Multivalent interactions by the set8 histone methyltransferase with its nucleosome substrate

Set8 is the only mammalian monomethyltransferase responsible for H4K20me1, a methyl mark critical for genomic integrity of eukaryotic cells. We present here a structural model for how Set8 uses multivalent interactions to bind and methylate the nucleosome based on crystallographic and solution studies of the Set8/nucleosome complex. Our studies indicate that Set8 employs its i-SET and c-SET domains to engage nucleosomal DNA 1 to 1.5 turns from the nucleosomal dyad and in doing so, it positions the SET domain for catalysis with H4 Lys20. Surprisingly, we find that a basic N-terminal extension to the SET domain plays an even more prominent role in nucleosome binding, possibly by making an arginine anchor interaction with the nucleosome H2A/H2B acidic patch. We further show that proliferating cell nuclear antigen and the nucleosome compete for binding to Set8 through this basic extension, suggesting a mechanism for how nucleosome binding protects Set8 from proliferating cell nuclear antigen-dependent degradation during the cell cycle

LAMPU LALU LINTAS UNTUK PENYEBERANG JALAN

Traffic lights for pedestrians are necessary to provide security and comfort for pedestrians and vehicle drivers in order to avoid accidents and traffic jams. During the design of the circuit, component selection analysis was performed for assembling the controller. The analysis showed that the industrial timer has the ease of setting intervals and ease of maintenance controller in the case of damage. The testing on the design showed that, aftercrossing demand button was pressed, the traffic lights worked well in one cycle to allow pedestrians and further provides the opportunity for passing vehicles until the crossing demand button was pressed again by a pedestrian.Lampu lalu lintas untuk penyeberang jalan, merupakan hal yang dibutuhkan untuk memberikan rasa aman dan nyaman bagi pejalan kaki maupun pengemudi kendaraan untuk menghindari terjadinya kecelakaan dan kemacetan lalu lintas. Dalam perancangan rangkaian dilakukan analisis pemilihan komponen untuk merakit kontroler. Analisis menunjukkan bahwa Timer industri memiliki kemudahan dalam melakukan pengaturanselang waktu dan kemudahan dalam perawatan kontroler jika terjadi kerusakan. Pengujian atas perancangan menunjukkan, setelah penekanan tombol permintaan menyeberang, lampulalu lintas bekerja baik sesuai satu siklus untuk memberi kesempatan penyeberang jalan, dan selanjutnya memberi kesempatan untuk kendaraan melintas sampai tombol permintaanmenyeberang ditekan oleh penyeberang selanjutnya

Correlations between serum hdyrogen peroxide level, oxidative damage indices and biochemical markers in end stage renal disease patients

Introduction: Hydrogen peroxide is an important intermediate ofendogenous free radical activity which could lead to the generation of more potent free radicals that cause macromolecular damage. An imbalance between the excessive generation of pro-oxidant(free radicals) and insufficient antioxidant defence leads to oxidative stress and this event is marked in end stage renal disease (ESRD) patients. The objective of this study is to assess the correlation between serum hydrogen peroxide level and oxidative damage indices as well as several biochemical markers in ESRD patients. Methods: Fasting blood samples were collected from patients (n=106) attending the University Malaya Medical Centre, Kuala Lumpur. The control subjects mainly comprised healthy blood donors with no known clinical/biochemical abnormality. The serum and plasrna were separated and the levels of hydrogen peroxide, oxidative damage indices (pentosidine, advanced oxidation protein products, malonaldehyde) and biochemical parameters (albumin, creatinine, fenitin, triglyceride, low density lipoproteins and total cholesterol) were estimated according to established rnethods. Results: Levels of hydrogen peroxide and the oxidative damage indices were significantly higher in the patients compared to healthy subjects. A strong positive correlation was present between hydrogen peroxide and the oxidative indices(r>0.80, p<0.001). Hydrogen peroxide was positively (weak) associated with the biochemical parameters except for albumin levels which showed a negative correlation with hydrogen peroxide levels in these patients (r: -0.40, p< 0.01). Conclusion: Serum hydrogen peroxide strongly correlates with oxidative damage indices and could serve as an additional marker of oxidative stress in end stage renal disease

High-resolution transthoracic echocardiography accurately detects pulmonary arterial pressure and decreased right ventricular contractility in a mouse model of pulmonary fibrosis and secondary pulmonary hypertension

BACKGROUND: To date, assessment of right ventricular (RV) function in mice has relied extensively on invasive measurements. Echocardiographic advances have allowed adaptation of measures used in humans for serial, noninvasive RV functional assessment in mice. We evaluated the diagnostic performance of tricuspid annular plane systolic excursion (TAPSE), RV peak systolic myocardial velocity (s'), RV myocardial performance index (MPI), and RV fractional area change (FAC) in a mouse model of pulmonary hypertension. METHODS AND RESULTS: Echocardiography was performed on mice at baseline and 3 weeks after induction of pulmonary hypertension using inhaled bleomycin or saline, including adapted measures of TAPSE, s', MPI, and FAC. RV systolic pressure was measured by invasive catheterization, and RV contractility was measured as the peak slope of the RV systolic pressure recording (maximum change pressure/change time). Postmortem morphological assessment of RV hypertrophy was performed. RV systolic pressure was elevated and maximum change pressure/change time was reduced in bleomycin versus control (n=8; P=0.002). Compared with controls, bleomycin mice had reduced TAPSE (0.79±0.05 versus 1.06±0.04 mm; P=0.003), s' (21.3±1.2 versus 29.2±1.3 mm/s; P<0.001), and FAC (20.3±0.7% versus 31.0±1.3%; P<0.001), whereas MPI was increased (0.51±0.03 versus 0.37±0.01; P=0.006). All measures correlated with RV systolic pressure and maximum change pressure/change time. Intraobserver and interobserver variability were minimal. Receiver operating characteristic curves demonstrated that TAPSE (<0.84 mm), s'(<23.3 mm/s), MPI (0.42), and FAC (<23.3%) identified maximum change pressure/change time ≤2100 mm Hg/s with high accuracy. CONSLUSIONS: TAPSE, s', MPI, and FAC are measurable consistently using high-resolution echocardiography in mice, and are sensitive and specific measures of pulmonary pressure and RV function. This validation opens the opportunity for serial noninvasive measures in mouse models of pulmonary hypertension, enhancing the statistical power of preclinical studies of novel therapeutics

The antiferromagnetic phi4 Model, II. The one-loop renormalization

It is shown that the four dimensional antiferromagnetic lattice phi4 model has the usual non-asymptotically free scaling law in the UV regime around the chiral symmetrical critical point. The theory describes a scalar and a pseudoscalar particle. A continuum effective theory is derived for low energies. A possibility of constructing a model with a single chiral boson is mentioned.Comment: To appear in Phys. Rev.

Experimental and modeling study of high performance direct carbon solid oxide fuel cell with in situ catalytic steam-carbon gasification reaction

This research is supported by a grant (PolyU 152127/14E) from Research Grant Council, University Grants Committee, Hong Kong SAR, a grant from Environment and Conservation Fund (ECF 54/2015), Hong Kong SAR, and a grant from Research Institute for Sustainable Urban Development (RISUD) (1-ZVEA). We gratefully acknowledge the financial support of the National Science Foundation of China (Grant No. 51406091).In this paper, 2D models for direct carbon solid oxide fuel cells (DC-SOFCs) with in situ catalytic steam-carbon gasification reaction are developed. The simulation results are found to be in good agreement with experimental data. The performance of DC-SOFCs with and without catalyst are compared at different operating potential, anode inlet gas flow rate and operating temperature. It is found that adding suitable catalyst can significantly speed up the in situ steam-carbon gasification reaction and improve the performance of DC-SOFC with H2O as gasification agent. The potential of syngas and electricity co-generation from the fuel cell is also evaluated, where the composition of H2 and CO in syngas can be adjusted by controlling the anode inlet gas flow rate. In addition, the performance DC-SOFCs and the percentage of fuel in the outlet gas are both increased with increasing operating temperature. At a reduced temperature (below 800 °C), good performance of DC-SOFC can still be obtained with in-situ catalytic carbon gasification by steam. The results of this study form a solid foundation to understand the important effect of catalyst and related operating conditions on H2O-assisted DC-SOFCs.PostprintPeer reviewe

Pilot-aided estimation and equalisation of a Radio-over-Fibre system in Wideband Code Division Multiple Access

In this study, the impact of a Radio-over-Fibre (RoF) subsystem on the capacity performance of wideband code division multiple access is evaluated. This study investigates the use of pilot-aided channel estimation to compensate for the optical subsystem non-linearities for different channel conditions, estimation intervals and coding schemes. The results show that pilot-aided channel estimation is an effective method for compensating the composite impairments of the optical subsystem and the radio frequency (RF) channel. It is found that there is always a suitable pilot power level which maximises the system capacity performance regardless of coding scheme and channel condition. Also, the peak capacity is only slightly affected by a decrease in the estimation interval

Stoichiometry of Heteromeric BAFF and APRIL Cytokines Dictates Their Receptor Binding and Signaling Properties.

The closely related TNF family ligands B cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) serve in the generation and maintenance of mature B-lymphocytes. Both BAFF and APRIL assemble as homotrimers that bind and activate several receptors that they partially share. However, heteromers of BAFF and APRIL that occur in patients with autoimmune diseases are incompletely characterized. The N and C termini of adjacent BAFF or APRIL monomers are spatially close and can be linked to create single-chain homo- or hetero-ligands of defined stoichiometry. Similar to APRIL, heteromers consisting of one BAFF and two APRILs (BAA) bind to the receptors B cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) but not to the BAFF receptor (BAFFR). Heteromers consisting of one APRIL and two BAFF (ABB) bind to TACI and BCMA and weakly to BAFFR in accordance with the analysis of the receptor interaction sites in the crystallographic structure of ABB. Receptor binding correlated with activity in reporter cell line assays specific for BAFFR, TACI, or BCMA. Single-chain BAFF (BBB) and to a lesser extent single-chain ABB, but not APRIL or single-chain BAA, rescued BAFFR-dependent B cell maturation in BAFF-deficient mice. In conclusion, BAFF-APRIL heteromers of different stoichiometries have distinct receptor-binding properties and activities. Based on the observation that heteromers are less active than BAFF, we speculate that their physiological role might be to down-regulate BAFF activity

Random and combinatorial mutagenesis for improved total production of secretory target protein in Escherichia coli

Signal peptides and secretory carrier proteins are commonly used to secrete heterologous recombinant protein in Gram-negative bacteria. The Escherichia coli osmotically-inducible protein Y (OsmY) is a carrier protein that secretes a target protein extracellularly, and we have previously applied it in the Bacterial Extracellular Protein Secretion System (BENNY) to accelerate directed evolution. In this study, we reported the first application of random and combinatorial mutagenesis on a carrier protein to enhance total secretory target protein production. After one round of random mutagenesis followed by combining the mutations found, OsmY(M3) (L6P, V43A, S154R, V191E) was identified as the best carrier protein. OsmY(M3) produced 3.1 ± 0.3 fold and 2.9 ± 0.8 fold more secretory Tfu0937 β-glucosidase than its wildtype counterpart in E. coli strains BL21(DE3) and C41(DE3), respectively. OsmY(M3) also produced more secretory Tfu0937 at different cultivation temperatures (37 °C, 30 °C and 25 °C) compared to the wildtype. Subcellular fractionation of the expressed protein confirmed the essential role of OsmY in protein secretion. Up to 80.8 ± 12.2% of total soluble protein was secreted after 15 h of cultivation. When fused to a red fluorescent protein or a lipase from Bacillus subtillis, OsmY(M3) also produced more secretory protein compared to the wildtype. In this study, OsmY(M3) variant improved the extracellular production of three proteins originating from diverse organisms and with diverse properties, clearly demonstrating its wide-ranging applications. The use of random and combinatorial mutagenesis on the carrier protein demonstrated in this work can also be further extended to evolve other signal peptides or carrier proteins for secretory protein production in E. coli

Effects of dose modifications on the safety and efficacy of dacomitinib for EGFR mutation-positive non-small-cell lung cancer

Aim: We evaluated reasons for dacomitinib dose reduction (DR) and examined adverse event (AE) incidence, key efficacy end points (progression-free survival [PFS]/overall survival [OS]), and pharmacokinetics in dose-reducing patients in the ARCHER 1050 trial. Patients & methods: Newly diagnosed patients with EGFR mutation-positive, advanced non-small-cell lung cancer received oral dacomitinib (45 mg once-daily [QD]), with stepwise toxicity-managing DR (30 and 15 mg QD) permitted. Results: Skin toxicities (62.7%) were the most common DR-leading AEs. The AE incidence and severity decreased following DRs. Initial plasma dacomitinib exposure (45 mg QD) was generally lower in patients remaining at 45 mg QD compared with dose-reducing patients. Median PFS and OS were similar in all dacomitinib-treated patients and dose-reducing patients. Conclusion: Tolerability-guided dose modifications enabled patients to continue with dacomitinib and benefit from PFS/OS improvement