The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated β-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Aβ oligomerization and fibrillization, as well as the cytotoxic effect of Aβ oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Aβ while immuno-staining of the 3rd instar larval brains showed a significant reduction in Aβ accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Aβ. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease.

Despite tremendous progress in genome sequencing, the basic goal of producing phased (haplotype-resolved) genome sequence with end-to-end contiguity for each chromosome at reasonable cost and effort is still unrealized. In this study, we describe a new approach to perform de novo genome assembly and experimental phasing by integrating the data from Illumina shortread sequencing, 10X Genomics Linked-Read sequencing, and BioNano Genomics genome mapping to yield a high-quality, phased, de novo assembled human genome.The completion of the human genome reference assembly in 2003 marked a major milestone in genome research. The reference human genome sequence (and the genome sequences of Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms Correspondence should be addressed to P.Y.K. (Pui.Kwok@ucsf.edu). Accession codes. Sequencing and assembly data are available under BioProject PRJNA315896 with Sequence Read Archive accession numbers: SRX1675529, SRX1675530 and SRX1675531.Author Contributions P.Y.K., J.D.W., and Y.M. conceived the project and provided resources and oversight for sequencing and algorithmic analysis. K.G. prepared long libraries for 10XG GemCode sequencing. C.C. and C.L. performed long DNA preparation and BNG genome mapping experiments. E.T.L., A.R.H., Ž. DŽ., J. Lee, and H.C. built initial genome maps and performed BNG alignment and SV calling. Y.M. and J. Lam performed scaffold analysis. E.T.L., A.R.H., and J. Lee performed hybrid genome assembly. P.M., K.G., and M.S.L. performed scaffold phasing. Y.M., M.L.S., E.T.L., J. Lam, J. Lee, and S.A.S. performed validation and quality measure analyses of the assembled data. Y.M., E.T.L., M.L.S., and P.Y.K. primarily wrote the manuscript and revisions, though many coauthors provided edits and methods sections.Competing Financial Interests Statement E.T.L., A.R.H., J. Lee, Ž. DŽ., H.C. are employees of BioNano Genomics. P.M., K.G., M.S.L. are employees of 10X Genomics, and P.Y.K. is on the scientific advisory board of BioNano Genomics. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript numerous other organisms) and the sequencing technologies developed for the Human Genome Project revolutionized biological research and hastened the discovery of causal mutations for many diseases 1,2 . Despite tremendous progress, the basic goal of producing phased (haplotype-resolved) genome sequence with end-to-end contiguity for each chromosome at reasonable cost and effort is still unrealized. Consequently, researchers who engage in human "whole-genome sequencing" have produced tens of thousands of genomes that are collections of short-read sequences aligned to the composite reference human genome sequence produced from several donors of various ethnic backgrounds. Similarly, de novo assemblies of other species generally consist of a set ...

The two main branches of bionanotechnology involve the self-assembly of either peptides or DNA. Peptide scaffolds offer chemical versatility, architectural flexibility and structural complexity, but they lack the precise base pairing and molecular recognition available with nucleic acid assemblies. Here, inspired by the ability of aromatic dipeptides to form ordered nanostructures with unique physical properties, we explore the assembly of peptide nucleic acids (PNAs), which are short DNA mimics that have an amide backbone. All 16 combinations of the very short di-PNA building blocks were synthesized and assayed for their ability to self-associate. Only three guanine-containing di-PNAs-CG, GC and GG-could form ordered assemblies, as observed by electron microscopy, and these di-PNAs efficiently assembled into discrete architectures within a few minutes. The X-ray crystal structure of the GC di-PNA showed the occurrence of both stacking interactions and Watson-Crick base pairing. The assemblies were also found to exhibit optical properties including voltage-dependent electroluminescence and wide-range excitation-dependent fluorescence in the visible region.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.

The human reference genome is used extensively in modern biological research. However, a single consensus representation is inadequate to provide a universal reference structure because it is a haplotype among many in the human population. Using 10× Genomics (10×G) “Linked-Read” technology, we perform whole genome sequencing (WGS) and de novo assembly on 17 individuals across five populations. We identify 1842 breakpoint-resolved non-reference unique insertions (NUIs) that, in aggregate, add up to 2.1 Mb of so far undescribed genomic content. Among these, 64% are considered ancestral to humans since they are found in non-human primate genomes. Furthermore, 37% of the NUIs can be found in the human transcriptome and 14% likely arose from Alu-recombination-mediated deletion. Our results underline the need of a set of human reference genomes that includes a comprehensive list of alternative haplotypes to depict the complete spectrum of genetic diversity across populations.

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Background: ␣-syn aggregation is a main pathology of PD. Results: Mannitol interferes with ␣-syn aggregation in vitro and in vivo, whereas no adverse effects were observed in control animals. Conclusion:In addition to its BBB-disrupting properties, mannitol, a chemical chaperon, may serve as a potential drug. Significance: mannitol may serve as a basis for a dual mechanism therapeutic agent for treating PD.