Whole-genome duplication (WGD) results in new genomic resources that can be exploited by evolution for rewiring genetic regulatory networks in organisms. In metazoans, WGD occurred before the last ...common ancestor of vertebrates, and has been postulated as a major evolutionary force that contributed to their speciation and diversification of morphological structures. Here, we have sequenced genomes from three of the four extant species of horseshoe crabs-Carcinoscorpius rotundicauda, Limulus polyphemus and Tachypleus tridentatus. Phylogenetic and sequence analyses of their Hox and other homeobox genes, which encode crucial transcription factors and have been used as indicators of WGD in animals, strongly suggests that WGD happened before the last common ancestor of these marine chelicerates >135 million years ago. Signatures of subfunctionalisation of paralogues of Hox genes are revealed in the appendages of two species of horseshoe crabs. Further, residual homeobox pseudogenes are observed in the three lineages. The existence of WGD in the horseshoe crabs, noted for relative morphological stasis over geological time, suggests that genomic diversity need not always be reflected phenotypically, in contrast to the suggested situation in vertebrates. This study provides evidence of ancient WGD in the ecdysozoan lineage, and reveals new opportunities for studying genomic and regulatory evolution after WGD in the Metazoa.
Abstract
The pedestal turbulence intensity required to convert the thin, laminar H-mode scrape-off layer (SOL) to a broad turbulent SOL is calculated using the theory of turbulence spreading. A lower ...bound on the pedestal turbulence level to exceed the neoclassical heuristic drift (HD) width is derived. A reduced model of SOL turbulence spreading is used to determine the SOL width as a function of intensity flux from the pedestal to the SOL. The cross-over value for exceeding the HD model width is then calculated. We determine the pedestal turbulence levels—and the critical scalings thereof—required to achieve this level of broadening. Both drift wave and ballooning mode turbulence are considered. A sensitivity analysis reveals that the key competition is that between spreading and linear
E
×
B
shear damping. The required pedestal turbulence levels scale with
ρ
/
R
.
KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and ...what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.
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•Pancreatic cells exhibit lower phosphofructokinase activity than other cell types•High glucose elevates O-GlcNAcylation and genomic alterations in pancreatic cells•Reduction of RNR activity leads to nucleotide pool imbalance and KRAS mutations•PFK activity alters the sensitivity to high-glucose-induced genomic effects
Most pancreatic ductal adenocarcinomas contain activated KRAS mutations required for cancer initiation and maintenance. Here, Hu et al. show that high glucose promotes O-GlcNAcylation on ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations preferentially in pancreatic cells.
The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, ...especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant Kras
. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KP
C mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.
Fenton’s oxidation is traditionally used to remove inorganic and organic pollutants from water in waster water treatment. It is an advanced oxidation process in which H
2O
2 is catalytically ...decomposed by ferrous irons into hydroxyl radicals (
OH) which have a higher oxidation potential (2.8
V) than H
2O
2. In the work reported here, we for the first time use Fenton’s oxidation to modify the surface of biomedical NiTi shape memory alloy (SMA). The influences of Fenton’s oxidation on the surface microstructure, blood compatibility, leaching of harmful Ni ions and corrosion resistance in simulated body fluids is assessed using scanning electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, inductively coupled plasma mass spectrometry, electrochemical tests, hemolysis analysis and the blood platelet adhesion test. The mechanical stability of the surface titania film produced by Fenton’s oxidation as well as their effects on the shape memory behavior of the SMA are studied by bending tests. Our results show that Fenton’s oxidation produces a novel nanostructured titania gel film with a graded structure on the NiTi substrate without an intermediate Ni-rich layer that is typical of high-temperature oxidation. Moreover, there is a clear Ni-free zone near the top surface of the titania film. The surface structural changes introduced by Fenton’s oxidation improve the electrochemical corrosion resistance and mitigate Ni release. The latter effects are comparable to those observed after oxygen plasma immersion ion implantation reported previously and better than those of high-temperature oxidation. Aging in boiling water improves the crystallinity of the titania film and further reduces Ni leaching. Blood platelet adhesion is remarkably reduced after Fenton’s oxidation, suggesting that the treated SMA has improved thrombo resistance. Enhancement of blood compatibility is believed to stem from the improved hemolysis resistance, the surface wettability and the intrinsic electrical characteristics of the titania film. The titania film produced by Fenton’s oxidation has good mechanical stability and does not adversely impact the shape memory behavior of NiTi. Our work suggests that Fenton’s oxidation is a promising low-temperature, low-cost surface modification method for improving the surface properties of biomedical NiTi SMA.
The MAJORANA DEMONSTRATOR is a leading experiment searching for neutrinoless double-beta decay with high purity germanium (HPGe) detectors. Machine learning provides a new way to maximize the amount ...of information provided by these detectors, but the data-driven nature makes it less interpretable compared to traditional analysis. An interpretability study reveals the machine’s decision-making logic, allowing us to learn from the machine to feed back to the traditional analysis. In this work, we present the first machine learning analysis of the data from the MAJORANA DEMONSTRATOR; this is also the first interpretable machine learning analysis of any germanium detector experiment. Two gradient boosted decision tree models are trained to learn from the data, and a game-theory-based model interpretability study is conducted to understand the origin of the classification power. By learning from data, this analysis recognizes the correlations among reconstruction parameters to further enhance the background rejection performance. Here, by learning from the machine, this analysis reveals the importance of new background categories to reciprocally benefit the standard MAJORANA analysis. This model is highly compatible with next-generation germanium detector experiments like LEGEND since it can be simultaneously trained on a large number of detectors.
For decades, searches for exotic spin interactions have used increasingly precise laboratory measurements to test various theoretical models of particle physics. However, most searches have focused ...on interaction length scales of ≳1mm, corresponding to hypothetical boson masses of ≲0.2meV. Recently, quantum sensors based on nitrogen-vacancy (NV) centers in diamond have emerged as a promising platform to probe spin interactions at the micrometer scale, opening the door to explore new physics at this length scale. Here, we propose experiments to search for several hypothetical interactions between NV electron spins and moving masses. We focus on potential interactions involving the coupling of NV spin ensembles to both spin-polarized and unpolarized masses attached to vibrating mechanical oscillators. For each interaction, we estimate the sensitivity, identify optimal experimental conditions, and analyze potential systematic errors. Using multipulse quantum sensing protocols with NV spin ensembles to improve sensitivity, we project constraints that are a ≳5-orders-of-magnitude improvement over previous constraints at the micrometer scale. We also identify a spin-polarized test mass, based on hyperpolarized ^{13}C nuclear spins in a thin diamond membrane, which offers a favorable combination of high spin density and low stray magnetic fields. Our analysis is timely in light of a recent preprint by Rong et al. (arXiv:2010.15667) reporting a surprising nonzero result of micrometer-scale spin-velocity interactions.
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