Biology subjects

Volker, U.

Publications and source records attributed to Volker, U..

7 recordsLinked to original sources

bioRxiv2025

Immunoglobulin sub-class levels define inter-donor plasma variability: a longitudinal dual-lab study

Advancements in mass spectrometry have transformed plasma proteomics, allowing for high-throughput analysis of large cohorts. This study utilized the TIMES cohort, consisting of 51 healthy participants monitored monthly over 12 months, to evaluate intra- and inter-individual variability in the plasma proteome. Approximately 600 samples were analyzed in two independent laboratories, revealing strong correlations despite methodological differences. The study focused on the stability of the plasma proteome within donors over a year, with larger differences observed between donors. A support vector machine model achieved a 98% median classification accuracy, confirming stable, donor-specific proteomic profiles. Immunoglobulins, often overlooked in plasma proteomics, were found to contribute significantly to donor-specific signatures, showing pronounced inter-individual variability but remarkable intra-donor stability. In contrast, C-reactive protein and other inflammation markers exhibited significant temporal fluctuations and donor-specific baseline levels. This inter-laboratory study highlights the importance of longitudinal sampling for biomarker discovery, the robustness of MS-based proteomic workflows, and provides new insights into immunoglobulin dynamics and variability in human plasma. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/686385v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1e7b501org.highwire.dtl.DTLVardef@11c85d7org.highwire.dtl.DTLVardef@1971a1dorg.highwire.dtl.DTLVardef@1338061_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LILongitudinal analysis of individual plasma proteomes over a one-year period revealed low intra-individual variability albeit high inter-individual differences. C_LIO_LICross-site laboratory comparisons confirmed strong concordance in analytical performance and measurement consistency. C_LIO_LIConversion of relative protein intensities to absolute concentrations revealed immunoglobulin levels on par with established clinical reference ranges. C_LIO_LIDonors were distinguishable based on their unique plasma proteome. C_LIO_LIThe immunoglobulin sub-classes are key discriminators defining inter- and intra-donor variability C_LI

molecular biology↗

bioRxiv2025

Lifestyle, Early-life, and Genetic Health Risk Factors Underlying the Brain Age Gap: A Mega-Analysis Across 3,934 Individuals from the ENIGMA MDD Consortium

BackgroundLarge-scale studies show that adults with major depressive disorder (MDD) generally have a higher imaging-predicted age relative to their chronological age (i.e., positive brain age gap) compared to controls, though considerable within-group variation exists. This study examines lifestyle, early-life, and genetic health risk factors contributing to the brain age gap. Identifying risk and resilience factors could help protect brain and mental health. MethodsUsing an established model trained on FreeSurfer-derived brain regions (www.photon-ai.com/enigma_brainage), we generated brain age predictions for 1,846 controls and 2,088 individuals with MDD (aged 18-75) from 12 international cohorts. Polygenic risk scores (PRS) were calculated for major depression, C-reactive protein, and body mass index (BMI) using large-scale GWAS results. Linear mixed models were applied to assess lifestyle (BMI, smoking, education), early-life childhood trauma, and genetic (PRS) health risk associations with the brain age gap. Additionally, we evaluated the link between the brain age gap and peripheral biological age indicators (epigenetic clocks). ResultsHigher brain age gaps were significantly associated with BMI ({beta}=0.01, PFDR=0.02) and smoking ({beta}=0.11, PFDR=0.02), while lower brain age gaps were linked to higher education ({beta}=-0.02, PFDR=0.02). Higher childhood trauma scores predicted a higher brain age gap ({beta}=0.04, P=0.01). Higher brain age gaps were positively associated with all PRS ({beta}s=0.04-0.16, PsFDR=0.02-0.03). There were no significant interactions between diagnosis and assessed factors on the brain age gap. In a multivariable model, only modifiable health factors--BMI, smoking, and education--remained uniquely associated with brain age gaps. ConclusionsGenetic liability for depression and related traits is linked to poorer brain health, but health behaviors potentially offer a key opportunity for intervention. This study underscores the importance of targeting modifiable lifestyle factors to mitigate poor brain health in depressed individuals, an approach perhaps under-recognized in clinical practice.

neuroscience↗

bioRxiv2023

Multi-omics investigations uncover unique pathogenic markers in clinical Klebsiella pneumoniae that could be leveraged as novel antimicrobial targets

BackgroundKlebsiella pneumoniae (KP), often multidrug-resistant (MDR), is a significant public health concern and frequently associated with various diseases including urinary-tract infection. In addition, in recent years, an increasing number of studies reports on the emergence of convergent KP that combine MDR with hypervirulence leading to severely limited treatment options and thus calling for alternative approaches. MethodsIn this study, we compared high-risk clonal KP lineages with less pathogenic Klebsiella variicola (KV) and Klebsiella quasipneumoniae (KQ) strains on multiple-omics levels and performed integrative data analysis to identify unique markers that could be subsequently leveraged as novel targets in alternative treatment strategies. ResultsOur initial genomic analysis revealed 107 genes as part of the patho-core genome in eight clinical KP that were associated with different metabolic pathways. Subsequent transcriptome and proteome analyses in infection-mimicking media demonstrated similar regulatory patterns among KP vs. other Klebsiella strains, again with metabolic responses playing a pivotal role. In total, we identified 193 KP-specific, differentially expressed genes on transcriptomic and/or proteomic levels. When then comparing these regulated genes to over 6,000 publicly available Klebsiella genomes, we identified unique markers either in KP genomes or adaptively regulated on transcriptomics and/or proteomics levels. An example for the latter was a gene cluster for the cellobiose phosphotransferase system that has been previously described in the context of bacterial virulence and biofilm formation. ConclusionIn conclusion, our study not only highlights that KP strains demonstrate metabolic flexibility in response to particular environmental conditions, which is potentially important for their success as opportunistic pathogens, but identified unique KP-markers. Subsequent studies are needed to explore whether these markers might be prospectively used as novel anti-virulence targets, providing alternatives to traditional antibiotics.

microbiology↗

bioRxiv2023

NAD+ metabolism is a key modulator of bacterial respiratory epithelial infections

1.Lower respiratory tract infections caused by StreptococcusOpneumoniae (Spn) are a leading cause of death globally. Here we investigate the bronchial epithelial response to Spn infection on a transcriptomic, proteomic and metabolic level. We found the NAD+ salvage pathway to be dysregulated upon infection in a cell line model, primary human lung tissue and in vivo in rodents, leading to a reduced production of NAD+. Knockdown of NAD+ salvage enzymes (NAMPT, NMNAT1) increased bacterial replication. NAD+ treatment of Spn inhibited its growth while growth of other respiratory pathogens improved. Boosting NAD+ production increased NAD+ levels in immortalized and primary cells and decreased bacterial replication upon infection. NAD+ treatment of Spn dysregulated the bacterial metabolism and reduced intrabacterial ATP. Enhancing the bacterial ATP metabolism abolished the antibacterial effect of NAD+. Thus, we identified the NAD+ salvage pathway as an antibacterial cascade in Spn infections, predicting a novel antibacterial mechanism of NAD+.

immunology↗

bioRxiv2022

Escherichia coli membrane microdomain SPFH protein HflC interacts with YajC and contributes to aminoglycoside and oxidative stress tolerance

Many eukaryotic membrane-dependent functions are often spatially and temporally regulated by membrane microdomains (FMMs) also known as lipid rafts. These domains are enriched in polyisoprenoid lipids and scaffolding proteins belonging to the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) protein superfamily that was also identified in Gram-positive bacteria. By contrast, little is still known about FMMs in Gram-negative bacteria. In Escherichia coli K12, 4 SPFH proteins, YqiK, QmcA, HflK, and HflC, were shown to localize in discrete polar or lateral inner-membrane locations, raising the possibility that E. coli SPFH proteins could contribute to the assembly of inner-membrane FMMs and the regulation of cellular processes. Here we studied the determinant of the localization of QmcA and HflC and showed that FMM-associated cardiolipin lipid biosynthesis is required for their native localization pattern. Using Biolog phenotypic arrays, we showed that a mutant lacking all SPFH genes displayed increased sensitivity to aminoglycosides and oxidative stress that is due to the absence of HflKC. Our study therefore provides further insights into the contribution of SPFH proteins to stress tolerance in E. coli. IMPORTANCEEukaryotic cells often segregate physiological processes in cholesterol-rich functional membrane micro-domains. These domains are also called lipid rafts and contain proteins of the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) superfamily, which are also present in prokaryotes but were mostly studied in Gram-positive bacteria. Here, we showed that the cell localization of the SPFH proteins QmcA and HflKC in the Gram-negative bacteria E. coli is altered in absence of cardiolipin lipid synthesis. This suggests that cardiolipins contribute to E. coli membrane microdomain assembly. Using a broad phenotypic analysis, we also showed that HflKC contribute to E. coli tolerance to aminoglycosides and oxidative stress. Our study, therefore, provides new insights into the cellular processes associated with SPFH proteins in E. coli.

microbiology↗

bioRxiv2019

Genome-wide scan identifies novel genetic loci regulating salivary metabolite levels

Saliva, as a biofluid, is inexpensive and non-invasive to obtain, and provides a vital tool to investigate oral health and its interaction with systemic health conditions. There is growing interest in salivary biomarkers for systemic diseases, notably cardiovascular disease. Whereas hundreds of genetic loci have been shown to be involved in the regulation of blood metabolites leading to unprecedented insights into the pathogenesis of complex human diseases, little is known about the impact of host genetics on salivary metabolites. Here we report the first genome-wide association study exploring 476 salivary metabolites in 1,419 subjects of European ancestry from the TwinsUK cohort (discovery phase). A total of 14 salivary metabolites were significantly associated (p<10-10) with genetic variants that mapped to 11 distinct loci, most of which replicated in the Study of Health in Pomerania (SHIP-2) cohort. Interestingly, while only a limited number of the loci that are known to regulate blood metabolites were also associated with salivary metabolites in our study, we identified several novel saliva-specific locus-metabolite associations, including associations for the AGMAT (with the metabolites 4-guanidinobutanoate and beta-guanidinopropanoate), ATP13A5 (with the metabolite creatinine) and DPYS (with the metabolites 3-ureidopropionate and 3-ureidoisobutyrate) loci. Our study suggests that there are biological pathways which are specific to the regulation of the salivary metabolome. In addition, some of our findings may have clinical relevance, such as the utility of the pyrimidine (uracil) degradation metabolites in predicting 5-fluorouracil toxicity and the role of the agmatine pathway metabolites as biomarkers of oral health.

genetics↗

bioRxiv2019

KCND3 is a novel susceptibility locus for early repolarization

The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. We assessed the ERP in 12-lead ECGs of 39,456 individuals and conducted a two-stage meta-analysis of genome-wide association studies (GWAS). In the discovery phase, we included 2,181 cases and 23,641 controls from eight European ancestry studies and identified 19 genome-wide significant (p<5E-8) variants in the KCND3 (potassium voltage gated channel subfamily D member 3) gene with a p-value of 4.6E-10. Replication of two loci in four additional studies including 1,124 cases and 12,510 controls confirmed the association at the KCND3 gene locus with a pooled odds ratio of 0.82, p=7.7E-12 (rs1545300 minor allele T). A subsequent GWAS meta-analysis combining all samples did not reveal additional loci. The lead SNP of the discovery stage (rs12090194) was in strong linkage disequilibrium with rs1545300 (r2=0.96, D=1). Summary statistics based conditional analysis did not reveal any secondary signals. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both the left ventricle of the heart and in tibial artery.\n\nIn this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, revealing a promising candidate for functional studies.

genetics↗