Mechanism of action of VP1-001 in cryAB(R120G)-associated and age-related cataracts

PurposeWe previously identified an oxysterol, VP1-001 (also known as compound 29), that partially restores the transparency of lenses with cataracts. To understand the mechanism of VP1-001, we tested the ability of its enantiomer, ent-VP1-001, to bind and stabilize αB-crystallin (cryAB) in vitro and to produce a similar therapeutic effect in cryAB(R120G) mutant and aged wild-type mice with cataracts. VP1-001 and ent-VP1-001 have identical physicochemical properties. These experiments are designed to critically evaluate whether stereoselective binding to cryAB is required for activity.MethodsWe compared the binding of VP1-001 and ent-VP1-001 to cryAB using in silico docking, differential scanning fluorimetry (DSF), and microscale thermophoresis (MST). Compounds were delivered by six topical administrations to mouse eyes over 2 weeks, and the effects on cataracts and lens refractive measures in vivo were examined. Additionally, lens epithelial and fiber cell morphologies were assessed via transmission electron microscopy.ResultsDocking studies suggested greater binding of VP1-001 into a deep groove in the cryAB dimer compared with ent-VP1-001. Consistent with this prediction, DSF and MST experiments showed that VP1-001 bound cryAB, whereas ent-VP1-001 did not. Accordingly, topical treatment of lenses with ent-VP1-001 had no effect, whereas VP1-001 produced a statistically significant improvement in lens clarity and favorable changes in lens morphology.ConclusionsThe ability of VP1-001 to bind native cryAB dimers is important for its ability to reverse lens opacity in mouse models of cataracts

RR-symmetric Gauge Mediation With Fayet-Iliopoulos Term

We have studied $R$-symmetrc gauge mediation models with Fayet-Iliopoulos terms. We give a concrete example of hidden sector with an $U(1)_H$ gauge theory and a Fayet-Iliopoulos term, which can induce distinctive soft terms in the visible sector, and help solving fine tuning problems in models of $R$-symmetric gauge mediation.Comment: 11 pages, 1 figur

Neutron Diffraction and Magnetic Studies of Nd₂Fe₁₇₋ₓTₓ (T=Si, Mn) Alloys

We have carried out neutron and magnetic studies on Nd2Fe17-xTx (T=Si, Mn) alloys. the unit cell of the compounds contracts with both Si and Mn substitution. Si atoms avoid the 6c site, prefer the 18h site strongly, fill the 9d site steadily and fill the 18f site only at relatively high Si concentration. Mn atoms avoid the 9d sites but prefer the 6c site strongly, while the 18f site and 18h site fill slowly. the Si site occupancies appear to be dominated by the crystal environment while the Mn site occupancies are dominated by steric considerations. the Curie temperature of the compound Nd2Fe17-xTx increases significantly with Si substitution but is only affected slightly by the Mn substitution. Although the unit cell contracts with increasing Si concentration, the average length of bonds to the Fe(6c) and the Fe(18f) sites increase slightly at x\u3c4

Hadronic Loop Corrections to the Muon Anomalous Magnetic Moment

The dominant theoretical uncertainties in both, the anomalous magnetic moment of the muon and the value of the electromagnetic coupling at the Z scale arise from their hadronic contributions. Since these will ultimately dominate the experimental errors, we study the correlation between them, as well as with other fundamental parameters. To this end we present analytical formulas for the QCD contribution from higher energies and from heavy quarks. Including these correlations affects the Higgs boson mass extracted from precision data.Comment: 4 page

Characterization analysis and polymorphism detection of the porcine Myd88 gene

The myeloid differentiation primary response protein 88 (Myd88) is an essential adaptor protein, which mediates in all Toll-like receptor (TLR) members signal transduction, except for TLR3. In this study, the 4464 bp genomic sequence of porcine Myd88 was first isolated, whereupon tissue distribution, chromosome mapping and single nucleotide polymorphism (SNP) were analyzed. Our results revealed that porcine Myd88 gene, which was located at chromosome 13 linked with marker S0288 (distance = 40 cR; LOD = 8.66), was widely expressed in all the examined tissues. There were 16 potential SNPs in the isolated genome fragment. SNP 797T/C in the first intron was studied, with no significant association being found between the genotype and immune traits in pigs (p > 0.05). The porcine Myd88 protein contained both the death domain (DD) and the Toll/IL-1 receptor domain (TIR). Leu residues, essential for its structure, were the most abundant encountered in the DD. The TIR contained two conserved motifs which may play important roles in the Myd88 function

Characterisation and Skin Distribution of Lecithin-Based Coenzyme Q10-Loaded Lipid Nanocapsules

The purpose of this study was to investigate the influence of the inner lipid ratio on the physicochemical properties and skin targeting of surfactant-free lecithin-based coenzyme Q10-loaded lipid nanocapsules (CoQ10-LNCs). The smaller particle size of CoQ10-LNCs was achieved by high pressure and a lower ratio of CoQ10/GTCC (Caprylic/capric triglyceride); however, the zeta potential of CoQ10-LNCs was above /− 60 mV/ with no distinct difference among them at different ratios of CoQ10/GTCC. Both the crystallisation point and the index decreased with the decreasing ratio of CoQ10/GTCC and smaller particle size; interestingly, the supercooled state of CoQ10-LNCs was observed at particle size below about 200 nm, as verified by differential scanning calorimetry (DSC) in one heating–cooling cycle. The lecithin monolayer sphere structure of CoQ10-LNCs was investigated by cryogenic transmission electron microscopy (Cryo-TEM). The skin penetration results revealed that the distribution of Nile red-loaded CoQ10-LNCs depended on the ratio of inner CoQ10/GTCC; moreover, epidermal targeting and superficial dermal targeting were achieved by the CoQ10-LNCs application. The highest fluorescence response was observed at a ratio of inner CoQ10/GTCC of 1:1. These observations suggest that lecithin-based LNCs could be used as a promising topical delivery vehicle for lipophilic compounds

Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity

Integrin-dependent adhesions are mechanosensitive structures in which talin mediates a linkage to actin laments either directly or indirectly by recruiting vinculin. Here, we report the development and validation of a talin tension sensor. We nd that talin in focal adhesions is under tension, which is higher in peripheral than central adhesions. Tension on talin is increased by vinculin and depends mainly on actin-binding site 2 (ABS2) within the middle of the rod domain, rather than ABS3 at the far C terminus. Unlike vinculin, talin is under lower tension on soft substrates. The difference between central and peripheral adhesions requires ABS3 but not vinculin or ABS2. However, differential stiffness sensing by talin requires ABS2 but not vinculin or ABS3. These results indicate that central versus peripheral adhesions must be orga- nized and regulated differently, and that ABS2 and ABS3 have distinct functions in spatial variations and stiffness sens- ing. Overall, these results shed new light on talin function and constrain models for cellular mechanosensing