Polymorphisms at amino acid residues 141 and 154 influence conformational variation in ovine PrP

Polymorphisms in ovine PrP at amino acid residues 141 and 154 are associated with susceptibility to ovine prion disease: Leu141Arg154 with classical scrapie and Phe141Arg154 and Leu141His154 with atypical scrapie. Classical scrapie is naturally transmissible between sheep, whereas this may not be the case with atypical scrapie. Critical amino acid residues will determine the range or stability of structural changes within the ovine prion protein or its functional interaction with potential cofactors, during conversion of PrPC to PrPSc in these different forms of scrapie disease. Here we computationally identified that regions of ovine PrP, including those near amino acid residues 141 and 154, displayed more conservation than expected based on local structural environment. Molecular dynamics simulations showed these conserved regions of ovine PrP displayed genotypic differences in conformational repertoire and amino acid side-chain interactions. Significantly, Leu141Arg154 PrP adopted an extended beta sheet arrangement in the N-terminal palindromic region more frequently than the Phe141Arg154 and Leu141His154 variants. We supported these computational observations experimentally using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP. Collectively, our observations show amino acid residues 141 and 154 influence secondary structure and conformational change in ovine PrP that may correlate with different forms of scrapie.This is the final published version. It is published by Hindawi in BioMed Research International here: http://www.hindawi.com/journals/bmri/2014/372491/

A CRY-BIC negative-feedback circuitry regulating blue light sensitivity of Arabidopsis.

Cryptochromes are blue light receptors that regulate various light responses in plants. Arabidopsis cryptochrome 1 (CRY1) and cryptochrome 2 (CRY2) mediate blue light inhibition of hypocotyl elongation and long-day (LD) promotion of floral initiation. It has been reported recently that two negative regulators of Arabidopsis cryptochromes, Blue light Inhibitors of Cryptochromes 1 and 2 (BIC1 and BIC2), inhibit cryptochrome function by blocking blue light-dependent cryptochrome dimerization. However, it remained unclear how cryptochromes regulate the BIC gene activity. Here we show that cryptochromes mediate light activation of transcription of the BIC genes, by suppressing the activity of CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1), resulting in activation of the transcription activator ELONGATED HYPOCOTYL 5 (HY5) that is associated with chromatins of the BIC promoters. These results demonstrate a CRY-BIC negative-feedback circuitry that regulates the activity of each other. Surprisingly, phytochromes also mediate light activation of BIC transcription, suggesting a novel photoreceptor co-action mechanism to sustain blue light sensitivity of plants under the broad spectra of solar radiation in nature

The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages

Inflammation is a complex biological response of tissues to harmful stimuli such as pathogens, cell damage, or irritants. Inflammation is considered to be a major cause of most chronic diseases, especially in more than 100 types of inflammatory diseases which include Alzheimer's disease, rheumatoid arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, hepatitis, and Parkinson's disease. Recently, an increasing number of studies have focused on inflammatory diseases. TBK1 is a serine/threonine-protein kinase which regulates antiviral defense, host-virus interaction, and immunity. It is ubiquitously expressed in mouse stomach, colon, thymus, and liver. Interestingly, high levels of active TBK1 have also been found to be associated with inflammatory diseases, indicating that TBK1 is closely related to inflammatory responses. Even though relatively few studies have addressed the functional roles of TBK1 relating to inflammation, this paper discusses some recent findings that support the critical role of TBK1 in inflammatory diseases and underlie the necessity of trials to develop useful remedies or therapeutics that target TBK1 for the treatment of inflammatory diseases

Activation of spleen tyrosine kinase is required for TNF-α-induced endothelin-1 upregulation in human aortic endothelial cells

AbstractEndothelin-1 (ET-1) promotes atherosclerosis. We tested whether spleen tyrosine kinase (Syk) mediates tumor necrosis factor-α (TNF-α)-induced ET-1 upregulation in human aortic endothelial cells (HAECs) and sought to identify the signal pathways involved. TNF-α-induced reactive oxygen species (ROS) activated Syk and phosphatidylinositol 3-kinase (PI3K), which was required for the activation of AP-1 and subsequent ET-1 gene transcription. ROS mediated c-Jun NH2-terminal kinase (JNK) is also required for AP-1 activation, but Syk and PI3K regulated AP-1 activation independently of JNK. Through regulation of ET-1 production, Syk could be implicated in atherosclerosis

Circulating CTRP1 Levels in Type 2 Diabetes and Their Association with FGF21

The goal of this study was to investigate whether circulating C1q/TNF-α-related protein 1 (CTRP1) levels are associated with diabetes. In addition, relationships between CTRP1 and other diabetes-related cytokines were elucidated, including adiponectin and fibroblast growth factor 21 (FGF21). A total of 178 subjects (78 men and 100 women) aged 29–70 years (mean age, 46.1 years) were randomly selected. The sera from a normal glucose tolerance group (n=68) and a prediabetes/type 2 diabetes group (n=110) were collected; then, circulating levels of CTRP1, adiponectin, and FGF21 were determined via enzyme-linked immunosorbent assay in all sera. Subjects with either prediabetes or diabetes exhibited higher circulating CTRP1 levels than healthy subjects. Sera analysis revealed that CTRP1 was positively correlated with age, body mass index, fasting blood glucose, and circulating FGF21 levels. However, CTRP1 was negatively correlated with total cholesterol and total circulating adiponectin levels in univariate analysis. In addition, multivariate analysis found that CTRP1 was independently associated with age, fasting blood glucose, and circulating FGF21 levels. CTRP1 was correlated with homeostasis model assessment-β (HOMA-β), but no correlation was observed with HOMA-insulin resistance. In conclusion, circulating CTRP1 levels are increased in subjects with type 2 diabetes and are positively associated with circulating FGF21 levels

Molecular environment and thermal X-ray spectroscopy of the semicircular young composite supernova remnant 3C 396

We have investigated the molecular environment of the semicircular composite supernova remnant (SNR) 3C396 and performed a Chandra spatially resolved thermal X-ray spectroscopic study of this young SNR. With our CO millimeter observations, we find that the molecular clouds (MCs) at V(LSR)~84km/s can better explain the multiwavelength properties of the remnant than the V(LSR)=67-72km/s MCs that are suggested by Lee et al. (2009). At around 84km/s, the western boundary of the SNR is perfectly confined by the western molecular wall. The CO emission fades out from west to east, indicating that the eastern region is of low gas density. In particular, an intruding finger/pillar-like MC, which may be shocked at the tip, can well explain the X-ray and radio enhancement in the southwest and some infrared filaments there. The SNR-MC interaction is also favored by the relatively elevated 12CO J=2-1/J=1-0 line ratios in the southwestern "pillar tip" and the molecular patch on the northwestern boundary. The redshifted 12CO (J=1-0 and J=2-1) wings (86-90km/s) of an eastern 81km/s molecular patch may be the kinematic evidence for shock-MC interaction. We suggest that the 69km/s MCs are in the foreground based on HI self-absorption while the 84km/s MCs at a distance of 6.2 kpc (the tangent point) are in physical contact with SNR 3C396. The X-ray spectral analysis suggests an SNR age of ~3kyr. The metal enrichment of the X-ray emitting gas in the north and south implies a 13-15Msun B1-B2 progenitor star.Comment: 17 amulateapj pages, including 11 figures and 3 tables. Accepted to ApJ. Version 2: minor correction

Investigation of grain-boundary effect on hydrogen behaviors in single- and poly- crystalline medium-entropy CrCoNi alloy

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Non-Kondo-like Electronic Structure in the Correlated Rare-Earth Hexaboride YbB6_6

We present angle-resolved photoemission studies on the rare-earth hexaboride YbB$_6$, which has recently been predicted to be a topological Kondo insulator. Our data do not agree with the prediction and instead show that YbB$_6$ exhibits a novel topological insulator state in the absence of a Kondo mechanism. We find that the Fermi level electronic structure of YbB$_6$ has three 2D Dirac cone like surface states enclosing the Kramers' points, while the f-orbital which would be relevant for the Kondo mechanism is $\sim1$ eV below the Fermi level. Our first-principles calculation shows that the topological state which we observe in YbB$_6$ is due to an inversion between Yb $d$ and B $p$ bands. These experimental and theoretical results provide a new approach for realizing novel correlated topological insulator states in rare-earth materials.Comment: 5 pages, 4 figures, Submitted in 2014. Published in 2015, Phys. Rev. Lett. 114, 01640