Biology subjects

Kurth, F.

Publications and source records attributed to Kurth, F..

14 recordsLinked to original sources

bioRxiv2025

Experimental Genetics Validation of Plasmodium falciparum Gametogenesis Essential Protein 1 (GEP1) as a Transmission Blocking Target

Transmission of Plasmodium parasites to the Anopheles vector critically depends on swift activation of mature gametocytes upon entry into the mosquito midgut. Induction of gametogenesis requires two simultaneous stimuli, a temperature drop and xanthurenic acid. Previous work in the murine malaria model Plasmodium yoelii identified a protein, termed gametogenesis essential protein (GEP1), with a suggested role in xanthurenic acid-dependent activation of gametes. Here, we present an experimental genetics characterization of GEP1 in the human pathogen Plasmodium falciparum. Using CRISPR-Cas9 gene editing we generated PfGEP1 loss-of-function lines and analyzed their progression until gametocyte maturation. We show a complete defect in both male and female gametogenesis caused by disruption of PfGEP1. Pfgep1(-) gametocytes do not produce gametes when activated with xan-thurenic acid or a drop in temperature. This defect could not be overcome by the phosphodiesterase inhibitor Zaprinast, which induces gametogenesis. We also explored GEP1 haplotypes in P. falciparum parasites circulating in endemic regions and show the presence of two non-synonymous SNPs, resulting in V241L and S263P mutations, in 12% and 20% of 49 sentinel samples, respectively. Together, our data indicate that GEP1 plays a central role in the gamete activation process independent of xanthurenic acid and validates PfGEP1 as a promising transmission blocking target.

molecular biology↗

bioRxiv2025

Increased Callosal Thickness in Early Trained Opera Singers

Extensive research has shown how the corpus callosum adapts to early sensorimotor training in instrumental musicians, yet less is known about these effects in professional singers. This study used high-resolution MRI to investigate variations in callosal thickness in relation to vocal training in 55 participants, including 27 professionally trained opera singers and 28 non-singers. Results indicated trend-level differences with thicker callosal regions in singers, particularly at the anterior-posterior midbody border and the isthmus, though these did not survive corrections for multiple comparisons. However, a significant negative correlation between age at first singing lesson and callosal thickness was found in the anterior third (rostrum, genu, rostral body), the anterior-posterior midbody border, and the isthmus, suggesting that early vocal training facilitates lasting neuroplastic adaptations in these regions. Additionally, a positive trend between years of professional singing and greater thickness in the midbody was observed but did not remain significant after correction for multiple comparisons. Greater callosal thickness likely enhances interhemispheric connectivity to meet the demands of operatic performance, highlighting the adaptability of the corpus callosum to early, sustained sensorimotor training. By extending evidence from instrumental musicians to singers, these results underscore developmental timing as a key factor in how sensorimotor training shapes brain structure.

neuroscience↗

bioRxiv2025

A Metabolite-Based Resistance Mechanism Against Malaria

Whether jaundice, a common presentation of Plasmodium (P.) falciparum malaria (1-3) arising from the accumulation of circulating bilirubin, represents an adaptive or maladaptive response to Plasmodium spp. infection is not understood (1-3). We found that asymptomatic P. falciparum infection was associated with a >10-fold higher ratio of unconjugated bilirubin over parasite burden, compared to symptomatic malaria. Genetic suppression of bilirubin synthesis by biliverdin reductase A (BVRA) (4) increased parasite virulence and malaria mortality in mice. Accumulation of unconjugated bilirubin in plasma, via genetic inhibition of hepatic conjugation by UDP glucuronosyltransferase family 1 member A1 (UGT1A1) (5), was protective against malaria in mice. Unconjugated bilirubin inhibited P. falciparum proliferation in red blood cells (RBC) via a mechanism that suppressed mitochondrial pyrimidine synthesis. Moreover, unconjugated bilirubin inhibited hemozoin (Hz) crystallization and compromised the parasites food vacuole. In conclusion, jaundice represents a metabolic response to Plasmodium spp. infection that limits malaria severity.

immunology↗

bioRxiv2024

Drugs Commonly Used in Fungal Infection Risk Conditions Promote Drug Tolerance or Resistance in Candida albicans

BackgroundFungal infections are an increasing concern, particularly among immunocompromised patients and those with comorbidities who require multiple medications. However, the effects of drugs targeting human pathways on fungal cells, and whether they influence antifungal drug responses, are poorly understood. MethodsWe systematically analyzed clinical guidelines to shortlist non-antifungal drugs commonly used in conditions that increase the likelihood of fungal infections. Focusing on the most prevalent fungal pathogen, we then tested how these drugs affected the antifungal response of Candida albicans to two commonly used antifungals, fluconazole and anidulafungin. Drug interactions identified were further assessed using checkerboard and disk diffusion assays. Finally, antifungal treatment efficacy of fluconazole in combination with negatively interacting drugs was evaluated in an in vivo Galleria mellonella model of disseminated C. albicans infection. FindingsOut of 119 drugs frequently co-administered with antifungals in 40 conditions associated with a high risk of fungal infections, 34 compounds affected the antifungal drug response in C. albicans, with most drugs reducing or antagonising antifungal efficacy, several through increasing resistance or tolerance. Notably, fluconazole combinations with carvedilol and loperamide promoted antifungal resistance in both fungal cultures and in Galleria mellonella. InterpretationOur findings suggest that medications frequently taken by patients at risk of fungal infections regularly act on the fungal pathogens and can affect the effectiveness of antifungals. We propose that human drugs acting on fungal pathogens may be an underestimated factor contributing to the evolution of antifungal tolerance and resistance.

microbiology↗

bioRxiv2022

Gut microbiota dysbiosis is associated with altered tryptophan metabolism and dysregulated inflammatory response in severe COVID-19

The clinical course of the 2019 coronavirus disease (COVID-19) is variable and to a substantial degree still unpredictable, especially in persons who have neither been vaccinated nor recovered from previous infection. We hypothesized that disease progression and inflammatory responses were associated with alterations in the microbiome and metabolome. To test this, we integrated metagenome, metabolome, cytokine, and transcriptome profiles of longitudinally collected samples from hospitalized COVID-19 patients at the beginning of the pandemic (before vaccines or variants of concern) and non-infected controls, and leveraged detailed clinical information and post-hoc confounder analysis to identify robust within- and cross-omics associations. Severe COVID-19 was directly associated with a depletion of potentially beneficial intestinal microbes mainly belonging to Clostridiales, whereas oropharyngeal microbiota disturbance appeared to be mainly driven by antibiotic use. COVID-19 severity was also associated with enhanced plasma concentrations of kynurenine, and reduced levels of various other tryptophan metabolites, lysophosphatidylcholines, and secondary bile acids. Decreased abundance of Clostridiales potentially mediated the observed reduction in 5-hydroxytryptophan levels. Moreover, altered plasma levels of various tryptophan metabolites and lower abundances of Clostridiales explained significant increases in the production of IL-6, IFN{gamma} and/or TNF. Collectively, our study identifies correlated microbiome and metabolome alterations as a potential contributor to inflammatory dysregulation in severe COVID-19. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=150 HEIGHT=200 SRC="FIGDIR/small/518860v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@afc4edorg.highwire.dtl.DTLVardef@1a9ac2aorg.highwire.dtl.DTLVardef@65fb46org.highwire.dtl.DTLVardef@153ee6a_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2022

Neutralization sensitivity of the SARS-CoV-2 Omicron BA.2.75 sublineage

The recently emerged BA.2.75 Omicron sublineage of SARS-CoV-2 identified in numerous countries is rapidly increasing in prevalence in regions of India. Compared with BA.2, the spike protein of BA.2.75 differs in nine amino acid residues. To determine the impact of the spike mutations on polyclonal and monoclonal antibody activity, we investigated the neutralization sensitivity of BA.2.75 in comparison with B.1, BA.2, BA.2.12.1, and BA.4/5. Analysis of post-boost samples from 30 vaccinated individuals revealed significantly lower serum neutralizing activity against BA.2.75 than against BA.2. However, BA.2.75 was more sensitive to serum neutralization than the widely circulating BA.4/5 sublineages. Moreover, evaluation of 17 clinical-stage monoclonal antibodies demonstrated individual differences in Omicron sublineage activity. Notably, some authorized antibodies with low activity against other Omicron sublineages demonstrated high BA.2.75 neutralizing potency. Our results indicate a less pronounced degree of antibody evasion of BA.2.75 compared with BA.4/5 and suggest that factors beyond immune evasion may be required for an expansion of BA.2.75 over BA.4/5.

immunology↗

bioRxiv2022

CAT - A Computational Anatomy Toolbox for the Analysis of Structural MRI Data

A large range of sophisticated brain image analysis tools have been developed by the neuroscience community, greatly advancing the field of human brain mapping. Here we introduce the Computational Anatomy Toolbox (CAT) - a powerful suite of tools for brain morphometric analyses with an intuitive graphical user interface, but also usable as a shell script. CAT is suitable for beginners, casual users, experts, and developers alike providing a comprehensive set of analysis options, workflows, and integrated pipelines. The available analysis streams - illustrated on an example dataset - allow for voxel-based, surface-based, as well as region-based morphometric analyses. Notably, CAT incorporates multiple quality control options and covers the entire analysis workflow, including the preprocessing of cross-sectional and longitudinal data, statistical analysis, and the visualization of results. The overarching aim of this article is to provide a complete description and evaluation of CAT, while offering a citable standard for the neuroscience community.

neuroscience↗

bioRxiv2022

OxoScan-MS: Oxonium ion scanning mass spectrometry facilitates plasma glycoproteomics in large scale

Protein glycosylation is a complex and heterogeneous post-translational modification. Specifically, the human plasma proteome is rich in glycoproteins, and as protein glycosylation is frequently dysregulated in disease, glycoproteomics is considered an underexplored resource for biomarker discovery. Here, we present OxoScan-MS, a data-independent mass spectrometric acquisition technology and data analysis software that facilitates sensitive, fast, and cost-effective glycoproteome profiling of plasma and serum samples in large cohort studies. OxoScan-MS quantifies glycosylated peptide features by exploiting a scanning quadrupole to assign precursors to oxonium ions, glycopeptide-specific fragments. OxoScan-MS reaches a high level of sensitivity and selectivity in untargeted glycopeptide profiling, such that it can be efficiently used with fast microflow chromatography without a need for experimental enrichment of glycopeptides from neat plasma. We apply OxoScan-MS to profile the plasma glycoproteomic in an inpatient cohort hospitalised due to severe COVID-19, and obtain precise quantities for 1,002 glycopeptide features. We reveal that severe COVID-19 induces differential glycosylation in disease-relevant plasma glycoproteins, including IgA, fibrinogen and alpha-1-antitrypsin. Thus, with OxoScan-MS we present a strategy for quantitatively mapping glycoproteomes that scales to hundreds and thousands of samples, and report glycoproteomic changes in severe COVID-19.

systems biology↗

bioRxiv2022

Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID- 19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV2.S and two-dose ChAdOx1 or combination ChAdOx1/mRNA vaccination. Plasma neutralizing activity as well as the magnitude, clonal composition and antibody maturation of the RBD-specific memory B cell compartment showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV2.S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

immunology↗

bioRxiv2022

Delineating antibody escape from Omicron variants

SARS-CoV-2 neutralizing antibodies play a critical role in prevention and treatment of COVID-19 but are challenged by viral evolution and antibody evasion, exemplified by the highly resistant Omicron BA.1 sublineage.1-12 Importantly, the recently identified Omicron sublineages BA.2.12.1 and BA.4/5 with differing spike mutations are rapidly emerging in various countries. By determining polyclonal serum activity of 50 convalescent or vaccinated individuals against BA.1, BA.1.1, BA.2, BA.2.12.1, and BA.4/5, we reveal a further reduction of BA.4/5 susceptibility to vaccinee sera. Most notably, delineation of the sensitivity to an extended panel of 163 antibodies demonstrates pronounced antigenic differences of individual sublineages with distinct escape patterns and increased antibody resistance of BA.4/5 compared to the most prevalent BA.2 sublineage. These results suggest that the antigenic distance from BA.1 and the increased resistance compared to BA.2 may favor immune escape-mediated expansion of BA.4/5 after the first Omicron wave. Finally, while most monoclonal antibodies in clinical stages are inactive against all Omicron sublineages, we identify promising novel antibodies with high pan-Omicron neutralizing potency. Our study provides a detailed understanding of the antibody escape from the most recently emerging Omicron sublineages that can inform on effective strategies to prevent and treat COVID-19.

immunology↗

bioRxiv2021

Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS-influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.

biochemistry↗

bioRxiv2020

A SARS-CoV-2 neutralizing antibody protects from lung pathology in a COVID-19 hamster model

The emergence of SARS-CoV-2 led to pandemic spread of coronavirus disease 2019 (COVID-19), manifesting with respiratory symptoms and multi-organ dysfunction. Detailed characterization of virus-neutralizing antibodies and target epitopes is needed to understand COVID-19 pathophysiology and guide immunization strategies. Among 598 human monoclonal antibodies (mAbs) from ten COVID-19 patients, we identified 40 strongly neutralizing mAbs. The most potent mAb CV07-209 neutralized authentic SARS-CoV-2 with IC50 of 3.1 ng/ml. Crystal structures of two mAbs in complex with the SARS-CoV-2 receptor-binding domain at 2.55 and 2.70 [A] revealed a direct block of ACE2 attachment. Interestingly, some of the near-germline SARS-CoV-2 neutralizing mAbs reacted with mammalian self-antigens. Prophylactic and therapeutic application of CV07-209 protected hamsters from SARS-CoV-2 infection, weight loss and lung pathology. Our results show that non-self-reactive virus-neutralizing mAbs elicited during SARS-CoV-2 infection are a promising therapeutic strategy.

immunology↗

bioRxiv2020

Cell-Derived Vesicles as TRPC1 Channel Delivery Systems for the Recovery of Cellular Respiratory and Proliferative Capacities

Pulsed electromagnetic fields (PEMFs) are capable of specifically activating a TRPC1-mitochondrial axis underlying cell expansion and mitohormetic survival adaptations. This study characterizes cell-derived vesicles (CDVs) generated from C2C12 murine myoblasts and shows that they are equipped with the sufficient molecular machinery to confer mitochondrial respiratory capacity and associated proliferative responses upon their fusion with recipient cells. CDVs derived from wild type C2C12 myoblasts include the cation-permeable transient receptor potential (TRP) channels, TRPC1 and TRPA1, and directly respond to PEMF exposure with TRPC1-mediated calcium entry. By contrast, CDVs derived from C2C12 muscle cells in which TRPC1 had been genetically knocked-down using CRISPR/Cas9 genome editing, do not. Wild type C2C12-derived CDVs are also capable of restoring PEMF-induced proliferative and mitochondrial activation in two C2C12-derived TRPC1 knockdown clonal cell lines in accordance to their endogenous degree of TRPC1 suppression. C2C12 wild type CDVs respond to menthol with calcium entry and accumulation, likewise verifying TRPA1 functional gating and further corroborating compartmental integrity. Proteomic and lipidomic analyses confirm the surface membrane origin of the CDVs providing an initial indication of the minimal cellular machinery required to recover mitochondrial function. CDVs hence possess the potential of restoring respiratory and proliferative capacities to senescent cells and tissues.

cell biology↗

bioRxiv2018

Engineered variants provide new insight into the structural properties important for activity of the highly dynamic, trimeric protein disulfide isomerase, PmScsC

Suppressor of copper sensitivity protein C from Proteus mirabilis (PmScsC) is a homotrimeric disulfide isomerase that plays a role in copper tolerance - a key virulence trait of the uropathogen. Each protomer of the enzyme has an N-terminal trimerisation stem (59 residues) containing a flexible linker (11 residues) connected to a thioredoxin-fold-containing catalytic domain (163 residues). Here, we characterise two PmScsC variants, PmScsC{Delta}N and PmScsC{Delta}Linker. PmScsC{Delta}N, is an N-terminally truncated form of the protomer with two helices of the trimerisation stem removed, generating a protein with dithiol oxidase rather than disulfide isomerase activity. The crystal structure of PmScsC{Delta}N reported here reveals - as expected - a monomer that is structurally similar to the catalytic domain of native PmScsC. The second variant PmScsC{Delta}Linker was designed to remove the 11 amino acid linker and we show that it generates a protein that has neither disulfide isomerase nor dithiol oxidase activity. The crystal structure of PmScsC{Delta}Linker reveals a trimeric arrangement, with the catalytic domains packed together very closely. Small angle X-ray scattering analysis found that native PmScsC is predominantly trimeric in solution even at low concentration, whereas PmScsC{Delta}Linker exists as an equilibrium between monomeric, dimeric and trimeric states, with the monomeric form dominating at low concentrations. These findings increase our understanding of disulfide isomerase activity, showing how (i) oligomerisation, (ii) spacing between, and (iii) dynamic motion of, catalytic domains in PmScsC all contribute to its native function.

biochemistry↗