Regulation of Ras–MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells

In response to retinoic acid, embryonic stem and carcinoma cells undergo differentiation to embryonic primitive endoderm cells, accompanied by a reduction in cell proliferation. Differentiation does not reduce the activation of cellular MAPK/Erk, but does uncouple mitogen-activated protein kinase (MAPK) activation from phosphorylation/activation of Elk-1 and results in inhibition of c-Fos expression, whereas phosphorylation of the cytoplasmic substrate p90RSK remains unaltered. Cell fractionation and confocal immunofluorescence microscopy demonstrated that activated MAPK is restricted to the cytoplasmic compartment after differentiation. An intact actin and microtubule cytoskeleton appears to be required for the restriction of MAPK nuclear entry induced by retinoic acid treatment because the cytoskeletal disrupting agents nocodazole, colchicine, and cytochalasin D are able to revert the suppression of c-Fos expression. Thus, suppression of cell proliferation after retinoic acid–induced endoderm differentiation of embryonic stem and carcinoma cells is achieved by restricting nuclear entry of activated MAPK, and an intact cytoskeleton is required for the restraint

Differential requirement for Dab2 in the development of embryonic and extra-embryonic tissues

BACKGROUND: Disabled-2 (Dab2) is an endocytic adaptor protein involved in clathrin-mediated endocytosis and cargo trafficking. Since its expression is lost in several cancer types, Dab2 has been suggested to be a tumor suppressor. In vitro studies indicate that Dab2 establishes epithelial cell polarity and organization by directing endocytic trafficking of membrane glycoproteins. Dab2 also modulates cellular signaling pathways by mediating the endocytosis and recycling of surface receptors and associated signaling components. Previously, two independent gene knockout studies have been reported, with some discrepancies in the observed embryonic phenotypes. To further clarify the in vivo roles of Dab2 in development and physiology, we designed a new floxed allele to delete dab2 gene. RESULTS: The constitutive dab2 deleted embryos showed a spectrum in the degree of endoderm disorganization in E5.5 and no mutant embryos persisted at E9.5. However, the mice were grossly normal when dab2 deletion was restricted to the embryo proper and the gene was retained in extraembryonic tissues using Meox2-Cre and Sox2-Cre. Adult Dab2-deficient mice had a small but statistically significant increase in serum cholesterol levels. CONCLUSION: The study of the new dab2 mutant allele in embryos and embryoid bodies confirms a role for Dab2 in extraembryonic endoderm development and epithelial organization. Experimental results with embryoid bodies suggest that additional endocytic adaptors such as Arh and Numb could partially compensate for Dab2 loss. Conditional deletion indicates that Dab2 is dispensable for organ development, when the vast majority of the embryonic cells are dab2 null. However, Dab2 has a physiological role in the endocytosis of lipoproteins and cholesterol metabolism

Towards Realistic Low-resource Relation Extraction: A Benchmark with Empirical Baseline Study

This paper presents an empirical study to build relation extraction systems in low-resource settings. Based upon recent pre-trained language models, we comprehensively investigate three schemes to evaluate the performance in low-resource settings: (i) different types of prompt-based methods with few-shot labeled data; (ii) diverse balancing methods to address the long-tailed distribution issue; (iii) data augmentation technologies and self-training to generate more labeled in-domain data. We create a benchmark with 8 relation extraction (RE) datasets covering different languages, domains and contexts and perform extensive comparisons over the proposed schemes with combinations. Our experiments illustrate: (i) Though prompt-based tuning is beneficial in low-resource RE, there is still much potential for improvement, especially in extracting relations from cross-sentence contexts with multiple relational triples; (ii) Balancing methods are not always helpful for RE with long-tailed distribution; (iii) Data augmentation complements existing baselines and can bring much performance gain, while self-training may not consistently achieve advancement to low-resource RE. Code and datasets are in https://github.com/zjunlp/LREBench.Comment: Accepted to EMNLP 2022 (Findings) and the project website is https://zjunlp.github.io/project/LREBench

Response of the mosquito protein interaction network to dengue infection

<p>Abstract</p> <p>Background</p> <p>Two fifths of the world's population is at risk from dengue. The absence of effective drugs and vaccines leaves vector control as the primary intervention tool. Understanding dengue virus (DENV) host interactions is essential for the development of novel control strategies. The availability of genome sequences for both human and mosquito host greatly facilitates genome-wide studies of DENV-host interactions.</p> <p>Results</p> <p>We developed the first draft of the mosquito protein interaction network using a computational approach. The weighted network includes 4,214 <it>Aedes aegypti </it>proteins with 10,209 interactions, among which 3,500 proteins are connected into an interconnected scale-free network. We demonstrated the application of this network for the further annotation of mosquito proteins and dissection of pathway crosstalk. Using three datasets based on physical interaction assays, genome-wide RNA interference (RNAi) screens and microarray assays, we identified 714 putative DENV-associated mosquito proteins. An integrated analysis of these proteins in the network highlighted four regions consisting of highly interconnected proteins with closely related functions in each of replication/transcription/translation (RTT), immunity, transport and metabolism. Putative DENV-associated proteins were further selected for validation by RNAi-mediated gene silencing, and dengue viral titer in mosquito midguts was significantly reduced for five out of ten (50.0%) randomly selected genes.</p> <p>Conclusions</p> <p>Our results indicate the presence of common host requirements for DENV in mosquitoes and humans. We discuss the significance of our findings for pharmacological intervention and genetic modification of mosquitoes for blocking dengue transmission.</p

Energy absorption ability of buckyball C720 at low impact speed: a numerical study based on molecular dynamics

The dynamic impact response of giant buckyball C720 is investigated by using molecular dynamics simulations. The non-recoverable deformation of C720 makes it an ideal candidate for high-performance energy absorption. Firstly, mechanical behaviors under dynamic impact and low-speed crushing are simulated and modeled, which clarifies the buckling-related energy absorption mechanism. One-dimensional C720 arrays (both vertical and horizontal alignments) are studied at various impact speeds, which show that the energy absorption ability is dominated by the impact energy per buckyball and less sensitive to the number and arrangement direction of buckyballs. Three-dimensional stacking of buckyballs in simple cubic, body-centered cubic, hexagonal, and face-centered cubic forms are investigated. Stacking form with higher occupation density yields higher energy absorption. The present study may shed lights on employing C720 assembly as an advanced energy absorption system against low-speed impacts

A Super Energy Mitigation Nanostructure at High Impact Speed Based on Buckyball System

The energy mitigation properties of buckyballs are investigated using molecular dynamics (MD) simulations. A one dimensional buckyball long chain is employed as a unit cell of granular fullerene particles. Two types of buckyballs i.e. C60 and C720 with recoverable and non-recoverable behaviors are chosen respectively. For C60 whose deformation is relatively small, a dissipative contact model is proposed. Over 90% of the total impact energy is proven to be mitigated through interfacial reflection of wave propagation, the van der Waals interaction, covalent potential energy and atomistic kinetic energy evidenced by the decent force attenuation and elongation of transmitted impact. Further, the C720 system is found to outperform its C60 counterpart and is able to mitigate over 99% of the total kinetic energy by using a much shorter chain thanks to its non-recoverable deformation which enhances the four energy dissipation terms. Systematic studies are carried out to elucidate the effects of impactor speed and mass, as well as buckyball size and number on the system energy mitigation performance. This one dimensional buckyball system is especially helpful to deal with the impactor of high impact speed but small mass. The results may shed some lights on the research of high-efficiency energy mitigation material selections and structure designs

A Study of the Merger History of the Galaxy Group HCG 62 Based on X-Ray Observations and SPH Simulations

We choose the bright compact group HCG 62, which was found to exhibit both excess X-ray emission and high Fe abundance to the southwest of its core, as an example to study the impact of mergers on chemical enrichment in the intragroup medium. We first reanalyze the high-quality Chandra and XMM-Newton archive data to search for the evidence for additional SN II yields, which is expected as a direct result of the possible merger-induced starburst. We reveal that, similar to the Fe abundance, the Mg abundance also shows a high value in both the innermost region and the southwest substructure, forming a high-abundance plateau, meanwhile all the SN Ia and SN II yields show rather flat distributions in $>0.1r_{200}$ in favor of an early enrichment. Then we carry out a series of idealized numerical simulations to model the collision of two initially isolated galaxy groups by using the TreePM-SPH GADGET-3 code. We find that the observed X-ray emission and metal distributions, as well as the relative positions of the two bright central galaxies with reference to the X-ray peak, can be well reproduced in a major merger with a mass ratio of 3 when the merger-induced starburst is assumed. The `best-match' snapshot is pinpointed after the third pericentric passage when the southwest substructure is formed due to gas sloshing. By following the evolution of the simulated merging system, we conclude that the effects of such a major merger on chemical enrichment are mostly restricted within the core region when the final relaxed state is reached.Comment: Accepted for publication in the Astrophysical Journa