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.

Pharmacokinetics of Tramadol and Celecoxib in Japanese and Caucasian Subjects Following Administration of Co-Crystal of Tramadol-Celecoxib (CTC): A Randomised, Open-Label Study.

Background And Objectives: Co-Crystal of Tramadol-Celecoxib (CTC) is a first-in-class active pharmaceutical ingredient (API-API) co-crystal of rac-tramadol.HCl and celecoxib in a 1:1 molecular ratio (100 mg CTC: 44 mg rac-tramadol.HCl and 56 mg celecoxib).

Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study.

Background And Aims: Take-home naloxone can prevent death from heroin/opioid overdose, but pre-provision is difficult because naloxone is usually given by injection. Non-injectable alternatives, including naloxone nasal sprays, are currently being developed. To be effective, the intranasal (i.

Competitive Ability of Maize Pollen Grains Requires Paralogous Serine Threonine Protein Kinases STK1 and STK2.

() and () are closely related maize paralogous genes predicted to encode serine/threonine protein kinases. Pollen mutated in or competes poorly with normal pollen, pointing to a defect in pollen tube germination or growth. Both genes are expressed in pollen, but not in most other tissues.

Maize mutant generated by insertion of a element in a gene encoding a highly conserved TTI2 cochaperone.

We have used the newly engineered transposable element to tag a gene that gives rise to a defective kernel () phenotype. requires the autonomous element for transposition. Upon excision, it leaves a short DNA footprint that can create in-frame and frameshift insertions in coding sequences.

Rolling-circle amplification of centromeric Helitrons in plant genomes.

The unusual eukaryotic Helitron transposons can readily capture host sequences and are, thus, evolutionarily important. They are presumed to amplify by rolling-circle replication (RCR) because some elements encode predicted proteins homologous to RCR prokaryotic transposases. In support of this replication mechanism, it was recently shown that transposition of a bat Helitron generates covalently closed circular intermediates.

Polarized gene conversion at the bz locus of maize.

Nucleotide diversity is greater in maize than in most organisms studied to date, so allelic pairs in a hybrid tend to be highly polymorphic. Most recombination events between such pairs of maize polymorphic alleles are crossovers. However, intragenic recombination events not associated with flanking marker exchange, corresponding to noncrossover gene conversions, predominate between alleles derived from the same progenitor.

HelitronScanner uncovers a large overlooked cache of Helitron transposons in many plant genomes.

Transposons make up the bulk of eukaryotic genomes, but are difficult to annotate because they evolve rapidly. Most of the unannotated portion of sequenced genomes is probably made up of various divergent transposons that have yet to be categorized. Helitrons are unusual rolling circle eukaryotic transposons that often capture gene sequences, making them of considerable evolutionary importance.

Variation in allelic expression associated with a recombination hotspot in Zea mays.

Gene expression is a complex process, requiring precise spatial and temporal regulation of transcription factor activity; however, modifications of individual cis- and trans-acting modules can be molded by natural selection to create a sizeable number of novel phenotypes. Results from decades of research indicate that developmental and phenotypic divergence among eukaryotic organisms is driven primarily by variation in levels of gene expression that are dictated by mutations, either in structural or regulatory regions, of genes. The relative contributions and interplay of cis- and trans-acting regulatory factors to this evolutionary process, however, remain poorly understood.

InsertionMapper: a pipeline tool for the identification of targeted sequences from multidimensional high throughput sequencing data.

Background: The advent of next-generation high-throughput technologies has revolutionized whole genome sequencing, yet some experiments require sequencing only of targeted regions of the genome from a very large number of samples. These regions can be amplified by PCR and sequenced by next-generation methods using a multidimensional pooling strategy. However, there is at present no available generalized tool for the computational analysis of target-enriched NGS data from multidimensional pools.

TED, an autonomous and rare maize transposon of the mutator superfamily with a high gametophytic excision frequency.

Mutator (Mu) elements, one of the most diverse superfamilies of DNA transposons, are found in all eukaryotic kingdoms, but are particularly numerous in plants. Most of the present knowledge on the transposition behavior of this superfamily comes from studies of the maize (Zea mays) Mu elements, whose transposition is mediated by the autonomous Mutator-Don Robertson (MuDR) element. Here, we describe the maize element TED (for Transposon Ellen Dempsey), an autonomous cousin that differs significantly from MuDR.

Gene tagging with engineered Ds elements in maize.

We describe here protocols for isolating genes in maize using Dissociation (Ds) transposons marked with a green fluorescent protein (GFP) transgene. The introduced marker enables the phenotypic scoring of the nonautonomous element and the anchoring of unique primers on the element to facilitate the isolation of the adjacent DNA by PCR. Transposons such as Ds transpose preferentially to sites closely linked to the Ds-launching platform.

The spectrum and frequency of self-inflicted and host gene mutations produced by the transposon Ac in maize.

The autonomous transposon Activator (Ac) is a powerful mutagen. Ac-induced mutations range from small footprints of host sequences to large rearrangements of transposon or host sequences. These mutations arise by different repair mechanisms of the double-strand break produced by Ac excision: footprints by nonhomologous end joining and rearrangements by various mechanisms, including DNA replication repair.

Dynamic evolution of bz orthologous regions in the Andropogoneae and other grasses.

Genome structure exhibits remarkable plasticity within Zea mays. To examine how haplotype structure has evolved within the Andropogoneae tribe, we have analyzed the bz gene-rich region of maize (Zea mays), the Zea teosintes mays ssp. mexicana, luxurians and diploperennis, Tripsacum dactyloides, Coix lacryma-jobi and Sorghum propinquum.

The complete Ac/Ds transposon family of maize.

Background: The nonautonomous maize Ds transposons can only move in the presence of the autonomous element Ac. They comprise a heterogeneous group that share 11-bp terminal inverted repeats (TIRs) and some subterminal repeats, but vary greatly in size and composition. Three classes of Ds elements can cause mutations: Ds-del, internal deletions of the 4.

The maize high-lysine mutant opaque7 is defective in an acyl-CoA synthetase-like protein.

Maize (Zea mays) has a large class of seed mutants with opaque or nonvitreous endosperms that could improve the nutritional quality of our food supply. The phenotype of some of them appears to be linked to the improper formation of protein bodies (PBs) where zein storage proteins are deposited. Although a number of genes affecting endosperm vitreousness have been isolated, it has been difficult to clone opaque7 (o7), mainly because of its low penetrance in many genetic backgrounds.

The polychromatic Helitron landscape of the maize genome.

Maize Helitron transposons are intriguing because of their notable ability to capture gene fragments and move them around the genome. To document more extensively their variability and their contribution to the remarkable genome structure variation of present-day maize, we have analyzed their composition, copy number, timing of insertion, and chromosomal distribution. First, we searched 2.

Haplotype structure strongly affects recombination in a maize genetic interval polymorphic for Helitron and retrotransposon insertions.

We have asked here how the remarkable variation in maize haplotype structure affects recombination. We compared recombination across a genetic interval of 9S in 2 highly dissimilar heterozygotes that shared 1 parent. The genetic interval in the common haplotype is approximately 100 kb long and contains 6 genes interspersed with gene-fragment-bearing Helitrons and retrotransposons that, together, comprise 70% of its length.

Excision of Helitron transposons in maize.

Helitrons are novel transposons discovered by bioinformatic analysis of eukaryotic genome sequences. They are believed to move by rolling circle (RC) replication because their predicted transposases are homologous to those of bacterial RC transposons. We report here evidence of somatic Helitron excision in maize, an unexpected finding suggesting that Helitrons can exhibit an excisive mode of transposition.

Macrotransposition and other complex chromosomal restructuring in maize by closely linked transposons in direct orientation.

Several observations indicate that compatible ends of separate, yet closely linked, transposable elements (TEs) can interact in alternative transposition reactions. First, pairs of TEs cause chromosome breaks with frequencies inversely related to the intertransposon distance. Second, some combinations of two TEs produce complex rearrangements that often include DNA adjacent to one or both elements.

Maize genome structure variation: interplay between retrotransposon polymorphisms and genic recombination.

Although maize (Zea mays) retrotransposons are recombinationally inert, the highly polymorphic structure of maize haplotypes raises questions regarding the local effect of intergenic retrotransposons on recombination. To examine this effect, we compared recombination in the same genetic interval with and without a large retrotransposon cluster. We used three different bz1 locus haplotypes, McC, B73, and W22, in the same genetic background.