Self‐Assembled Cyclic d,l‐α‐Peptides as Generic Conformational Inhibitors of the α‐Synuclein Aggregation and Toxicity: In Vitro and Mechanistic Studies

Many peptides and proteins with large sequences and structural differences self‐assemble into disease‐causing amyloids that share very similar biochemical and biophysical characteristics, which may contribute to their cross‐interaction. Here, we demonstrate how the self‐assembled, cyclic d,l ‐α‐peptide CP‐2 , which has similar structural and functional properties to those of amyloids, acts as a generic inhibitor of the Parkinson′s disease associated α‐synuclein (α‐syn) aggregation to toxic oligomers by an ?off‐pathway“ mechanism. We show that CP‐2 interacts with the N‐terminal and the non‐amyloid‐β component region of α‐syn, which are responsible for α‐syn′s membrane intercalation and self‐assembly, thus changing the overall conformation of α‐syn. CP‐2 also remodels α‐syn fibrils to nontoxic amorphous species and permeates cells through endosomes/lysosomes to reduce the accumulation and toxicity of intracellular α‐syn in neuronal cells overexpressing α‐syn. Our studies suggest that targeting the common structural conformation of amyloids may be a promising approach for developing new therapeutics for amyloidogenic diseases.     

An isothermal amplification reactor with an integrated isolation membrane for point-of-care detection of infectious diseases

A simple, point of care, inexpensive, disposable cassette for the detection of nucleic acids extracted from pathogens was designed, constructed, and tested. The cassette utilizes a single reaction chamber for isothermal amplification of nucleic acids. The chamber is equipped with an integrated, flow-through, Flinders Technology Associates (Whatman FTA?) membrane for the isolation, concentration, and purification of DNA and/or RNA. The nucleic acids captured by the membrane are used directly as templates for amplification without elution, thus simplifying the cassette's flow control. The FTA membrane also serves another critical role-enabling the removal of inhibitors that dramatically reduce detection sensitivity. Thermal control is provided with a thin film heater external to the cassette. The amplification process was monitored in real time with a portable, compact fluorescent reader. The utility of the integrated, single-chamber cassette was demonstrated by detecting the presence of HIV-1 in oral fluids. The HIV RNA was reverse transcribed and subjected to loop-mediated, isothermal amplification (LAMP). A detection limit of less than 10 HIV particles was demonstrated. The cassette is particularly suitable for resource poor regions, where funds and trained personnel are in short supply. The cassette can be readily modified to detect nucleic acids associated with other pathogens borne in saliva, urine, and other body fluids as well as in water and food.     

In-plane dynamics of membranes with immobile inclusions

Cell membranes are anchored to the cytoskeleton via immobile inclusions. We investigate the effect of such anchors on the in-plane dynamics of a fluid membrane and mobile inclusions (proteins) embedded in it. The immobile particles lead to a decreased diffusion coefficient of mobile ones and suppress the correlated diffusion of particle pairs. Because of the long-range, quasi-two-dimensional nature of membrane flows, these effects become significant at a low area fraction (below 1%) of immobile inclusions.     

A measure of the symmetry of random walks

We derive the probability density for a simple measure of the asymmetry of a one-dimensional random walk, namely the ratio of the minimum of the two maximum displacements in the positive and negative directions, to the maximum. We show that in the diffusion limit the asymmetry is independent of time. These results are shown to apply to random walks in which individual steps have a stable law distribution as well as to multidimensional random walks.     

Simple Approximations for the GI/G/c Queue-II: The Moments,the Inverse Distribution Function and the Loss Function of the Number in the System and of the Queue Delay

Based on results obtained in part I of this paper, approximations for the first four moments of the number in the system are developed and thence used to approximate the inverse distribution function (IDF) and the loss functions (LF), employing Shore's general approximations. Existing approximations for the first two moments of queueing time in a GI/G/l queue serve to approximate the IDF and the LF of queueing time in the corresponding GI/G/c queue. The accuracy attained is generally satisfactory, while a remarkable algebraic simplicity is preserved. A numerical example demonstrates the applicability of some of the new approximations to solve optimization problems.     

MA(σ-centered): Cohen reals,strong measure zero sets and strongly meager sets

We prove thatMA(σ-centered) + the Dual Borel Conjecture is consistent; and thatMA(σ-centered) + the non-additivity of the ideal of the strong measure zero sets also is consistent. Jaime Ihoda.     

The borel conjecture

We show the Borel Conjecture is consistent with the continuum large.     

A dynamical theory for the rishon model

We propose a composite model for quarks and leptons based on an exact SU(3)_C × SU(3)_H gauge theory and two fundamental $\text{J=}\text{1}\text{2}$ fermions: a charged T-rishon and a neutral V-rishon. Quarks, leptons and W-bosons are SU(3)_H-singlet composites of rishons. A dynamically broken effective SU(3)_C × SU(2)_L × SU(2)_R × U(1)_B?L gauge theory emerges at the composite level. The theory is “natural”, anomaly free, has no fundamental scalar particles, and describes at least three generations of quarks and leptons.     

Measured rates of fluoride/metal association correlate with rates of superoxide/metal reactions for Fe(III)EDTA(H2O)- and related complexes

The effects of 10 paramagnetic metal complexes (Fe(III)EDTA(H2O)-, Fe(III)EDTA(OH)2-, Fe(III)PDTA-, Fe(III)DTPA2-, Fe(III)2O(TTHA)2-, Fe(III)(CN)6(3-), Mn(II)EDTA(H2O)2-, Mn(II)PDTA2-, Mn(II)beta-EDDADP2-, and Mn(II)PO4(-)) on F- ion 19F NMR transverse relaxation rates (R2 = 1/T2) were studied in aqueous solutions as a function of temperature. Consistent with efficient relaxation requiring formation of a metal/F- bond, only the substitution inert complexes Fe(III)(CN)6(3-) and Fe(III)EDTA(OH)2- had no measured effect on T2 relaxation of the F- 19F resonance. For the remaining eight complexes, kinetic parameters (apparent second-order rate constants and activation enthalpies) for metal/F- association were determined from the dependence of the observed relaxation enhancements on complex concentration and temperature. Apparent metal/F- association rate constants for these complexes (k(app,F-)) spanned 5 orders of magnitude. In addition, we measured the rates at which O2*- reacts with Fe(III)PDTA-, Mn(II)EDTA(H2O)2-, Mn(II)PDTA2-, and Mn(II)beta-EDDADP2- by pulse radiolysis. Although no intermediate is observed during the reduction of Fe(III)PDTA- by O2*-, each of the Mn(II) complexes reacts with formation of a transient intermediate presumed to form via ligand exchange. These reactivity patterns are consistent with literature precedents for similar complexes. With these data, both k(app,O2-) and k(app,F-) are available for each of the eight reactive complexes. A plot of log(k(app,O2-)) versus log(k(app,F-)) for these eight showed a linear correlation with a slope approximately 1. This correlation suggests that rapid metal/O2*- reactions of these complexes occur via an inner-sphere mechanism whereas formation of an intermediate coordination complex limits the overall rate. This hypothesis is also supported by the very low rates at which the substitution inert complexes (Fe(III)(CN)6(3-) and Fe(III)EDTA(OH)2-) are reduced by O2*-. These results suggest that F- 19F NMR relaxation can be used to predict the reactivities of other Fe(III) complexes toward reduction by O2*-, a key step in the biological production of reactive oxygen species.