146 results on '"Sachs N"'
Search Results
2. Participation of T helper cell-mediated negative regulation of coagulation in human arterial thrombosis
- Author
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Luo, J, additional, Langheinrich, T, additional, Radev, M, additional, Sachs, N, additional, Kempf, W, additional, Maegdefessel, L, additional, and Engelmann, B, additional
- Published
- 2023
- Full Text
- View/download PDF
3. The circular RNA Ataxia-telangiectasia mutated (cATM) regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms
- Author
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Fasolo, F., primary, Winski, G., additional, Li, Z., additional, Wu, Z., additional, Winter, H., additional, Glukha, N., additional, Roy, J., additional, Hultgren, R., additional, Pauli, J., additional, Busch, A., additional, Sachs, N., additional, Knappich, C., additional, Eckstein, H.H., additional, Boon, R.A., additional, Paloschi, V., additional, and Maegdefessel, L., additional
- Published
- 2022
- Full Text
- View/download PDF
4. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3 S,4 S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2 H-pyran-4-yl)-1,5-dihydro-4 H-pyrazolo[3,4- d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents
- Author
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Hutson, P.H., Finger, E.N., Magliaro, B.C., Smith, S.M., Converso, A., Sanderson, P.E., Mullins, D., Hyde, L.A., Eschle, B.K., Turnbull, Z., Sloan, H., Guzzi, M., Zhang, X., Wang, A., Rindgen, D., Mazzola, R., Vivian, J.A., Eddins, D., Uslaner, J.M., Bednar, R., Gambone, C., Le-Mair, W., Marino, M.J., Sachs, N., Xu, G., and Parmentier-Batteur, S.
- Published
- 2011
- Full Text
- View/download PDF
5. Targeting miR29b in a Porcine Model of Aortic Aneurysm Disease: A Novel Endovascular Treatment Option
- Author
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Hanft, K., Metschl, S., Winter, H., Pauli, J., Sachs, N., Boon, R., Dimmeler, S., Knappich, C., Busch, A., and Mägdefessel, L.
- Published
- 2024
- Full Text
- View/download PDF
6. A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder
- Author
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Sachs, N A, Sawa, A, Holmes, S E, Ross, C A, DeLisi, L E, and Margolis, R L
- Published
- 2005
- Full Text
- View/download PDF
7. In Vitro Motion of the Proximal Sesamoid Bones under Physiological Midstance Loads
- Author
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SK, Shaffer, additional, Sachs, N, additional, TC, Garcia, additional, and SM, Stover, additional
- Published
- 2020
- Full Text
- View/download PDF
8. BRCA-deficient mouse mammary tumour organoids as a rapid tool to study anti-cancer drug resistance
- Author
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Rottenberg, S., primary, Duarte, A., additional, Duarte, E., additional, Francica, P., additional, Mutlu, M., additional, Blatter, S., additional, Sachs, N., additional, Clevers, H., additional, and Jonkers, J., additional
- Published
- 2019
- Full Text
- View/download PDF
9. T-02-09: Participation of T helper cell-mediated negative regulation of coagulation in human arterial thrombosis.
- Author
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Luo, J., Langheinrich, T., Radev, M., Sachs, N., Kempf, W., Maegdefessel, L., and Engelmann, B.
- Published
- 2023
- Full Text
- View/download PDF
10. Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome
- Author
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Nicolaou, N., Margadant, C., Kevelam, S.H., Lilien, M.R., Oosterveld, M.J., Kreft, M., Eerde, A.M. van, Pfundt, R., Terhal, P.A., Van der Zwaag, B., Nikkels, P.G., Sachs, N., Goldschmeding, R., Knoers, N.V.A.M., Renkema, K.Y., Sonnenberg, A., Nicolaou, N., Margadant, C., Kevelam, S.H., Lilien, M.R., Oosterveld, M.J., Kreft, M., Eerde, A.M. van, Pfundt, R., Terhal, P.A., Van der Zwaag, B., Nikkels, P.G., Sachs, N., Goldschmeding, R., Knoers, N.V.A.M., Renkema, K.Y., and Sonnenberg, A.
- Abstract
Contains fulltext : 107969.pdf (publisher's version ) (Open Access), Integrins are transmembrane alphabeta glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin alpha3beta1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, alpha3beta1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin alpha3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the alpha3 precursor prevented its heterodimerization with beta1, whereas CD151 association with the alpha3 subunit occurred normally. Consequently, the beta1 precursor accumulated in the ER, and the mutant alpha3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional alpha3beta1, causing a fatal multiorgan disorder.
- Published
- 2012
11. On the biomechanics of stem cell niche formation in the gut--modelling growing organoids
- Author
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Buske, P., Przybilla, J., Loeffler, M., Sachs, N., Sato, T., Clevers, H., Galle, J., Buske, P., Przybilla, J., Loeffler, M., Sachs, N., Sato, T., Clevers, H., and Galle, J.
- Abstract
In vitro culture of intestinal tissue has been attempted for decades. Only recently did Sato et al. [Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) Nature 459, 262-265] succeed in establishing long-term intestinal culture, demonstrating that cells expressing the Lgr5 gene can give rise to organoids with crypt-like domains similar to those found in vivo. In these cultures, Paneth cells provide essential signals supporting stem cell function. We have recently developed an individual cell-based computational model of the intestinal tissue [Buske, P., Galle, J., Barker, N., Aust, G., Clevers, H. & Loeffler, M. (2011) PLoS Comput Biol 7, e1001045]. The model is capable of quantitatively reproducing a comprehensive set of experimental data on intestinal cell organization. Here, we present a significant extension of this model that allows simulation of intestinal organoid formation in silico. For this purpose, we introduce a flexible basal membrane that assigns a bending modulus to the organoid surface. This membrane may be re-organized by cells attached to it depending on their differentiation status. Accordingly, the morphology of the epithelium is self-organized. We hypothesize that local tissue curvature is a key regulatory factor in stem cell organization in the intestinal tissue by controlling Paneth cell specification. In simulation studies, our model closely resembles the spatio-temporal organization of intestinal organoids. According to our results, proliferation-induced shape fluctuations are sufficient to induce crypt-like domains, and spontaneous tissue curvature induced by Paneth cells can control cell number ratios. Thus, stem cell expansion in an organoid depends sensitively on its biomechanics. We suggest a number of experiments that will enable new insights into mechano-transduction in the intestine, and suggest model extensions in the field of gl, In vitro culture of intestinal tissue has been attempted for decades. Only recently did Sato et al. [Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) Nature 459, 262-265] succeed in establishing long-term intestinal culture, demonstrating that cells expressing the Lgr5 gene can give rise to organoids with crypt-like domains similar to those found in vivo. In these cultures, Paneth cells provide essential signals supporting stem cell function. We have recently developed an individual cell-based computational model of the intestinal tissue [Buske, P., Galle, J., Barker, N., Aust, G., Clevers, H. & Loeffler, M. (2011) PLoS Comput Biol 7, e1001045]. The model is capable of quantitatively reproducing a comprehensive set of experimental data on intestinal cell organization. Here, we present a significant extension of this model that allows simulation of intestinal organoid formation in silico. For this purpose, we introduce a flexible basal membrane that assigns a bending modulus to the organoid surface. This membrane may be re-organized by cells attached to it depending on their differentiation status. Accordingly, the morphology of the epithelium is self-organized. We hypothesize that local tissue curvature is a key regulatory factor in stem cell organization in the intestinal tissue by controlling Paneth cell specification. In simulation studies, our model closely resembles the spatio-temporal organization of intestinal organoids. According to our results, proliferation-induced shape fluctuations are sufficient to induce crypt-like domains, and spontaneous tissue curvature induced by Paneth cells can control cell number ratios. Thus, stem cell expansion in an organoid depends sensitively on its biomechanics. We suggest a number of experiments that will enable new insights into mechano-transduction in the intestine, and suggest model extensions in the field of gl
- Published
- 2012
12. Kidney failure in mice lacking the tetraspanin CD151.
- Author
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Sachs, N., Kreft, M., Bergh Weerman, M. van der, Beynon, A.J., Peters, T.A., Weening, J.J., Sonnenberg, A., Sachs, N., Kreft, M., Bergh Weerman, M. van der, Beynon, A.J., Peters, T.A., Weening, J.J., and Sonnenberg, A.
- Abstract
Contains fulltext : 50755.pdf (publisher's version ) (Open Access), The tetraspanin CD151 is a cell-surface molecule known for its strong lateral interaction with the laminin-binding integrin alpha3beta1. Patients with a nonsense mutation in CD151 display end-stage kidney failure associated with regional skin blistering and sensorineural deafness, and mice lacking the integrin alpha3 subunit die neonatally because of severe abnormalities in the lung and kidney epithelia. We report the generation of Cd151-null mice that recapitulate the renal pathology of human patients, i.e., with age they develop massive proteinuria caused by focal glomerulosclerosis, disorganization of the glomerular basement membrane, and tubular cystic dilation. However, neither skin integrity nor hearing ability are impaired in the Cd151-null mice. Furthermore, we generated podocyte-specific conditional knockout mice for the integrin alpha3 subunit that show renal defects similar to those in the Cd151 knockout mice. Our results support the hypothesis that CD151 plays a key role in strengthening alpha3beta1-mediated adhesion in podocytes.
- Published
- 2006
13. The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents
- Author
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Hutson, P.H., primary, Finger, E.N., additional, Magliaro, B.C., additional, Smith, S.M., additional, Converso, A., additional, Sanderson, P.E., additional, Mullins, D., additional, Hyde, L.A., additional, Eschle, B.K., additional, Turnbull, Z., additional, Sloan, H., additional, Guzzi, M., additional, Zhang, X., additional, Wang, A., additional, Rindgen, D., additional, Mazzola, R., additional, Vivian, J.A., additional, Eddins, D., additional, Uslaner, J.M., additional, Bednar, R., additional, Gambone, C., additional, Le-Mair, W., additional, Marino, M.J., additional, Sachs, N., additional, Xu, G., additional, and Parmentier-Batteur, S., additional
- Published
- 2011
- Full Text
- View/download PDF
14. Continuous movement decoding using a target-dependent model with EMG inputs
- Author
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Sachs, N. A., primary, Corbett, E. A., additional, Miller, L. E., additional, and Perreault, E. J., additional
- Published
- 2011
- Full Text
- View/download PDF
15. Dealing with noisy gaze information for a target-dependent neural decoder
- Author
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Corbett, E. A., primary, Sachs, N. A., additional, Kording, K. P., additional, and Perreault, E. J., additional
- Published
- 2011
- Full Text
- View/download PDF
16. The near triad and associated visual problems
- Author
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Emslie, R., primary, Sachs, N., additional, Claassens, A., additional, and Walters, I., additional
- Published
- 2007
- Full Text
- View/download PDF
17. Multimodal injectable sensors for neural prosthetic proprioception.
- Author
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Wei Tan, Sachs, N., Ruo Guo, Qiang Zou, Jasspreet Singh, and Loeb, G.E.
- Published
- 2005
- Full Text
- View/download PDF
18. RF-powered BIONs™ for stimulation and sensing.
- Author
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Loeb, G.E., Richmond, F.J.R., Singh, J., Peck, R.A., Tan, W., Zou, Q., and Sachs, N.
- Published
- 2004
- Full Text
- View/download PDF
19. 412. Baseline hypofrontality and divalproex response in bipolar disorders
- Author
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Ketter, T.A., primary, Wang, P.W., additional, Winsberg, M.E., additional, Sachs, N., additional, Tate, D.L., additional, Strong, C.M., additional, and Seagall, G.M., additional
- Published
- 2000
- Full Text
- View/download PDF
20. 276. Impaired facial fear recognition in manic but not euthymic bipolar patients
- Author
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Lembke, A., primary, Sachs, N., additional, Ekman, P., additional, and Ketter, T.A., additional
- Published
- 2000
- Full Text
- View/download PDF
21. Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder
- Author
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Winsberg, M. E., Sachs, N., Tate, D. L., Adalsteinsson, E., Spielman, D., and Ketter, T. A.
- Published
- 2000
- Full Text
- View/download PDF
22. Using ADPCM for Image Compression
- Author
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Sachs, N.
- Subjects
Image Encoding ,Data Compression ,Pulse Code Modulation ,Image Processing ,New Technique - Published
- 1984
23. Differential ergoline and ergopeptine binding to 5-hydroxytryptamine2A receptors: ergolines require an aromatic residue at position 340 for high affinity binding.
- Author
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Choudhary, M S, Sachs, N, Uluer, A, Glennon, R A, Westkaemper, R B, and Roth, B L
- Abstract
In this paper we show that a highly conserved aromatic residue, phenylalanine at the 340-position, is essential for ergoline binding to 5-hydroxytryptamine2A receptors. We hypothesized that F340 was essential for a specific aromatic-aromatic interaction (e.g., pi-pi or hydrophobic) between the phenyl moiety of F340 and the aromatic ring of the ergoline nucleus. To test this hypothesis, eight point mutations of adjacent (F340 and F339) and nonadjacent (F125) phenylanaines were made, using conservative (phenylalanine to tyrosine) and nonconservative (phenylalanine to leucine, alanine, or serine) substitutions. The binding affinities of all of the tested simple ergolines were greatly reduced by specific mutations of F340 in which aromatic-aromatic interactions (e.g., F340A and F340L) were abolished, but they were unaffected when the replacement residue was aromatic (e.g., F340Y). In contrast, the binding affinities of four ergopeptines (bromocryptine, ergocryptine, ergocornine, and ergotamine) were relatively unaffected by the F340L substitution. Neither ergoline nor ergopeptine affinities were consistently altered by F339 mutations. These results support the notion that aromatic-aromatic interactions (either pi-pi of hydrophobic) with F340 are essential for the binding of simple ergolines but not ergopeptines to 5-hydroxytryptamine2A receptors. Our findings support models of ergoline and ergopeptine binding to serotonin receptors that suggest that the nature of the substituent at the 8-position of the ergoline nucleus may give rise to different modes of binding for the two classes of agents, particularly with respect to the phenyl ring of F340.
- Published
- 1995
24. 5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation.
- Author
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Roth, B L, Palvimaki, E P, Berry, S, Khan, N, Sachs, N, Uluer, A, and Choudhary, M S
- Abstract
The connection between agonist-induced desensitization and down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors was examined in a clonal cell line that stably expresses the 5-HT2A receptor. Brief (2-hr) and prolonged (24-hr) exposure to the agonist quipazine or the agonist 4-iodo-(2,5-dimethoxy)- phenylisopropylamine (DOI) diminished 5-HT2A receptor-mediated phosphoinositide hydrolysis; no change in 5-HT2A receptor number or affinity was measured after 24 hr of exposure to DOI or quipazine. Immunohistochemical studies demonstrated that a 24-hr exposure to DOI did not alter surface 5-HT2A receptor immunoreactivity. Western blot analysis with G alpha q- and G alpha 11-selective antibodies indicate that a 24-hr agonist exposure did not alter the levels of phospholipase C-dependent G proteins. These results suggest that desensitization after prolonged DOI exposure can occur via a process independent of the levels of phospholipase C-coupled G proteins. Studies with a mutant 5-HT2A receptor (F340L) indicated that binding per se is not sufficient for desensitization. Down-regulation of the protein kinase C isozymes alpha and epsilon by overnight exposure to phorbol-12,13-dibutyrate attenuated the intermediate phase (i.e., after 2-6 hr of agonist exposure) of DOI- and quipazine-induced desensitization. These results indicate that the intermediate phase of DOI-induced desensitization is mediated by the alpha- and/or epsilon-protein kinase C isozymes but that neither is involved in the later phase (i.e., after 24 hr of agonist exposure) of desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
25. In Vitro Motion of the Proximal Sesamoid Bones under Physiological Midstance Loads
- Author
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SK, Shaffer, Sachs, N, TC, Garcia, and SM, Stover
- Published
- 2020
- Full Text
- View/download PDF
26. MT1-MMP collagenolytic activity is regulated through association with tetraspanin CD151 in primary endothelial cells
- Author
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Yañez-Mó M, Barreiro O, Gonzalo P, Batista A, Megías D, Genís L, Sachs N, Sala-Valdés M, Ma, Alonso, Mc, Montoya, Sonnenberg A, Ag, Arroyo, and Francisco Sánchez-Madrid
27. Digital Signal Processor: Receiver forTouch-Tone®; Service
- Author
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Boddie, J. R., primary, Sachs, N., additional, and Tow, J., additional
- Published
- 1981
- Full Text
- View/download PDF
28. RF-powered BIONs/spl trade/ for stimulation and sensing
- Author
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Loeb, G.E., primary, Richmond, F.J.R., additional, Singh, J., additional, Peck, R.A., additional, Tan, W., additional, Zou, Q., additional, and Sachs, N., additional
- Full Text
- View/download PDF
29. Religion and the Body
- Author
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Cave, David and Sachs Norris, Rebecca
- Subjects
Religion & science ,bic Book Industry Communication::H Humanities::HR Religion & beliefs::HRA Religion: general::HRAM Religious issues & debates::HRAM3 Religion & science - Abstract
This book reflects on the implications of neurobiology and the scientific worldview on aspects of religious experience, belief, and practice, focusing especially on the body and the construction of religious meaning. Readership: All those interested in neurobiology and religion, contemporary culture and religion, theology and embodiment, anthropology, sociology, and psychology of religion, including scholars, students, educated laymen, academic and public libraries.
- Published
- 2012
- Full Text
- View/download PDF
30. Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome.
- Author
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Nicolaou N, Margadant C, Kevelam SH, Lilien MR, Oosterveld MJ, Kreft M, van Eerde AM, Pfundt R, Terhal PA, van der Zwaag B, Nikkels PG, Sachs N, Goldschmeding R, Knoers NV, Renkema KY, Sonnenberg A, Nicolaou, Nayia, Margadant, Coert, Kevelam, Sietske H, and Lilien, Marc R
- Abstract
Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin α3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional α3β1, causing a fatal multiorgan disorder. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
31. 74. Decreased dorsolateral prefrontal n-acetyl aspartate in bipolar disorder
- Author
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Winsberg, M.E., Sachs, N., Tate, D.L., Dunai, M., Strong, C.M., Spielman, D.M., and Ketter, T.A.
- Published
- 1998
- Full Text
- View/download PDF
32. A garden at a crisis shelters for woman and children survivors of domestic violence: Danner's Garden, Copenhagen, Denmark
- Author
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Lygum, Victoria Linn, Stigsdotter, Ulrika K., Cooper Marcus, C., and Sachs, N. A.
- Published
- 2013
33. Myeloid cannabinoid CB1 receptor deletion confers atheroprotection in male mice by reducing macrophage proliferation in a sex-dependent manner.
- Author
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Wang Y, Li G, Chen B, Shakir G, Volz M, van der Vorst EPC, Maas SL, Geiger M, Jethwa C, Bartelt A, Li Z, Wettich J, Sachs N, Maegdefessel L, Nazari Jahantigh M, Hristov M, Lacy M, Lutz B, Weber C, Herzig S, Guillamat Prats R, and Steffens S
- Subjects
- Animals, Female, Humans, Male, Aortic Diseases genetics, Aortic Diseases pathology, Aortic Diseases prevention & control, Aortic Diseases metabolism, Aortic Diseases enzymology, Carotid Artery Diseases genetics, Carotid Artery Diseases pathology, Carotid Artery Diseases metabolism, Carotid Artery Diseases prevention & control, Estradiol pharmacology, Estrogen Receptor alpha metabolism, Estrogen Receptor alpha genetics, Estrogen Receptor alpha deficiency, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Sex Factors, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 deficiency, Atherosclerosis genetics, Atherosclerosis pathology, Atherosclerosis metabolism, Atherosclerosis prevention & control, Atherosclerosis enzymology, Cell Proliferation, Disease Models, Animal, Macrophages metabolism, Macrophages pathology, Plaque, Atherosclerotic, Receptor, Cannabinoid, CB1 metabolism, Receptor, Cannabinoid, CB1 genetics, Signal Transduction
- Abstract
Aims: Although the cannabinoid CB1 receptor has been implicated in atherosclerosis, its cell-specific effects in this disease are not well understood. To address this, we generated a transgenic mouse model to study the role of myeloid CB1 signalling in atherosclerosis., Methods and Results: Here, we report that male mice with myeloid-specific Cnr1 deficiency on atherogenic background developed smaller lesions and necrotic cores than controls, while only minor genotype differences were observed in females. Male Cnr1-deficient mice showed reduced arterial monocyte recruitment and macrophage proliferation with less inflammatory phenotype. The sex-specific differences in proliferation were dependent on oestrogen receptor (ER)α-oestradiol signalling. Kinase activity profiling identified a CB1-dependent regulation of p53 and cyclin-dependent kinases. Transcriptomic profiling further revealed chromatin modifications, mRNA processing, and mitochondrial respiration among the key processes affected by CB1 signalling, which was supported by metabolic flux assays. Chronic administration of the peripherally restricted CB1 antagonist JD5037 inhibited plaque progression and macrophage proliferation, but only in male mice. Finally, CNR1 expression was detectable in human carotid endarterectomy plaques and inversely correlated with proliferation, oxidative metabolism, and inflammatory markers, suggesting a possible implication of CB1-dependent regulation in human pathophysiology., Conclusion: Impaired macrophage CB1 signalling is atheroprotective by limiting their arterial recruitment, proliferation, and inflammatory reprogramming in male mice. The importance of macrophage CB1 signalling appears to be sex-dependent., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Published
- 2024
- Full Text
- View/download PDF
34. Unilateral Sensorineural Hearing Loss in Congenital Cytomegalovirus Retrospective Observational Study.
- Author
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Alkoby-Meshulam L, Rosenthal-Shtern D, Snapiri O, Levy D, Sachs N, Sokolov M, and Bilavsky E
- Abstract
Background: The leading nonhereditary cause of childhood sensorineural hearing loss has been attributed to congenital cytomegalovirus (cCMV). Sensorineural hearing loss can be unilateral (UHL) or bilateral (BHL), and may be progressive. Our objective was to describe the characteristics, clinical nature and follow-up of ears in cCMV-associated UHL., Methods: This 16-year retrospective study was performed at Schneider's Medical Center, Israel. Data were collected from all cCMV infants with UHL at birth who were treated with antiviral treatment initiated within the first 4 weeks of life and had a follow-up period of at least 1 year., Results: We enrolled 67 infants diagnosed with UHL at birth: 17 (25%) with mild hearing loss, 22 (33%) with moderate hearing loss and 28 (42%) with severe hearing loss. At the last follow-up visit, 7 (41%) ears in the mild hearing loss group improved to normal hearing, 8 (47%) ears exhibited no change and 2 (12%) ears deteriorated. In the moderate hearing loss group, 9 (41%) ears improved, 7 (32%) remained static and 6 (27%) deteriorated to the severe hearing loss group. One (4%) ear in the severe hearing loss group showed improvement. Of the 67 ears with normal hearing at birth, 4 (6%) ears deteriorated., Conclusions: This study assessed and elucidated the characteristics, clinical nature and long-term follow-up of both the affected and unaffected ears diagnosed with UHL due to cCMV. These data are crucial when medical and/or surgical interventions are considered., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
35. Candida lusitaniae Fungemia in Children: A multicenter case series of emerging pathogen.
- Author
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Snapiri O, Danziger CR, Sachs N, Krause I, Zvi HB, Danino D, Kriger O, Shachor-Meyouhas Y, Averbuch D, and Bilavsky E
- Subjects
- Child, Preschool, Female, Humans, Male, Candidemia microbiology, Candidemia epidemiology, Fungemia microbiology, Fungemia mortality, Microbial Sensitivity Tests, Retrospective Studies, Risk Factors, Tertiary Care Centers statistics & numerical data, Antifungal Agents therapeutic use, Antifungal Agents pharmacology, Candida drug effects, Candida genetics, Candida isolation & purification, Candida pathogenicity
- Abstract
Candida lusitaniae fungemia is a serious infection that is rarely reported in children. The aim of this study is to describe a case series of C. lusitaniae fungemia and review previous publications regarding this rare pathogen. This is a multicenter case series of children diagnosed with C. lusitaniae fungemia. A total of 18 cases that occurred over a 15-year period in five tertiary hospitals were included. Additionally, a review of the literature regarding C. lusitaniae fungemia in children was performed. A total of 18 cases were enrolled; 11/18 (61%) were males, with a mean age of 2.3 years. All patients had severe underlying diseases and risk factors for opportunistic infection, most commonly prematurity and malignancies. More than one-third of cases occurred during the last 2 years of the study period. All isolates were susceptible to all tested antifungals. The survival rate following the acute infection was 94%, whereas the survival rate of 14 previously published cases was 71%, with the most common underlying diseases being CGD and malignancies. Candida lusitaniae fungemia is not a common event in the pediatric population, occurring exclusively in children with severe underlying diseases and significant risk factors. This cohort revealed better clinical outcomes than previously reported. All tested isolates were susceptible to all antifungal agents; variability in susceptibility as previously reported was not found in this study. The allegedly higher rate of infection in recent years is in need of further investigation in larger prospective studies in order to conclude if a real trend is at play., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)
- Published
- 2024
- Full Text
- View/download PDF
36. Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.
- Author
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Pan H, Ho SE, Xue C, Cui J, Johanson QS, Sachs N, Ross LS, Li F, Solomon RA, Connolly ES Jr, Patel VI, Maegdefessel L, Zhang H, and Reilly MP
- Subjects
- Animals, Humans, Mice, Muscle, Smooth, Vascular pathology, Muscle, Smooth, Vascular metabolism, Atherosclerosis pathology, Atherosclerosis metabolism, Myocytes, Smooth Muscle pathology, Myocytes, Smooth Muscle metabolism
- Abstract
Background: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis., Methods: We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis., Results: SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant Kras
G12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models., Conclusions: Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease., Competing Interests: Disclosures None.- Published
- 2024
- Full Text
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37. Autoimmune encephalitis in Israeli children - A retrospective nationwide study.
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Sachs N, Zohar-Dayan E, Ben Zeev B, Gilboa T, Kurd M, Latzer IT, Meirson H, Krause I, Dizitzer Y, and Cohen EG
- Subjects
- Humans, Female, Male, Child, Israel epidemiology, Retrospective Studies, Child, Preschool, Adolescent, Infant, Magnetic Resonance Imaging, Electroencephalography, Hashimoto Disease, Immunoglobulins, Intravenous therapeutic use, Infant, Newborn, Encephalitis immunology, Encephalitis diagnosis
- Abstract
Immune-mediated or autoimmune encephalitis (AE) is a relatively new, rare and elusive form of encephalitis in children. We retrospectively collected seropositive children (0-18 years old) with well characterized antibodies through 3 reference laboratories in Israel. Clinical symptoms, MRI and EEG findings and treatment courses were described. A total of 16 patients were included in the study, with 10 females. Anti NMDA encephalitis was most common followed by anti HU and anti mGLuR1. Psychiatric symptoms, abnormal movements, seizures and behavioral changes were the most common presentation. Pathological MRI and EEG findings were described in 37% and 56% of children, respectively. Treatment with corticosteroids, Intravenous immunoglobulins (IVIG) was first line in most children. Following inadequate response children were treated with plasmapheresis and/or rituximab. Two patients relapsed following both first and second line protocols. In terms of long term prognosis, 9 children (56%) had one or more residual behavioral, psychiatric or neurologic findings. Three children required hospitalization for rehabilitation. AE remains a rare diagnosis with variable presenting symptoms, requiring a high index of suspicion. Consensus recommended treatment is generally effective in the pediatric population. Female gender was associated with a higher chance of severe disease. Larger cohorts would be needed to identify prognostic factors in the pediatric population., (© 2024 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2024
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38. High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.
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Bashore AC, Yan H, Xue C, Zhu LY, Kim E, Mawson T, Coronel J, Chung A, Sachs N, Ho S, Ross LS, Kissner M, Passegué E, Bauer RC, Maegdefessel L, Li M, and Reilly MP
- Subjects
- Humans, Endothelial Cells metabolism, Epitopes metabolism, Myocytes, Smooth Muscle metabolism, Atherosclerosis pathology, Plaque, Atherosclerotic pathology, Carotid Artery Diseases pathology
- Abstract
Background: Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, our understanding of the comprehensive transcriptional and phenotypic landscape of the cells within these lesions is limited., Methods: To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology., Results: We identified 25 cell populations, each with a unique multiomic signature, including macrophages, T cells, NK (natural killer) cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Among the macrophages, we identified 2 proinflammatory subsets enriched in IL-1B (interleukin-1B) or C1Q expression, 2 TREM2-positive foam cells (1 expressing inflammatory genes), and subpopulations with a proliferative gene signature and SMC-specific gene signature with fibrotic pathways upregulated. Further characterization revealed various subsets of SMCs and fibroblasts, including SMC-derived foam cells. These foamy SMCs were localized in the deep intima of coronary atherosclerotic lesions. Utilizing cellular indexing of transcriptomes and epitopes by sequencing data, we developed a flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Lastly, we observed reduced proportions of efferocytotic macrophages, classically activated endothelial cells, and contractile and modulated SMC-derived cells, while inflammatory SMCs were enriched in plaques of clinically symptomatic versus asymptomatic patients., Conclusions: Our multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. These findings facilitate both the mapping of cardiovascular disease susceptibility loci to specific cell types and the identification of novel molecular and cellular therapeutic targets for the treatment of the disease., Competing Interests: Disclosures None.
- Published
- 2024
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39. Utilization of an Artery-on-a-Chip to Unravel Novel Regulators and Therapeutic Targets in Vascular Diseases.
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Paloschi V, Pauli J, Winski G, Wu Z, Li Z, Botti L, Meucci S, Conti P, Rogowitz F, Glukha N, Hummel N, Busch A, Chernogubova E, Jin H, Sachs N, Eckstein HH, Dueck A, Boon RA, Bausch AR, and Maegdefessel L
- Subjects
- Humans, Arteries, Disease Progression, Lab-On-A-Chip Devices, Aortic Aneurysm, Abdominal drug therapy, Atherosclerosis drug therapy
- Abstract
In this study, organ-on-chip technology is used to develop an in vitro model of medium-to-large size arteries, the artery-on-a-chip (AoC), with the objective to recapitulate the structure of the arterial wall and the relevant hemodynamic forces affecting luminal cells. AoCs exposed either to in vivo-like shear stress values or kept in static conditions are assessed to generate a panel of novel genes modulated by shear stress. Considering the crucial role played by shear stress alterations in carotid arteries affected by atherosclerosis (CAD) and abdominal aortic aneurysms (AAA) disease development/progression, a patient cohort of hemodynamically relevant specimens is utilized, consisting of diseased and non-diseased (internal control) vessel regions from the same patient. Genes activated by shear stress follow the same expression pattern in non-diseased segments of human vessels. Single cell RNA sequencing (scRNA-seq) enables to discriminate the unique cell subpopulations between non-diseased and diseased vessel portions, revealing an enrichment of flow activated genes in structural cells originating from non-diseased specimens. Furthermore, the AoC served as a platform for drug-testing. It reproduced the effects of a therapeutic agent (lenvatinib) previously used in preclinical AAA studies, therefore extending the understanding of its therapeutic effect through a multicellular structure., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)
- Published
- 2024
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40. Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.
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Fidler TP, Dunbar A, Kim E, Hardaway B, Pauli J, Xue C, Abramowicz S, Xiao T, O'Connor K, Sachs N, Wang N, Maegdefessel L, Levine R, Reilly M, and Tall AR
- Abstract
Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr
-/- mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1β antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF during plaque regression promoted fibroblast accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap., Competing Interests: Competing interests The remaining authors declare no competing interests.- Published
- 2024
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41. Correction: Completing the view - histologic insights from circular AAA specimen including 3D imaging : A methodologic approach towards histologic analysis of circumferential AAA samples.
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Menges AL, Nackenhorst M, Müller JR, Engl ML, Hegenloh R, Pelisek J, Geibelt E, Hofmann A, Reeps C, Biro G, Eckstein HH, Zimmermann A, Magee D, Falk M, Sachs N, and Busch A
- Published
- 2023
- Full Text
- View/download PDF
42. Trackman 4: Within and between-session reliability and inter-relationships of launch monitor metrics during indoor testing in high-level golfers.
- Author
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Bishop C, Wells J, Ehlert A, Turner A, Coughlan D, Sachs N, and Murray A
- Subjects
- Humans, Reproducibility of Results, Benchmarking, Biomechanical Phenomena, Athletic Performance, Golf
- Abstract
The aims of the present study were to: 1) investigate the within and between-session reliability of the Trackman 4 launch monitor system, and 2) determine the inter-relationships of some of these commonly used metrics. Golfers attended two test sessions at an indoor golf academy and performed 10 shots using their own driver. Results showed excellent within and between-session reliability for CHS (ICC = 0.99; SEM = 1.64-1.67 mph), ball speed (ICC = 0.97-0.99; SEM = 2.46-4.42 mph) and carry distance (ICC = 0.91-0.97; SEM = 7.80-14.21 mph). In contrast, spin rate showed the worst reliability (ICC = 0.02-0.60; SEM = 240.93-454.62 º/s) and also exhibited significant differences between test sessions ( g = -0.41; p < 0.05), as did smash factor ( g = 0.47; p < 0.05) and dynamic loft ( g = -0.21; p < 0.05). Near perfect associations were evident in both test sessions between CHS and ball speed ( r = 0.98-0.99), CHS and carry distance ( r = 0.94-0.95), ball speed and carry distance ( r = 0.97-0.98), and launch angle and dynamic loft ( r = 0.98-0.99). Collectively, CHS, ball speed and carry distance serve as the most consistently reliable metrics making them excellent choices for practitioners working with golfers.
- Published
- 2023
- Full Text
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43. ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1.
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Sharifi MA, Wierer M, Dang TA, Milic J, Moggio A, Sachs N, von Scheidt M, Hinterdobler J, Müller P, Werner J, Stiller B, Aherrahrou Z, Erdmann J, Zaliani A, Graettinger M, Reinshagen J, Gul S, Gribbon P, Maegdefessel L, Bernhagen J, Sager HB, Mann M, Schunkert H, and Kessler T
- Subjects
- Animals, Humans, Mice, Collagen metabolism, Matrix Metalloproteinase 9, Mice, Knockout, ApoE, ADAMTS7 Protein genetics, Atherosclerosis genetics, Coronary Artery Disease genetics, Plaque, Atherosclerotic metabolism, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-1 metabolism
- Abstract
Background: The ADAMTS7 locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis., Methods: Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe
-/- and Apoe-/- Adamts7-/- mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer-based protein-protein interaction assays. ADAMTS7 expression was measured in fibrous caps of human carotid artery plaques., Results: In humans, ADAMTS7 expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe-/- mice, atherosclerotic aortas of Apoe-/- mice lacking Adamts-7 (Apoe-/- Adamts7-/- ) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe-/- and Apoe-/- Adamts7-/- mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe-/- as compared to Apoe-/- Adamts7-/- mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer-based assay targeting the ADAMTS-7 catalytic site., Conclusions: ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events., Competing Interests: Disclosures Dr Schunkert has received personal fees from MSD SHARP & DOHME, AMGEN, Bayer Vital GmbH, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Servier, Brahms, Bristol-Myers-Squibb, Medtronic, Sanofi Aventis, Synlab, Pfizer, and Vifor T as well as grants and personal fees from Astra-Zeneca outside the submitted work. Drs Schunkert and Kessler are named inventors on a patent application for prevention of restenosis after angioplasty and stent implantation outside the submitted work. Dr Kessler received lecture fees from Bayer, Bristol-Myers Squibb, Abbott, and Astra-Zeneca, which are unrelated to this work. Dr Bernhagen is an inventor on patents related to anti-MIF and antichemokine strategies in inflammation and CVD (cardiovascular diseases) outside the submitted work. The other authors report no conflicts.- Published
- 2023
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44. The circular RNA Ataxia Telangiectasia Mutated regulates oxidative stress in smooth muscle cells in expanding abdominal aortic aneurysms.
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Fasolo F, Winski G, Li Z, Wu Z, Winter H, Ritzer J, Glukha N, Roy J, Hultgren R, Pauli J, Busch A, Sachs N, Knappich C, Eckstein HH, Boon RA, Paloschi V, and Maegdefessel L
- Abstract
An abdominal aortic aneurysm (AAA) is a pathological widening of the aortic wall characterized by loss of smooth muscle cells (SMCs), extracellular matrix degradation, and local inflammation. This condition is often asymptomatic until rupture occurs, leading to high morbidity and mortality rates. Diagnosis is mostly accidental and the only currently available treatment option remains surgical intervention. Circular RNAs (circRNAs) represent a novel class of regulatory non-coding RNAs that originate from backsplicing. Their highly stable loop structure, combined with a remarkable enrichment in body fluids, make circRNAs promising disease biomarkers. We investigated the contribution of circRNAs to AAA pathogenesis and their potential application to improve AAA diagnostics. Gene expression analysis revealed the presence of deregulated circular transcripts stemming from AAA-relevant gene loci . Among these, the circRNA to the Ataxia Telangiectasia Mutated gene (c ATM ) was upregulated in human AAA specimens, in AAA-derived SMCs, and serum samples collected from aneurysm patients. In primary aortic SMCs, c ATM increased upon angiotensin II and doxorubicin stimulation, while its silencing triggered apoptosis. Higher c ATM levels made AAA-derived SMCs less vulnerable to oxidative stress, compared with control SMCs. These data suggest that c ATM contributes to elicit an adaptive oxidative-stress response in SMCs and provides a reliable AAA disease signature., Competing Interests: L.M. is a scientific consultant and adviser for Novo Nordisk (Malov, Denmark), DrugFarm (Shanghai, China), and Angiolutions (Hannover, Germany), and received research funds from Roche Diagnostics (Rotkreuz, Switzerland)., (© 2023 The Authors.)
- Published
- 2023
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45. A novel SLC25A13 gene splice site variant causes Citrin deficiency in an infant.
- Author
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Sachs N, Wechsberg O, Landau YE, Krause I, Elgali II, Darawshe M, Shomron N, Lidzbarsky G, and Orenstein N
- Subjects
- Infant, Newborn, Female, Humans, Infant, Mutation, Mitochondrial Membrane Transport Proteins genetics, Base Sequence, Calcium-Binding Proteins genetics, Citrullinemia genetics, Organic Anion Transporters genetics
- Abstract
Citrin deficiency is an autosomal recessive disorder associated with SLC25A13 gene pathogenic variants, with more than a hundred known at present. It manifests in neonates as failure to thrive and acute liver insufficiency. We herein describe a case of a 4-week-old infant who presented with insufficient weight gain and liver failure accompanied by hyperammonemia. She was diagnosed with Citrin deficiency after a thorough biochemical and molecular analysis including amino acid profile, DNA sequencing of genes of interest and RNA splice site evaluation, to reveal a yet unknown damaging variant of the SLC25A13 gene., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)
- Published
- 2023
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46. Apolipoprotein E (ApoE) Rescues the Contractile Smooth Muscle Cell Phenotype in Popliteal Artery Aneurysm Disease.
- Author
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Pauli J, Reisenauer T, Winski G, Sachs N, Chernogubova E, Freytag H, Otto C, Reeps C, Eckstein HH, Scholz CJ, Maegdefessel L, and Busch A
- Subjects
- Humans, Male, Phenotype, Myocytes, Smooth Muscle metabolism, Apolipoproteins E genetics, Apolipoproteins E metabolism, Apolipoproteins metabolism, Popliteal Artery Aneurysm, Aortic Aneurysm, Abdominal metabolism
- Abstract
Popliteal artery aneurysm (PAA) is the most frequent peripheral aneurysm, primarily seen in male smokers with a prevalence below 1%. This exploratory study aims to shed light on cellular mechanisms involved in PAA progression. Sixteen human PAA and eight non-aneurysmatic popliteal artery samples, partially from the same patients, were analyzed by immunohistochemistry, fluorescence imaging, Affymetrix mRNA expression profiling, qPCR and OLink proteomics, and compared to atherosclerotic ( n = 6) and abdominal aortic aneurysm (AAA) tissue ( n = 19). Additionally, primary cell culture of PAA-derived vascular smooth muscle cells (VSMC) was established for modulation and growth analysis. Compared to non-aneurysmatic popliteal arteries, VSMCs lose the contractile phenotype and the cell proliferation rate increases significantly in PAA. Array analysis identified APOE higher expressed in PAA samples, co-localizing with VSMCs. APOE stimulation of primary human PAA VSMCs significantly reduced cell proliferation. Accordingly, contractile VSMC markers were significantly upregulated. A single case of osseous mechanically induced PAA with a non-diseased VSMC profile emphasizes these findings. Carefully concluded, PAA pathogenesis shows similar features to AAA, yet the mechanisms involved might differ. APOE is specifically higher expressed in PAA tissue and could be involved in VSMC phenotype rescue.
- Published
- 2023
- Full Text
- View/download PDF
47. The Incidence of IgG4-Related and Inflammatory Abdominal Aortic Aneurysm Is Rare in a 101 Patient Cohort.
- Author
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Nackenhorst MC, Kapalla M, Weidle S, Kirchhoff F, Zschäpitz D, Sieber S, Reeps C, Eckstein HH, Schneider H, Thaler M, Moog P, Busch A, and Sachs N
- Abstract
Abdominal aortic aneurysms (AAA) are the most frequent aortic dilation, with considerable morbidity and mortality. Inflammatory (infl) and IgG4-positive AAAs represent specific subtypes of unclear incidence and clinical significance. Here, histologic and serologic analyses with retrospective clinical data acquisition are investigated via detailed histology, including morphologic (HE, EvG: inflammatory subtype, angiogenesis, and fibrosis) and immunhistochemic analyses (IgG and IgG4). In addition, complement factors C3/C4 and immunoglobulins IgG, IgG2, IgG4 and IgE were measured in serum samples and clinical data uses patients' metrics, as well as through semi-automated morphometric analysis (diameter, volume, angulation and vessel tortuosity). A total of 101 eligible patients showed five (5%) IgG4 positive (all scored 1) and seven (7%) inflammatory AAAs. An increased degree of inflammation was seen in IgG4 positive and inflAAA, respectively. However, serologic analysis revealed no increased levels of IgG or IgG4. The operative procedure time was not different for those cases and the short-term clinical outcomes were equal for the entire AAA cohort. Overall, the incidence of inflammatory and IgG4-positive AAA samples seems very low based on histologic and serum analyses. Both entities must be considered distinct disease phenotypes. Short-term operative outcomes were not different for both sub-cohorts.
- Published
- 2023
- Full Text
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48. Completing the view - histologic insights from circular AAA specimen including 3D imaging : A methodologic approach towards histologic analysis of circumferential AAA samples.
- Author
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Menges AL, Nackenhorst M, Müller JR, Engl ML, Hegenloh R, Pelisek J, Geibelt E, Hofmann A, Reeps C, Biro G, Eckstein HH, Zimmermann A, Magee D, Falk M, Sachs N, and Busch A
- Subjects
- Humans, Animals, Mice, Imaging, Three-Dimensional, Calcinosis
- Abstract
Abdominal aortic aneurysm (AAA) is a pathologic enlargement of the infrarenal aorta with an associated risk of rupture. However, the responsible mechanisms are only partially understood. Based on murine and human samples, a heterogeneous distribution of characteristic pathologic features across the aneurysm circumference is expected. Yet, complete histologic workup of the aneurysm sac is scarcely reported. Here, samples from five AAAs covering the complete circumference partially as aortic rings are investigated by histologic means (HE, EvG, immunohistochemistry) and a new method embedding the complete ring. Additionally, two different methods of serial histologic section alignment are applied to create a 3D view. The typical histopathologic features of AAA, elastic fiber degradation, matrix remodeling with collagen deposition, calcification, inflammatory cell infiltration and thrombus coverage were distributed without recognizable pattern across the aneurysm sac in all five patients. Analysis of digitally scanned entire aortic rings facilitates the visualization of these observations. Immunohistochemistry is feasible in such specimen, however, tricky due to tissue disintegration. 3D image stacks were created using open-source and non-generic software correcting for non-rigid warping between consecutive sections. Secondly, 3D image viewers allowed visualization of in-depth changes of the investigated pathologic hallmarks. In conclusion, this exploratory descriptive study demonstrates a heterogeneous histomorphology around the AAA circumference. Warranting an increased sample size, these results might need to be considered in future mechanistic research, especially in reference to intraluminal thrombus coverage. 3D histology of such circular specimen could be a valuable visualization tool for further analysis., (© 2023. The Author(s).)
- Published
- 2023
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49. Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.
- Author
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Winter H, Winski G, Busch A, Chernogubova E, Fasolo F, Wu Z, Bäcklund A, Khomtchouk BB, Van Booven DJ, Sachs N, Eckstein HH, Wittig I, Boon RA, Jin H, and Maegdefessel L
- Subjects
- Animals, Mice, Apoptosis genetics, Cell Proliferation genetics, Disease Progression, Fibroblast Growth Factor 2 genetics, Fibroblast Growth Factor 2 metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Swine, Oligonucleotides, Antisense, Aortic Aneurysm, Abdominal genetics, Aortic Aneurysm, Abdominal therapy, Aortic Aneurysm, Abdominal metabolism, Carotid Artery Diseases, RNA, Long Noncoding genetics, RNA, Long Noncoding metabolism
- Abstract
Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases., Competing Interests: Declaration of interests L.M. is a scientific consultant and adviser for Novo Nordisk (Malov, Denmark), DrugFarm (Shanghai, China), and Angiolutions (Hannover, Germany), and received research funds from Roche Diagnostics (Rotkreuz, Switzerland) and Novo Nordisk (Malov, Denmark)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
50. The Effect of the COVID-19 Pandemic on Pediatric Respiratory Hospitalizations.
- Author
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Sachs N, Goldberg L, Levinsky Y, Dizitzer Y, Vardi Y, Krause I, Scheuerman O, Livni G, Bilavsky E, and Bilavsky-Yarden H
- Subjects
- Male, Adult, Child, Humans, Adolescent, Female, Pandemics prevention & control, Retrospective Studies, Hospitalization, COVID-19 epidemiology, COVID-19 prevention & control, Influenza, Human, Bacterial Infections
- Abstract
Background: During coronavirus disease 2019 (COVID-19) pandemic, less isolation of common winter viruses was reported in the southern hemisphere., Objectives: To evaluate annual trends in respiratory disease-related admissions in a large Israeli hospital during and before the pandemic., Methods: A retrospective analysis of medical records from November 2020 to January 2021 (winter season) was conducted and compared to the same period in two previous years. Data included number of admissions, epidemiological and clinical presentation, and isolation of respiratory pathogens., Results: There were 1488 respiratory hospitalizations (58% males): 632 in 2018-2019, 701 in 2019-2020, and 155 in 2020-2021. Daily admissions decreased significantly from a median value of 6 (interquartile range [IQR] 4-9) and 7 per day (IQR 6-10) for 2018-2019 and 2019-2020, respectively, to only 1 per day (IQR 1-3) in 2020-2021 (P-value < 0.001). The incidence of all respiratory viruses decreased significantly during the COVID-19 pandemic, with no hospitalizations due to influenza and only one with respiratory syncytial virus. There was also a significant decline in respiratory viral and bacterial co-infections during the pandemic (P-value < 0.001)., Conclusions: There was a significant decline in pediatric respiratory admission rates during the COVID-19 pandemic. Possible etiologies include epidemiological factors such as mask wearing and social distancing, in addition to biological factors such as viral interference. A herd protection effect of adults and older children wearing masks may also have had an impact.
- Published
- 2023
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