O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.

Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein bearing a site-specific O-GlcNAc modification at the physiologically relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory effect on α-synuclein aggregation, while not affecting the membrane binding or bending properties of α-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of α-synuclein in vitro and block the toxicity of α-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation

Genetic and biochemical characterization of an acquired subgroup B3 metallo-β-lactamase gene, blaAIM-1, and its unique genetic context in Pseudomonas aeruginosa from Australia

Three clinical Pseudomonas aeruginosa isolates (WCH2677, WCH2813, and WCH2837) isolated from the Women's and Children's Hospital, Adelaide, Australia, produced a metallo-β-lactamase (MBL)-positive Etest result. All isolates were PCR negative for known MBL genes. A gene bank was created, and an MBL gene, designated bla, was cloned and fully characterized. The encoded enzyme, AIM-1, is a group B3 MBL that has the highest level of identity to THIN-B and L1. It is chromosomal and flanked by two copies (one intact and one truncated) of an ISCR element, ISCR15. Southern hybridization studies indicated the movement of both ISCR15 and bla within the three different clinical isolates. AIM-1 hydrolyzes most β-lactams, with the exception of aztreonam and, to a lesser extent, ceftazidime; however, it possesses significantly higher k values for cefepime and carbapenems than most other MBLs. AIM-1 was the first mobile group B3 enzyme detected and signals further problems for already beleaguered antimicrobial regimes to treat serious P. aeruginosa and other Gram-negative infections

Deprojection technique for galaxy cluster considering point spread function

We present a new method for the analysis of Abell 1835 observed by XMM-Newton. The method is a combination of the Direct Demodulation technique and deprojection. We eliminate the effects of the point spread function (PSF) with the Direct Demodulation technique. We then use a traditional depro-jection technique to study the properties of Abell 1835. Compared to that of deprojection method only, the central electron density derived from this method increases by 30%, while the temperature profile is similar.Comment: accepted for publication in Sciences in China -- G, the Black Hole special issu

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Chinonmethidâ Dimere wurden durch milde anodische Oxidation vermittelt durch eine preiswerte und leicht verfügbare Aminbase mit exzellenter Ausbeute und Regiokontrolle hergestellt. Diese Strategie ermöglicht raschen Zugang zu Zwischenprodukten für die katalytische Synthese von Phenylpropenoidâ Oligomeren und bietet ein neues Werkzeug für die Totalsynthese dieser komplexen Moleküle.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/1/ange201810870.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/2/ange201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146959/3/ange201810870-sup-0001-misc_information.pd

Electrochemical Dimerization of Phenylpropenoids and the Surprising Antioxidant Activity of the Resultant Quinone Methide Dimers

A simple method for the dimerization of phenylpropenoid derivatives is reported. It leverages electrochemical oxidation of pâ unsaturated phenols to access the dimeric materials in a biomimetic fashion. The mild nature of the transformation provides excellent functional group tolerance, resulting in a unified approach for the synthesis of a range of natural products and related analogues with excellent regiocontrol. The operational simplicity of the method allows for greater efficiency in the synthesis of complex natural products. Interestingly, the quinone methide dimer intermediates are potent radicalâ trapping antioxidants; more so than the phenols from which they are derivedâ or transformed toâ despite the fact that they do not possess a labile Hâ atom for transfer to the peroxyl radicals that propagate autoxidation.Quinone methide dimers are prepared via mild anodic oxidation mediated by a cheap and readily available amine base with excellent yield and regiocontrol. This strategy provides rapid access to intermediates for the synthesis of phenylpropenoid oligomers in a catalytic fashion, providing a new tool for the total synthesis of these complex molecules.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/1/anie201810870-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/2/anie201810870_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147117/3/anie201810870.pd

Two-Proton Correlations from 14.6A GeV/c Si+Pb and 11.5A GeV/c Au+Au Central Collisions

Two-proton correlation functions have been measured in Si+Pb collisions at 14.6A GeV/c and Au+Au collisions at 11.5A GeV/c by the E814/E877 collaboration. Data are compared with predictions of the transport model RQMD and the source size is inferred from this comparison. Our analysis shows that, for both reactions, the characteristic size of the system at freeze-out exceeds the size of the projectile, suggesting that the fireball created in the collision has expanded. For Au+Au reactions, the observed centrality dependence of the two-proton correlation function implies that more central collisions lead to a larger source sizes.Comment: RevTex, 12 pages, 5 figure

Applying laboratory thermal desorption data in an interstellar context: sublimation of methanol thin films

Methods by which experimental measurements of thermal desorption can be applied in astrophysical environments have been developed, using the sublimation of solid methanol as an example. The temperature programmed desorption of methanol from graphitic, amorphous silica and polycrystalline gold substrates was compared, with the kinetic parameters of desorption extracted by either a leading edge analysis or by fitting using a stochastic integration method. At low coverages, the desorption shows a substrate-dependent fractional order. However, at higher coverages methanol desorption is zeroth order with kinetic parameters independent of substrate. Using a kinetic model based on the stochastic integration analyses, desorption under astrophysically relevant conditions can be simulated. We find that the chemical and morphological nature of the substrate has relatively little impact on the desorption temperature of solid methanol, and that the substrate independent zeroth-order kinetics can provide a satisfactory model for desorption in astrophysical environments. Uncertainties in the heating rate and the distribution of grain sizes will have the largest influence on the range of desorption temperature. These conclusions are likely to be generally applicable to all species in dust grain ice mantles

The impact of mergers on relaxed X-ray clusters - III. Effects on compact cool cores

(Abridged) We use the simulations presented in Poole et al. 2006 to examine the effects of mergers on compact cool cores in X-ray clusters. We propose a scheme for classifying the morphology of clusters based on their surface brightness and entropy profiles. Three dominant morphologies emerge: two hosting compact cores and central temperatures which are cool (CCC systems) or warm (CWC systems) and one hosting extended cores which are warm (EWC systems). We find that CCC states are disrupted only after direct collisions between cluster cores in head-on collisions or during second pericentric passage in off-axis mergers. By the time they relax, our remnant cores have generally been heated to warm core (CWC or EWC) states but subsequently recover CCC states. The only case resulting in a long-lived EWC state is a slightly off-axis 3:1 merger for which the majority of shock heating occurs during the accretion of a low-entropy stream formed from the disruption of the secondary's core. Compression prevents core temperatures from falling until after relaxation thus explaining the observed population of relaxed CWC systems with no need to invoke AGN feedback. The morphological segregation observed in the L_x-T_x and beta-r_c scaling relations is reflected in our simulations as well. However, none of the cases we have studied produce sufficiently high remnant central entropies to account for the most under-luminous EWC systems observed. Lastly, systems which initially host central metallicity gradients do not yield merger remnants with flat metallicity profiles. Taken together, these results suggest that once formed, compact core systems are remarkably stable against disruption from mergers. It remains to be demonstrated exactly how the sizable observed population of extended core systems was formed.Comment: 19 pages, 8 figures, submitted for publication in MNRA

Children and older adults exhibit distinct sub-optimal cost-benefit functions when preparing to move their eyes and hands

"© 2015 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited"Numerous activities require an individual to respond quickly to the correct stimulus. The provision of advance information allows response priming but heightened responses can cause errors (responding too early or reacting to the wrong stimulus). Thus, a balance is required between the online cognitive mechanisms (inhibitory and anticipatory) used to prepare and execute a motor response at the appropriate time. We investigated the use of advance information in 71 participants across four different age groups: (i) children, (ii) young adults, (iii) middle-aged adults, and (iv) older adults. We implemented 'cued' and 'non-cued' conditions to assess age-related changes in saccadic and touch responses to targets in three movement conditions: (a) Eyes only; (b) Hands only; (c) Eyes and Hand. Children made less saccade errors compared to young adults, but they also exhibited longer response times in cued versus non-cued conditions. In contrast, older adults showed faster responses in cued conditions but exhibited more errors. The results indicate that young adults (18 -25 years) achieve an optimal balance between anticipation and execution. In contrast, children show benefits (few errors) and costs (slow responses) of good inhibition when preparing a motor response based on advance information; whilst older adults show the benefits and costs associated with a prospective response strategy (i.e., good anticipation)