119 results on '"Johannes CM"'
Search Results
2. A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
- Author
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Reem Abdel-Haq, Johannes CM Schlachetzki, Joseph C Boktor, Thaisa M Cantu-Jungles, Taren Thron, Mengying Zhang, John W Bostick, Tahmineh Khazaei, Sujatha Chilakala, Livia H Morais, Greg Humphrey, Ali Keshavarzian, Jonathan E Katz, Matthew Thomson, Rob Knight, Viviana Gradinaru, Bruce R Hamaker, Christopher K Glass, and Sarkis K Mazmanian
- Subjects
parkinson's disease ,diet ,microglia ,microbiome ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Parkinson’s disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.
- Published
- 2022
- Full Text
- View/download PDF
3. Gene expression and chromatin conformation of microglia in virally suppressed people with HIV
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Schlachetzki, Johannes CM, Gianella, Sara, Ouyang, Zhengyu, Lana, Addison J, Yang, Xiaoxu, O’Brien, Sydney, Challacombe, Jean F, Gaskill, Peter J, Jordan-Sciutto, Kelly L, Chaillon, Antoine, Moore, David, Achim, Cristian L, Ellis, Ronald J, Smith, Davey M, and Glass, Christopher K
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Sexually Transmitted Infections ,HIV/AIDS ,Neurosciences ,Genetics ,Infectious Diseases ,2.1 Biological and endogenous factors ,Infection ,Microglia ,Humans ,HIV Infections ,Chromatin ,Male ,HIV-1 ,Virus Latency ,RNA ,Viral ,Brain ,Female ,Adult ,Middle Aged ,Gene Expression ,Viral Load ,Biological sciences ,Biomedical and clinical sciences - Abstract
The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.
- Published
- 2024
4. Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management
- Author
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Ellis, Ronald J, Marquine, María J, Kaul, Marcus, Fields, Jerel Adam, and Schlachetzki, Johannes CM
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Medical Microbiology ,Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Brain Disorders ,Sexually Transmitted Infections ,HIV/AIDS ,Neurodegenerative ,Neurosciences ,Infectious Diseases ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Infection ,Good Health and Well Being ,Humans ,HIV Infections ,Central Nervous System Diseases ,Cognitive Dysfunction ,Clinical sciences - Abstract
People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.
- Published
- 2023
5. RANK ligand converts the NCoR/HDAC3 co-repressor to a PGC1β- and RNA-dependent co-activator of osteoclast gene expression
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Abe, Yohei, Kofman, Eric R, Almeida, Maria, Ouyang, Zhengyu, Ponte, Filipa, Mueller, Jasmine R, Cruz-Becerra, Grisel, Sakai, Mashito, Prohaska, Thomas A, Spann, Nathanael J, Resende-Coelho, Ana, Seidman, Jason S, Stender, Joshua D, Taylor, Havilah, Fan, Weiwei, Link, Verena M, Cobo, Isidoro, Schlachetzki, Johannes CM, Hamakubo, Takao, Jepsen, Kristen, Sakai, Juro, Downes, Michael, Evans, Ronald M, Yeo, Gene W, Kadonaga, James T, Manolagas, Stavros C, Rosenfeld, Michael G, and Glass, Christopher K
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Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,1.1 Normal biological development and functioning ,Underpinning research ,Humans ,Mice ,Animals ,Co-Repressor Proteins ,RNA ,Osteoclasts ,RANK Ligand ,Nuclear Receptor Co-Repressor 1 ,Gene Expression ,AP-1 ,H3K27ac ,HDAC3 ,NCoR ,NF-κB ,PGC1β ,RANK ,co-activator ,deacetylation ,gene expression ,non-coding RNA ,osteoclast ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts.
- Published
- 2023
6. The innate immune system in Parkinson′s disease: a novel target promoting endogenous neuroregeneration
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Johannes CM Schlachetzki and Jürgen Winkler
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Neurology. Diseases of the nervous system ,RC346-429 - Published
- 2015
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7. Distinct effects of chronic dopaminergic stimulation on hippocampal neurogenesis and striatal doublecortin expression in adult mice
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Rachele eSalvi, Tobias eSteigleder, Johannes CM eSchlachetzki, Elisabeth eWaldmann, Beate eWinner, Stefan eSchwab, Jürgen eWinkler, and Zacharias eKohl
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Dentate Gyrus ,Parkinson Disease ,Striatum ,adult neurogenesis ,Dopamine receptor ,doublecortin ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g. the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX) and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2'-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 hours after a 14-day-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and NeuN 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-day DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active and quiescent neurogenic niches, might be related to the proportional higher D3 receptor affinity of PPX, non-dopaminergic effects of PPX, or altered motor behavior.
- Published
- 2016
- Full Text
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8. Purification of baculovirus vectors using heparin affinity chromatography
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Md Nasimuzzaman, Danielle Lynn, Johannes CM van der Loo, and Punam Malik
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Genetics ,QH426-470 ,Cytology ,QH573-671 - Abstract
Baculoviruses are commonly used for recombinant protein and vaccine production. Baculoviruses are nonpathogenic to vertebrates, have a large packaging capacity, display broad host and cell type tropism, infect both dividing and nondividing cells, and do not elicit strong immune or allergic responses in vivo. Hence, their use as gene delivery vehicles has become increasingly popular in recent years. Moreover, baculovirus vectors carrying mammalian regulatory elements can efficiently transduce and express transgenes in mammalian cells. Based on the finding that heparan sulfate, which is structurally similar to heparin, is an attachment receptor for baculovirus, we developed a novel scalable baculovirus purification method using heparin-affinity chromatography. Baculovirus supernatants were loaded onto a POROS heparin column, washed to remove unbound materials, and eluted with 1.5 mol/l NaCl, which yielded a recovery of purified baculovirus of 85%. After ultracentrifugation, baculovirus titers increased from 200- to 700-fold with overall yields of 26–29%. We further show that baculovirus particles were infectious, normal in morphology and size, despite high-salt elution and shear forces used during purification and concentration. Our chromatography-based purification method is scalable and, together with ultracentrifugation and/or tangential flow filtration, will be suitable for large-scale manufacturing of baculovirus stocks for protein and vaccine production and in gene therapy applications.
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- 2016
- Full Text
- View/download PDF
9. Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice
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Han, Rafael T, Vainchtein, Ilia D, Schlachetzki, Johannes CM, Cho, Frances S, Dorman, Leah C, Ahn, Eunji, Kim, Dong Kyu, Barron, Jerika J, Nakao-Inoue, Hiromi, Molofsky, Ari B, Glass, Christopher K, Paz, Jeanne T, and Molofsky, Anna V
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Biomedical and Clinical Sciences ,Neurosciences ,Brain Disorders ,Pediatric ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Mice ,Microglia ,Interleukin-33 ,Synapses ,Brain ,Seizures ,Mice ,Inbred C57BL ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement.
- Published
- 2023
10. A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice.
- Author
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Abdel-Haq, Reem, Schlachetzki, Johannes CM, Boktor, Joseph C, Cantu-Jungles, Thaisa M, Thron, Taren, Zhang, Mengying, Bostick, John W, Khazaei, Tahmineh, Chilakala, Sujatha, Morais, Livia H, Humphrey, Greg, Keshavarzian, Ali, Katz, Jonathan E, Thomson, Matthew, Knight, Rob, Gradinaru, Viviana, Hamaker, Bruce R, Glass, Christopher K, and Mazmanian, Sarkis K
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Substantia Nigra ,Microglia ,Animals ,Mice ,Inbred C57BL ,Mice ,Parkinson Disease ,Disease Models ,Animal ,Diet ,alpha-Synuclein ,Prebiotics ,diet ,infectious disease ,microbiology ,microbiome ,microglia ,mouse ,neuroscience ,parkinson's disease ,Neurodegenerative ,Aging ,Nutrition ,Digestive Diseases ,Parkinson's Disease ,Brain Disorders ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mouse ,Biochemistry and Cell Biology - Abstract
Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.
- Published
- 2022
11. CSF1R-Mediated Myeloid Cell Depletion Prolongs Lifespan But Aggravates Distinct Motor Symptoms in a Model of Multiple System Atrophy
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Battis, Kristina, Florio, Jazmin B, Mante, Michael, Lana, Addison, Naumann, Isabel, Gauer, Carina, Lambrecht, Vera, Müller, Simon Julian, Cobo, Isidoro, Fixsen, Bethany, Kim, Ha Yeon, Masliah, Eliezer, Glass, Christopher K, Schlachetzki, Johannes CM, Rissman, Robert A, Winkler, Jürgen, and Hoffmann, Alana
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Biomedical and Clinical Sciences ,Neurosciences ,Acquired Cognitive Impairment ,Brain Disorders ,Neurodegenerative ,Rare Diseases ,Genetics ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Mice ,Multiple System Atrophy ,Longevity ,Organic Chemicals ,Microglia ,Receptors ,Granulocyte-Macrophage Colony-Stimulating Factor ,Disease Models ,Animal ,Myeloid Cells ,Receptors ,Colony-Stimulating Factor ,colony-stimulating factor 1 receptor ,motor function ,multiple system atrophy ,myeloid cells ,neuron-micro-glia interaction ,PLX5622 ,neuron–microglia interaction ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed the gene expression profile of microglia in a mouse model of MSA (MBP29-hα-syn) and identified a disease-associated expression profile and upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that CSF1 receptor-mediated depletion of myeloid cells using PLX5622 modifies the disease progression and neuropathological phenotype in this mouse model. Intriguingly, sex-balanced analysis of myeloid cell depletion in MBP29-hα-syn mice revealed a two-faced outcome comprising an improved survival rate accompanied by a delayed onset of neurological symptoms in contrast to severely impaired motor functions. Furthermore, PLX5622 reversed gene expression profiles related to myeloid cell activation but reduced gene expression associated with transsynaptic signaling and signal release. While transcriptional changes were accompanied by a reduction of dopaminergic neurons in the SNpc, striatal neuritic density was increased upon myeloid cell depletion in MBP29-hα-syn mice. Together, our findings provide insight into the complex, two-faced role of myeloid cells in the context of MSA emphasizing the importance to carefully balance the beneficial and adverse effects of CSF1R inhibition in different models of neurodegenerative disorders before its clinical translation.SIGNIFICANCE STATEMENT Myeloid cells have been implicated as detrimental in the disease pathogenesis of multiple system atrophy. However, long-term CSF1R-dependent depletion of these cells in a mouse model of multiple system atrophy demonstrates a two-faced effect involving an improved survival associated with a delayed onset of disease and reduced inflammation which was contrasted by severely impaired motor functions, synaptic signaling, and neuronal circuitries. Thus, this study unraveled a complex role of myeloid cells in multiple system atrophy, which indicates important functions beyond the previously described disease-associated, destructive phenotype and emphasized the need of further investigation to carefully and individually fine-tune immunologic processes in different neurodegenerative diseases.
- Published
- 2022
12. Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
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Manzoni, Claudia, Kia, Demis A., Ferrari, Raffaele, Leonenko, Ganna, Costa, Beatrice, Saba, Valentina, Jabbari, Edwin, Tan, Manuela MX., Albani, Diego, Alvarez, Victoria, Alvarez, Ignacio, Andreassen, Ole A., Angiolillo, Antonella, Arighi, Andrea, Baker, Matt, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Blackburn, Daniel J., Boada, Merce, Boeve, Bradley F., Borrego-Ecija, Sergi, Borroni, Barbara, Bråthen, Geir, Brooks, William S., Bruni, Amalia C., Caroppo, Paola, Bandres-Ciga, Sara, Clarimon, Jordi, Colao, Rosanna, Cruchaga, Carlos, Danek, Adrian, de Boer, Sterre CM., de Rojas, Itziar, di Costanzo, Alfonso, Dickson, Dennis W., Diehl-Schmid, Janine, Dobson-Stone, Carol, Dols-Icardo, Oriol, Donizetti, Aldo, Dopper, Elise, Durante, Elisabetta, Ferrari, Camilla, Forloni, Gianluigi, Frangipane, Francesca, Fratiglioni, Laura, Kramberger, Milica G., Galimberti, Daniela, Gallucci, Maurizio, García-González, Pablo, Ghidoni, Roberta, Giaccone, Giorgio, Graff, Caroline, Graff-Radford, Neill R., Grafman, Jordan, Halliday, Glenda M., Hernandez, Dena G., Hjermind, Lena E., Hodges, John R., Holloway, Guy, Huey, Edward D., Illán-Gala, Ignacio, Josephs, Keith A., Knopman, David S., Kristiansen, Mark, Kwok, John B., Leber, Isabelle, Leonard, Hampton L., Libri, Ilenia, Lleo, Alberto, Mackenzie, Ian R., Madhan, Gaganjit K., Maletta, Raffaele, Marquié, Marta, Maver, Ales, Menendez-Gonzalez, Manuel, Milan, Graziella, Miller, Bruce L., Morris, Christopher M., Morris, Huw R., Nacmias, Benedetta, Newton, Judith, Nielsen, Jørgen E., Nilsson, Christer, Novelli, Valeria, Padovani, Alessandro, Pal, Suvankar, Pasquier, Florence, Pastor, Pau, Perneczky, Robert, Peterlin, Borut, Petersen, Ronald C., Piguet, Olivier, Pijnenburg, Yolande AL., Puca, Annibale A., Rademakers, Rosa, Rainero, Innocenzo, Reus, Lianne M., Richardson, Anna MT., Riemenschneider, Matthias, Rogaeva, Ekaterina, Rogelj, Boris, Rollinson, Sara, Rosen, Howard, Rossi, Giacomina, Rowe, James B., Rubino, Elisa, Ruiz, Agustin, Salvi, Erika, Sanchez-Valle, Raquel, Sando, Sigrid Botne, Santillo, Alexander F., Saxon, Jennifer A., Schlachetzki, Johannes CM., Scholz, Sonja W., Seelaar, Harro, Seeley, William W., Serpente, Maria, Sorbi, Sandro, Sordon, Sabrina, St George-Hyslop, Peter, Thompson, Jennifer C., Van Broeckhoven, Christine, Van Deerlin, Vivianna M., Van der Lee, Sven J., Van Swieten, John, Tagliavini, Fabrizio, van der Zee, Julie, Veronesi, Arianna, Vitale, Emilia, Waldo, Maria Landqvist, Yokoyama, Jennifer S., Nalls, Mike A., Momeni, Parastoo, Singleton, Andrew B., Hardy, John, and Escott-Price, Valentina
- Published
- 2024
- Full Text
- View/download PDF
13. Somatic mosaicism reveals clonal distributions of neocortical development
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Breuss, Martin W, Yang, Xiaoxu, Schlachetzki, Johannes CM, Antaki, Danny, Lana, Addison J, Xu, Xin, Chung, Changuk, Chai, Guoliang, Stanley, Valentina, Song, Qiong, Newmeyer, Traci F, Nguyen, An, O’Brien, Sydney, Hoeksema, Marten A, Cao, Beibei, Nott, Alexi, McEvoy-Venneri, Jennifer, Pasillas, Martina P, Barton, Scott T, Copeland, Brett R, Nahas, Shareef, Van Der Kraan, Lucitia, Ding, Yan, Glass, Christopher K, and Gleeson, Joseph G
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Neurosciences ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Neurological ,Cell Lineage ,Cells ,Cultured ,Clone Cells ,Humans ,Microglia ,Mosaicism ,Neocortex ,NIMH Brain Somatic Mosaicism Network ,General Science & Technology - Abstract
The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders1,2. We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and clade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain.
- Published
- 2022
14. Gene regulatory networks underlying human microglia maturation
- Author
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Han, Claudia, Li, Rick, Hansen, Emily, Bennett, Hunter, Poirion, Olivier, Buchanan, Justin, Challacombe, Jean, Fixsen, Bethany, Trescott, Samantha, Schlachetzki, Johannes CM, Preissl, Sebastian, Wang, Allen, O’Connor, Carolyn, Warden, Anna, Shriram, Shreya, Kim, Roy, Nguyen, Celina, Schafer, Danielle, Ramirez, Gabriela, Anavim, Samuel, Johnson, Avalon, Sajti, Eniko, Gupta, Mihir, Levy, Michael, Ben-Haim, Sharona, Gonda, David, Laurent, Louise, Glass, Christopher, and Coufal, Nicole
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Pediatric ,Biotechnology ,Human Genome ,Neurosciences ,Genetics ,Brain Disorders ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Neurological - Abstract
The fetal period is a critical time for brain development, characterized by neurogenesis, neural migration, and synaptogenesis 1-3 . Microglia, the tissue resident macrophages of the brain, are observed as early as the fourth week of gestation 4 and are thought to engage in a variety of processes essential for brain development and homeostasis 5-11 . Conversely, microglia phenotypes are highly regulated by the brain environment 12-14 . Mechanisms by which human brain development influences the maturation of microglia and microglia potential contribution to neurodevelopmental disorders remain poorly understood. Here, we performed transcriptomic analysis of human fetal and postnatal microglia and corresponding cortical tissue to define age-specific brain environmental factors that may drive microglia phenotypes. Comparative analysis of open chromatin profiles using bulk and single-cell methods in conjunction with a new computational approach that integrates epigenomic and single-cell RNA-seq data allowed decoding of cellular heterogeneity with inference of subtype- and development stage-specific transcriptional regulators. Interrogation of in vivo and in vitro iPSC-derived microglia models provides evidence for roles of putative instructive signals and downstream gene regulatory networks which establish human-specific fetal and postnatal microglia gene expression programs and potentially contribute to neurodevelopmental disorders.
- Published
- 2021
15. Incorporation of a nucleoside analog maps genome repair sites in postmitotic human neurons
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Reid, Dylan A, Reed, Patrick J, Schlachetzki, Johannes CM, Nitulescu, Ioana I, Chou, Grace, Tsui, Enoch C, Jones, Jeffrey R, Chandran, Sahaana, Lu, Ake T, McClain, Claire A, Ooi, Jean H, Wang, Tzu-Wen, Lana, Addison J, Linker, Sara B, Ricciardulli, Anthony S, Lau, Shong, Schafer, Simon T, Horvath, Steve, Dixon, Jesse R, Hah, Nasun, Glass, Christopher K, and Gage, Fred H
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Stem Cell Research ,Neurosciences ,Regenerative Medicine ,Aging ,Genetics ,Human Genome ,Underpinning research ,1.1 Normal biological development and functioning ,DNA Damage ,DNA Repair ,DNA ,Intergenic ,Deoxyuridine ,Embryonic Stem Cells ,Genome ,Human ,Genomic Instability ,Histones ,Humans ,Mitosis ,Mutation ,Nervous System Diseases ,Neurons ,Promoter Regions ,Genetic ,RNA-Binding Proteins ,Sequence Analysis ,DNA ,Transcription ,Genetic ,General Science & Technology - Abstract
Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system.
- Published
- 2021
16. Gene Expression Imputation Across Multiple Tissue Types Provides Insight Into the Genetic Architecture of Frontotemporal Dementia and Its Clinical Subtypes
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Reus, Lianne M, Pasaniuc, Bogdan, Posthuma, Danielle, Boltz, Toni, Consortium, International FTD-Genomics, Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, Pietro, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St. George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, and Gu, Wei
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Biological Sciences ,Genetics ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Aging ,Dementia ,Neurodegenerative ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Prevention ,Alzheimer's Disease Related Dementias (ADRD) ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Frontotemporal Dementia ,Gene Expression ,Humans ,International FTD-Genomics Consortium ,17q21.31 inversion region ,Dorsolateral prefrontal cortex ,Expression quantitative trait loci ,Frontotemporal dementia ,SEC22B ,Transcriptome-wide association study ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry ,Biological sciences ,Biomedical and clinical sciences ,Psychology - Abstract
BackgroundThe etiology of frontotemporal dementia (FTD) is poorly understood. To identify genes with predicted expression levels associated with FTD, we integrated summary statistics with external reference gene expression data using a transcriptome-wide association study approach.MethodsFUSION software was used to leverage FTD summary statistics (all FTD: n = 2154 cases, n = 4308 controls; behavioral variant FTD: n = 1337 cases, n = 2754 controls; semantic dementia: n = 308 cases, n = 616 controls; progressive nonfluent aphasia: n = 269 cases, n = 538 controls; FTD with motor neuron disease: n = 200 cases, n = 400 controls) from the International FTD-Genomics Consortium with 53 expression quantitative loci tissue type panels (n = 12,205; 5 consortia). Significance was assessed using a 5% false discovery rate threshold.ResultsWe identified 73 significant gene-tissue associations for FTD, representing 44 unique genes in 34 tissue types. Most significant findings were derived from dorsolateral prefrontal cortex splicing data (n = 19 genes, 26%). The 17q21.31 inversion locus contained 23 significant associations, representing 6 unique genes. Other top hits included SEC22B (a gene involved in vesicle trafficking), TRGV5, and ZNF302. A single gene finding (RAB38) was observed for behavioral variant FTD. For other clinical subtypes, no significant associations were observed.ConclusionsWe identified novel candidate genes (e.g., SEC22B) and previously reported risk regions (e.g., 17q21.31) for FTD. Most significant associations were observed in dorsolateral prefrontal cortex splicing data despite the modest sample size of this reference panel. This suggests that our findings are specific to FTD and are likely to be biologically relevant highlights of genes at different FTD risk loci that are contributing to the disease pathology.
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- 2021
17. Nuclei isolation of multiple brain cell types for omics interrogation
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Nott, Alexi, Schlachetzki, Johannes CM, Fixsen, Bethany R, and Glass, Christopher K
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Biological Sciences ,Genetics ,Human Genome ,Neurosciences ,Biotechnology ,1.1 Normal biological development and functioning ,Underpinning research ,Neurological ,Animals ,Astrocytes ,Brain ,Brain Chemistry ,Cell Nucleus ,Chromatin ,Epigenomics ,Flow Cytometry ,Genomics ,Humans ,Neurons ,Protein Processing ,Post-Translational ,Chemical Sciences ,Medical and Health Sciences ,Bioinformatics - Abstract
We present a nuclei isolation protocol for genomic and epigenomic interrogation of multiple cell type populations in the human and rodent brain. The nuclei isolation protocol allows cell type-specific profiling of neurons, microglia, oligodendrocytes, and astrocytes, being compatible with fresh and frozen samples obtained from either resected or postmortem brain tissue. This 2-day procedure consists of tissue homogenization with fixation, nuclei extraction, and antibody staining followed by fluorescence-activated nuclei sorting (FANS) and does not require specialized skillsets. Cell type-specific nuclei populations can be used for downstream omic-scale sequencing applications with an emphasis on epigenomic interrogation such as histone modifications, transcription factor binding, chromatin accessibility, and chromosome architecture. The nuclei isolation protocol enables translational examination of archived healthy and diseased brain specimens through utilization of existing medical biorepositories.
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- 2021
18. Author Correction: A monocyte gene expression signature in the early clinical course of Parkinson's disease.
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Schlachetzki, Johannes CM, Prots, Iryna, Tao, Jenhan, Chun, Hyun B, Saijo, Kaoru, Gosselin, David, Winner, Beate, Glass, Christopher K, and Winkler, Jürgen
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
19. Brain cell type–specific enhancer–promoter interactome maps and disease-risk association
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Nott, Alexi, Holtman, Inge R, Coufal, Nicole G, Schlachetzki, Johannes CM, Yu, Miao, Hu, Rong, Han, Claudia Z, Pena, Monique, Xiao, Jiayang, Wu, Yin, Keulen, Zahara, Pasillas, Martina P, O'Connor, Carolyn, Nickl, Christian K, Schafer, Simon T, Shen, Zeyang, Rissman, Robert A, Brewer, James B, Gosselin, David, Gonda, David D, Levy, Michael L, Rosenfeld, Michael G, McVicker, Graham, Gage, Fred H, Ren, Bing, and Glass, Christopher K
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Biological Sciences ,Genetics ,Brain Disorders ,Dementia ,Alzheimer's Disease ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Human Genome ,Stem Cell Research ,Acquired Cognitive Impairment ,Neurodegenerative ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adaptor Proteins ,Signal Transducing ,Alzheimer Disease ,Brain ,Cells ,Cultured ,Chromatin ,Enhancer Elements ,Genetic ,Gene Regulatory Networks ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Microglia ,Nuclear Proteins ,Promoter Regions ,Genetic ,Sequence Deletion ,Tumor Suppressor Proteins ,General Science & Technology - Abstract
Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function.
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- 2019
20. Liver-Derived Signals Sequentially Reprogram Myeloid Enhancers to Initiate and Maintain Kupffer Cell Identity
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Sakai, Mashito, Troutman, Ty D, Seidman, Jason S, Ouyang, Zhengyu, Spann, Nathanael J, Abe, Yohei, Ego, Kaori M, Bruni, Cassi M, Deng, Zihou, Schlachetzki, Johannes CM, Nott, Alexi, Bennett, Hunter, Chang, Jonathan, Vu, BaoChau T, Pasillas, Martina P, Link, Verena M, Texari, Lorane, Heinz, Sven, Thompson, Bonne M, McDonald, Jeffrey G, Geissmann, Frederic, and Glass, Christopher K
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Biomedical and Clinical Sciences ,Immunology ,Genetics ,Liver Disease ,Stem Cell Research ,Human Genome ,Digestive Diseases ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Animals ,Cell Differentiation ,Cells ,Cultured ,Cellular Microenvironment ,Cellular Reprogramming ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,Intracellular Signaling Peptides and Proteins ,Kupffer Cells ,Liver ,Liver X Receptors ,Macrophages ,Membrane Proteins ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Myeloid Cells ,Phenotype ,Signal Transduction ,Transforming Growth Factor beta - Abstract
Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-β) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.
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- 2019
21. Microbiome–microglia connections via the gut–brain axis
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Abdel-Haq, Reem, Schlachetzki, Johannes CM, Glass, Christopher K, and Mazmanian, Sarkis K
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Neurosciences ,Digestive Diseases ,Brain Disorders ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Animals ,Brain ,Gastrointestinal Microbiome ,Humans ,Intestines ,Microglia ,Neurodegenerative Diseases ,Neurodevelopmental Disorders ,Medical and Health Sciences ,Immunology - Abstract
Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest that the gut microbiome plays a pivotal role in regulating microglial maturation and function, and altered microbial community composition has been reported in neurological disorders with known microglial involvement in humans. Collectively, these findings suggest that bidirectional crosstalk between the gut and the brain may influence disease pathogenesis. Herein, we discuss recent studies showing a role for the gut microbiome in modulating microglial development and function in homeostatic and disease conditions and highlight possible future research to develop novel microbial treatments for disorders of the brain.
- Published
- 2019
22. Epigenomic landscape of the human dorsal root ganglion: sex differences and transcriptional regulation of nociceptive genes
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Franco-Enzástiga, Úrzula, primary, Inturi, Nikhil N, additional, Natarajan, Keerthana, additional, Mwirigi, Juliet M, additional, Mazhar, Khadijah, additional, Schlachetzki, Johannes CM, additional, Schumacher, Mark, additional, and Price, Theodore J, additional
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- 2024
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23. An environment-dependent transcriptional network specifies human microglia identity
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Gosselin, David, Skola, Dylan, Coufal, Nicole G, Holtman, Inge R, Schlachetzki, Johannes CM, Sajti, Eniko, Jaeger, Baptiste N, O'Connor, Carolyn, Fitzpatrick, Conor, Pasillas, Martina P, Pena, Monique, Adair, Amy, Gonda, David D, Levy, Michael L, Ransohoff, Richard M, Gage, Fred H, and Glass, Christopher K
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Neurodegenerative ,Biotechnology ,Neurosciences ,2.1 Biological and endogenous factors ,Underpinning research ,Aetiology ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Brain Neoplasms ,Cells ,Cultured ,Environment ,Epilepsy ,Female ,Gene Expression Profiling ,Gene Expression Regulation ,Gene Regulatory Networks ,Humans ,Male ,Mice ,Mice ,Inbred C57BL ,Microglia ,General Science & Technology - Abstract
Microglia play essential roles in central nervous system (CNS) homeostasis and influence diverse aspects of neuronal function. However, the transcriptional mechanisms that specify human microglia phenotypes are largely unknown. We examined the transcriptomes and epigenetic landscapes of human microglia isolated from surgically resected brain tissue ex vivo and after transition to an in vitro environment. Transfer to a tissue culture environment resulted in rapid and extensive down-regulation of microglia-specific genes that were induced in primitive mouse macrophages after migration into the fetal brain. Substantial subsets of these genes exhibited altered expression in neurodegenerative and behavioral diseases and were associated with noncoding risk variants. These findings reveal an environment-dependent transcriptional network specifying microglia-specific programs of gene expression and facilitate efforts to understand the roles of microglia in human brain diseases.
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- 2017
24. Frontotemporal dementia and its subtypes: a genome-wide association study
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Ferrari, Raffaele, Hernandez, Dena G, Nalls, Michael A, Rohrer, Jonathan D, Ramasamy, Adaikalavan, Kwok, John BJ, Dobson-Stone, Carol, Brooks, William S, Schofield, Peter R, Halliday, Glenda M, Hodges, John R, Piguet, Olivier, Bartley, Lauren, Thompson, Elizabeth, Haan, Eric, Hernández, Isabel, Ruiz, Agustín, Boada, Mercè, Borroni, Barbara, Padovani, Alessandro, Cruchaga, Carlos, Cairns, Nigel J, Benussi, Luisa, Binetti, Giuliano, Ghidoni, Roberta, Forloni, Gianluigi, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Scarpini, Elio, Clarimón, Jordi, Lleó, Alberto, Blesa, Rafael, Waldö, Maria Landqvist, Nilsson, Karin, Nilsson, Christer, Mackenzie, Ian RA, Hsiung, Ging-Yuek R, Mann, David MA, Grafman, Jordan, Morris, Christopher M, Attems, Johannes, Griffiths, Timothy D, McKeith, Ian G, Thomas, Alan J, Pietrini, P, Huey, Edward D, Wassermann, Eric M, Baborie, Atik, Jaros, Evelyn, Tierney, Michael C, Pastor, Pau, Razquin, Cristina, Ortega-Cubero, Sara, Alonso, Elena, Perneczky, Robert, Diehl-Schmid, Janine, Alexopoulos, Panagiotis, Kurz, Alexander, Rainero, Innocenzo, Rubino, Elisa, Pinessi, Lorenzo, Rogaeva, Ekaterina, St George-Hyslop, Peter, Rossi, Giacomina, Tagliavini, Fabrizio, Giaccone, Giorgio, Rowe, James B, Schlachetzki, Johannes CM, Uphill, James, Collinge, John, Mead, Simon, Danek, Adrian, Van Deerlin, Vivianna M, Grossman, Murray, Trojanowski, John Q, van der Zee, Julie, Deschamps, William, Van Langenhove, Tim, Cruts, Marc, Van Broeckhoven, Christine, Cappa, Stefano F, Le Ber, Isabelle, Hannequin, Didier, Golfier, Véronique, Vercelletto, Martine, Brice, Alexis, Nacmias, Benedetta, Sorbi, Sandro, Bagnoli, Silvia, Piaceri, Irene, Nielsen, Jørgen E, Hjermind, Lena E, Riemenschneider, Matthias, Mayhaus, Manuel, Ibach, Bernd, Gasparoni, Gilles, Pichler, Sabrina, Gu, Wei, and Rossor, Martin N
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Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Brain Disorders ,Alzheimer's Disease Related Dementias (ADRD) ,Genetics ,Neurodegenerative ,Dementia ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Aging ,Human Genome ,Clinical Research ,Rare Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Aged ,Aged ,80 and over ,Female ,Frontotemporal Dementia ,Genome-Wide Association Study ,Genotype ,Humans ,Male ,Middle Aged ,Neurology & Neurosurgery ,Clinical sciences - Abstract
BackgroundFrontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72--have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.MethodsWe did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p
- Published
- 2014
25. Correction: A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
- Author
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Abdel-Haq, Reem, primary, Schlachetzki, Johannes CM, additional, Boktor, Joseph C, additional, Cantu-Jungles, Thaisa M, additional, Thron, Taren, additional, Zhang, Mengying, additional, Bostick, John W, additional, Khazaei, Tahmineh, additional, Chilakala, Sujatha, additional, Morais, Livia H, additional, Humphrey, Greg, additional, Keshavarzian, Ali, additional, Katz, Jonathan E, additional, Thomson, Matthew, additional, Knight, Rob, additional, Gradinaru, Viviana, additional, Hamaker, Bruce R, additional, Glass, Christopher K, additional, and Mazmanian, Sarkis K, additional
- Published
- 2023
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26. Complete genome sequence of Syntrophobacter fumaroxidans strain (MPOB(T)).
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Plugge, Caroline M, Henstra, Anne M, Worm, Petra, Swarts, Daan C, Paulitsch-Fuchs, Astrid H, Scholten, Johannes CM, Lykidis, Athanasios, Lapidus, Alla L, Goltsman, Eugene, Kim, Edwin, McDonald, Erin, Rohlin, Lars, Crable, Bryan R, Gunsalus, Robert P, Stams, Alfons JM, and McInerney, Michael J
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Anaerobic ,Gram-negative ,Methanospirillum hungatei ,Syntrophobacter fumaroxidans ,Syntrophobacteraceae ,host-defense systems ,mesophile ,propionate conversion ,sulfate reducer ,syntrophy ,Biochemistry and Cell Biology ,Genetics - Abstract
Syntrophobacter fumaroxidans strain MPOB(T) is the best-studied species of the genus Syntrophobacter. The species is of interest because of its anaerobic syntrophic lifestyle, its involvement in the conversion of propionate to acetate, H2 and CO2 during the overall degradation of organic matter, and its release of products that serve as substrates for other microorganisms. The strain is able to ferment fumarate in pure culture to CO2 and succinate, and is also able to grow as a sulfate reducer with propionate as an electron donor. This is the first complete genome sequence of a member of the genus Syntrophobacter and a member genus in the family Syntrophobacteraceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,990,251 bp long genome with its 4,098 protein-coding and 81 RNA genes is a part of the Microbial Genome Program (MGP) and the Genomes to Life (GTL) Program project.
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- 2012
27. Paradoxical kinesia in Parkinson's disease revisited: Anticipation of temporal constraints is critical
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Distler, Michael, Schlachetzki, Johannes CM, Kohl, Zacharias, Winkler, Jürgen, and Schenk, Thomas
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- 2016
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28. A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
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Abdel-Haq, Reem, primary, Schlachetzki, Johannes CM, additional, Boktor, Joseph C, additional, Cantu-Jungles, Thaisa M, additional, Thron, Taren, additional, Zhang, Mengying, additional, Bostick, John W, additional, Khazaei, Tahmineh, additional, Chilakala, Sujatha, additional, Morais, Livia H, additional, Humphrey, Greg, additional, Keshavarzian, Ali, additional, Katz, Jonathan E, additional, Thomson, Matthew, additional, Knight, Rob, additional, Gradinaru, Viviana, additional, Hamaker, Bruce R, additional, Glass, Christopher K, additional, and Mazmanian, Sarkis K, additional
- Published
- 2022
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- View/download PDF
29. Author response: A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
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Reem Abdel-Haq, Johannes CM Schlachetzki, Joseph C Boktor, Thaisa M Cantu-Jungles, Taren Thron, Mengying Zhang, John W Bostick, Tahmineh Khazaei, Sujatha Chilakala, Livia H Morais, Greg Humphrey, Ali Keshavarzian, Jonathan E Katz, Matthew Thomson, Rob Knight, Viviana Gradinaru, Bruce R Hamaker, Christopher K Glass, and Sarkis K Mazmanian
- Published
- 2022
30. Author response: A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
- Author
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Abdel-Haq, Reem, primary, Schlachetzki, Johannes CM, additional, Boktor, Joseph C, additional, Cantu-Jungles, Thaisa M, additional, Thron, Taren, additional, Zhang, Mengying, additional, Bostick, John W, additional, Khazaei, Tahmineh, additional, Chilakala, Sujatha, additional, Morais, Livia H, additional, Humphrey, Greg, additional, Keshavarzian, Ali, additional, Katz, Jonathan E, additional, Thomson, Matthew, additional, Knight, Rob, additional, Gradinaru, Viviana, additional, Hamaker, Bruce R, additional, Glass, Christopher K, additional, and Mazmanian, Sarkis K, additional
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- 2022
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31. Cell type‐specific enhancer‐promoter connectivity maps in the human brain and associations with Alzheimer’s disease risk
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Nott, Alexi, primary, Holtman, Inge, additional, Coufal, Nicole, additional, Schlachetzki, Johannes CM, additional, Yu, Miao, additional, Rissman, Robert A, additional, Brewer, James B, additional, Ren, Bing, additional, Gage, Fred H, additional, and Glass, Christopher K, additional
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- 2020
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32. Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
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de Oliveira Antonio CP, Candelario-Jalil Eduardo, Langbein Julia, Wendeburg Lena, Bhatia Harsharan S, Schlachetzki Johannes CM, Biber Knut, and Fiebich Bernd L
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microglia ,phosphatidylinositol 3-kinase ,mammalian target of rapamycin ,glycogen synthase kinase-3 ,Akt ,prostaglandins ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E2 and PGD2. Findings We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE2 and PGD2 without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE2 and PGD2. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE2 and PGD2 levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE2 in non-stimulated microglia. Conclusion Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.
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- 2012
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33. Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia
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Candelario-Jalil Eduardo, de Oliveira Antonio CP, Haake Elisabeth, Fiebich Bernd L, Schlachetzki Johannes CM, Heneka Michael T, and Hüll Michael
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Recent studies suggest an important role for neurotransmitters as modulators of inflammation. Neuroinflammatory mediators such as cytokines and molecules of the arachidonic acid pathway are generated and released by microglia. The monoamine norepinephrine reduces the production of cytokines by activated microglia in vitro. However, little is known about the effects of norepinephrine on prostanoid synthesis. In the present study, we investigate the role of norepinephrine on cyclooxygenase- (COX-)2 expression/synthesis and prostaglandin (PG)E2 production in rat primary microglia. Results Interestingly, norepinephrine increased COX-2 mRNA, but not protein expression. Norepinephrine strongly enhanced COX-2 expression and PGE2 production induced by lipopolysaccharide (LPS). This effect is likely to be mediated by β-adrenoreceptors, since β-, but not α-adrenoreceptor agonists produced similar results. Furthermore, β-adrenoreceptor antagonists blocked the enhancement of COX-2 levels induced by norepinephrine and β-adrenoreceptor agonists. Conclusions Considering that PGE2 displays different roles in neuroinflammatory and neurodegenerative disorders, norepinephrine may play an important function in the modulation of these processes in pathophysiological conditions.
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- 2010
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34. A Reversible Region-Specific Innate Immune Fingerprint in the Brain Induced by Chronic Peripheral Inflammation
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Süß, Patrick, primary, Hoffmann, Alana, additional, Rothe, Tobias, additional, Baum, Wolfgang, additional, Staszewski, Ori, additional, Schett, Georg, additional, Prinz, Marco, additional, Krönke, Gerhard, additional, Glass, Christopher K., additional, Winkler, Jürgen, additional, and Schlachetzki, Johannes CM, additional
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- 2018
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35. Varicella zoster virus cerebellitis in a 66-year-old patient without herpes zoster
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Ratzka, Peter, Schlachetzki, Johannes CM, Bahr, Mathias, and Nau, Roland
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- 2006
36. Posttranslational modification and mutation of histidine 50 trigger alpha synuclein aggregation and toxicity
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Wei, Xiang, Stefanie, Menges, Johannes Cm, Schlachetzki, Holger, Meixner, Anna-Carin, Hoffmann, Ursula, Schlötzer-Schrehardt, Cord-Michael, Becker, Jürgen, Winkler, and Jochen, Klucken
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Neurons ,Cell Death ,4-hydroxy-2-nonenal ,Parkinson Disease ,Histidine 50 ,Protein Aggregates ,Mutation ,H50Q mutation ,alpha-Synuclein ,Parkinson’s disease ,Humans ,Alpha synuclein ,Histidine ,Posttranslational modification ,Protein Processing, Post-Translational ,Cells, Cultured ,Research Article - Abstract
Background Aggregation and aggregation-mediated formation of toxic alpha synuclein (aSyn) species have been linked to the pathogenesis of sporadic and monogenic Parkinson’s disease (PD). A novel H50Q mutation of aSyn, resulting in the substitution of histidine by glutamine, has recently been identified in PD patients. We have previously shown that the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) induces the formation of HNE-aSyn adducts, thereby promoting aSyn oligomerization and increasing its extracellular toxicity to human dopaminergic neurons. Intriguingly, we identified histidine 50 (H50) of aSyn as one of the HNE modification target residues. These converging lines of evidence support the hypothesis that changes in H50 via posttranslational modification (PTM) and mutation trigger the formation of aggregated, toxic aSyn species, which interfere with cellular homeostasis. In the present study, we aim to elucidate 1) the role of H50 in HNE-mediated aSyn aggregation and toxicity, and 2) the impact of H50 mutation on aSyn pathology. Besides the PD-related H50Q, we analyze a PD-unrelated control mutation, in which H50 is replaced by an arginine residue (H50R). Results Analysis of HNE-treated aSyn revealed that H50 is the most susceptible residue of aSyn to HNE modification and is crucial for HNE-mediated aSyn oligomerization. Overexpression of aSyn with substituted H50 in H4 neuroglioma cells reduced HNE-induced cell damage, indicating a pivotal role of H50 in HNE modification-induced aSyn toxicity. Furthermore, we showed in vitro that H50Q/R mutations substantially increase the formation of high density and fibrillar aSyn species, and potentiate the oligomerization propensity of aSyn in the presence of a nitrating agent. Cell-based experiments also revealed that overexpression of H50Q aSyn in H4 cells promotes aSyn oligomerization. Importantly, overexpression of both H50Q/R aSyn mutants in H4 cells significantly increased cell death when compared to wild type aSyn. This increase in cell death was further exacerbated by the application of H2O2. Conclusion A dual approach addressing alterations of H50 showed that either H50 PTM or mutation trigger aSyn aggregation and toxicity, suggesting an important role of aSyn H50 in the pathogenesis of both sporadic and monogenic PD. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0004-0) contains supplementary material, which is available to authorized users.
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- 2014
37. Purification of baculovirus vectors using heparin affinity chromatography
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Nasimuzzaman, Md, primary, Lynn, Danielle, additional, van der Loo, Johannes CM, additional, and Malik, Punam, additional
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- 2016
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38. Pharmacological inhibition of Akt and downstream pathways modulates the expression of COX-2 and mPGES-1 in activated microglia
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de Oliveira, Antonio CP, Candelario-Jalil, Eduardo, Langbein, Julia, Wendeburg, Lena, Bhatia, Harsharan S, Schlachetzki, Johannes CM, Biber, Knut, and Fiebich, Bernd L
- Subjects
phosphatidylinositol 3-kinase ,Medizinische Fakultät -ohne weitere Spezifikation ,Immunology ,Short Report ,microglia ,lcsh:RC346-429 ,prostaglandins ,Cellular and Molecular Neuroscience ,Polysaccharides ,Animals ,ddc:610 ,Enzyme Inhibitors ,Rats, Wistar ,lcsh:Neurology. Diseases of the nervous system ,Cells, Cultured ,Prostaglandin-E Synthases ,mammalian target of rapamycin ,glycogen synthase kinase-3 ,Cerebral Cortex ,TOR Serine-Threonine Kinases ,Akt ,Rats ,Intramolecular Oxidoreductases ,Oncogene Protein v-akt ,Neurology ,Animals, Newborn ,Gene Expression Regulation ,Cyclooxygenase 2 ,lipids (amino acids, peptides, and proteins) ,Signal Transduction - Abstract
Background Microglia are considered a major target for modulating neuroinflammatory and neurodegenerative disease processes. Upon activation, microglia secrete inflammatory mediators that contribute to the resolution or to further enhancement of damage in the central nervous system (CNS). Therefore, it is important to study the intracellular pathways that are involved in the expression of the inflammatory mediators. Particularly, the role of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and glycogen synthase kinase-3 (GSK-3) pathways in activated microglia is unclear. Thus, in the present study we investigated the role of Akt and its downstream pathways, GSK-3 and mTOR, in lipopolysaccharide (LPS)-activated primary rat microglia by pharmacological inhibition of these pathways in regard to the expression of cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1 (mPGES-1) and to the production of prostaglandin (PG) E2 and PGD2. Findings We show that inhibition of Akt by the Akt inhibitor X enhanced the production of PGE2 and PGD2 without affecting the expression of COX-2, mPGES-1, mPGES-2 and cytosolic prostaglandin E synthase (cPGES). Moreover, inhibition of GSK-3 reduced the expression of both COX-2 and mPGES-1. In contrast, the mTOR inhibitor rapamycin enhanced both COX-2 and mPGES-1 immunoreactivity and the release of PGE2 and PGD2. Interestingly, NVP-BEZ235, a dual PI3K/mTOR inhibitor, enhanced COX-2 and reduced mPGES-1 immunoreactivity, albeit PGE2 and PGD2 levels were enhanced in LPS-stimulated microglia. However, this compound also increased PGE2 in non-stimulated microglia. Conclusion Taken together, we demonstrate that blockade of mTOR and/or PI3K/Akt enhances prostanoid production and that PI3K/Akt, GSK-3 and mTOR differently regulate the expression of mPGES-1 and COX-2 in activated primary microglia. Therefore, these pathways are potential targets for the development of novel strategies to modulate neuroinflammation.
- Published
- 2012
39. Cytoreductive surgery followed by chemotherapy versus chemotherapy alone for recurrent platinum-sensitive epithelial ovarian cancer (SOCceR trial): a multicenter randomised controlled study
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van de Laar, Rafli, primary, Zusterzeel, Petra LM, additional, Van Gorp, Toon, additional, Buist, Marrije R, additional, van Driel, Willemien J, additional, Gaarenstroom, Katja N, additional, Arts, Henriette JG, additional, van Huisseling, Johannes CM, additional, Hermans, Ralph HM, additional, Pijnenborg, Johanna MA, additional, Schutter, Eltjo MJ, additional, Pelikan, Harold MP, additional, Vollebergh, Jos HA, additional, Engelen, Mirjam JA, additional, IntHout, Joanna, additional, Kruitwagen, Roy FPM, additional, and Massuger, Leon FAG, additional
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- 2014
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40. Norepinephrine enhances the LPS-induced expression of COX-2 and secretion of PGE2 in primary rat microglia
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Schlachetzki, Johannes CM, primary, Fiebich, Bernd L, additional, Haake, Elisabeth, additional, de Oliveira, Antonio CP, additional, Candelario-Jalil, Eduardo, additional, Heneka, Michael T, additional, and Hüll, Michael, additional
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- 2010
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41. Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy
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Frank, Tobias, primary, Schlachetzki, Johannes CM, additional, Göricke, Bettina, additional, Meuer, Katrin, additional, Rohde, Gundula, additional, Dietz, Gunnar PH, additional, Bähr, Mathias, additional, Schneider, Armin, additional, and Weishaupt, Jochen H, additional
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- 2009
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42. Stable Multilineage Hematopoietic Chimerism in α-Thalassemic Mice Induced by a Bone Marrow Subpopulation That Excludes the Majority of Day-12 Spleen Colony-Forming Units
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van der Loo, Johannes CM., van den Bos, Cor, Baert, Miranda R.M., Wagemaker, Gerard, and Ploemacher, Rob E.
- Abstract
We have investigated the contribution of highly purified day-12 spleen colony-forming units (CFU-S-12) as well as more primitive cells to sustained blood cell production using in vivo and in vitro assays that allow frequency analysis. Normal or day-6 post-5-fluorouracil light-density bone marrow (BM) was sorted on the basis of differences in rhodamine-123 (Rh123) retention or wheat germ agglutinin (WGA) affinity and tested in vivo using a recently developed α-thalassemic chimeric mouse model. In addition, short-term and long-term clonal activity was assessed in vitro using a limiting dilution-type long-term BM culture, the cobblestone area forming cell assay. When sublethally irradiated α-thalassemic mice were transplanted with as many as 281 purified WGAbrightCFU-S-12, derived from a fraction containing 95% of all CFU-S-12 from day-6 post-5-fluorouracil light-density BM of wild-type mice, detectable chimerism was not observed at 6 months posttransplantation. In contrast, only three CFU-S-12 were included in the Rh123dulland WGAdimsubpopulations that induced 29% to 58% and 21% to 31% stable multilineage donor-type chimerism of erythrocytes and leukocytes, respectively. The Rh123dulland WGAdimcells were up to 240-fold enriched for long-term repopulating ability (LTRA) as compared with unseparated BM. A comparable level of chimerism was found in the different hematopoietic organs and at the level of BM CFU-S-12. The frequency of the LTRA unit capable of inducing a 10% sustained level of donor-type erythrocytes was calculated to be 1 to 2 per 105BM cells. Several reports have suggested that LTRA and spleen colony formation could be capacities of the same stem cell subset. However, the present results show that the majority of CFU-S-12 have only short-term repopulating ability and are physically separable from more primitive stem cells with long-term multilineage reconstituting capacities.
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- 1994
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43. Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy
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Dietz Gunnar PH, Rohde Gundula, Meuer Katrin, Göricke Bettina, Schlachetzki Johannes CM, Frank Tobias, Bähr Mathias, Schneider Armin, and Weishaupt Jochen H
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules. Results We found that the G-CSF receptor is robustly expressed by RGCs in vivo and in vitro. We thus evaluated G-CSF as a neuroprotectant for RGCs and found a dose-dependent neuroprotective effect of G-CSF on axotomized RGCs when given subcutaneously. As stem stell mobilization had previously been discussed as a possible contributor to the neuroprotective effects of G-CSF, we compared the local treatment of RGCs by injection of G-CSF into the vitreous body with systemic delivery by subcutaneous application. Both routes of application reduced retinal ganglion cell death to a comparable extent. Moreover, G-CSF enhanced the survival of immunopurified RGCs in vitro. Conclusion We thus show that G-CSF neuroprotection is at least partially independent of potential systemic effects and provide further evidence that the clinically applicable G-CSF could become a treatment option for both neurodegenerative diseases and glaucoma.
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- 2009
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44. New Therapies in Veterinary Oncology.
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Mullin C, Clifford CA, and Johannes CM
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- Humans, Animals, Dogs, Medical Oncology, Neoplasms therapy, Neoplasms veterinary, Dog Diseases therapy
- Abstract
The expanding number of specialized oncology therapeutics available in veterinary oncology can make staying updated on the most recent advances challenging. This article summarizes the mechanism of action, available supporting data, and clinical use of three key veterinary cancer/supportive care therapeutics: Laverdia-CA1, Canalevia-CA1, and Stelfonta. This information will help guide clinical use within your practice and can be incorporated into discussions with clients regarding the newest available options for their dogs with cancer., Competing Interests: Disclosure C. Mullin: No disclosures to report. C.A. Clifford: Speaker, advisory board member and consultant with Jaguar Animal Health and Anivive. C.M. Johannes: Speaker, advisory board member and consultant with QBiotics Group; advisory board member with Jaguar Animal Health., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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45. Retrospective evaluation of toceranib phosphate (Palladia) use in the treatment of feline pancreatic carcinoma.
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Rosario CO, Musser ML, Yuan L, Mochel JP, Talbott J, Johannes CM, and Berger EP
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- Humans, Cats, Animals, Retrospective Studies, Indoles therapeutic use, Pancreatic Neoplasms, Antineoplastic Agents therapeutic use, Cat Diseases drug therapy
- Abstract
Objective: To retrospectively assess the biological response in cats with pancreatic carcinoma treated with toceranib phosphate., Animals: Twenty-six client-owned cats., Procedure: Patient information from multiple institutions was solicited via an emailed REDCap survey. For inclusion, cats were required to have a confirmed diagnosis of exocrine pancreatic carcinoma either by histopathology, cytology, or both; to have received treatment with toceranib phosphate; and to have adequate follow-up data for analysis., Results: Twenty cats were treated for gross disease and 6 for microscopic disease/incomplete margins. Clinical benefit (complete response, partial response, or stable disease ≥ 10 wk) was observed in 9/20 cats treated in the gross disease setting (45%; complete response: n = 1, stable disease: n = 8). The remaining 11 cats with gross disease did not respond to toceranib phosphate. In the cats with microscopic disease, response was mixed. The median survival time for all cats was 97 d (range: 1 to 1666 d)., Conclusion: Toceranib phosphate was well-tolerated and provided modest clinical benefit to a subset of cats treated., Clinical Relevance: Although feline exocrine pancreatic carcinoma continues to be a challenging disease to treat, toceranib phosphate appeared to provide potential clinical benefit., (Copyright and/or publishing rights held by the Canadian Veterinary Medical Association.)
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- 2023
46. APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.
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Haney MS, Pálovics R, Munson CN, Long C, Johansson P, Yip O, Dong W, Rawat E, West E, Schlachetzki JC, Tsai A, Guldner IH, Lamichhane BS, Smith A, Schaum N, Calcuttawala K, Shin A, Wang YH, Wang C, Koutsodendris N, Serrano GE, Beach TG, Reiman EM, Glass CK, Abu-Remaileh M, Enejder A, Huang Y, and Wyss-Coray T
- Abstract
Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD., Competing Interests: Competing financial interests T.G.B. is a paid consultant to Aprinoia Therapeutics and Biogen. E.M.R. is a scientific advisor to Alzheon, Aural Analytics, Denali, Retromer Therapeutics, and Vaxxinity and a co-founder and advisor to ALZPath. The other authors declare no competing financial interests.
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- 2023
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47. Pilot safety evaluation of doxorubicin chemotherapy combined with non-specific immunotherapy (Immunocidin®) for canine splenic hemangiosarcoma.
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Musser ML, Coto GM, Lingnan Y, Mochel JP, and Johannes CM
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- Animals, Dogs, Doxorubicin adverse effects, Immunotherapy, Prospective Studies, Dog Diseases drug therapy, Hemangiosarcoma drug therapy, Hemangiosarcoma veterinary, Splenic Neoplasms veterinary
- Abstract
Canine splenic hemangiosarcoma (HSA) is an aggressive tumor with a short overall survival time (OST) despite treatment with splenectomy and adjuvant doxorubicin. Modulation of the immune system has been shown to be effective for a variety of human tumors, and may be effective for canine tumors, including HSA. Immunocidin® is a non-specific immunotherapy based on a mycobacterial cell wall fraction. Preliminary work suggests Immunocidin® is safe to give intravenously (IV) in tumor-bearing dogs. This work aimed to evaluate the safety of doxorubicin and Immunocidin® combination in dogs with naturally occurring splenic HSA. A secondary aim of this study was to collect preliminary efficacy data to support a subsequent comprehensive, prospective clinical trial in canine patients with HSA, if the combination of doxorubicin and Immunocidin® was found to be safe. Eighteen dogs with stage II-III splenic HSA were recruited to receive 5 doses of sequential IV doxorubicin and Immunocidin® at two-week intervals following splenectomy. Adverse events (AEs) were graded according to the Veterinary Cooperative Oncology Group v1.1 (VCOG) scheme. Overall survival time was calculated from the date of splenectomy to date of death or loss to follow-up. AEs during administration were infrequent, the most common being hypertension. One patient developed limb and facial twitching and was removed from the study. After infusion, common AEs included lethargy, hyporexia, and diarrhea. One patient developed VCOG grade 5 diarrhea, thrombocytopenia, and anemia. Modifications in the treatment regimen were made to prevent these signs in subsequent patients. The median OST in dogs treated with the combination therapy was estimated at 147 days (range: 39-668 days). Although generally safe, the combination of doxorubicin and Immunocidin® appeared to cause more gastrointestinal effects than doxorubicin alone, and no apparent improvement in OST was noted in this population of dogs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Musser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2022
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48. Can veterinary medicine improve diversity in post-graduate training programs? Current state of academic veterinary medicine and recommendations on best practices.
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Chun R, Davis E, Frank N, Green HW, Greenhill L, Jandrey KE, Johannes CM, Levine J, Marks SL, Polisetti S, Rogers KS, and Sanchez LC
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- United States, Animals, Humans, Workforce, Health Personnel, Cultural Diversity, Education, Veterinary
- Abstract
The American Association of Veterinary Clinicians (AAVC) convened a Diversity, Equity, and Inclusivity working group in March 2021 to address the limited diversity (including but not limited to ethnic, racial, and cultural diversity) in clinical post-DVM graduate training programs and academic faculty. Concurrent with a working group formation, the AAVC developed a strategic plan. The central mission of the AAVC is to develop, support, and connect academic leaders to fuel the future of the veterinary medical profession. House officers and their training programs are central to all goals outlined in the strategic plan. Amongst other strategic goals, the working group identified best practices for intern and resident recruitment and selection. We report herein from the current health profession literature ways to identify and recruit talented, diverse candidates especially those with non-traditional (atypical) preparation and experience. We also provide recommendations on best practices for intern and resident selection. This document highlights holistic approaches, some of which are incrementally being incorporated into the Veterinary Intern Resident Matching Program application, that emphasize diversity as a selection criteria for intern and resident selection an important step towards building a more resilient and inclusive workforce. These include expanding candidate assessment beyond grades and class rank into a more standardized method for screening candidates that includes consideration of life experiences and talents outside of veterinary medicine.
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- 2022
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49. Randomised trial evaluating chemotherapy alone or chemotherapy and a novel monoclonal antibody for canine T-cell lymphoma: A multicentre US study.
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Musser ML, Clifford CA, Bergman PJ, Treml LS, McAnulty LCC, McNiel EA, and Johannes CM
- Abstract
Background: Canine peripheral nodal T-cell lymphoma is considered chemotherapy resistant and carries a relatively poor prognosis. Prospective evaluations reporting the impact of chemotherapy on progression-free survival (PFS) and overall survival time for dogs with T-cell lymphoma are lacking. This study examined the impact of L-CHOP (L-asparaginase, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy or L-CHOP in combination with AT-005, a US Department of Agriculture-licensed caninised monoclonal antibody, on PFS and response rates in dogs with clinical intermediate- and high-grade peripheral nodal T-cell lymphoma., Methods: A prospective, randomised, placebo-controlled, investigator- and owner-blinded, multicentre study was completed. All dogs received a 19-week L-CHOP chemotherapy protocol with randomisation (1:1) into placebo or AT-005 groups. Response was evaluated via the Veterinary Cooperative Oncology Group criteria for canine lymphoma., Results: Forty-nine dogs were enrolled (25 received placebo and 24 received AT-005). Most demographic factors were similar between the two groups, with the exception that more dogs with stage IV and V disease were treated with AT-005 (34% vs. 8%; p = 0.03). Median PFS was 103 days (95% confidence interval [CI], 56-118) in the placebo group versus 64 days (95% CI, 36-118) in the AT-005 group. The overall response rate (ORR) for all dogs was 98% (48 of 49); complete response rate in the placebo group (64%) was not different from the AT-005 group (67%)., Conclusions: To the best of the authors' knowledge, this is the first prospective study to document that treatment with L-CHOP chemotherapy, with or without AT-005, may result in a high ORR, but relatively brief PFS in dogs with clinical intermediate- and high-grade T-cell lymphoma., Competing Interests: Chad Johannes, Laura Treml and Lydia Cook McAnulty are former employees of Aratana Therapeutics, Inc. and were employed by Aratana Therapeutics, Inc. during the study period. Elizabeth McNiel is a former employee of Elanco Animal Health. Chad Johannes, Craig Clifford and Philip Bergman are advisory board members for Elanco Animal Health and receive honoraria. Margaret Musser has not declared any conflicts of interest., (© 2022 The Authors. Veterinary Record Open published by John Wiley & Sons Ltd on behalf of British Veterinary Association.)
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- 2022
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50. Evaluation of coated platelets, a subset of highly procoagulant platelets, in healthy dogs and dogs with neoplasia.
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Makielski KM, Fox LE, Johannes CM, Rendahl AK, Schulte AJ, Kim JH, Husbands BD, Walz JZ, Henson MS, Modiano JF, and LeVine DN
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- Animals, Blood Platelets, Dogs, Fibrinogen, Platelet Activation, Thrombin, Dog Diseases, Neoplasms veterinary
- Abstract
Objective: To determine if dogs with neoplasia produce more coated platelets, a subpopulation of activated platelets generated by dual stimulation with thrombin and convulxin, a glycoprotein VI agonist, than healthy control dogs., Animals: Client-owned dogs diagnosed with lymphoma (n = 19) or solid tumors (14) and healthy control dogs (14)., Procedures: Platelets were stimulated ex vivo with thrombin and convulxin. Flow cytometry was used to quantify the percentage of coated platelets based on high levels of surface fibrinogen. To compare the percentage of coated platelets between the three groups, an ANOVA was performed followed by pairwise 95% confidence intervals (CI) adjusted for multiple comparisons using Tukey's method., Results: We observed a greater mean percentage of coated platelets in dogs with solid tumors, compared with healthy control dogs, by 10.9 percentage points (95% CI: -1.0, 22.8), and a mean percentage of coated platelets in dogs with lymphoma that was less than healthy control dogs by 0.3 percentage points (95% CI: -11.4, 10.8)., Clinical Relevance: This study provides the first data-based evidence that dogs with solid tumors may have a greater mean coated platelet percentage when compared with healthy control dogs, although there is overlap between groups. Further studies are needed investigating coated platelets in specific subsets of neoplasia and investigating additional mechanisms of hypercoagulability in dogs with neoplasia.
- Published
- 2022
- Full Text
- View/download PDF
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