Czech economic thought during 1948 - 1969 (from the Stalinist terror to the Prague spring)

Czech economic thought during the 1948 - 1969 was full of sudden turns. Its development was determined by political conditions and spiritual climate that were result of Stalinist soviet type socialism. During the first half of the 1950s the plurality of economic ideas was substituted by the Stalinist version of marxist-leninist political economy using violent methods. Low efficiency of the command system and emerging reform climate in the USSR under N. S. Khrushchev opened the door to the reform thinking of the second half of 1950s and the 1960s in Czechoslovakia. During the 1960s the development of the reform thinking together with renaissance of the theoretical economic thinking culminated in the economic reform of Otto Šik and his team, and democratization process of the Prague Spring of 1968. Promising developments ended as a consequence of the Warsaw Treaty troops invasion in August 1968.history of the Czech economic thought, marxian political economy, economic reform, soviet-type socialism, market socialism, central planning, plan and market

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer’s Disease

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer’s disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer’s Disease

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer’s disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia

Structural, Kinetic, and Pharmacodynamic Mechanisms of d‑Amino Acid Oxidase Inhibition by Small Molecules

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (<i>K</i>_d ≈ 2–4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (<i>K</i>_d ≈ 100–200 nM) and slow release kinetics (<i>k</i> < 0.01 s^–1) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role