DNA methylation at the 5-position of cytosine (5mC) plays vital roles in mammalian development. DNA methylation is catalyzed by DNA methyltransferases (DNMTs), and the two DNMT families, DNMT3 and ...DNMT1, are responsible for methylation establishment and maintenance, respectively. Since their discovery, biochemical and structural studies have revealed the key mechanisms underlying how DNMTs catalyze de novo and maintenance DNA methylation. In particular, recent development of low-input genomic and epigenomic technologies has deepened our understanding of DNA methylation regulation in germ lines and early stage embryos. In this review, we first describe the methylation machinery including the DNMTs and their essential cofactors. We then discuss how DNMTs are recruited to or excluded from certain genomic elements. Lastly, we summarize recent understanding of the regulation of DNA methylation dynamics in mammalian germ lines and early embryos with a focus on both mice and humans.
Polycomb repressive complexes 1 and 2 (PRC1/2) maintain transcriptional silencing of developmental genes largely by catalyzing the formation of mono-ubiquitinated histone H2A at lysine 119 ...(H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3), respectively. How Polycomb domains are reprogrammed during mammalian preimplantation development remains largely unclear. Here we show that, although H2AK119ub1 and H3K27me3 are highly colocalized in gametes, they undergo differential reprogramming dynamics following fertilization. H3K27me3 maintains thousands of maternally biased domains until the blastocyst stage, whereas maternally biased H2AK119ub1 distribution in zygotes is largely equalized at the two-cell stage. Notably, while maternal PRC2 depletion has a limited effect on global H2AK119ub1 in early embryos, it disrupts allelic H2AK119ub1 at H3K27me3 imprinting loci including Xist. By contrast, acute H2AK119ub1 depletion in zygotes does not affect H3K27me3 imprinting maintenance, at least by the four-cell stage. Importantly, loss of H2AK119ub1, but not H3K27me3, causes premature activation of developmental genes during zygotic genome activation (ZGA) and subsequent embryonic arrest. Thus, our study reveals distinct dynamics and functions of H3K27me3 and H2AK119ub1 in mouse preimplantation embryos.
With advantages such as high theoretical capacity, low cost, and nontoxicity, Zn metal has been widely investigated as an anode for aqueous batteries. However, the problems of dendrite formation and ...sustained corrosion originating from severe interfacial side reactions and uncontrolled Zn electrodeposition in aqueous electrolytes significantly slows down the practical application of Zn metal anodes. To address these issues, herein, an anti‐corrosion elastic constraint (AEC) is introduced that is built with nanosized TiO2 and polyvinylidene fluoride (PVDF) matrix to Zn anode, where the PVDF layer serves as an elastic H2O/O2‐blocking layer and the decorated TiO2 nanoparticles assist uniform Zn electrodeposition. With this corrosion‐inhibition and electrodeposition‐redirection coating, the electrodeposition consistency and thermodynamic stability of the Zn anode are significantly improved, enabling a long‐term stable plating/stripping performance for 2000 h with an ultralow overpotential (<50 mV) and a high average Coulombic efficiency (>99.4%) for 1000 cycles without obvious dendrite formation. Even at a high current density of 8.85 mA cm−2 with limited Zn supply (DODZn = 60%), stable Zn deposition is achieved over 250 h. When coupled with a MnO2 cathode, the AEC‐Zn anode shows a remarkably enhanced full‐cell cycling stability, indicative of high reliability of aqueous Zn batteries for practical application.
An anti‐corrosion elastic constraint is developed to redirect the Zn electrodeposition for aqueous zinc‐ion batteries. With this corrosion‐inhibition and electrodeposition‐redirection coating, the electrodeposition consistency and thermodynamic stability of Zn anodes are significantly improved, enabling a long‐term stable plating/stripping performance for 2000 h with an ultralow overpotential (<50 mV) and a high Coulombic efficiency (>99.4%) for 1000 cycles.
Genomic imprinting is essential for mammalian development. Recent studies have revealed that maternal histone H3 Lys27 trimethylation (H3K27me3) can mediate DNA methylation-independent genomic ...imprinting. However, the regulatory mechanisms and functions of this new imprinting mechanism are largely unknown. Here we demonstrate that maternal Eed, an essential component of the Polycomb group complex 2 (PRC2), is required for establishing H3K27me3 imprinting. We found that all H3K27me3-imprinted genes, including
, lose their imprinted expression in
maternal knockout (matKO) embryos, resulting in male-biased lethality. Surprisingly, although maternal X-chromosome inactivation (XmCI) occurs in
matKO embryos at preimplantation due to loss of
imprinting, it is resolved at peri-implantation. Ultimately, both X chromosomes are reactivated in the embryonic cell lineage prior to random XCI, and only a single X chromosome undergoes random XCI in the extraembryonic cell lineage. Thus, our study not only demonstrates an essential role of
in H3K27me3 imprinting establishment but also reveals a unique XCI dynamic in the absence of
imprinting.
A highly efficient multicomponent reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, alcohol, and α,β-unsaturated aldehyde or ketone is disclosed, which generates the diverse ...H-pyrazolo5,1-aisoquinolines in good yields. This reaction proceeds with good functional group tolerance under mild conditions with high efficiency and excellent selectivity. Preliminary biological assays show that some of these compounds display promising activities as CDC25B inhibitor, TC-PTP inhibitor, and PTP1B inhibitor.
AbstractObjectiveTo provide global, regional, and national estimates of target population sizes for coronavirus disease 2019 (covid-19) vaccination to inform country specific immunisation strategies ...on a global scale.DesignDescriptive study.Setting194 member states of the World Health Organization.PopulationTarget populations for covid-19 vaccination based on country specific characteristics and vaccine objectives (maintaining essential core societal services; reducing severe covid-19; reducing symptomatic infections and stopping virus transmission).Main outcome measureSize of target populations for covid-19 vaccination. Estimates use country specific data on population sizes stratified by occupation, age, risk factors for covid-19 severity, vaccine acceptance, and global vaccine production. These data were derived from a multipronged search of official websites, media sources, and academic journal articles.ResultsTarget population sizes for covid-19 vaccination vary markedly by vaccination goal and geographical region. Differences in demographic structure, presence of underlying conditions, and number of essential workers lead to highly variable estimates of target populations at regional and country levels. In particular, Europe has the highest share of essential workers (63.0 million, 8.9%) and people with underlying conditions (265.9 million, 37.4%); these two categories are essential in maintaining societal functions and reducing severe covid-19, respectively. In contrast, South East Asia has the highest share of healthy adults (777.5 million, 58.9%), a key target for reducing community transmission. Vaccine hesitancy will probably impact future covid-19 vaccination programmes; based on a literature review, 68.4% (95% confidence interval 64.2% to 72.6%) of the global population is willing to receive covid-19 vaccination. Therefore, the adult population willing to be vaccinated is estimated at 3.7 billion (95% confidence interval 3.2 to 4.1 billion).ConclusionsThe distribution of target groups at country and regional levels highlights the importance of designing an equitable and efficient plan for vaccine prioritisation and allocation. Each country should evaluate different strategies and allocation schemes based on local epidemiology, underlying population health, projections of available vaccine doses, and preference for vaccination strategies that favour direct or indirect benefits.
Abstract In previous work, we demonstrated that machine-learning techniques based on mixture density networks (MDNs) are successful in inferring the interior structure of rocky exoplanets with large ...compositional diversity. In this study, we compare the performance of a well-trained MDN model with the conventional Bayesian inversion method based on the Markov chain Monte Carlo (MCMC) method, under the same observable constraints. Considering that MCMC inversion is generally performed with the prior knowledge of planetary mass, radius, and bulk molar ratios of Fe/Mg and Si/Mg, we regenerate a substantial data set of interior structure data for rocky exoplanets and train a new MDN model with inputs of planetary mass, radius, Fe/Mg, and Si/Mg. It has been found that the well-trained MDN model has comparable performance to that of the MCMC method but requires significantly less computation time. The MDN model presents a practical alternative to the traditional MCMC method, surpassing the latter with minimal requirements for specialized knowledge, faster prediction, and greater adaptability. The developed MDN model is made publicly available on GitHub for the broader scientific community’s utilization. With the advent of the James Webb Space Telescope, we are ushering in a new epoch in exoplanetary explorations. In this evolving landscape, the MDN model stands out as a valuable asset, particularly for its ability to rapidly assimilate and interpret new data, thereby substantially advancing our understanding of the interior and habitability of exoplanetary systems.
Adriamycin (Adr) and docetaxel (Doc) are two chemotherapeutic agents commonly used in the treatment of breast cancer. However, patients with breast cancer who are treated by the drugs often develop ...resistance to them and some other drugs. Recently studies have shown that microRNAs (miRNAs, miRs) play an important role in drug-resistance. In present study, miRNA expression profiles of MCF-7/S and its two resistant variant MCF-7/Adr and MCF-7/Doc cells were analyzed using microarray and the results were confirmed by real-time quantitative polymerase chain reaction. Here, 183 differentially expressed miRNAs were identified in the two resistant sublines compared to MCF-7/S. Then, five up-regulated miRNAs (miR-100, miR-29a, miR-196a, miR-222 and miR-30a) in both MCF-7/Adr and MCF-7/Doc were selected to explore their roles in acquisition of drug-resistance using transfection experiment. The results showed that miR-222 and miR-29a mimics and inhibitors had partially changed the drug-resistance of breast cancer cells, which was also confirmed by apoptosis assay. Western blot results suggested that miR-222 and -29a could regulate the expression of PTEN, maybe through which the two miRNAs conferred Adr and Doc resistance in MCF-7 cells. Finally, pathway mapping tools were employed to further analyze signaling pathways affected by the two miRNAs. In summary, this study demonstrates that altered miRNA expression pattern is involved in acquiring resistance to Adr and Doc in breast cancer MCF-7 cells, and that there are some miRNAs who displayed consistent up- or down-regulated expression changes in the two resistant sublines. The most importance is that we identify two miRNAs (miR-222 and miR-29a) involved in drug-resistance, at least in part via targeting PTEN.
•We analyze miRNA expression profiles of the sensitive and resistant MCF-7 cells.•miR-222 and miR-29a confer adriamycin and docetaxel resistance in MCF-7 cells.•We use pathway mapping tools to analyze pathways affected by miR-222 and miR-29a.•miR-222 and miR-29a regulate the expression of PTEN.
In high-power applications, selective harmonic elimination pulsewidth modulation (SHEPWM) method is widely used to eliminate low-order harmonics in three-level inverters with low power losses. ...However, it faces the challenges that the conventional optimization methods for solving harmonic elimination equations in SHEPWM are easy to be trapped in local optimum. Moreover, the neutral point (NP) voltage of three-level inverter cannot be balanced under low-voltage ride-through (LVRT) condition with conventional SHEPWM method. To address these problems, a SHEPWM scheme is proposed, which is on the basis of an improved particle swarm optimization (IPSO) algorithm to solve the harmonic elimination equations and an enhanced NP balance control method in LVRT operation. First, an IPSO algorithm is proposed to calculate the switching angles of the transcendental equations for harmonic elimination. The IPSO algorithm defines a nonlinear negative exponential inertia weight considering the current and optimal fitness value, which can dynamically adjust the local and global searching speed and step size according to the actual situation, greatly improving the convergence speed and solution accuracy and avoiding falling into the local optimum. Then, by increasing the degree of freedom of the output current direction and combining with the NP voltage deviation, an enhanced NP voltage balance control method of SHEPWM in LVRT operation is proposed. The validity of the proposed method is proved by simulation and experimental results.
From the viewpoint of synthetic accessibility and functional group compatibility, photoredox-catalyzed sulfur dioxide insertion strategy enables in situ generation of functionalized sulfonyl radicals ...from easily accessible starting materials under mild conditions, thereby conferring broader application potential. Here we present two complementary photoinduced sulfur dioxide insertion systems to trigger radical asymmetric Truce-Smiles rearrangements for preparing a variety of chiral sulfones that bear a quaternary carbon stereocenter. This protocol features broad substrate scope and excellent stereospecificity. Aside from scalability, the introduction of a quaternary carbon stereocenter at position β to bioactive molecule-derived sulfones further demonstrates the practicality and potential of this methodology.
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