Pharmacokinetics and brain σ1 receptor occupancy of MR309, a selective σ1 receptor antagonist.

Aims: Preclinical studies of MR309, a selective sigma-1 receptor (σ1R) antagonist, support a potential role in treating neuropathic pain. We report 2 studies that provide insight into the pharmacokinetics (PK) and brain σ1R binding of MR309.

Methods: Steady-state PK of MR309 (400 mg once daily and 200 mg twice-daily [BID] for 10 days; EudraCT 2015-001818-99 [PK study]) and the relationship between MR309 plasma exposure and brain σ1R occupancy (EudraCT 2017-000670-11 [positron emission tomography study]) were investigated in healthy volunteers.

mimics heat and drought stress and encodes a protoxylem-specific transcription factor in maize.

Maintaining sufficient water transport during flowering is essential for proper organ growth, fertilization, and yield. Water deficits that coincide with flowering result in leaf wilting, necrosis, tassel browning, and sterility, a stress condition known as "tassel blasting." We identified a mutant, (), that mimics tassel blasting and drought stress and reveals the genetic mechanisms underlying these processes.

The unusual retrotransposon is abundant, highly mutagenic, and mobilized only in the second pollen mitosis of some maize lines.

The frequent mutations recovered recently from the pollen of select maize lines resulted from the meiotic mobilization of specific low-copy number long-terminal repeat (LTR) retrotransposons, which differ among lines. Mutations that arise at male meiosis produce kernels with concordant mutant phenotypes in both endosperm and embryo because the two sperms that participate in double fertilization are genetically identical. Those are in a majority.

Spontaneous mutations in maize pollen are frequent in some lines and arise mainly from retrotranspositions and deletions.

While studying spontaneous mutations at the maize () locus, we made the unexpected discovery that specific low-copy number retrotransposons are mobile in the pollen of some maize lines, but not of others. We conducted large-scale genetic experiments to isolate new mutations from several stocks and recovered spontaneous stable mutations only in the pollen parent in reciprocal crosses. Most of the new stable mutations resulted from either insertions of low-copy number long terminal repeat (LTR) retrotransposons or deletions, the same two classes of mutations that predominated in a collection of spontaneous mutations [Wessler S (1997) , pp 385-386].

The maize W22 genome provides a foundation for functional genomics and transposon biology.

The maize W22 inbred has served as a platform for maize genetics since the mid twentieth century. To streamline maize genome analyses, we have sequenced and de novo assembled a W22 reference genome using short-read sequencing technologies. We show that significant structural heterogeneity exists in comparison to the B73 reference genome at multiple scales, from transposon composition and copy number variation to single-nucleotide polymorphisms.