Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core

Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington's disease (HD). Fragments coinciding with mutant huntingtin exon1 aggregate in vivo and induce HD-like pathology in mouse models. The resulting aggregates can have different structures that affect their biochemical behaviour and cytotoxic activity. Here we report our studies of the structure and functional characteristics of multiple mutant htt exon1 fibrils by complementary techniques, including infrared and solid-state NMR spectroscopies. Magic-angle-spinning NMR reveals that fibrillar exon1 has a partly mobile α-helix in its aggregation-accelerating N terminus, and semi-rigid polyproline II helices in the proline-rich flanking domain (PRD). The polyglutamine-proximal portions of these domains are immobilized and clustered, limiting access to aggregation-modulating antibodies. The polymorphic fibrils differ in their flanking domains rather than the polyglutamine amyloid structure. They are effective at seeding polyglutamine aggregation and exhibit cytotoxic effects when applied to neuronal cells

Dzyaloshinskii-Moriya Interaction and Spiral Order in Spin-orbit Coupled Optical Lattices

We show that the recent experimental realization of spin-orbit coupling in ultracold atomic gases can be used to study different types of spin spiral order and resulting multiferroic effects. Spin-orbit coupling in optical lattices can give rise to the Dzyaloshinskii-Moriya (DM) spin interaction which is essential for spin spiral order. By taking into account spin-orbit coupling and an external Zeeman field, we derive an effective spin model in the Mott insulator regime at half filling and demonstrate that the DM interaction in optical lattices can be made extremely strong with realistic experimental parameters. The rich finite temperature phase diagrams of the effective spin models for fermions and bosons are obtained via classical Monte Carlo simulations.Comment: 7 pages, 5 figure

ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

K

Temperature effects on activated carbon adsorption in fixed-beds

Call number: LD2668 .T4 1985 L56Master of Scienc

Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling

Although concern remains about the athero-thrombotic risk posed by cyclo-oxygenase (COX)-2-selective inhibitors, recent data implicates rofecoxib, while celecoxib appears equivalent to NSAIDs naproxen and ibuprofen. We investigated the hypothesis that celecoxib activates AMP kinase (AMPK) signalling to enhance vascular endothelial protection. In human arterial and venous endothelial cells (EC), and in contrast to ibuprofen and naproxen, celecoxib induced the protective protein heme oxygenase-1 (HO-1). Celecoxib derivative 2,5-dimethyl-celecoxib (DMC) which lacks COX-2 inhibition also upregulated HO-1, implicating a COX-2-independent mechanism. Celecoxib activated AMPKα(Thr172) and CREB-1(Ser133) phosphorylation leading to Nrf2 nuclear translocation. Importantly, these responses were not reproduced by ibuprofen or naproxen, while AMPKα silencing abrogated celecoxib-mediated CREB and Nrf2 activation. Moreover, celecoxib induced H-ferritin via the same pathway, and increased HO-1 and H-ferritin in the aortic endothelium of mice fed celecoxib (1000 ppm) or control chow. Functionally, celecoxib inhibited TNF-α-induced NF-κB p65(Ser536) phosphorylation by activating AMPK. This attenuated VCAM-1 upregulation via induction of HO-1, a response reproduced by DMC but not ibuprofen or naproxen. Similarly, celecoxib prevented IL-1β-mediated induction of IL-6. Celecoxib enhances vascular protection via AMPK-CREB-Nrf2 signalling, a mechanism which may mitigate cardiovascular risk in patients prescribed celecoxib. Understanding NSAID heterogeneity and COX-2-independent signalling will ultimately lead to safer anti-inflammatory drugs

On the second order of Zeta functional equations for Riemann Type

This paper discuss a new class of functional equations by using both Poisson summation formula and Jacobi type theta a function. The class of Riemann type functional equations are derived from self-reciprocal probability density functions. Finally, the second order Zeta functional equations for Riemann type is also investigated.Comment: 24 page

Profiles of Everyday Thought Suppression

The present research assessed whether levels of depression, anxiety and worry, obsessive-compulsive distress, and psychopathy were differentially related to distinct thought suppression profiles. As a means to achieving this goal, the Profiles of Everyday Thought Suppression (PETS) scale was constructed to measure the frequencies with which various target thoughts are suppressed. The PETS scale demonstrated good internal consistency and test-retest reliability, and scores were positively correlated with the general tendency to experience intrusions, the general tendency to suppress thoughts, neuroticism, and health complaints. Although the proportions of time people suppress thoughts was positively associated with the frequencies with which the thoughts are experienced, the strength of the associations differed across thought contents, suggesting that not all frequently experienced thoughts are invariably subject to suppression attempts. The frequency with which thoughts are generally suppressed was positively associated with overall levels of subclinical psychopathology experienced during the past month. When comparing across the various thought categories, results from multiple analytic strategies converged to suggest that specific subclinical psychopathological states are associated with particular sets of thoughts that are frequently suppressed.Psycholog

Bithiazole: An Intriguing Electron-Deficient Building for Plastic Electronic Applications.

The heterocyclic thiazole unit has been extensively used as electron-deficient building block in π-conjugated materials over the last decade. Its incorporation into organic semiconducting materials is particularly interesting due to its structural resemblance to the more commonly used thiophene building block, thus allowing the optoelectronic properties of a material to be tuned without significantly perturbing its molecular structure. Here, we discuss the structural differences between thiazole- and thiophene-based organic semiconductors, and the effects on the physical properties of the materials. An overview of thiazole-based polymers is provided, which have emerged over the past decade for organic electronic applications and it is discussed how the incorporation of thiazole has affected the device performance of organic solar cells and organic field-effect transistors. Finally, in conclusion, an outlook is presented on how thiazole-based polymers can be incorporated into all-electron deficient polymers in order to obtain high-performance acceptor polymers for use in bulk-heterojunction solar cells and as organic field-effect transistors. Computational methods are used to discuss some newly designed acceptor building blocks that have the potential to be polymerized with a fused bithiazole moiety, hence propelling the advancement of air-stable n-type organic semiconductors

EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality

Peer reviewe