Insights into RAG Evolution from the Identification of "Missing Link" Family A RAGL Transposons.

A series of "molecular domestication" events are thought to have converted an invertebrate RAG-like (RAGL) transposase into the RAG1-RAG2 (RAG) recombinase, a critical enzyme for adaptive immunity in jawed vertebrates. The timing and order of these events are not well understood, in part because of a dearth of information regarding the invertebrate RAGL-A transposon family. In contrast to the abundant and divergent RAGL-B transposon family, RAGL-A most closely resembles RAG and is represented by a single orphan RAG1-like (RAG1L) gene in the genome of the hemichordate Ptychodera flava (PflRAG1L-A). Here, we provide evidence for the existence of complete RAGL-A transposons in the genomes of P. flava and several echinoderms. The predicted RAG1L-A and RAG2L-A proteins encoded by these transposons intermingle sequence features of jawed vertebrate RAG and RAGL-B transposases, leading to a prediction of DNA binding, catalytic, and transposition activities that are a hybrid of RAG and RAGL-B. Similarly, the terminal inverted repeats (TIRs) of the RAGL-A transposons combine features of both RAGL-B transposon TIRs and RAG recombination signal sequences. Unlike all previously described RAG2L proteins, RAG2L-A proteins contain an acidic hinge region, which we demonstrate is capable of efficiently inhibiting RAG-mediated transposition. Our findings provide evidence for a critical intermediate in RAG evolution and argue that certain adaptations thought to be specific to jawed vertebrates (e.g. the RAG2 acidic hinge) actually arose in invertebrates, thereby focusing attention on other adaptations as the pivotal steps in the completion of RAG domestication in jawed vertebrates.

Insights into RAG evolution from the identification of "missing link" family A RAGL transposons.

A series of "molecular domestication" events are thought to have converted an invertebrate RAG-like (RAGL) transposase into the RAG1-RAG2 (RAG) recombinase, a critical enzyme for adaptive immunity in jawed vertebrates. The timing and order of these events is not well understood, in part because of a dearth of information regarding the invertebrate RAGL-A transposon family. In contrast to the abundant and divergent RAGL-B transposon family, RAGL-A most closely resembles RAG and is represented by a single orphan RAG1-like (RAG1L) gene in the genome of the hemichordate Ptychodera flava (PflRAG1L-A). Here, we provide evidence for the existence of complete RAGL-A transposons in the genomes of P. flava and several echinoderms. The predicted RAG1L-A and RAG2L-A proteins encoded by these transposons intermingle sequence features of jawed vertebrate RAG and RAGL-B transposases, leading to a prediction of DNA binding, catalytic, and transposition activities that are a hybrid of RAG and RAGL-B. Similarly, the terminal inverted repeats (TIRs) of the RAGL-A transposons combine features of both RAGL-B transposon TIRs and RAG recombination signal sequences. Unlike all previously described RAG2L proteins, PflRAG2L-A and echinoderm RAG2L-A contain an acidic hinge region, which we demonstrate is capable of efficiently inhibiting RAG-mediated transposition. Our findings provide evidence for a critical intermediate in RAG evolution and argue that certain adaptations thought to be specific to jawed vertebrates (e.g., the RAG2 acidic hinge) actually arose in invertebrates, thereby focusing attention on other adaptations as the pivotal steps in the completion of RAG domestication in jawed vertebrates.

Electrochemical Performances of Nickel-Rich Single-Crystal LiNi0.83 Co0.12 Mn0.05 O2 Cathode Material for Lithium-Ion Batteries Synthesized by Tuning Li+ /Ni2+ Mixing.

Single-crystal nickel-rich materials are promising alternatives to polycrystalline cathodes owing to their excellent structure stability and cycle performance while the cathode material usually appears high cation mixing, which may have a negative effect on its electrochemical performance. The study presents the structural evolution of single-crystal LiNi0.83 Co0.12 Mn0.05 O2 in the temperature-composition space using temperature-resolved in situ XRD and the cation mixing is tuned to improve electrochemical performances. The as-synthesized single-crystal sample shows high initial discharge specific capacity (195.5 mAh g-1 at 1 C), and excellent capacity retention (80.1 % after 400 cycles at 1 C), taking account of lower structure disorder (Ni2+ occupying Li sites is 1.56 %) and integrated grains with an average of 2-3 µm. In addition, the single-crystal material also displays a superior rate capability of 159.1 mAh g-1 at the rate of 5 C. This excellent performance is attributed to the rapid Li+ transportation within the crystal structure with fewer Ni2+ cations in Li layer as well as intactly single grains. In sum, the regulation of Li+ /Ni2+ mixing provides a feasible strategy for boosting single-crystal nickel-rich cathode material.

Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity.

DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPAN321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPAN321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA-mutated leukemia with DNA-hypomethylating agents.

The comparative safety of human papillomavirus vaccines: A Bayesian network meta-analysis.

BACKGROUND AND AIMS: The safety of human papillomavirus (HPV) vaccines, one of the major challenges to public vaccination, has been controversial. This study assessed the adverse reactions of various HPV vaccines, including bivalent HPV (2vHPV), quadrivalent HPV (4vHPV), and 9-valent HPV (9vHPV) vaccines. METHODS: PubMed, Embase, and Central databases were searched for randomized controlled trials (RCTs) on the comparative safety of HPV vaccines. A network meta-analysis was performed based on the Bayesian framework random-effects model. RESULTS: This study included 23 RCTs. Analysis across these reports indicated that the 2vHPV vaccine was associated with significantly more systemic adverse events than the 4vHPV vaccine (risk ratio [RR]: 1.28, 95% credible interval [CrI]: 1.14-1.44), 9vHPV vaccine (RR: 1.25, 95% CrI: 1.06-1.49), and placebo (RR: 1.31, 95% CrI: 1.18-1.46). However, there were no statistically significant differences in serious adverse events between the vaccinated and placebo groups. For injection-site adverse events, there were substantial inconsistencies between the direct and indirect effects; therefore, the analysis results of the safety were presented only for systemic and serious adverse events. CONCLUSIONS: The 2vHPV vaccine resulted in more systemic adverse events than other vaccines and placebo. No significant differences in serious adverse events were observed. Further studies are needed to obtain more information regarding the safety of HPV vaccines.

The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination.

Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1-383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.

Structural insight into autoinhibition and histone H3-induced activation of DNMT3A.

DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 Å resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.

Basic level scene understanding: categories, attributes and structures.

A longstanding goal of computer vision is to build a system that can automatically understand a 3D scene from a single image. This requires extracting semantic concepts and 3D information from 2D images which can depict an enormous variety of environments that comprise our visual world. This paper summarizes our recent efforts toward these goals. First, we describe the richly annotated SUN database which is a collection of annotated images spanning 908 different scene categories with object, attribute, and geometric labels for many scenes. This database allows us to systematically study the space of scenes and to establish a benchmark for scene and object recognition. We augment the categorical SUN database with 102 scene attributes for every image and explore attribute recognition. Finally, we present an integrated system to extract the 3D structure of the scene and objects depicted in an image.

Structural insight into coordinated recognition of trimethylated histone H3 lysine 9 (H3K9me3) by the plant homeodomain (PHD) and tandem tudor domain (TTD) of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) protein.

UHRF1 is an important epigenetic regulator connecting DNA methylation and histone methylations. UHRF1 is required for maintenance of DNA methylation through recruiting DNMT1 to DNA replication forks. Recent studies have shown that the plant homeodomain (PHD) of UHRF1 recognizes the N terminus of unmodified histone H3, and the interaction is inhibited by methylation of H3R2, whereas the tandem tudor domain (TTD) of UHRF1 recognizes trimethylated histone H3 lysine 9 (H3K9me3). However, how the two domains of UHRF1 coordinately recognize histone methylations remains elusive. In this report, we identified that PHD largely enhances the interaction between TTD and H3K9me3. We present the crystal structure of UHRF1 containing both TTD and PHD (TTD-PHD) in complex with H3K9m3 peptide at 3.0 Å resolution. The structure shows that TTD-PHD binds to the H3K9me3 peptide with 1:1 stoichiometry with the two domains connected by the H3K9me3 peptide and a linker region. The TTD interacts with residues Arg-8 and trimethylated Lys-9, and the PHD interacts with residues Ala-1, Arg-2, and Lys-4 of the H3K9me3 peptide. The biochemical experiments indicate that PHD-mediated recognition of unmodified H3 is independent of the TTD, whereas TTD-mediated recognition of H3K9me3 PHD. Thus, both TTD and PHD are essential for specific recognition of H3K9me3 by UHRF1. Interestingly, the H3K9me3 peptide induces conformational changes of TTD-PHD, which do not affect the autoubiquitination activity or hemimethylated DNA binding affinity of UHRF1 in vitro. Taken together, our studies provide structural insight into the coordinated recognition of H3K9me3 by the TTD and PHD of UHRF1.

[A sero-epidemiology study on hepatitis E virus infection in Fujian province].

OBJECTIVE: To understand the sero-prevalence of hepatitis E virus (HEV) infection among different populations and animals in Fujian province. METHODS: One thousand one hundred and fifty-one serum samples were collected from 5 species of animals including swine, dog, cow, sheep and rat. A total of 2209 and 1722 serum samples from the general population and from the exposed population were collected. Anti-HEV IgG was detected by ELISA. The general population was composed of healthy blood donors and the individuals who had attended physical examination including farmers, handlers, veterinarians, cooks who worked with pigs or chickens while the poultry wholesale suppliers made up the exposure population. RESULTS: The infection rates of HEV in animals were different between species (chi2 = 406.25, P < 0.01) with the highest seen in the pig group. With pigs being kept at home, the rates were between 70.00% and 94.12% but the rate was 39.77% for those families that keeping the pigs at farms. The infection rate of HEV was 23.3% in the general population and 33.3% in the exposed populations, respectively. A significantly higher infection rate for anti-HEV was found in the exposed population when comparing with general population. The positive rate of anti-HEV IgG was significantly higher in the exposed population that closely having had contact with chickens than those who had contact with pigs. The increasing trend of HEV infection rate with age had been found but there was no significant difference between males and females in the general population. In the exposed population, the infection rate in males was significantly higher than that in females. CONCLUSION: The infection ratse of HEV in pigs and in the exposure population were much higher, especially for those persons in close contact with chickens or pigs, suggesting that the sub-clinical infection for HEV might exist. These data further supported the hypothesis that HEV might have been an zoonotic disease.