BAY-9835: Discovery of the First Orally Bioavailable ADAMTS7 Inhibitor.

The matrix metalloprotease ADAMTS7 has been identified by multiple genome-wide association studies as being involved in the development of coronary artery disease. Subsequent research revealed the proteolytic function of the enzyme to be relevant for atherogenesis and restenosis after vessel injury. Based on a publicly known dual ADAMTS4/ADAMTS5 inhibitor, we have in silico designed an ADAMTS7 inhibitor of the catalytic domain, which served as a starting point for an optimization campaign.

Enantioselective Alkynylation of Unstabilized Cyclic Iminium Ions.

An enantioselective copper-catalyzed alkynylation of unstabilized cyclic iminium ions has been developed. Whereas such alkynylations typically utilize pyridinium, quinolinium and isoquinolinium intermediates, this method enables use of cyclic iminium ions unstabilized by resonance. With the use of a Lewis acid and copper catalyst, these iminium ions are generated from readily available hemiaminal methyl ethers and transformed into highly enantioenriched α-alkynylated cyclic amines.

PERK Regulates Working Memory and Protein Synthesis-Dependent Memory Flexibility.

PERK (EIF2AK3) is an ER-resident eIF2α kinase required for memory flexibility and metabotropic glutamate receptor-dependent long-term depression, processes known to be dependent on new protein synthesis. Here we investigated PERK's role in working memory, a cognitive ability that is independent of new protein synthesis, but instead is dependent on cellular Ca2+ dynamics. We found that working memory is impaired in forebrain-specific Perk knockout and pharmacologically PERK-inhibited mice.

Energetics of vertical kilometer foot races; is steeper cheaper?

Vertical kilometer foot races consist of a 1,000-m elevation gain in <5,000 m of overall distance, and the inclines of the fastest courses are ∼30°. Previous uphill locomotion studies have focused on much shallower angles. We aimed to quantify the metabolic costs of walking and running on very steep angles and to biomechanically distinguish walking from running.