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.
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. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization.
A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal.
Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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. Patterns of intron-position correspondence between widely diverged eukaryotic species have provided insights into the origins of the vast differences in intron number between eukaryotic species, and studies of specific cases of intron loss and gain have led to progress in understanding the underlying molecular mechanisms and the forces that control intron 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 ≈ 2× 10-9to 2× 10-10per year. Rates of gain vary from 6× 10-13to 4× 10-12per possible intron insertion site per year. There is an inverse correspondence between rates of intron loss and gain, leading to a 20-fold variation among lineages in the ratio of the rates of the two processes. The observed rates of intron gain are insufficient to explain the large number of introns estimated to have been present in the plant-animal ancestor, suggesting that introns present in early eukaryotes may have been created by a fundamentally different process than more recently gained introns.
Complex Early Genes Roy, Scott W.; Gilbert, Walter
Proceedings of the National Academy of Sciences - PNAS,
02/2005, Letnik:
102, Številka:
6
Journal Article
Recenzirano
Odprti dostop
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. Intron losses outnumber gains over a large range of eukaryotic lineages. These results show that early eukaryotic gene structures were very complex, and that simplification, not embellishment, has dominated subsequent evolution.
The Pattern of Intron Loss Roy, Scott W.; Gilbert, Walter
Proceedings of the National Academy of Sciences - PNAS,
01/2005, Letnik:
102, Številka:
3
Journal Article
Recenzirano
Odprti dostop
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. Directly contrary to the expectations of some, introns that do not interrupt codons (phase zero) are more, not less, likely to be lost, an intriguing and previously unappreciated result. Adjacent introns with matching phases are not more likely to be retained, as would be expected if they enjoyed a relative selective advantage. The findings of 3′ and phase zero intron loss biases are in direct contradiction to an extremely recent study of fungi intron evolution. All patterns are less pronounced in the lineage leading to Caenorhabditis elegans, suggesting that the process of intron loss may be qualitatively different in nematodes. Our results support a reverse transcriptase-mediated model of intron loss.
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. Among 1,459 positions in rat-mouse comparisons, we found evidence for one loss in rat but neither loss in mouse nor gain in either lineage. In each case, the intron losses were exact, without change in the surrounding coding sequence, and involved introns that are extremely short, with an average of 200 bp, an order of magnitude shorter than the mammalian average. These results favor a model whereby introns are lost through gene conversion with intronless copies of the gene. In addition, the finding of widespread conservation of intron-exon structure, even over large evolutionary distances, suggests that comparative methods employing information about gene structures should be very successful in correctly predicting exon boundaries in genomic sequences.
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. Overall we find that 10% of the animal introns match plant positions, and a further 7% are "slides." Fifteen percent of fungal introns match animal positions, and 13% match plant positions. Furthermore, the number of alignments with high numbers of matches deviates greatly from the Poisson expectation. The 30 animal-plant alignments with the highest matches (for which 44% of animal introns match plant positions) when aligned with fungal genes are also highly enriched for triple matches: 39% of the fungal introns match both animal and plant positions. This is strong evidence for ancestral introns predating the animal-plant-fungal divergence, and in complete opposition to any expectations based on random insertion. In examining the slid introns, we show that at least half are caused by imperfections in the alignments, and are most likely to be actual matches at common positions. Thus, our final estimates are that ≈14% of animal introns match plant positions, and that ≈17-18% of fungal introns match animal or plant positions, all of these being likely to be ancestral in the eukaryotes.
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. We find that only the ecdysozoa grouping satisfies these predictions, with$P<10^{-6}$. Simulations show that our method, unlike some previous methods, is largely insensitive to rate variation between branches.
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.
Discrete chromatic series Walter, Gilbert G.
Applicable analysis,
03/2011, Letnik:
90, Številka:
3-4
Journal Article
Recenzirano
Chromatic series are series expansions in which the coefficients are linear combinations of derivatives of a function. They were introduced by Ignjatovic (Introduction to Signal Processing Based on ...Differential Operators, Tech. Rep. 1, Kromos Technology, available at
http://www.kromos.com
, February 2001.) as a replacement for Taylor's series and are based on orthogonal polynomials. However, real data usually involves the values of a function and not its derivatives which are needed in both theories. In this article, we replace the derivatives by discrete values in the calculations of the coefficients.
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