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"Rare animals Cloning."
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De-extinction : the science of bringing lost species back to life
In the twenty-first century, because of climate change and other human activities, many animal species have become extinct, and many others are at risk of extinction. Once they are gone, we cannot bring them back or can we?
Book
Small, but surprisingly repetitive genomes: transposon expansion and not polyploidy has driven a doubling in genome size in a metazoan species complex
Background
The causes and consequences of genome size variation across Eukaryotes, which spans five orders of magnitude, have been hotly debated since before the advent of genome sequencing. Previous studies have mostly examined variation among larger taxonomic units (e.g., orders, or genera), while comparisons among closely related species are rare. Rotifers of the
Brachionus plicatilis
species complex exhibit a seven-fold variation in genome size and thus represent a unique opportunity to study such changes on a relatively short evolutionary timescale. Here, we sequenced and analysed the genomes of four species of this complex with nuclear DNA contents spanning 110–422 Mbp. To establish the likely mechanisms of genome size change, we analysed both sequencing read libraries and assemblies for signatures of polyploidy and repetitive element content. We also compared these genomes to that of
B. calyciflorus
, the closest relative with a sequenced genome (293 Mbp nuclear DNA content).
Results
Despite the very large differences in genome size, we saw no evidence of ploidy level changes across the
B. plicatilis
complex. However, repetitive element content explained a large portion of genome size variation (at least 54%). The species with the largest genome,
B. asplanchnoidis,
has a strikingly high 44% repetitive element content, while the smaller
B. plicatilis
genomes contain between 14 and 25% repetitive elements. According to our analyses, the
B. calyciflorus
genome contains 39% repetitive elements, which is substantially higher than previously reported (21%), and suggests that high repetitive element load could be widespread in monogonont rotifers.
Conclusions
Even though the genome sizes of these species are at the low end of the metazoan spectrum, their genomes contain substantial amounts of repetitive elements. Polyploidy does not appear to play a role in genome size variations in these species, and these variations can be mostly explained by changes in repetitive element content. This contradicts the naïve expectation that small genomes are streamlined, or less complex, and that large variations in nuclear DNA content between closely related species are due to polyploidy.
Journal Article
mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare disease of women in which
TSC2
deficient ‘LAM cells’ with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
Lymphangioleiomyomatosis (LAM) is a rare disease in women where TSC2 deficient mTOR signalling aberrant LAM cells and fibroblasts form nodules causing lung cysts and respiratory failure. Here the authors examine how mTOR dependent IL-6 causes senescence in alveolar type 2 cells which may result in impaired lung repair.
Journal Article
Monoallelic variants resulting in substitutions of MAB21L1 Arg51 Cause Aniridia and microphthalmia
Classical aniridia is a congenital and progressive panocular disorder almost exclusively caused by heterozygous loss-of-function variants at the PAX6 locus. We report nine individuals from five families with severe aniridia and/or microphthalmia (with no detectable PAX6 mutation) with ultrarare monoallelic missense variants altering the Arg51 codon of MAB21L1 . These mutations occurred de novo in 3/5 families, with the remaining families being compatible with autosomal dominant inheritance. Mice engineered to carry the p.Arg51Leu change showed a highly-penetrant optic disc anomaly in heterozygous animals with severe microphthalmia in homozygotes. Substitutions of the same codon (Arg51) in MAB21L2 , a close homolog of MAB21L1 , cause severe ocular and skeletal malformations in humans and mice. The predicted nucleotidyltransferase function of MAB21L1 could not be demonstrated using purified protein with a variety of nucleotide substrates and oligonucleotide activators. Induced expression of GFP-tagged wildtype and mutant MAB21L1 in human cells caused only modest transcriptional changes. Mass spectrometry of immunoprecipitated protein revealed that both mutant and wildtype MAB21L1 associate with transcription factors that are known regulators of PAX6 (MEIS1, MEIS2 and PBX1) and with poly(A) RNA binding proteins. Arg51 substitutions reduce the association of wild-type MAB21L1 with TBL1XR1, a component of the NCoR complex. We found limited evidence for mutation-specific interactions with MSI2/Musashi-2, an RNA-binding proteins with effects on many different developmental pathways. Given that biallelic loss-of-function variants in MAB21L1 result in a milder eye phenotype we suggest that Arg51-altering monoallelic variants most plausibly perturb eye development via a gain-of-function mechanism.
Journal Article
Germplasm Rescue of Postmortem Critically Endangered Yangtze Sturgeon (Acipenser dabryanus) by Cell Preservation
With the growing sophistication of cloning technology, rescuing cell resources is of great significance for the protection of endangered animals. The Yangtze sturgeon (Acipenser dabryanus), one of the three Acipenseriformes species in the Yangtze River, is critically endangered. Natural reproduction of the Yangtze sturgeon has not been detected since 2000. Less than 20 wild individuals are kept in husbandry, and all are too old to breed. Therefore, it is urgent to rescue the genetic resources of every wild Yangtze sturgeon. Here, we isolated and preserved viable cells from critically endangered postmortem Yangtze sturgeon for the first time. Attempts to rescue and preserve cell resources were carried out from 8 tissues, brain, kidney, gonad, fin, liver, skin, spleen, and muscle of an over 35-year-old female wild Yangtze sturgeon between 11 and 14 hours after death at 19.8°C in an outdoor concrete pond, and only muscle tissue cells could be successfully subcultured and preserved. Furthermore, the cultured cells showed high post-thaw cell viability and normal growth with a population doubling time of 52.98 h. Moreover, they were fibronectin- and desmin-positive, characterizing them as fibroblastic confirmed muscle cells with fibroblastic properties and myogenic origin. Tests for microbial contamination of the cell lines were negative. Chromosome analysis demonstrated that muscle cells possess a modal polyploid chromosome number of 264. The mitochondrial sequence data of COI genes and 12S rRNA confirmed that the developed cell line originated from A. dabryanus. Furthermore, transfection results indicate that muscle cells could be used for gene manipulation and functional studies. These results suggest that viable muscle cells could also be successfully isolated and cryopreserved from the wild Yangtze sturgeon in a short time after death. This report is not only of great significance for the germplasm rescue of critically endangered Yangtze sturgeon but also provides some scientific reference for the germplasm preservation of other endangered fish.
Journal Article
Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I
Fumarylacetoacetate hydrolase (FAH) is the fifth enzyme in the tyrosine catabolism pathway. A deficiency in human FAH leads to hereditary tyrosinemia type I (HT1), an autosomal recessive disorder that results in the accumulation of toxic metabolites such as succinylacetone, maleylacetoacetate, and fumarylacetoacetate in the liver and kidney, among other tissues. The disease is severe and, when untreated, it can lead to death. A low tyrosine diet combined with the herbicidal nitisinone constitutes the only available therapy, but this treatment is not devoid of secondary effects and long-term complications. In this study, we targeted FAH for the first-time to discover new chemical modulators that act as pharmacological chaperones, directly associating with this enzyme. After screening several thousand compounds and subsequent chemical redesign, we found a set of reversible inhibitors that associate with FAH close to the active site and stabilize the (active) dimeric species, as demonstrated by NMR spectroscopy. Importantly, the inhibitors are also able to partially restore the normal phenotype in a newly developed cellular model of HT1.
Journal Article
Predicting ligand binding affinity using on- and off-rates for the SAMPL6 SAMPLing challenge
Interest in ligand binding kinetics has been growing rapidly, as it is being discovered in more and more systems that ligand residence time is the crucial factor governing drug efficacy. Many enhanced sampling methods have been developed with the goal of predicting ligand binding rates (\\[k_{\\text {on}}\\]) and/or ligand unbinding rates (\\[k_{\\text {off}}\\]) through explicit simulation of ligand binding pathways, and these methods work by very different mechanisms. Although there is not yet a blind challenge for ligand binding kinetics, here we take advantage of experimental measurements and rigorously computed benchmarks to compare estimates of \\[K_D\\] calculated as the ratio of two rates: \\[k_{\\text {off}}/k_{\\text {on}}\\]. These rates were determined using a new enhanced sampling method based on the weighted ensemble framework that we call “REVO”: Reweighting of Ensembles by Variance Optimization. This is a further development of the WExplore enhanced sampling method, in which trajectory cloning and merging steps are guided not by the definition of sampling regions, but by maximizing trajectory variance. Here we obtain estimates of \\[k_{\\text {on}}\\] and \\[k_{\\text {off}}\\] that are consistent across multiple simulations, with an average log10-scale standard deviation of 0.28 for on-rates and 0.56 for off-rates, which is well within an order of magnitude and far better than previously observed for previous applications of the WExplore algorithm. Our rank ordering of the three host–guest pairs agrees with the reference calculations, however our predicted \\[\\Delta G\\] values were systematically lower than the reference by an average of 4.2 kcal/mol. Using tree network visualizations of the trajectories in the REVO algorithm, and conformation space networks for each system, we analyze the results of our sampling, and hypothesize sources of discrepancy between our \\[K_D\\] values and the reference. We also motivate the direct inclusion of \\[k_{\\text {on}}\\] and \\[k_{\\text {off}}\\] challenges in future iterations of SAMPL, to further develop the field of ligand binding kinetics prediction and modeling.
Journal Article
Cloning Wild Life
pThe natural world is marked by an ever-increasing loss of varied habitats, a growing number of species extinctions, and a full range of new kinds of dilemmas posed by global warming. At the same time, humans are also working to actively shape this natural world through contemporary bioscience and biotechnology. In Cloning Wild Life, Carrie Friese posits that cloned endangered animals in zoos sit at the apex of these two trends, as humans seek a scientific solution to environmental crisis. Often fraught with controversy, cloning technologies, Friese argues, significantly affect our conceptualizations of and engagements with wildlife and nature. By studying animals at different locations, Friese explores the human practices surrounding the cloning of endangered animals. She visits zoos—the San Diego Zoological Park, the Audubon Center in New Orleans, and the Zoological Society of London—to see cloning and related practices in action, as well as attending academic and medical conferences and interviewing scientists, conservationists, and zookeepers involved in cloning. Ultimately, she concludes that the act of recalibrating nature through science is what most disturbs us about cloning animals in captivity, revealing that debates over cloning become, in the end, a site of political struggle between different human groups. Moreover, Friese explores the implications of the social role that animals at the zoo play in the first place—how they are viewed, consumed, and used by humans for our own needs. A unique study uniting sociology and the study of science and technology, Cloning Wild Life demonstrates just how much bioscience reproduces and changes our ideas about the meaning of life itself./p
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