A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo

Targeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules

Entwicklung und Plastizität glutamaterger Synapsen im visuellen Cortex von Ratten

Während der Entwicklung des visuellen Cortex von Ratten zeigt ein Teil der glutamatergen Synapsen rein NMDA-Rezeptor vermittelte Transmission. Diese sogenannten "silent synapses" besitzen keine, oder nicht funktionelle AMPA-Rezeptoren und können aktivitätsabhängig in einem schnellen, stufenartigen Prozess in funktionelle Synapsen umgewandelt werden. Der Anteil an "silent synapses" wird während der cortikalen Differenzierung in den supra- und infragranulären Schichten reziprok reguliert, was zu einer funktionellen Kompensation von Unterschieden in der Dichte glutamaterger Synapsen führt. Im reifen visuellen Cortex lassen sich infolge fokaler Läsionen Änderungen in der Expression von NMDA-Rezeptoruntereinheiten beobachten, die an Expressionsmuster in der früheren Entwicklung erinnern

Modeling fashion as an emergent collective behavior of bored individuals

Abstract Boredom is an aversive mental state that is typically evoked by monotony and drives individuals to seek novel information. Despite this effect on individual behavior, the consequences of boredom for collective behavior remain elusive. Here, we introduce an agent-based model of collective fashion behavior in which simplified agents interact randomly and repeatedly choose alternatives from a circular space of color variants. Agents are endowed with a memory of past experiences and a boredom parameter, promoting avoidance of monotony. Simulating collective color trends with this model captures aspects of real trends observed in fashion magazines. We manipulate the two parameters and observe that the boredom parameter is essential for perpetuating fashion dynamics in our model. Furthermore, highly bored agents lead future population trends, when acting coherently or being highly popular. Taken together, our study illustrates that highly bored individuals can guide collective dynamics of a population to continuously explore different variants of behavior

Inhibitory connectivity defines the realm of excitatory plasticity

International audienc

Intrinsic volatility of synaptic connections — a challenge to the synaptic trace theory of memory

International audienc

PSD-95 is required for activity-driven synapse stabilization

The activity-dependent regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors and the stabilization of synapses are critical to synaptic development and plasticity. One candidate molecule implicated in maturation, synaptic strengthening, and plasticity is PSD-95. Here we find that acute knockdown of PSD-95 in brain slice cultures by RNAi arrests the normal development of synaptic structure and function that is driven by spontaneous activity. Surprisingly, PSD-95 is not necessary for the induction and early expression of long-term potentiation (LTP). However, knockdown of PSD-95 leads to smaller increases in spine size after chemically induced LTP. Furthermore, although at this age spine turnover is normally low and LTP produces a transient increase, in cells with reduced PSD-95 spine turnover is high and remains increased after LTP. Taken together, our data support a model in which appropriate levels of PSD-95 are required for activity-dependent synapse stabilization after initial phases of synaptic potentiation