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- Fasi, Massimiliano, 1989-, et al.
(författare)
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Numerical behavior of NVIDIA tensor cores
- 2021
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Ingår i: PeerJ Computer Science. - : PeerJ, Inc. - 2376-5992. ; 7, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- We explore the floating-point arithmetic implemented in the NVIDIA tensor cores, which are hardware accelerators for mixed-precision matrix multiplication available on the Volta, Turing, and Ampere microarchitectures. Using Volta V100, Turing T4, and Ampere A100 graphics cards, we determine what precision is used for the intermediate results, whether subnormal numbers are supported, what rounding mode is used, in which order the operations underlying the matrix multiplication are performed, and whether partial sums are normalized. These aspects are not documented by NVIDIA, and we gain insight by running carefully designed numerical experiments on these hardware units. Knowing the answers to these questions is important if one wishes to: (1) accurately simulate NVIDIA tensor cores on conventional hardware; (2) understand the differences between results produced by code that utilizes tensor cores and code that uses only IEEE 754-compliant arithmetic operations; and (3) build custom hardware whose behavior matches that of NVIDIA tensor cores. As part of this work we provide a test suite that can be easily adapted to test newer versions of the NVIDIA tensor cores as well as similar accelerators from other vendors, as they become available. Moreover, we identify a non-monotonicity issue affecting floating point multi-operand adders if the intermediate results are not normalized after each step.
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- Mantas, Ioannis, et al.
(författare)
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TAAR1-Dependent and-Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition
- 2021
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 90:1, s. 16-27
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Monoamine oxidase inhibitors (MAOIs) exert therapeutic actions by elevating extracellular levels of monoamines in the brain. Irreversible MAOIs cause serious hypertensive crises owing to peripheral accumulation of tyramine, but the role of tyramine in the central effects of MAOIs remains elusive, an issue addressed herein. To achieve robust inhibition of MAOA/B, the clinically used antidepressant tranylcypromine (TCP) was employed. METHODS: Behavioral, histological, mass spectrometry imaging, and biosensor-mediated measures of glutamate were conducted with MAOIs in wild-type and TAAR1-knockout (KO) mice. RESULTS: Both antidepressant and locomotion responses to TCP were enhanced in TAAR1-KO mice. A recently developed fluoromethylpyridinium-based mass spectrometry imaging method revealed robust accumulation of striatal tyramine on TCP administration. Furthermore, tyramine accumulation was higher in TAAR1-KO versus wild type mice, suggesting a negative feedback mechanism for TAAR1 in sensing tyramine levels. Combined histoenzymological and immunohistological studies revealed hitherto unknown TAAR1 localization in brain areas projecting to the substantia nigra/ventral tegmental area. Using an enzyme-based biosensor technology, we found that both TCP and tyramine reduced glutamate release in the substantia nigra in wild-type but not in TAAR1-KO mice. Moreover, glutamate measures in freely moving animals treated with TCP demonstrated that TAAR1 prevents glutamate accumulation in the substantia nigra during hyperlocomotive states. CONCLUSIONS: These observations suggest that tyramine, in interaction with glutamate, is involved in centrally mediated behavioral, transcriptional, and neurochemical effects of MAOIs.
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- Pansieri, Jonathan, et al.
(författare)
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Templating S100A9 amyloids on Aβ fibrillar surfaces revealed by charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses
- 2020
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Ingår i: Chemical Science. - : Royal Society of Chemistry. - 2041-6520 .- 2041-6539. ; 11:27, s. 7031-7039
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Tidskriftsartikel (refereegranskat)abstract
- The mechanism of amyloid co-aggregation and its nucleation process are not fully understood in spite of extensive studies. Deciphering the interactions between proinflammatory S100A9 protein and Aβ42 peptide in Alzheimer's disease is fundamental since inflammation plays a central role in the disease onset. Here we use innovative charge detection mass spectrometry (CDMS) together with biophysical techniques to provide mechanistic insight into the co-aggregation process and differentiate amyloid complexes at a single particle level. Combination of mass and charge distributions of amyloids together with reconstruction of the differences between them and detailed microscopy reveals that co-aggregation involves templating of S100A9 fibrils on the surface of Aβ42 amyloids. Kinetic analysis further corroborates that the surfaces available for the Aβ42 secondary nucleation are diminished due to the coating by S100A9 amyloids, while the binding of S100A9 to Aβ42 fibrils is validated by a microfluidic assay. We demonstrate that synergy between CDMS, microscopy, kinetic and microfluidic analyses opens new directions in interdisciplinary research.
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- Saarinen, Marcus, et al.
(författare)
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TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-383856
- 2022
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 47, s. 2319-2329
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Tidskriftsartikel (refereegranskat)abstract
- SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.
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- Zhang, Xiaoqun, et al.
(författare)
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Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or beta-Phenylethylamine
- 2018
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Ingår i: Frontiers in Pharmacology. - : FRONTIERS MEDIA SA. - 1663-9812. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (beta-PEA) compared to 3-iodothyronamine (T(1)AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wildtype (WT) and TAAR1 knockout (KO) mice. T(1)AM increased TH phosphorylation at both Ser(19) and Ser(40), actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T(1)AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser(845) phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser(19) (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T(1)AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T(1)AM in the brain, but detected T(1)AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser(845)-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, beta-PEA reduced Ser(40)-TH and tended to promote Ser845-GluA1 phosphorylation. The D-1 receptor antagonist SCH23390 blocked tyramine-induced Ser(845)-GluA1 phosphorylation, but had no effect on tyramine-or beta-PEA-induced Ser(40)-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T(1)AM, but not tyramine and beta-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.
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