anxiety. These findings are consistent with two potentially separable contributions to symptom burden: weakened interoceptive signalling between brainstem and sensory cortex, and heightened visceromotor influence of threat processing on autonomic control, rather than anxiety-driven misperception alone.

neuroscience↗

bioRxiv2024

AbrB antirepressor AbbA is a competitive inhibitor of AbrB-phyC interaction

In Bacillus species, the interaction between the repressor AbrB and the antirepressor AbbA is vital for regulating gene expression. Our study reveals that AbrB binds DNA cooperatively the promoter of the phyC gene through multiple tetramers, forming a complex regulatory mechanism. AbbA disrupts AbrBs DNA binding by competing for its DNA-binding sites, as shown by surface plasmon resonance (SPR) and gel shift assays. Circular dichroism (CD) confirmed that AbbA does not bind directly to the phyC promoter but mimics DNA to interfere with AbrB. Small-angle X-ray scattering (SAXS) data suggest that AbbA resembles a deformed DNA double helix. Our results indicate that AbbA binds to AbrBs DNA-binding sites located with the N-terminal domain causing AbrB displacement. The interaction exhibits negative cooperativity, with both high- and low-affinity binding sites, as evidenced by Scatchard plots and kinetic studies. Our findings suggest that AbbA effectively mimics DNA to displace AbrB, activating transition-state genes. This research enhances our understanding of bacterial gene regulation and provides insights into the complex mechanisms controlling transcription in Bacillus species.

molecular biology↗

bioRxiv2024

Modulating Cardiac Energetics in Cardio-Metabolic Syndromes: A mechanistic, hyperpolarized MR Trial of Ninerafaxstat Treatment

BackgroundType 2 diabetes (T2D) and obesity are key contributors for heart failure (HF)- development, especially for HF with a preserved ejection fraction (HFpEF). On a molecular basis, excessive use of fatty acids (FA) induces lipotoxicity which in turn promotes inflammation, reduces mitochondrial pyruvate dehydrogenase (PDH) activity and impairs myocardial energetics and -function. Harnessing in-vivo, real time measurement of cellular metabolism via hyperpolarized pyruvate MR, we aimed to assess the effects of ninerafaxstat, a selective FA oxidation inhibitor, on cardiac energetics, metabolism & diastolic function in patients with cardio-metabolic syndromes. MethodsIMPROVE-DiCE was an open-label, mechanistic phase 2a trial. 21 participants received 200mg ninerafaxstat twice daily for four (n=5) or eight weeks (n=16). Myocardial energetics (phosphocreatine to adenosine triphosphate ratio, PCr/ATP), metabolism and function were assessed pre-& post-treatment using magnetic resonance imaging (MRI), 31P- and 1H-MR spectroscopy (MRS). We utilised hyperpolarized [1-13C]pyruvate MRS to assess in-vivo PDH-flux (n=9) and plasma metabolomics and proteomics to assess whole body metabolism. ResultsPatients presented with impaired PCr/ATP, (median 1.6 [IQR 1.4, 2.1]), myocardial steatosis (2.2 % [IQR 1.5, 3.2]) and LV diastolic dysfunction (peak circumferential diastolic strain rate 0.86/s [IQR 0.82, 1.06]) at baseline. Ninerafaxstat treatment improved myocardial energetics by 32% (p<0.01), reduced myocardial triglyceride content by 34% (p=0.03) and showed a trend towards improved PDH-flux (mean 45% increase, p=0.08). Diastolic function was significantly improved post-treatment (peak diastolic strain rate by 10%, peak LV filling rate by 11%, both p<0.05). ConclusionsMetabolic modulation with ninerafaxstat significantly improved myocardial energetics, reduced myocardial steatosis and improved LV diastolic filling. Combining hyperpolarized MRS and metabolomics, is a powerful approach to examine the mechanism of action of novel metabolic modulators. REGISTRATIONURL: https://clinicaltrials.gov; Unique identifier: NCT04826159 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=121 SRC="FIGDIR/small/591019v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@86fae1org.highwire.dtl.DTLVardef@1c1037eorg.highwire.dtl.DTLVardef@cc5ca9org.highwire.dtl.DTLVardef@d789d1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Water-Only Look-Locker Inversion recovery (WOLLI) T1 mapping

PurposeModified Look-Locker Inversion recovery (MOLLI) and Shortened MOLLI (ShMOLLI) T1 values can deviate substantially from the water T1 in voxels containing large amounts of water and fat. We introduce Water-Only Look-Locker Inversion recovery (WOLLI) to map water T1 in tissue containing fat. TheoryWOLLI comprises adiabatic water-selective inversion and several balanced steady-state free precession (bSSFP) readouts, followed immediately by adiabatic fat-selective inversion and bSSFP readout(s). Data are fitted pixel-wise and an adapted Deichmann-Haase saturation-correction gives the water T1. MethodsWe compared two WOLLI protocols (WOLLI-w7f1 and WOLLI-w7f2f1), ShMOLLI and single-voxel spectroscopy at 3T in: simulations, fat/water phantoms, and 12 subjects livers. ResultsIn simulations with 0-40% fat fraction, T1 varied by: <0.5% (WOLLI-w7f1), <12% (WOLLI-w7f2f1), and >100% (MOLLI). In phantoms, the accuracy of the methods (i.e. worst-case T1w difference vs spectroscopy) was: WOLLI-w7f1 (best, maximum difference of 10.2%), WOLLI-w7f2f1 (max. 10.5%), and ShMOLLI (max. 81.5%). In the liver, the root-mean-squared deviations vs spectroscopy were: 374ms (WOLLI-w7f1), 645ms (WOLLI-w7f2f1), and 700ms (ShMOLLI). ConclusionCompared to ShMOLLI, WOLLI is less influenced by fat, but more by B0-inhomogeneity. WOLLI was a clear improvement in phantoms but less so in vivo. WOLLI may be suited to scan organs with high fat content such as the liver.

biophysics↗

bioRxiv2021

Disentangling cortical functional connectivity strength and topography reveals divergent roles of genes and environment

The human brain varies across individuals in its morphology, function, and cognitive capacities. Variability is particularly high in phylogenetically modern regions associated with higher order cognitive abilities, but its relationship to the layout and strength of functional networks is poorly understood. In this study we disentangled the variability of two key aspects of functional connectivity: strength and topography. We then compared the genetic and environmental influences on these two features. Genetic contribution is heterogeneously distributed across the cortex and differs for strength and topography. In heteromodal areas genes predominantly affect the topography of networks, while their connectivity strength is shaped primarily by random environmental influence such as learning. We identified peak areas of genetic control of topography overlapping with parts of the processing stream from primary areas to network hubs in the default mode network, suggesting the coordination of spatial configurations across those processing pathways. These findings provide a detailed map of the diverse contribution of heritability and individual experience to the strength and topography of functional brain architecture.

neuroscience↗

bioRxiv2019

Enhanced prediction of gene and missense rare-variant pathogenicity by joint analysis of gene burden and amino-acid residue position

BackgroundAlthough rare-missense variants in Mendelian disease-genes have been noted to cluster in specific regions of proteins, it is not clear how to consider this information when evaluating the pathogenicity of a gene or variant. Here we introduce methods for gene-association and variant-interpretation that utilise this powerful signal. MethodsWe present a case-control rare-variant association test, ClusterBurden, that combines information on both variant-burden and variant-clustering. We then introduce a data-driven modelling framework to estimate mutational hotspots in genes with missense variant-clustering and integrate further in-silico predictors into the models. ResultsWe show that ClusterBurden can increase statistical power to scan for putative disease-genes, driven by missense variants, in simulated data and a 34-gene panel dataset of 5,338 cases of hypertrophic cardiomyopathy. We demonstrate that data-driven models can allow quantitative application of the ACMG criteria PM1 and PP3, to resolve a wide range of pathogenicity potential amongst variants of uncertain significance. A web application (Pathogenicity_by_Position) is accessible for missense variant risk prediction of six sarcomeric genes and an R package is available for association testing using ClusterBurden. ConclusionThe inclusion of missense residue position enhances the power of disease-gene association and improves rare-variant pathogenicity interpretation.

genetics↗