C-Type LECTIN receptor-like kinase 1 and ACTIN DEPOLYMERIZING FACTOR 3 are key components of plasmodesmata callose modulation.

Plasmodesmata (PDs) are intercellular organelles carrying multiple membranous nanochannels that allow the trafficking of cellular signalling molecules. The channel regulation of PDs occurs dynamically and is required in various developmental and physiological processes. It is well known that callose is a critical component in regulating PD permeability or symplasmic connectivity, but the understanding of the signalling pathways and mechanisms of its regulation is limited. Here, we used the reverse genetic approach to investigate the role of C-type lectin receptor-like kinase 1 (CLRLK1) in the aspect of PD callose-modulated symplasmic continuity. Here, we found that loss-of-function mutations in CLRLK1 resulted in excessive PD callose deposits and reduced symplasmic continuity, resulting in an accelerated gravitropic response. The protein interactome study also found that CLRLK1 interacted with actin depolymerizing factor 3 (ADF3) in vitro and in plants. Moreover, mutations in ADF3 result in elevated PD callose deposits and faster gravitropic response. Our results indicate that CLRLK1 and ADF3 negatively regulate PD callose accumulation, contributing to fine-tuning symplasmic opening apertures. Overall, our studies identified two key components involved in the deposits of PD callose and provided new insights into how symplasmic connectivity is maintained by the control of PD callose homoeostasis.

Discovery of novel FGFR4 inhibitors through a build-up fragment strategy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments.

Discovery of orally active sulfonylphenyl thieno[3,2-d]pyrimidine derivatives as GPR119 agonists.

G-protein-coupled receptor 119 (GPR119) has great potential as a therapeutic target for the treatment of type II diabetes. Novel thieno[3,2-d]pyrimidine derivatives were discovered as GPR119 agonists through a bioisosteric replacement strategy. The sulfonylphenyl thieno[3,2-d] pyrimidine scaffold was introduced, and its derivatives exhibited potent agonistic activity for GPR119 in cell-based assays. The representative derivative 43 displayed excellent pharmacokinetic profiles in rodents and significantly improved glucose tolerance in vivo. In OGTT study, compound 43 reduced significantly blood glucose levels in both mice and rats.

Progression of dissection due to residual dissection after intracoronary stenting for spontaneous coronary dissection at bifurcation site of LAD and diagonal artery.

A 34-year old male patient visited our hospital due to severe chest pain. Initial ECG showed ST elevation at precordial leads and all cardiac enzymes were markedly elevated. Coronary angiography showed a long, longitudinal coronary dissection with dissected flap extending from the proximal LAD to the mid segment of the vessel and proximal diagonal artery. IVUS showed dissected flap and false lumen communicating with true lumen from proximal to mid-LAD. We implanted two paclitaxel-eluting stents using crushing technique at bifurcation lesion and overlapped another paclitaxel-eluting stent at proximal LAD for full coverage of dissection. Final angiography showed good distal flow. However, despite of maximal pressure of post stent ballooning, a residual dissection was noted at proximal LAD. IVUS examination also showed encircling gap that was noted between stent and vessel wall at proximal LAD stent area. Because distal flow was good and there was no ischemic symptom and sign, the patient was discharged. Six months later from index procedure, routine follow-up angiography and IVUS examination were performed and revealed more progressed previous residual coronary dissection at proximal LAD which was extended to bifurcation site. Our case showed, although intracoronary stenting might be an attractive approach by closure of the inlet and the false lumen, complete resolution of dissection by stenting is very important for long-term prognosis.