SUMMARYThrough a sensitized screen for novel components of pathways regulating organ separation in Arabidopsis flowers, we have found that the leucine-rich repeat receptor-like kinase SOMATIC EMBRYOGENESIS RECEPTOR-LIKE KINASE1 (SERK1) acts as a negative regulator of abscission. Mutations in SERK1 dominantly rescue abscission in flowers without functional NEVERSHED (NEV), an ADP-ribosylation factor GTPaseactivating protein required for floral organ shedding. We previously reported that the organization of the Golgi apparatus and location of the trans-Golgi network (TGN) are altered in nev mutant flowers. Disruption of SERK1 restores Golgi structure and the close association of the TGN in nev flowers, suggesting that defects in these organelles may be responsible for the block in abscission. We have also found that the abscission zones of nev serk1 flowers are enlarged compared to wild-type. A similar phenotype was previously observed in plants constitutively expressing a putative ligand required for organ separation, INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), suggesting that signalling through IDA and its proposed receptors, HAESA and HAESA-LIKE2, may be deregulated in nev serk1 abscission zone cells. Our studies indicate that in addition to its previously characterized roles in stamen development and brassinosteroid perception, SERK1 plays a unique role in modulating the loss of cell adhesion that occurs during organ abscission.

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Novel Rho kinase (ROCK) inhibitors were tested for attenuation of airway hyperreactivity (AHR) and pulmonary inflammation. Two distinct profiles of molecules were explored: orally bioavailable molecules, represented by INS117758, suitable for oral product development; and orally nonbioavailable molecules, represented by INS117509, suitable for development as an inhaled product with limited systemic exposure. INS117758 and INS117509 potently inhibit ROCK2 (Ki values of 3.8 and 3.3 nM, respectively). While INS117758 is orally bioavailable in rats following 10 mg/kg p.o. dosing (Cmax= 5.6 μM, Tmax = 0.83 hours, T1/2 = 1.55 hours), INS117509 was not detectable in rat plasma following p.o. dosing. INS117758 and INS117509 relaxed carbachol‐precontracted tracheal rings (242 nM and 103 nM IC50s, respectively). Dosing of INS117758 p.o. at 5 mg/kg and INS117509 intratracheally (i.t.) at 1.5 mg/kg fully reversed AHR and reduced eosinophilia in OVA‐sensitized mice and neutrophilia in LPS‐exposed mice. In conclusion, Inspire novel ROCK inhibitors are suitable for treatment of respiratory diseases with AHR and pulmonary inflammation via oral route of delivery as well as inhaled route of delivery with limited systemic exposure.Funded by Inspire Pharmaceuticals.