Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis.

An orally administered, fixed-dose coformulation of sodium phenylbutyrate-taurursodiol (PB-TURSO) significantly slowed functional decline in a randomized, placebo-controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long-term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB-TURSO or placebo.

Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis.

Background: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known.

Methods: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months.

Publisher Correction: DNA sequencing at 40: past, present and future.

In this Review, the year of publication of reference 54 should be 2005, not 2015. In Box 2, "1982: GenBank ( https://www.ncbi.

DNA sequencing at 40: past, present and future.

This review commemorates the 40th anniversary of DNA sequencing, a period in which we have already witnessed multiple technological revolutions and a growth in scale from a few kilobases to the first human genome, and now to millions of human and a myriad of other genomes. DNA sequencing has been extensively and creatively repurposed, including as a 'counter' for a vast range of molecular phenomena. We predict that in the long view of history, the impact of DNA sequencing will be on a par with that of the microscope.

An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A.

Background: Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol).

The most conserved genome segments for life detection on Earth and other planets.

On Earth, very simple but powerful methods to detect and classify broad taxa of life by the polymerase chain reaction (PCR) are now standard practice. Using DNA primers corresponding to the 16S ribosomal RNA gene, one can survey a sample from any environment for its microbial inhabitants. Due to massive meteoritic exchange between Earth and Mars (as well as other planets), a reasonable case can be made for life on Mars or other planets to be related to life on Earth.

The evolution of spliceosomal introns: patterns, puzzles and progress.

The origins and importance of spliceosomal introns comprise one of the longest-abiding mysteries of molecular evolution. Considerable debate remains over several aspects of the evolution of spliceosomal introns, including the timing of intron origin and proliferation, the mechanisms by which introns are lost and gained, and the forces that have shaped intron evolution. Recent important progress has been made in each of these areas.

Rates of intron loss and gain: implications for early eukaryotic evolution.

We study the intron-exon structures of 684 groups of orthologs from seven diverse eukaryotic genomes and provide maximum likelihood estimates for rates and numbers of intron losses and gains in these same genes for a variety of lineages. Rates of intron loss vary from approximately 2 x 10(-9) to 2 x 10(-10) per year. Rates of gain vary from 6 x 10(-13) to 4 x 10(-12) per possible intron insertion site per year.

Resolution of a deep animal divergence by the pattern of intron conservation.

The relationship between three biologically important groups, arthropods, nematodes, and deuterostomes, remains unresolved. It is unknown whether arthropods are more closely related to nematodes (consistent with the "ecdysozoa" hypothesis) or to deuterostomes (consistent with "coelomata"). We present a method in which we use the pattern of spliceosomal intron conservation to develop a series of inequalities that characterize each possible relationship.

Complex early genes.

We use the pattern of intron conservation in 684 groups of orthologs from seven fully sequenced eukaryotic genomes to provide maximum likelihood estimates of the number of introns present in the same orthologs in various eukaryotic ancestors. We find: (i) intron density in the plant-animal ancestor was high, perhaps two-thirds that of humans and three times that of Drosophila; and (ii) intron density in the ancestral bilateran was also high, equaling that of humans and four times that of Drosophila. We further find that modern introns are generally very old, with two-thirds of modern bilateran introns dating to the ancestral bilateran and two-fifths of modern plant, animal, and fungus introns dating to the plant-animal ancestor.

The pattern of intron loss.

We studied intron loss in 684 groups of orthologous genes from seven fully sequenced eukaryotic genomes. We found that introns closer to the 3' ends of genes are preferentially lost, as predicted if introns are lost through gene conversion with a reverse transcriptase product of a spliced mRNA. Adjacent introns tend to be lost in concert, as expected if such events span multiple intron positions.

Mystery of intron gain.

For nearly 15 years, it has been widely believed that many introns were recently acquired by the genes of multicellular organisms. However, the mechanism of acquisition has yet to be described for a single animal intron. Here, we report a large-scale computational analysis of the human, Drosophila melanogaster, Caenorhabditis elegans, and Arabidopsis thaliana genomes.

The universe of exons revisited.

We study the distribution of exons in eukaryotic genes to determine whether one can detect the reuse of exon sequences and to use the frequency of such reuse to estimate how many ancestral exon sequences there might have been. We use two databases of exons. One contained 56,276 internal exons from putatively unrelated genes (less than 20% sequence identity) and the second contained 8917 internal exons from regions of these genes that are homologous and colinear with prokaryotic genes; these are ancient conserved regions (ACRs).

Large-scale comparison of intron positions in mammalian genes shows intron loss but no gain.

We compared intron-exon structures in 1,560 human-mouse orthologs and 360 mouse-rat orthologs. The origin of differences in intron positions between species was inferred by comparison with an outgroup, Fugu for human-mouse and human for mouse-rat. Among 10,020 intron positions in the human-mouse comparison, we found unequivocal evidence for five independent intron losses in the mouse lineage but no evidence for intron loss in humans or for intron gain in either lineage.

Phylogenetically older introns strongly correlate with module boundaries in ancient proteins.

The hypothesis that some (but not all) introns were used to construct ancient genes by exon shuffling of modules at the earliest stages of evolution is supported by the finding of an excess of phase-zero intron positions in the boundary regions of such modules in 276 ancient proteins (defined as common to eukaryotes and prokaryotes). Here we show further that as phase-zero intron positions are shared by distant taxa, and thus are truly phylogenetically ancient, their excess in the boundaries becomes greater, rising to an 80% excess if shared by four out of the five taxa: vertebrates, invertebrates, fungi, plants, and protists.

Large-scale comparison of intron positions among animal, plant, and fungal genes.

We purge large databases of animal, plant, and fungal intron-containing genes to a 20% similarity level and then identify the most similar animal-plant, animal-fungal, and plant-fungal protein pairs. We identify the introns in each BLAST 2.0 alignment and score matched intron positions and slid (near-matched, within six nucleotides) intron positions automatically.

The signal of ancient introns is obscured by intron density and homolog number.

In ancient genes whose products have known 3-dimensional structures, an excess of phase zero introns (those that lie between the codons) appear in the boundaries of modules, compact regions of the polypeptide chain. These excesses are highly significant and could support the hypothesis that ancient genes were assembled by exon shuffling involving compact modules. (Phase one and two introns, and many phase zero introns, appear to arise later.

Do introns favor or avoid regions of amino acid conservation?

Are intron positions correlated with regions of high amino acid conservation? For a set of ancient conserved proteins, with intronless prokaryotic but intron-containing eukaryotic homologs, multiple sequence alignments identified residues invariant throughout evolution. Intron positions between codons show no preferences. However, introns lying after the first base of a codon prefer conserved regions, markedly in glycines.

Regularities of context-dependent codon bias in eukaryotic genes.

Nucleotides surrounding a codon influence the choice of this particular codon from among the group of possible synonymous codons. The strongest influence on codon usage arises from the nucleotide immediately following the codon and is known as the N1 context. We studied the relative abundance of codons with N1 contexts in genes from four eukaryotes for which the entire genomes have been sequenced: Homo sapiens, Drosophila melanogaster, Caenorhabditis elegans and Arabidopsis thaliana.

Retinoic acid in the anteroposterior patterning of the zebrafish trunk.

Retinoic acid has been linked to pattern formation in the vertebrate anteroposterior axis. This report describes the spatial and temporal distributions of both endogenous retinoic acid and retinoic acid synthase activity along the anteroposterior axis of neurulating zebrafish embryos, as detected by a transient transgenic assay and by a zymography bioassay. Both retinoic acid levels and synthase activity were found to be highest in anterior regions of the trunk at all of the stages which were analysed.