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RNA polymerase II–mediated eukaryotic transcription starts with the assembly of the preinitiation complex (PIC) on core promoters. The +1 nucleosome is well positioned about 40 base pairs downstream of the transcription start site (TSS) and is commonly known as a barrier of transcription. The +1 nucleosome–bound PIC-Mediator structures show that PIC-Mediator prefers binding to T40N nucleosome located 40 base pairs downstream of TSS and contacts T50N but not the T70N nucleosome. The nucleosome facilitates the organization of PIC-Mediator on the promoter by binding TFIIH subunit p52 and Mediator subunits MED19 and MED26 and may contribute to transcription initiation. PIC-Mediator exhibits multiple nucleosome-binding patterns, supporting a structural role of the +1 nucleosome in the coordination of PIC-Mediator assembly. Our study reveals the molecular mechanism of PIC-Mediator organization on chromatin and underscores the significance of the +1 nucleosome in regulating transcription initiation.

In eukaryotes, histone acetylation levels directly regulate downstream gene expression. As a plant-specific histone deacetylase (HDAC), HD2D is involved in plant development and abiotic stress. However, the response of HD2D to drought stress and its interacting proteins, is still unclear. In this study, we analysed HD2D gene expression patterns in Arabidopsis, revealing that HD2D gene was highly expressed in roots and rosette leaves, but poorly expressed in other tissues such as stems, flowers, and young siliques. The HD2D gene expression was induced by d-mannitol. We investigated the responses to drought stress in the wild-type plant, HD2D overexpression lines, and hd2d mutants. HD2D-overexpressing lines showed abscisic acid (ABA) hypersensitivity and drought tolerance, and these phenotypes were not present in hd2d mutants. RNA-seq analysis revealed the transcriptome changes caused by HD2D under drought stress, and showed that HD2D responded to drought stress via the ABA signalling pathway. In addition, we demonstrated that CASEIN KINASE II (CKA4) directly interacted with HD2D. The phosphorylation of Ser residues on HD2D by CKA4 enhanced HD2D enzymatic activity. Furthermore, the phosphorylation of HD2D was shown to contribute to lateral root development and ABA sensing in Arabidopsis, but, these phenotypes could not be reproduced by the overexpression of Ser-phospho-null HD2D lines. Collectively, this study suggests that HD2D responded to drought stress by regulating the ABA signalling pathway, and the expression of drought stress-related genes. The regulatory mechanism of HD2D mediated by CKII phosphorylation provides new insights into the ABA response and lateral root development in Arabidopsis.

To investigate pharmacokinetic changes in newer antiepileptic drugs (AEDs) and assess seizure frequencies and risk factors of increased seizures during pregnancy in women with epilepsy (WWE).A total of 56 pregnancies in 53 WWE who received newer antiepileptic drugs (AEDs) were enrolled. Data on seizure activity and types, daily dose, and AEDs blood levels were derived from routine clinical follow-up. Changes in AEDs clearance were compared between each trimester and nonpregnant baseline. The ratio of AED levels of each trimester to their targets (nonpregnant baseline) concentrations (RTC) was compared between patients with and without an increased seizure. A binary logistic regression was used to investigate the risk factors contributing to seizure worsening during pregnancy.Increased clearances of LTG, LEV, and OXC were observed in all trimesters versus nonpregnant baseline. The peak changes in the clearance of LTG (3.42-fold baseline clearance) (p 0.001) and LEV (2.78-fold) (p 0.001) occurred in the second trimester during pregnancy, followed by oxcarbazepine (2.11-fold) in the third trimester (p 0.03). Plasma concentrations of LTG and LEV during pregnancy were significantly decreased compared to baseline levels, except for OXC. However, no significant differences in RTC values were observed between patients with and without seizure worsening. Some risk factors as seizures for the prior nine months could significantly affect seizure frequency during pregnancy.We found substantial changes in the pharmacokinetics of multiple newer AEDs in WWE, reinforcing the need for therapeutic drug monitoring (TDM) during pregnancy. We would encourage at least one monitoring every trimester and probably more frequently for women with poorly seizure control before pregnancy, and AEDs dose adjustment should keep up with clearance changes. In addition, a well-controlled seizure nine months before pregnancy could lower the risks of seizure during pregnancy, highlighting the importance of pre-pregnancy counseling and seizure management before pregnancy.

Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Ten-eleven translocation (TET) enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes. We start with brief descriptions of the mechanisms of TET-mediated 5mC oxidation and TET-dependent DNA demethylation. We then discuss the TET-mediated epigenetic reprogramming in pluripotency maintenance and embryogenesis, as well as in tumorigenesis and neural system. We further describe the structural basis for substrate recognition and preference in TET-mediated 5mC oxidation. Finally, we summarize the chemical molecules and interacting proteins that regulate TET's activity.

Items with high value are often remembered better than those with low value. It is not clear, however, whether this value effect extends to the binding of associative details (e.g., word colour) in episodic memory. Here, we explored whether value enhances memory for associative information in two different scenarios that might support a more effective process of binding between identity and colour. Experiment 1 examined incidental binding between item and colour using coloured images of familiar objects, whereas Experiment 2 examined intentional learning of word colour. In both experiments, increasing value led to improvements in memory for both item and colour, and these effects persisted after approximately 24 hr. Experiment 3a and Experiment 3b replicated the value effect on intentional word–colour memory from Experiment 2 while also demonstrating this effect to be less reliable when word colour is incidental to the encoding phase. Thus, value-directed prioritisation can facilitate episodic associative memory when conditions for binding are optimised through the use of appropriate to-be remembered materials and encoding conditions.

Supplemental material, sj-docx-1-qjp-10.1177_17470218211014439 for The effect of value on long-term associative memory by Xiaotong Yin, Jelena Havelka and Richard J Allen in Quarterly Journal of Experimental Psychology

Hindered phenols have been reported effective to remarkably enhance the damping property of acrylic polymers. In this work, the long–term stability of these novel damping materials were investigated on the basis of thermodynamic phase diagrams. The Flory–Huggins interaction parameter χ between different small molecules and poly(butyl methacrylate) (PBMA) were determined through the melting point depression method proposed by Nishi and Wang. The calculated phase diagram curves agreed well with small-angle light scattering, wide-angle X-ray diffraction, and optical transparency measurements. χ gradually decreased to a negative value as temperature increased and the phase diagrams exhbited an upper critical solution temperature-type spinodal curve. The mixtures with the small-molecule loading of less than 28 vol% were found miscibile at temperatures near the glass-transition temperature. Increasing the intermolecular hydrogen bonding strength between the phenol and carbonyl groups of PBMA could effectively reduce the χ value. Meanwhile, increasing the steric hindrance of the phenolic hydroxyl groups and the sizes of small molecules may sufficiently weaken intramolecular hydrogen bonding interactions. These effects suppress the self-aggregation of small molecules and improve the long-term stability of the damping materials.

A two-step synthesis method of a new hybrid coating was discussed. Zirconium silicate hybrid sol was prepared by in-situ hydrolysis polymerization of zirconium acetate (ZrAc) and Octyltrimethoxy silane (OTMS) in alcohol water system. FTIR characterization showed that ZrAc was hydrolyzed and polymerized in situ to form zirconium sol. Octyl trimethoxysilane (OTMS) was hydrolyzed and grafted onto zirconium sol to form octyl coated silicon zirconium hybrid micelles. The co-hydrolysis time of OTMS and ZrAc sol is an important factor affecting the octyl content in ZrAc-OTMS micelles, which affects the hydrophobicity, hardness and light transmittance of the coating. Once appropriately prolonging the co-hydrolysis time, the octyl content in ZrAc-OTMS micelles, hydrophobic angle and light transmittance of the composite coating will increase while the hardness will decrease. Too long co-hydrolysis time will lead to the opposite results. When the co-hydrolysis time is 50 min, the film is drawn on the common glass substrate by one step immersion method. The hydrophobic angle of the coating reaches 132.01°at room temperature. The hardness of pencil is higher than 3 H. The bonding force is Grade 0. The visible light transmittance is 95.30%, and the visible light transmittance of glass matrix is increased by 2.54%. XPS and SEM analysis results showed that the ZrAc-OTMS hybrid coating has a lamellar, micro porous structure with a diameter about 60–200 nm, and low surface energy modified by octyl hydrophobic groups on the micelles, which plays a lotus leaf effect and improves the hydrophobicity of the coating.

Self-referential processing has been proven to be effective in improving source memory. However, it is unclear whether different types of source information would be consistently enhanced when an item is self-referentially processed. In two experiments, the authors examined the influence of the self (compared with other-referencing and semantic processing) as well as learning intention (incidental/intentional learning) on memory for two types of source information (spatial location and colour) that differ in the amount of cognitive resources they require to be encoded in memory. Results show that self-referencing has enhanced memory for spatial location of words whatever this information is learned intentionally or incidentally, whereas it cannot facilitate memory for the colour of words under the intentional learning condition, nor can it under the incidental condition. These findings suggest that self-referential processing is beneficial in memory improvement but not all-powerful, a source self-reference effect is subject to source information type.

Recently, nuclear magnetic resonance spectroscopy (NMR)-based metabolomics analysis and multivariate statistical techniques have been incorporated into a multidisciplinary approach to profile changes in small molecules associated with the onset and progression of human diseases. The purpose of these efforts is to identify unique metabolite biomarkers in a specific human disease so as to (1) accurately predict and diagnose diseases, including separating distinct disease stages; (2) provide insights into underlying pathways in the pathogenesis and progression of the malady and (3) aid in disease treatment and evaluate the efficacy of drugs. In this review we discuss recent developments in the application of NMR-based metabolomics in searching disease biomarkers in human blood samples in the last 5 years.

High-Tg polymers exhibit high fragilities in general. Here, we report for the first time that small molecules with double phenolic end groups are effective to independently mediate the dynamic fragility (m) and glass transition temperature (Tg) of acrylic polymers. Broad band dielectric spectrometer (BDS), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimeter (DSC) measurements showed that the addition of small molecules with a concentration lower than 30 wt % leads to a narrower relaxation time distribution of the intermolecular cooperative rearrangement motion because of the formation of hydrogen bonding networks. These acrylic polymers exhibited a significant decrease in m while showing a linear increase in Tg by changing the loading of the small molecules. Further experimental results demonstrated that m decreases monotonically with intermolecular hydrogen bonding strength for a given host polymer matrix. The m/Tg value diminishes with increasing small molecule content,...

Histone demethylases play important roles in various biological processes in a manner dependent on their demethylase activities. However, little is known about their demethylase-independent activities. Here, we report that LSD2, a well-known histone H3K4me1/me2 demethylase, possesses an unexpected E3 ubiquitin ligase activity. LSD2 directly ubiquitylates and promotes proteasome-dependent degradation of O-GlcNAc transferase (OGT), and inhibits A549 lung cancer cell growth in a manner dependent on its E3 ligase activity, but not demethylase activity. The depletion of LSD2 stabilizes OGT and promotes colony formation of 293T cells. LSD2 regulates distinct groups of target genes through histone demethylase and E3 ligase activities, respectively. Such regulation suggests a mechanism through which LSD2 suppresses tumorigenesis by promoting the degradation of OGT and other substrates yet to be discovered. Our study reveals an antigrowth function of LSD2 dependent on its E3 ligase activity and establishes a connection between histone demethylase and ubiquitin-dependent pathway.

Suitable area is an important index when selecting air cleaners. The suitable area's models in corresponding standards in American, Canada and Japan are all set up according to the particulate matters concentration equation. The suitable area can be calculated by multiplying a coefficient with CADR. However, air cleaners are also used to remove indoor gaseous chemical contaminants. The suitable area for particulate matters may not be reasonable for gaseous chemical contaminants. A new model to calculate the suitable area for indoor gaseous chemical contaminants has been set up. Using the CADRs of six tested air cleaners on the market, we compared the suitable areas of the air cleaners in different contaminant concentration levels. The results show suitable areas for gaseous chemical contaminants are much smaller than those for particulate matters. It is of great importance to distinguish suitable areas for different contaminants and the new model has a great reference value.

Poly(styrene-co-ethyl acrylate) [P(St-co-EA)] with different ratios of St/EA was mixed with the small molecule 4,4′-thio-bis(6-tert-butyl-m-methyl phenol) (AO300) to investigate the influence of hydrogen bonding strength on the glass transition behavior. The glass transition temperature (Tg) linearly increased after adding AO300, and the slope value decreased with increased St/EA ratio. All lines could be extended to 62 °C, demonstrating that Tg of the small molecule in situ detected by the polymer chain was much higher than that by small molecule itself (29 °C). Fourier transform infrared spectroscopy analysis showed that the small molecules began to be self-associated at a concentration where the hydrogen bonded carbonyl ratio of the bulk polymer was approximately 0.5 and irrespective of the St/EA ratio. Above the critical loading, the mixture's Tg negatively deviated from the linearly extended lines because of self-association of the small molecules. The apparent Tg of AO300 was found to strongly depend on intermolecular hydrogen bonding number and strength. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2015, 53, 400–408

DNA-dependent protein kinase (DNA-PK) is a serine/threonine protein kinase complex composed of a catalytic subunit (DNA-PKcs) and KU70/80 heterodimer bound to DNA. DNA-PK holoenzyme plays a critical role in non-homologous end joining (NHEJ), the major DNA repair pathway. Here, we determined cryo-electron microscopy structure of human DNA-PK holoenzyme at 6.6 A resolution. In the complex structure, DNA-PKcs, KU70, KU80 and DNA duplex form a 650-kDa heterotetramer with 1:1:1:1 stoichiometry. The N-terminal α-solenoid (∼2 800 residues) of DNA-PKcs adopts a double-ring fold and connects the catalytic core domain of DNA-PKcs and KU70/80-DNA. DNA-PKcs and KU70/80 together form a DNA-binding tunnel, which cradles ∼30-bp DNA and prevents sliding inward of DNA-PKcs along with DNA duplex, suggesting a mechanism by which the broken DNA end is protected from unnecessary processing. Structural and biochemical analyses indicate that KU70/80 and DNA coordinately induce conformational changes of DNA-PKcs and allosterically stimulate its kinase activity. We propose a model for activation of DNA-PKcs in which allosteric signals are generated upon DNA-PK holoenzyme formation and transmitted to the kinase domain through N-terminal HEAT repeats and FAT domain of DNA-PKcs. Our studies suggest a mechanism for recognition and protection of broken DNA ends and provide a structural basis for understanding the activation of DNA-PKcs and DNA-PK-mediated NHEJ pathway.

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.

Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). TET enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes.

Mammalian DNA methylation mainly occurs at the carbon-C5 position of cytosine (5mC). TET enzymes were discovered to successively oxidize 5mC to 5-hydromethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). TET enzymes and oxidized 5mC derivatives play important roles in various biological and pathological processes, including regulation of DNA demethylation, gene transcription, embryonic development, and oncogenesis. In this chapter, we will discuss the discovery of TET-mediated 5mC oxidation and the structure, function, and regulation of TET enzymes.

DNA methylation is an important epigenetic modification(1-3). Ten-eleven translocation (TET) proteins are involved in DNA demethylation through iteratively oxidizing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC)(4-8). Here we show that human TET1 and TET2 are more active on 5mC-DNA than 5hmC/5fC-DNA substrates. We determine the crystal structures of TET2-5hmC-DNA and TET2-5fC-DNA complexes at 1.80 angstrom and 1.97 angstrom resolution, respectively. The cytosine portion of 5hmC/5fC is specifically recognized by TET2 in a manner similar to that of 5mC in the TET2-5mC-DNA structure(9), and the pyrimidine base of 5mC/5hmC/5fC adopts an almost identical conformation within the catalytic cavity. However, the hydroxyl group of 5hmC and carbonyl group of 5fC face towards the opposite direction because the hydroxymethyl group of 5hmC and formyl group of 5fC adopt restrained conformations through forming hydrogen bonds with the 1-carboxylate of NOG and N4 exocyclic nitrogen of cytosine, respectively. Biochemical analyses indicate that the substrate preference of TET2 results from the different efficiencies of hydrogen abstraction in TET2-mediated oxidation. The restrained conformation of 5hmC and 5fC within the catalytic cavity may prevent their abstractable hydrogen(s) adopting a favourable orientation for hydrogen abstraction and thus result in low catalytic efficiency. Our studies demonstrate that the substrate preference of TET2 results from the intrinsic value of its substrates at their 5mC derivative groups and suggest that 5hmC is relatively stable and less prone to further oxidation by TET proteins. Therefore, TET proteins are evolutionarily tuned to be less reactive towards 5hmC and facilitate the generation of 5hmC as a potentially stable mark for regulatory functions.

Ozone as a major ambient gas pollutant needs to be removed for many indoor environments due to its adverse health effect. The objective of this study is to investigate the ozone removal performance of a Hopcalite catalyst CuO/MnO2 under different operation conditions. The effect of relative humidity (15-80%), temperature (30-160°C) and ozone concentration (200-2000ppb) was experimentally tested. Then the catalyst was coated on fiberglass media for application. The influence of preparation method was also investigated. Finally, the application analysis of such material is discussed for building environment control situation.