A blood-brain penetrant RNA-targeted small molecule triggers elimination of r(GC) in c9ALS/FTD via the nuclear RNA exosome.

A hexanucleotide repeat expansion in intron 1 of the gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia, or c9ALS/FTD. The RNA transcribed from the expansion, r(GC), causes various pathologies, including intron retention, aberrant translation that produces toxic dipeptide repeat proteins (DPRs), and sequestration of RNA-binding proteins (RBPs) in RNA foci. Here, we describe a small molecule that potently and selectively interacts with r(GC) and mitigates disease pathologies in spinal neurons differentiated from c9ALS patient-derived induced pluripotent stem cells (iPSCs) and in two c9ALS/FTD mouse models.

Development of a putative Zn-chelating but highly selective MMP-13 inhibitor.

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn ion for chelating the metal ion.

Prospective analysis of Artisan aphakia intraocular lens implantation for nontraumatic ectopia lentis in children.

Purpose: To report long-term outcomes of iris claw aphakia intraocular lens (IOL) implantation for nontraumatic ectopia lentis (EL) in children.

Methods: In this prospective study, children who underwent Artisan Aphakia IOL placement were included if they have a minimum of 1-year follow-up after implantation. Main outcome measures were: best-corrected distance visual acuity, reoperations, change in central corneal thickness (CCT), and corneal endothelial cell counts (ECC).

Ribonuclease recruitment using a small molecule reduced c9ALS/FTD r(GC) repeat expansion in vitro and in vivo ALS models.

The most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) is an expanded GC RNA repeat [r(GC)] in chromosome 9 open reading frame 72 (), which elicits pathology through several mechanisms. Here, we developed and characterized a small molecule for targeted degradation of r(GC). The compound was able to selectively bind r(GC)’s structure and to assemble an endogenous nuclease onto the target, provoking removal of the transcript by native RNA quality control mechanisms.

Increases in glucocorticoids are sufficient but not necessary to increase cooperative burrowing in Damaraland mole-rats.

Despite widespread interest in the evolution of cooperative behaviour, the physiological mechanisms shaping their expression remain elusive. We tested the hypothesis that glucocorticoid (GC) hormones affect cooperative behaviour using captive Damaraland mole-rats (Fukomys damarensis), a cooperatively breeding mammal. Within groups, individuals routinely contribute to public goods that include foraging tunnels, which provide all group members access to the tubers of desert plants they feed on, communal food stores and nests.