Life & Brain (Germany)

Cellular polarization plays a crucial role in regulating immunological processes and is often associated with reorientation of the centrosome. During immune synapse formation, centrosome repositioning in lymphocytes assists in T cell activation. While a single centrosome, consisting of two centrioles, is present in T cells, antigen-presenting cells such as dendritic cells amplify centrioles during maturation and immune activation. How centriole amplification in antigen-presenting cells affects immune synapse formation and T cell activation is unclear. In this study, we combine experimental data with mathematical and computational modelling to provide evidence that extra centrioles in dendritic cells form over-active microtubule organizing centers, which cluster during dendritic cell-T cell interactions and, unlike in T cells, localize close to the cell center. Perturbing either centrosome integrity or centriole numbers and configuration in dendritic cells results in impaired T cell activation. Collectively, our results highlight a crucial role for centriole amplification and optimal centrosome positioning in antigen-presenting cells for controlling T cell responses.

Lipids play a critical role in atherosclerosis. Low-density lipoprotein (LDL)-cholesterol and certain lipid classes like sphingomyelins are associated with inflammation and poor cardiovascular outcomes. Phosphatidylserine (PS), on the other hand, is a negatively charged anti-inflammatory phospholipid class involved in efferocytosis. In this study, we sought to investigate its anti-atherosclerotic properties through a combination of complementary human lipidomics analyses, in vitro assays and in vivo experiments in Apoe -/- mice. Human lipidomics studies were performed on the 300OB cohort comprising 300 obese and overweight individuals at risk of cardiovascular disease. In vitro assays were carried out using human monocytes and macrophages, and in vivo experiments included histopathological, immunophenotyping and single-cell transcriptomic analyses. In humans, we identified PS as an anti-inflammatory and atheroprotective biomarker. Hence, we developed a high-density lipoprotein (HDL)-like formulation enriched in PS to exploit its properties in a targeted fashion in mice. In vitro , this formulation potently inhibited inflammatory cytokine production on human myeloid cells. Our in-depth in vivo experiments provided evidence of the formulation's potent plaque-stabilizing and anti-inflammatory actions. These effects were mediated by a shift in the monocyte/macrophage compartment toward homeostatic/repairing phenotypes. Collectively, our results demonstrate that HDL-associated PS potently suppresses inflammation and atheroprogression, and holds promise as a viable approach to improve immunomodulatory therapies.

Metapopulation epidemic models help capture the spatial dimension of infectious disease spread by dividing heterogeneous populations into separate but interconnected communities, represented by nodes in a network. In the event of an epidemic, an important research question is, to what degree is the spatial information (i.e., regional or national) relevant for mitigation and (local) policymakers? This study investigates the impact of different levels of information on nationwide epidemic outcomes, modeling the reaction to the measured hazard as a feedback loop reducing contact rates in a metapopulation model based on ordinary differential equations (ODEs). Using COVID-19 and high-resolution mobility data for Germany of 2020 as a case study, our model revealed two markedly different regimes depending on the maximum contact reduction. In the first regime of (modest) mitigation , gradually increasing maximum contact reduction from zero to moderate levels delayed and spread out the onset of infection waves while gradually reducing the peak values. This effect was more pronounced when the contribution of regional information was low relative to national data. In the opposite suppression regime, the feedback-induced contact reduction is strong enough to extinguish local outbreaks and decrease the mean and variance of the peak day distribution, thus regional information was more important. When suppression or elimination is impossible, ensuring local epidemics are desynchronized helps to avoid hospitalization or intensive care bottlenecks by reallocating resources from less-affected areas. • Metapopulation model with dynamic contact regulation on different spatial scales. • Dynamic contact regulation yields two regimes: disease mitigation and suppression. • Modest regulation (mitigation) desynchronizes and delays the onset of epidemic waves. • High regulation (suppression) extinguishes local outbreaks but synchronizes them. • Mitigation benefits from national data; suppression, from regional data.

Abstract Disease surveillance and epidemiological modeling are critical to guide public health interventions, but model performance depends on data availability and quality. While clinical reports often suffer from under-ascertainment and delays, wastewater-based surveillance (WBS) can rapidly capture community infection dynamics by detecting viral RNA from both symptomatic and asymptomatic cases. However, WBS data can be difficult to interpret. Here, we present a coupled model of infectious disease and wastewater dynamics designed for scalability to large cities. We calibrate the model to the first COVID-19 wave in the city of Munich and quantify how sampling protocols, precipitation infiltration, viral decay, normalization strategies, and intervention timing can shape the relationship between wastewater measurements and disease prevalence, thereby improving the interpretability and practical value of wastewater data for epidemiological decision-making. We find that when appropriate sampling, normalization, and analysis strategies are utilized, wastewater data can reveal changes in prevalence earlier than clinical reports and provide advance warning of upcoming increases in disease burden. Our results guide WBS design and integration into predictive early-warning systems. Our modeling framework is generalizable to other COVID-19-like pathogens to help enable robust, cost-efficient disease monitoring.

Invasive, high-mortality yeast infections caused by pathogenic Candida species are the most common fungal nosocomial bloodstream infections. The World Health Organization (WHO) has called for improved prevention and diagnostic strategies for fungal pathogens. Here, we demonstrate that Candida-related antibodies can be detected using glycan microarrays containing synthetic glycans to guide the discovery of oligosaccharide epitopes for diagnostics and vaccine design. Pure, synthetic mannans and β-glucans, resembling carbohydrates found on the surface of Candida spp., were employed to screen and compare sera from infected humans and mice with noninfected individuals. IgM antibodies directed toward β-glucans were observed shortly after infection, and after a longer time of infection, IgM and IgG antibodies that preferentially recognize mannans. Phosphodiester-linked mannosides and the β-(1,2)-mannose monomer help to distinguish different Candida spp. The tetrasaccharide antigen β-(1,2)Man-α-(1,2)Man-α-(1,2)Man-α-(1,2)Man, and the pentasaccharide antigens α-(1,2)Man-α-(1,3)Man-α-(1,2)Man-α-(1,2)Man-α-(1,2)Man and β-(1,3)Glc-β-(1,3)Glc-β-(1,3)Glc-[β-(1,6)Glc]-β-(1,3)Glc were identified as potential epitopes for detection, e.g., through monoclonal antibody lateral flow tests, and the development of glycoconjugate or monoclonal antibody vaccines against Candida.

The RNA-binding protein TRIM71 is essential for brain development, and recent genetic studies in humans have identified TRIM71 as a risk gene for congenital hydrocephal-us (CH). Here, we show that monoallelic missense mutations in TRIM71 are associated with hearing loss (HL) and inner ear aplasia in humans. Utilizing conditional Trim71 knockout mice carrying a CH and HL-associated mutation, we demonstrate that loss of TRIM71 function during early otic development (embryonic day 9 to 10) causes severe HL. While inner ear morphogenesis occurs normally in Trim71 knockout mice, we find that early otic loss of TRIM71 function disrupts the highly stereotyped timing of cell cycle exit and differentiation within the inner ear auditory sensory organ (cochlea), resulting in the premature formation and innervation of mechanosensory hair cells. Transcriptomic profiling of Trim71-deficient cochlear progenitor cells identifies Inhba and Tgfbr2 as targets of TRIM71 repression, and our analysis of Inhba-Tgfbr1 double knockout mice indicates that TRIM71 maintains hair cell progenitors in a proliferative and undifferentiated state by restricting TGFβ-type signaling. Characterization of hair cells and their associated neurons in adult Trim71 knockout mice revealed reduced presynaptic terminals and neuronal degeneration in the outer hair cell region, providing a basis for the observed hearing deficits in Trim71 knockout mice.

BackgroundUrate concentration and the physiological regulation of urate homeostasis exhibit clear sex differences. DNA methylation has been shown to explain a substantial proportion of serum urate variance, mediate the genetic effect on urate concentration, and co-regulate with cardiometabolic traits. However, whether urate concentration is associated with DNA methylation in a sex-dependent manner is unknown. Additionally, it is worth investigating if urate changes after perturbations, such as vaccination, are associated with DNA methylation in a sex-specific manner.MethodsWe investigated the association between DNA methylation and serum urate concentrations in a Dutch cohort of 325 healthy individuals. Urate concentration and DNA methylation were measured before and after Bacillus Calmette-Guérin (BCG) vaccination, used as a perturbation associated with increased gout flares. The association analysis included united, interaction, and sex-stratified analysis.Results215 CpG sites are associated with serum urate in males, while 5 CpG sites are associated with serum urate in females, indicating sex-specific associations. Circulating urate concentrations significantly increase after BCG vaccination, and baseline DNA methylation is associated with differences in urate concentration before and after vaccination in a sex-specific manner. The CpG sites associated with urate concentration in males are enriched in neuro-protection pathways, whereas in females, the urate change-associated CpG sites are related to lipid and glucose metabolism.ConclusionsOur study enhances the understanding of how epigenetic factors contribute to regulating serum urate levels in a sex-specific manner. These insights highlight the importance of personalized and sex-specific approaches in medicine.

Due to their small size, stability, and cost-effectiveness compared to antibodies, aptamers developed by systematic evolution of ligands by exponential enrichment (SELEX) are promising candidates for the detection of small molecules. In SELEX, a small target molecule is usually covalently immobilized on a surface to separate bound from unbound nucleic acid sequences. However, this immobilization alters the molecule, that is, additional chemical entities are added and the electron distribution is altered, compromising the enrichment properties. To overcome this problem, a capture SELEX method has been successfully developed in which the RNA or DNA libraries are bound to a surface via a complementary oligodeoxynucleotide, and the soluble ligand is used to capture nucleic acids that bind to it from that surface. Herein, the development of an automated version of the capture SELEX method for the identification of RNA aptamers that bind small molecules is described. This method is fully automated and performs up to 12 iterative selection cycles without manual interference in 72 h. The approach is therefore suitable as rapid route to aptamers and enables resource-efficient test selections to assess "aptamerogenicity" of a target.