Large-scale analysis of posttranslational modifications in the hippocampus of patients with Alzheimer’s disease using pI shift and label-free quantification without enrichment

Posttranslational modifications modulate protein function in cells. Global analysis of multiple posttranslational modifications can provide insight into physiology and disease, but presents formidable challenges. In the present study, we used a technique that does not require target enrichment to analyze alterations in the phosphorylation and ubiquitination of proteins from patients with Alzheimer’s disease (AD). Guided by our previous findings, we applied three strategies to further our understanding of the dysregulation of posttranslationally modified proteins. We first identified phosphorylation sites by determining peptide pI shifts using OFFGEL. Second, using tandem mass spectrometry, we determined the ubiquitination status of the proteins using an assay for a trypsin digestion remnant of ubiquitination (Gly-Gly). Third, for large-scale discovery, we quantified the global differences in protein expression. Of the proteins expressed in AD tissue at levels of 2.0 or greater compared with controls, 60 were phosphorylated and 56 were ubiquitinated. Of the proteins expressed at levels of 0.5 or lower compared with controls, 81 were phosphorylated and 56 were ubiquitinated. Approximately 98 % of the phosphopeptides exhibited a pI shift. We identified 112 new phosphorylation sites (51.38 %), and 92 new ubiquitination sites (96.84 %). Taken together, our findings suggest that analysis of the alterations in posttranslationally modified proteins may contribute to understanding the pathogenesis of AD and other diseases.     

Attitudes of Israeli Muslims at risk of genetic disorders towards pregnancy termination

OBJECTIVES: (1) To examine attitudes towards termination of pregnancy (TOP) among high-risk and non-high-risk (for cystic fibrosis) Arab-Muslims, and (2) to examine the effect of an intervention, which among other things related explicitly to TOP. METHODS: The study comprised three groups: (1) an intervention group at high risk for CF, which received community genetic counseling; (2) a control group at high risk for CF, and (3) a control group from the general population. The latter two groups were exposed to minimal intervention. Attitudes were measured two or three times during a 1-year period (for the control and intervention groups, respectively). RESULTS: Predictors of an affected fetus being considered a legitimate cause for TOP were religiosity, familiarity with an affected child, and benefits of the test. Predictors of individuals (hypothetically) choosing abortion in the case of an affected fetus were education and age. No change occurred in the attitudes of participants (either experimental or control groups) in the course of 1 year. CONCLUSIONS: Other possible intervention options are discussed, and specifically, the advantages of using opinion leaders such as clergy and medical staff.     

The Zassenhaus filtration,Massey products,and representations of profinite groups

We consider the p  -Zassenhaus filtration (_Gn)$(G_n)$ of a profinite group G  . Suppose that G=S/N$G=S/N$ for a free profinite group S and a normal subgroup N of S   contained in _Sn$S_n$. Under a cohomological assumption on the n-fold Massey products (which holds, e.g., if G has p  -cohomological dimension ≤ 1), we prove that _Gn+1$G_{n+1}$ is the intersection of all kernels of upper-triangular unipotent (n+1)$(n+1)$-dimensional representations of G   over _Fp${\mathbb{F}}_p$. This extends earlier results by Miná?, Spira, and the author on the structure of absolute Galois groups of fields.     

Dynamics of the continued fraction map and the spectral theory of SL (2, Z)

Oblatum 15-V-1992 & 2-II-1993     

On structural transitions in a discontinuous micellar cubic phase loaded with sodium diclofenac

An intermediate mesophase of lyotropic liquid crystalline structure from the ternary mixtures of glycerol monooleate, water, and ethanol was recently characterized in our lab. This mesophase, termed Q(L), consists of discrete discontinuous micelles arranged in a cubic array. The Q(L) phase can solubilize very significant loads of water-insoluble anti-inflamatory drug sodium diclofenac (Na-DFC). Close examination of the internal structures of the lyotropic liquid structure upon increasing the solubilization loads reveals the existence of three structural transitions controlled by the Na-DFC levels. Up to 0.4 wt% Na-DFC, the Q(L) structure remains intact with some influence on the hydration of the headgroups and on the intermicellar forces. However, at 0.8 to 1.2 wt% Na-DFC, the discontinuous micellar cubic phase is transformed into a more condensed mesophase of a bicontinuous cubic phase. At > or =1.2 wt% Na-DFC, the cubic phase is converted into a lamellar phase (L(alpha)). Within 5.5 to 7.3 wt% Na-DFC the mesophase is progressively transformed into a less ordered lamellar structure. At 12 wt% Na-DFC crystals tend to precipitate out. At low Na-DFC concentrations the drug behaves like a lyotropic or kosmotropic salt and can salt-out the surfactant from its water layer, but at higher levels it behaves like a hydrotropic, chaotropic salt and can salt-in the surfactant. The Na-DFC location and position within the interface as well as its polarization and partial ionization are strongly affected by its solubilization contents and the structure that it is inducing. In the cubic phase the drug is located less close to the hydration layer while once transition occurs it is exposed more to the water layer and the surfactant headgroups.     

Light-activated antibacterial surfaces comprise photosensitizers

Antibacterial surfaces were prepared using a base polyethylene sheet topped with a layer containing a mixed powder of poly (vinylidene fluoride) and photosensitizers (PSs). A crimpled stamp was placed on the mixed powder, and then it was passed through a heating and pressing device. The three chosen PSs were rose bengal, toluidine blue O and methylene blue. Scanning electron microscope analysis showed that the PS surface texture was coarse and highly developed. Measurement of the apparent contact angles of the droplets deposited on the PS surfaces using goniometry showed that all three surfaces were hydrophobic. Photodynamic analysis of the surfaces into which the PSs were incorporated indicated significant reactive oxygen species formation after illumination with light fluency rate of 1.46 mW cm(-2) for 30 min. Photodynamic inactivation assays performed in nutrient broth demonstrated more than 4 log reduction of the attached Escherichia coli after illumination (1.46 mW cm(-2)) for 24 h when the inoculum was 10(3) CFU mL(-1). However, more than 4 log reduction of Staphylococcus aureus occurred even when the cultures were illuminated for only 6 h. Our results provide an inexpensive, simple, state-of-the-art method for preparing antibacterial surfaces that may help prevent infections in hospital surroundings and in some medical devices.     

Phenylethylidene-3,4-dihydro-1H-quinoxalin-2-ones: promising building blocks for Cu recognition

A series of sulfonamido-substituted phenylethylidene-3,4-dihydro-1H-quinoxalin-2-one derivatives in which both of the fluorophore and ionophore are integrated into one structural unit, have been investigated. They all exhibit high selectivity toward Cu²⁺ in ethanol in the presence of other metallic ions (Zn²⁺, Mg²⁺, Co²⁺, Ni²⁺, Mn²⁺, Ca²⁺, and Ag⁺), as well as fast, stable, and reversible binding, as is evidenced by the observation of a red shift in the UV-vis spectrum, ‘ON-OFF’ fluorescence response. In addition, titration and MALDI-TOF measurements indicated that a 1:1 (and possibly also 2:1 (organic ligand: Cu²⁺) complexes were formed, depending on the relative amount of Cu²⁺ added to the solution of the organic ligand. It was also found that the binding constant could be tuned by modifying the nature and position of the substituents attached to the central benzene ring in the quinoxalone derivative. In acetonitrile, unlike in ethanol, these ligands undergo oxidation-decomposition by Cu²⁺ and therefore, no UV-vVis absorption bands could be observed. However, due to color change (from yellow to transparent) they could be useful as dosimeters in this solvent.     

Pro-P galois groups of function fields over local fields

For non-archimedean local field K and a prime number p we compute the finitely generated pro-p (closed) subgroups of the absolute Galois group of K(t). In addition, we characterize the finitely generated pro-p groups which occur as the maximal pro-p Galois group of algebraic extensions of K(t) containing a primitive pth root of unity.