In this trial, 443 patients with pulmonary arterial hypertension were assigned to placebo or to the soluble guanylate cyclase stimulator riociguat. At 12 weeks, riociguat significantly improved the ...6-minute walk distance and pulmonary vascular resistance.
Pulmonary arterial hypertension is a life-threatening disease that is characterized by increased pulmonary vascular resistance owing to progressive vascular remodeling, which can ultimately lead to right heart failure and death.
1
,
2
Current treatments include phosphodiesterase type 5 inhibitors, prostanoids, and endothelin-receptor antagonists.
1
However, mortality remains high despite treatment,
3
and there is a considerable unmet medical need in the management of this disorder.
As noted elsewhere in this issue of the
Journal,
4
riociguat is a member of a novel therapeutic class known as soluble guanylate cyclase stimulators. Riociguat has a dual mode of action, acting in synergy with endogenous nitric oxide . . .
Scaling up dynamic time warping for datamining applications Keogh, Eamonn J.; Pazzani, Michael J.
Conference on Knowledge Discovery in Data: Proceedings of the sixth ACM SIGKDD international conference on Knowledge discovery and data mining; 20-23 Aug. 2000,
08/2000
Conference Proceeding
Polyploidy has played an important role in evolution across the tree of life but it is still unclear how polyploid lineages may persist after their initial formation. While both common and ...well-studied in plants, polyploidy is rare in animals and generally less understood. The Australian burrowing frog genus Neobatrachus is comprised of six diploid and three polyploid species and offers a powerful animal polyploid model system. We generated exome-capture sequence data from 87 individuals representing all nine species of Neobatrachus to investigate species-level relationships, the origin and inheritance mode of polyploid species, and the population genomic effects of polyploidy on genus-wide demography. We describe rapid speciation of diploid Neobatrachus species and show that the three independently originated polyploid species have tetrasomic or mixed inheritance. We document higher genetic diversity in tetraploids, resulting from widespread gene flow between the tetraploids, asymmetric inter-ploidy gene flow directed from sympatric diploids to tetraploids, and isolation of diploid species from each other. We also constructed models of ecologically suitable areas for each species to investigate the impact of climate on differing ploidy levels. These models suggest substantial change in suitable areas compared to past climate, which correspond to population genomic estimates of demographic histories. We propose that Neobatrachus diploids may be suffering the early genomic impacts of climate-induced habitat loss, while tetraploids appear to be avoiding this fate, possibly due to widespread gene flow. Finally, we demonstrate that Neobatrachus is an attractive model to study the effects of ploidy on the evolution of adaptation in animals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Enzymes that catalyse CpG methylation in DNA, including the DNA methyltransferases 1 (DNMT1), 3A (DNMT3A) and 3B (DNMT3B), are indispensable for mammalian tissue development and homeostasis
. They ...are also implicated in human developmental disorders and cancers
, supporting the critical role of DNA methylation in the specification and maintenance of cell fate. Previous studies have suggested that post-translational modifications of histones are involved in specifying patterns of DNA methyltransferase localization and DNA methylation at promoters and actively transcribed gene bodies
. However, the mechanisms that control the establishment and maintenance of intergenic DNA methylation remain poorly understood. Tatton-Brown-Rahman syndrome (TBRS) is a childhood overgrowth disorder that is defined by germline mutations in DNMT3A. TBRS shares clinical features with Sotos syndrome (which is caused by haploinsufficiency of NSD1, a histone methyltransferase that catalyses the dimethylation of histone H3 at K36 (H3K36me2)
), which suggests that there is a mechanistic link between these two diseases. Here we report that NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions. Genome-wide analysis shows that the binding and activity of DNMT3A colocalize with H3K36me2 at non-coding regions of euchromatin. Genetic ablation of Nsd1 and its paralogue Nsd2 in mouse cells results in a redistribution of DNMT3A to H3K36me3-modified gene bodies and a reduction in the methylation of intergenic DNA. Blood samples from patients with Sotos syndrome and NSD1-mutant tumours also exhibit hypomethylation of intergenic DNA. The PWWP domain of DNMT3A shows dual recognition of H3K36me2 and H3K36me3 in vitro, with a higher binding affinity towards H3K36me2 that is abrogated by TBRS-derived missense mutations. Together, our study reveals a trans-chromatin regulatory pathway that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth.
Background
Recent data propose a diagnostic and prognostic capacity for citrullinated histone H3 (H3Cit), a marker of neutrophil extracellular traps (NETs), in pathologic conditions such as cancer ...and thrombosis. However, current research is hampered by lack of standardized assays.
Objectives
We aimed to develop an assay to reliably quantify nucleosomal H3Cit in human plasma.
Methods
We assessed the common practice of in vitro enzymatically modified histone H3 as calibration standards and the specificity of available intrapeptidyl citrulline antibodies. Based on our findings, we developed and validated a novel assay to quantify nucleosomal H3Cit in human plasma.
Results
We show that enzymatically citrullinated H3 proteins are compromised by high enzyme‐dependent lot variability as well as instability in plasma. We furthermore demonstrate that the majority of commercially available antibodies against intrapeptidyl citrulline display poor specificity for their reported target when tested against a panel of semi‐synthetic nucleosomes containing distinct histone H3 citrullinations. Finally, we present a novel assay utilizing highly specific monoclonal antibodies and semi‐synthetic nucleosomes containing citrulline in place of arginine at histone H3, arginine residues 2, 8, and 17 (H3R2,8,17Cit) as calibration standards. Rigorous validation of this assay shows its capacity to accurately and reliably quantify nucleosomal H3Cit levels in human plasma with clear elevations in cancer patients compared to healthy individuals.
Conclusions
Our novel approach using defined nucleosome controls enables reliable quantification of H3Cit in human plasma. This assay will be broadly applicable to study the role of histone citrullination in disease and its utility as a biomarker.
Abstract Objectives To examine outcome of bilateral extracranial to intracranial (EC-IC) bypass surgeries for a Down syndrome patient with hard-to-treat epilepsy and moyamoya. Materials and methods ...Superficial temporal arteries were anastamosed using an indirect bypass technique to middle cerebral arteries bilaterally to help limit perfusion deficits and seizure controls. Results Two superficial temporal to middle cerebral artery indirect bypass surgeries were performed within 3 months. Post-revascularization improvements included seizure control, gait, perfusion, wakefulness, language and quality of life. Conclusion In patients with Down syndrome and moyamoya, improvements in seizure control and quality of life may occur with EC-IC bypass procedures.
Global biodiversity loss is a profound consequence of human activity. Disturbingly, biodiversity loss is greater than realized because of the unknown number of undocumented species. Conservation ...fundamentally relies on taxonomic recognition of species, but only a fraction of biodiversity is described. Here, we provide a new quantitative approach for prioritizing rigorous taxonomic research for conservation. We implement this approach in a highly diverse vertebrate group—Australian lizards and snakes. Of 870 species assessed, we identified 282 (32.4%) with taxonomic uncertainty, of which 17.6% likely comprise undescribed species of conservation concern. We identify 24 species in need of immediate taxonomic attention to facilitate conservation. Using a broadly applicable return-on-investment framework, we demonstrate the importance of prioritizing the fundamental work of identifying species before they are lost.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To date, cross-species comparisons of genetic interactomes have been restricted to small or functionally related gene sets, limiting our ability to infer evolutionary trends. To facilitate a more ...comprehensive analysis, we constructed a genome-scale epistasis map (E-MAP) for the fission yeast Schizosaccharomyces pombe, providing phenotypic signatures for ∼60% of the nonessential genome. Using these signatures, we generated a catalog of 297 functional modules, and we assigned function to 144 previously uncharacterized genes, including mRNA splicing and DNA damage checkpoint factors. Comparison with an integrated genetic interactome from the budding yeast Saccharomyces cerevisiae revealed a hierarchical model for the evolution of genetic interactions, with conservation highest within protein complexes, lower within biological processes, and lowest between distinct biological processes. Despite the large evolutionary distance and extensive rewiring of individual interactions, both networks retain conserved features and display similar levels of functional crosstalk between biological processes, suggesting general design principles of genetic interactomes.
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► Genetic interaction map in fission yeast covering 60% of the nonessential genome ► ∼300 functional modules identified, providing function for uncharacterized genes ► Individual interactions between genes in different processes are poorly conserved ► Overall levels of genetic crosstalk between pairs of processes are highly conserved
3,4-diaminopyridine (3,4-DAP) is an effective, symptomatic treatment for Lambert-Eaton myasthenic syndrome (LEMS). Several trials have studied the effects of 3,4-DAP in small numbers of LEMS ...patients. We systematically reviewed all randomized trials of 3,4-DAP in LEMS to determine the efficacy of this treatment using meta-analysis of clinical and electrophysiological end points. Data from four randomized, placebo-controlled trials revealed that muscle-strength scores increased significantly with 3,4-DAP. Limited metaanalysis performed on two trials using the quantitative myasthenia gravis score indicated that the clinical benefits seen were modest, with an improvement in quantitative myasthenia gravis score of 2.44 points (95% confidence interval: 1.2-3.6). Meta-analysis of the mean change in compound muscle action potential amplitude following 3,4-DAP treatment revealed a significant improvement compared to placebo (1.36 mV, 95% confidence interval: 0.99-1.72). 3,4-DAP is an effective, safe, first-line symptomatic treatment for LEMS, with significant clinical and electrophysiological benefits demonstrated by meta-analysis. Keywords: Lambert-Eaton myasthenic syndrome, 3,4-diaminopyridine, meta-analysis
Aim: The mesic biome, encompassing both rain forest and open sclerophyllous forests, is central to understanding the evolution of Australia's terrestrial biota and has long been considered the ...ancestral biome of the continent. Our aims are to review and refine key hypotheses derived from palaeoclimatic data and the fossil record that are critical to understanding the evolution of the Australian mesic biota. We examine predictions arising from these hypotheses using available molecular phylogenetic and phylogeographical data. In doing so, we increase understanding of the mesic biota and highlight data deficiencies and fruitful areas for future research. Location: The mesic biome of Australia, along the eastern coast of Australia, and in the south-east and south-west, including its rain forest and sclerophyllous, often eucalypt-dominated, habitats. Methods: We derived five hypotheses based on palaeoclimatic and fossil data regarding the evolution of the Australian mesic biota, particularly as it relates to the mesic biome. We evaluated predictions formulated from these hypotheses using suitable molecular phylogenies of terrestrial plants and animals and freshwater invertebrates. Results: There was support for the ancestral position of mesic habitat in most clades, with support for rain forest habitat ancestry in some groups, while evidence of ancestry in mesic sclerophyllous habitats was also demonstrated for some plants and herpetofauna. Contraction of mesic habitats has led to extinction of numerous lineages in many clades and this is particularly evident in the rain forest component. Species richness was generally higher in sclerophyllous clades than in rain forest clades, probably due to higher rates of net speciation in the former and extinction in the latter. Although extinction has been prominent in rain forest communities, tropical rain forests appear to have experienced extensive immigration from northern neighbours. Pleistocene climatic oscillations have left genetic signatures at multiple levels of divergence and with complex geographical structuring, even in areas with low topographical relief and few obvious geographical barriers. Main conclusions: Our review confirms long-held views of the ancestral position of the Australian mesic biome but also reveals new insights into the complexity of the processes of contraction, fragmentation, extinction and invasion during the evolution of this biome.
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