Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity.

The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of β-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the β-structures presents a challenge to developing a model system of β-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust β-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid β-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-β peptide associated with Alzheimer's disease, β(2)-microglobulin associated with dialysis-related amyloidosis, α-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles

Health-related quality of life after mandibular resection for oral cancer: reconstruction with free fibula flap

Objectives: Mandibular resection for oral cancer is often necessary to achieve an adequate margin of tumor clear - ance. Mandibular resection has been associated with a poor health-related quality of life (HRQOL), particularly before free fibula flap to reconstruct the defect. The aim of this study was to evaluate health-related quality of life in patients who have had mandibular resections of oral cancer and reconstruction with free fibula flap. Study D esigns: There were 115 consecutive patients between 2008 and 2011 who were treated by primary surgery for oral squamous cell carcinoma, 34 patients had a mandibular resection. HRQOL was assessed by means of the 14-item Oral Health Impact Profile (OHIP-14) and University of Washington Quality of Life (UW-QOL) question - naires after 12 months postoperatively. Results: In the UW-QOL the best-scoring domain was mood, whereas the lowest scores were for chewing and saliva. In the OHIP-14 the lowest-scoring domain was social disability, followed by handicap, and psychological disability. Conclusions: Mandible reconstruction with free fibula flap would have significantly influenced on patients' quality of life and oral functions. The socio-cultural data show a fairly low level of education for the majority of patients

Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta.

Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer's, Parkinson's, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer's disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers. DOI:http://dx.doi.org/10.7554/eLife.00857.001

CMB Temperature and Matter Power Spectrum in a Decay Vacuum Dark Energy Model

In this paper, a decay vacuum model $\bar{\rho}_\Lambda=3\sigma M_p^2H_0 H$ is revisited by detailed analysis of background evolution and perturbation equations. We show the imprints on CMB temperature and matter power spectrum from the effective coupling terms between dark sectors by comparing to the standard cosmological constant model and observational data points (WMAP7 and SDSS DR7). We find that the decay vacuum model can describe the expansion rate at late times as well as the standard cosmological constant model but it fails to simultaneously reproduce the observed CMB and matter power spectrum. Its generalization $\bar{\rho}_\Lambda=3M_p^2(\xi_1 H_0 H+\xi_2 H^2)$ is also discussed. Detailed analysis of the background evolution shows that the dimensionless parameter $\xi_{2}$ would be zero to avoid the unnatural 'fine tuning' and to keep the positivity of energy density of dark matter and dark energy in the early epoch

CTCF Mediates the Cell-Type Specific Spatial Organization of the Kcnq5 Locus and the Local Gene Regulation

Chromatin loops play important roles in the dynamic spatial organization of genes in the nucleus. Growing evidence has revealed that the multivalent functional zinc finger protein CCCTC-binding factor (CTCF) is a master regulator of genome spatial organization, and mediates the ubiquitous chromatin loops within the genome. Using circular chromosome conformation capture (4C) methodology, we discovered that CTCF may be a master organizer in mediating the spatial organization of the kcnq5 gene locus. We characterized the cell-type specific spatial organization of the kcnq5 gene locus mediated by CTCF in detail using chromosome conformation capture (3C) and 3C-derived techniques. Cohesion also participated in mediating the organization of this locus. RNAi-mediated knockdown of CTCF sharply diminished the interaction frequencies between the chromatin loops of the kcnq5 gene locus and down-regulated local gene expression. Functional analysis showed that the interacting chromatin loops of the kcnq5 gene locus can repress the gene expression in a luciferase reporter assay. These interacting chromatin fragments were a series of repressing elements whose contacts were mediated by CTCF. Therefore, these findings suggested that the dynamical spatial organization of the kcnq5 locus regulates local gene expression

Model-driven Learning for Generic MIMO Downlink Beamforming With Uplink Channel Information

Accurate downlink channel information is crucial to the beamforming design, but it is difficult to obtain in practice. This paper investigates a deep learning-based optimization approach of the downlink beamforming to maximize the system sum rate, when only the uplink channel information is available. Our main contribution is to propose a model-driven learning technique that exploits the structure of the optimal downlink beamforming to design an effective hybrid learning strategy with the aim to maximize the sum rate performance. This is achieved by jointly considering the learning performance of the downlink channel, the power and the sum rate in the training stage. The proposed approach applies to generic cases in which the uplink channel information is available, but its relation to the downlink channel is unknown and does not require an explicit downlink channel estimation. We further extend the developed technique to massive multiple-input multiple-output scenarios and achieve a distributed learning strategy for multicell systems without an inter-cell signalling overhead. Simulation results verify that our proposed method provides the performance close to the state of the art numerical algorithms with perfect downlink channel information and significantly outperforms existing data-driven methods in terms of the sum rate

Intein-mediated backbone cyclization of entolimod confers enhanced radioprotective activity in mouse models

Background Entolimod is a Salmonella enterica flagellin derivate. Previous work has demonstrated that entolimod effectively protects mice and non-human primates from ionizing radiation. However, it caused a “flu-like” syndrome after radioprotective and anticancer clinical application, indicating some type of immunogenicity and toxicity. Cyclization is commonly used to improve the in vivo stability and activity of peptides and proteins. Methods We designed and constructed cyclic entolimod using split Nostoc punctiforme DnaE intein with almost 100% cyclization efficiency. We adopted different strategies to purify the linear and circular entolimod due to their different topologies. Both of linear and circular entolimod were first purified by Ni-chelating affinity chromatography, and then the linear and circular entolimod were purified by size-exclusion and ion-exchange chromatography, respectively. Results The circular entolimod showed significantly increased both the in vitro NF-κB signaling and in vivo radioprotective activity in mice. Conclusion Our data indicates that circular entolimod might be a good candidate for further clinical investigation