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- Heinrich Heine University cooperates with numerous research institutions and networks beyond the boundaries of the faculties. The HHU's affiliated institutes in particular act as a link to industry. As independent institutions, they maintain close contact with research in the faculties and participate in the training of young academics.
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Recent Submissions
Supporting Information for "Molecular mechanisms underlying single nucleotide polymorphism-induced reactivity decrease in CYP2D6"
(N/A, 2024-02) Becker, Daniel; Gohlke, Holger
Cytochrome P450 2D6 (CYP2D6) is one of the most important enzymes involved in drug metabolism. Genetic polymorphism can influence drug metabolism by CYP2D6 such that a therapy is seriously affected by under- or overdosing of drugs. However, a general explanation at the atomistic level for poor activity is missing so far. Here we show for the 20 most common single nucleotide polymorphisms (SNPs) of CYP2D6 that poor metabolism is driven by four mechanisms. We found in extensive all-atom molecular dynamics simulations that the rigidity of the I-helix (central helix), distance between central phenylalanines (stabilizing bound substrate), availability of basic residues on the surface of CYP2D6 (binding of Cytochrome P450 reductase), and position of arginine 132 (electron transfer to heme) are essential for an extensive function of the enzyme. These results were applied to SNPs with unknown effects and potential SNPs that may lead to poor drug metabolism were identified. The revealed molecular mechanisms might be important for other drug-metabolizing Cytochrome P450 enzymes.
Petersilie et al. 2024 - Supplementary Figure
(iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
Brain organoids derived from human pluripotent stem cells are a promising tool for studying human
neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain
organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
Petersilie et al. 2024 - Figure 4
(iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
Brain organoids derived from human pluripotent stem cells are a promising tool for studying human
neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain
organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
Petersilie et al. 2024 - Figure 6
(iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
Brain organoids derived from human pluripotent stem cells are a promising tool for studying human
neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain
organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
Petersilie et al. 2024 - Figure 7
(iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
Brain organoids derived from human pluripotent stem cells are a promising tool for studying human
neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain
organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.
Petersilie et al. 2024 - Figure 3
(iScience, 2024) Petersilie, Laura; Heiduschka, Sonja; Nelson, Joel S. E.; Neu, Louis A.; Le, Stephanie; Anand, Ruchika; Kafitz, Karl W.; Prigione, Alessandro; Rose, Christine R.
Brain organoids derived from human pluripotent stem cells are a promising tool for studying human neurodevelopment and related disorders. Here, we generated long-term cultures of cortical brain organoid slices (cBOS) grown at the air-liquid interphase from regionalized cortical organoids. We show that cBOS host mature neurons and astrocytes organized in complex architecture. Whole-cell patch clamp demonstrated subthreshold synaptic inputs and action potential firing of neurons. Spontaneous intracellular calcium signals turned into synchronous large-scale oscillations upon combined disinhibition of NMDA receptors and blocking of GABAA receptors. Brief metabolic inhibition to mimic transient energy restriction in the ischemic brain induced reversible intracellular calcium loading of cBOS. Moreover, metabolic inhibition induced a reversible decline in neuronal ATP as revealed by ATeam1.03YEMK. Overall, cBOS provide a powerful platform to assess morphological and functional aspects of human neural cells in intact minimal networks and to address the pathways that drive cellular damage during brain ischemia.