Ludwig-Maximilians-Universität München
Open Access LMU ( Ludwig-Maximilians-Univ. München)Not a member yet
40914 research outputs found
Sort by
Design, Synthesis and Preclinical Evaluation of a Brain-Permeable PET Tracer for P2Y12 Receptor Imaging in the Brain
No full textMicroglia, the innate immune cells of the central nervous system (CNS), act as first responders to brain injury. Their ability to switch between different neuroprotective and neurotoxic phenotypes, plays a central role in maintaining brain homeostasis. Recently, the P2Y12 receptor (P2Y12R) has been identified as a promising molecular biomarker for microglia activity, as its expression level is dependent on microglia phenotype and function. P2Y12R positron emission tomography (PET) might be a valuable diagnostic tool, however, tracers with sufficient brain retention have not been reported so far. Herein, we report a brain-permeable P2Y12R PET tracer for in vivo imaging of P2Y12R-positive microglia. Nicotinate [18F]12 exhibited nanomolar affinity and specificity for the target receptor and showed a reduced uptake in microglia-depleted (PLX) mice, in comparison to WT and Trem2 knockout (Trem2–/–) mice. Ex vivo immunohistochemistry (IHC) and PET data revealed a strong correlation between microglia abundance, P2Y12R expression levels and tracer uptake
Machine learning in Alzheimer’s disease genetics
No full textTraditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer’s disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics
Neurobiological correlates of schizophrenia-specific and highly pleiotropic genetic risk scores for neuropsychiatric disorders
No full textImage-Derived Blood Normalization of Antibody-Based TREM2 PET in Mouse Models of Amyloidosis and Myocardial Infarction
No full textThe triggering receptor expressed on myeloid cells 2 (TREM2) plays a pivotal role in the activation of myeloid cells and is currently being investigated as a potential therapeutic target in several diseases. In this study, we established enhanced quantification of PET images of a 64Cu-labeled antibody-based PET radiotracer as a noninvasive tool for the assessment of TREM2 expression in the brain and peripheral organs of mice. We used TREM2 knockout mice that lack target expression to investigate data-driven blood normalization of PET images against percentage of injected dose normalization. Methods: TREM2 knockout and wild-type mice (n = 11 each) were injected with the radiotracer [64Cu]Cu-NODAGA-ATV:4D9 (ATV is antibody transport vehicle). Twenty hours after injection, TREM2 PET was conducted and blood samples were collected. A voxelwise analysis with statistical parametric mapping served to determine voxels that correlate with ex vivo blood radioactivity levels. Furthermore, TREM2 PET signals were compared between mice with and those without TREM2 expression using image-derived blood normalization. Correlation with TREM2 protein expression levels in the lung, liver, spleen, and bone marrow was used to validate organ-specific PET results. Disease models of brain amyloidosis and myocardial infarction were investigated to test for the value of image-derived normalization in mice. Results: Blood radioactivity levels derived from a statistical parametric mapping–derived region of interest demonstrated a robust correlation with radioactivity measurements obtained from ex vivo blood samples. Voxelwise clusters of TREM2 PET signals were more robustly detected after blood normalization of the PET images. Significant voxelwise clusters of TREM2 PET signals in peripheral organs correlated with TREM2 protein expression levels. Furthermore, image-derived normalization enhanced the significance of voxelwise clusters of TREM2 in the brains of AppSAA;TfRmu/hu mice, as well as the TREM2 signal in the myocardial infarct region. Both strongly correlated with ex vivo autoradiography. Conclusion: Normalization of PET images to account for blood levels enhanced the detection of TREM2. This improved methodology for TREM2 PET analysis provides a promising basis for future assessments of TREM2 imaging
The impact of CT-based adipose tissue distribution and sarcopenia on treatment outcomes in patients with high-risk soft tissue sarcoma
No full textBackground: The prognostic and predictive value of obesity and sarcopenia remains poorly defined in patients with high-risk soft tissue sarcoma (HR-STS). We sought to correlate clinical outcomes with CT-based body composition parameters in patients with HR-STS undergoing a multimodal preoperative therapy. The impact of radiologic and histopathologic response to preoperative treatment was correlated with individual fat and muscle distribution.
Methods: Patients with locally advanced non-abdominal HR-STS and treatment with preoperative chemotherapy + regional hyperthermia (RHT) +/- radiotherapy (RT) followed by surgery between 2015 and 2022 were retrospectively evaluated. Body composition parameters measured on baseline CT scans were correlated with clinical outcomes including event-free survival (EFS) and overall survival (OS) as well as radiologic and histopathologic treatment response.
Results: A total of 85 patients were included. Body composition parameters showed no significant correlation with radiologic or histopathologic treatment response. High total fat indices such as the total fat index (TFI, HR 3.56, p = 0.005) and high total fat to muscle ratio (FMR, HR 3.22, p = 0.020) were strongly associated with poor OS. Parameters for sarcopenia including skeletal muscle index (SMI) were not significantly linked to survival outcomes.
Conclusion: High fat indices and a high FMR are strong predictors of poor OS in patients with HR-STS. Larger studies are warranted to further clarify the prognostic impact of sarcopenia and the predictive value of body composition parameters on preoperative treatment response
Vanguard Visions of Vertical Farming: Envisaging and Contesting an Emerging Food Production System
Get PDFVertical farming is an emerging urban food growth proposal that has gained considerable attention for its ability to be space-efficient, independent of outside weather conditions, and to address a dismal agricultural system and ecoclimatic crises. VF is also a field riddled with debates on the unsustainability and high (energy) costs of a highly automated, indoor growth system that produces only a small range of perishable food. This paper explores arguments, visions, and internal disagreements among scientists, engineers, consultants, and entrepreneurs who form a heterogeneous, elite group of sociotechnical vanguards that popularize not yet widely accepted vanguard visions of future urban food production. It demonstrates that for the dominant vertical farm vanguard vision, a majority of vanguards borrow popular concepts and imaginaries from other sectors: containment of plant growth, cleanliness, the capability to feed the world, and the land-sparing narrative. The findings suggest three dimensions that add to the theorization of vanguard visions: the central role of mobilized problem-scripts; internal disagreements that indicate the contingency of vanguard visions and the existence of fringe visions; and that disagreements can reveal caveat politics, where a technical system, like VF, is not seen as the solution, but one of many
Ezh2 Shapes T Cell Plasticity to Drive Atherosclerosis
Get PDFBackground:The activation and polarization of T cells play a crucial role in atherosclerosis and dictate athero-inflammation. The epigenetic enzyme EZH2 (enhancer of zeste homolog 2) mediates the H3K27me3 (trimethylation of histone H3 lysine 27) and is pivotal in controlling T cell responses.
Methods:To detail the role of T cell EZH2 in atherosclerosis, we used human carotid endarterectomy specimens to reveal plaque expression and geography of EZH2. Atherosclerosis-prone Apoe (apolipoprotein E)–deficient mice with CD (cluster of differentiation) 4+ or CD8+ T cell–specific Ezh2 deletion (Ezh2cd4-knockout [KO], Ezh2cd8-KO) were analyzed to unravel the role of T cell Ezh2 in atherosclerosis and T cell–associated immune status.
Results:EZH2 expression is elevated in advanced human atherosclerotic plaques and primarily expressed in the T cell nucleus, suggesting the importance of canonical EZH2 function in atherosclerosis. Ezh2cd4-KO, but not Ezh2cd8-KO, mice showed reduced atherosclerosis with fewer advanced plaques, which contained less collagen and macrophages, indicating that Ezh2 in CD4+ T cells drives atherosclerosis. In-depth analysis of CD4+ T cells of Ezh2cd4-KO mice revealed that absence of Ezh2 results in a type 2 immune response with increased Il-4 (interleukin 4) gene and protein expression in the aorta and lymphoid organs. In vitro, Ezh2-deficient T cells polarized macrophages toward an anti-inflammatory phenotype. Single-cell RNA-sequencing of splenic T cells revealed that Ezh2 deficiency reduced naive, Ccl5+ (C-C motif chemokine ligand 5) and regulatory T cell populations and increased the frequencies of memory T cells and invariant natural killer T (iNKT) cells. Flow cytometric analysis identified a shift toward Th2 (type 2 T helper) effector CD4+ T cells in Ezh2cd4-KO mice and confirmed a profound increase in splenic iNKT cells with increased expression of Plzf (promyelocytic leukemia zinc finger), which is the characteristic marker of the iNKT2 subset. Likewise, Zbtb16 ([zinc finger and BTB domain containing 16], a Plzf-encoding gene) transcripts were elevated in the aorta of Ezh2cd4-KO mice, suggesting an accumulation of iNKT2 cells in the plaque. H3K27me3–chromatin immunoprecipitation followed by quantitative polymerase chain reaction showed that T cell–Ezh2 regulates the transcription of the Il-4 and Zbtb16 genes.
Conclusions:Our study uncovers the importance of T cell EZH2 in human and mouse atherosclerosis. Inhibition of Ezh2 in CD4+ T cells drives type 2 immune responses, resulting in an accumulation of iNKT2 and Th2 cells, memory T cells and anti-inflammatory macrophages that limit the progression of atherosclerosis
Multi-shank 1024 channels active SiNAPS probe for large multi-regional topographical electrophysiological mapping of neural dynamics
Get PDFMulti-parametric [18F]PI-2620 tau PET/MRI for the phenotyping of different Alzheimer’s disease variants
Get PDFPurpose : Heterogeneity in clinical phenotypes has led to the description of different phenotypes of Alzheimer’s disease (AD). Besides the most frequent amnestic variant of AD (aAD), patients presenting with language deficits are diagnosed with logopenic variant primary progressive aphasia (lvPPA), whereas patients presenting with visual deficits are classified as posterior cortical atrophy (PCA).
Methods : This study set out to investigate the value of a multi-parametric [18F]PI-2620 tau PET/MRI protocol to distinguish aAD, lvPPA and PCA to support clinical diagnosis in 32 patients. Phenotype-specific information about tau accumulation, relative perfusion, grey matter density, functional network alterations and white matter microstructural alterations was collected.
Results : The aAD patients showed significantly higher tau accumulation, relative hypoperfusion and grey matter density loss in the temporal lobes compared to PCA and lvPPA patients. PCA patients, on the other hand, showed significantly higher tau accumulation in the occipital lobe as compared to aAD patients. Relative hypoperfusion in the occipital lobe and loss of functional connectivity of the posterior cingulate cortex to supplementary visual cortical regions helped to distinguish PCA from lvPPA. Tau accumulation in the cerebellum and microstructural changes in the cingulum were found to help differentiate lvPPA from aAD.
Conclusion : This study highlights structural and functional differences between patients with different AD phenotypes. Differences in regional tau PET signals suggest that refinements in the Braak staging system are needed for the non-aAD cases. These patterns of tau accumulation align with the cascading network failure hypothesis, though more research is needed to warrant the here presented results in larger patient cohorts
Determination of absolute intramolecular distances in proteins using anomalous X-ray scattering interferometry
Get PDFBiomolecular structures are typically determined using frozen or crystalline samples. Measurement of intramolecular distances in solution can provide additional insights into conformational heterogeneity and dynamics of biological macromolecules and their complexes. The established molecular ruler techniques used for this (NMR, FRET, and EPR) are, however, limited in their dynamic range and require model assumptions to determine absolute distance or distance distributions. Here, we introduce anomalous X-ray scattering interferometry (AXSI) for intramolecular distance measurements in proteins, which are labeled at two sites with small gold nanoparticles of 0.7 nm radius. We apply AXSI to two different cysteine-variants of maltose binding protein in the presence and absence of its ligand maltose and find distances in quantitative agreement with single-molecule FRET experiments. Our study shows that AXSI enables determination of intramolecular distance distributions under virtually arbitrary solution conditions and we anticipate its broad use to characterize protein conformational ensembles and dynamics