WFS1-Associated Optic Neuropathy : Genotype-Phenotype Correlations and Disease Progression

center dot OBJECTIVE: To evaluate the pattern of vision loss and genotype-phenotype correlations in WFS1-associated optic neuropathy (WON).center dot DESIGN: Multicenter cohort study. center dot METHODS: The study involved 37 patients with WON carrying pathogenic or candidate pathogenic WFS1 variants. Genetic and clinical data were retrieved from the medical records. Thirteen patients underwent additional comprehensive ophthalmologic assessment. Deep phenotyping involved visual electrophysiology and advanced psychophysical testing with a complementary metabolomic study. Main Outcome Measures: WFS1 variants, functional and structural optic nerve and retinal parameters, and metabolomic profile.center dot RESULTS: Twenty-two recessive and 5 dominant WFS1 variants were identified. Four variants were novel. All WFS1 variants caused loss of macular retinal ganglion cells (RGCs) as assessed by optical coherence tomography (OCT) and visual electrophysiology. Advanced psychophysical testing indicated involvement of the major RGC subpopulations. Modeling of vision loss showed an accelerated rate of deterioration with increasing age. Dominant WFS1 variants were associated with abnormal reflectivity of the outer plexiform layer (OPL) on OCT imaging. The dominant variants tended to cause less severe vision loss compared with recessive WFS1 variants, which resulted in more variable phenotypes ranging from isolated WON to severe multisystem disease depending on the WFS1 alleles. The metabolomic profile included markers seen in other neurodegenerative diseases and type 1 diabetes mellitus. center dot CONCLUSIONS: WFS1 variants result in heterogenous phenotypes influenced by the mode of inheritance and the disease-causing alleles. Biallelic WFS1 variants cause more variable, but generally more severe, vision and RGC loss compared with heterozygous variants. Abnormal cleftlike lamination of the OPL is a distinctive OCT feature that strongly points toward dominant WON. (Am J Ophthalmol 2022;241: 927. (c) 2022 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ ))Peer reviewe

Genome Stability of Lyme Disease Spirochetes: Comparative Genomics of Borrelia burgdorferi Plasmids

Lyme disease is the most common tick-borne human illness in North America. In order to understand the molecular pathogenesis, natural diversity, population structure and epizootic spread of the North American Lyme agent, Borrelia burgdorferi sensu stricto, a much better understanding of the natural diversity of its genome will be required. Towards this end we present a comparative analysis of the nucleotide sequences of the numerous plasmids of B. burgdorferi isolates B31, N40, JD1 and 297. These strains were chosen because they include the three most commonly studied laboratory strains, and because they represent different major genetic lineages and so are informative regarding the genetic diversity and evolution of this organism. A unique feature of Borrelia genomes is that they carry a large number of linear and circular plasmids, and this work shows that strains N40, JD1, 297 and B31 carry related but non-identical sets of 16, 20, 19 and 21 plasmids, respectively, that comprise 33–40% of their genomes. We deduce that there are at least 28 plasmid compatibility types among the four strains. The B. burgdorferi ∼900 Kbp linear chromosomes are evolutionarily exceptionally stable, except for a short ≤20 Kbp plasmid-like section at the right end. A few of the plasmids, including the linear lp54 and circular cp26, are also very stable. We show here that the other plasmids, especially the linear ones, are considerably more variable. Nearly all of the linear plasmids have undergone one or more substantial inter-plasmid rearrangements since their last common ancestor. In spite of these rearrangements and differences in plasmid contents, the overall gene complement of the different isolates has remained relatively constant

Asymmetric returns, gradual bubbles and sudden crashes

By applying the deterministic heterogenous agent model developed by Huang et al. [Financial crises and interacting heterogeneous agents. Journal of Economic Dynamics and Control 34, no. 6: 1105–22], this paper examines the phenomena of asymmetric returns, gradual bubbles and sudden crashes. It shows that (i) returns are asymmetric because the most positive returns initiated by fundamentalist are attenuated by the selling force of chartists, while the most negative return initiated by chartists is hardly affected by the buying force of fundamentalists; (ii) bubbles arise gradually while crashes happen suddenly as the upward price movements are counterbalanced while the downward movements are enhanced by fundamentalists. It also shows for the first time that deterministic dynamic model can simultaneously generate a wide range of stylized facts common across financial markets, including those hardly duplicated by current heterogeneous agent models, such as long-range dependence

Financial crises and interacting heterogeneous agents

In this paper we examine various types of financial crises and conjecture their underlying mechanisms using a deterministic heterogeneous agent model (HAM). In a market-maker framework, forward-looking investors update their price expectations according to psychological trading windows and cluster themselves strategically to optimize their expected profits. The switches between trading strategies lead to price dynamics in market that subsequently move price up and down, and in the extreme case, cause financial crises. The model suggests that both fundamentalists and chartists could potentially contribute to the financial crises.Financial crisis Chaos Multi-phase heterogeneous beliefs Discounted expected profits

An Enzyme-Catalyzed Multistep DNA Refolding Mechanism in Hairpin Telomere Formation

<div><p>Hairpin telomeres of bacterial linear chromosomes are generated by a DNA cutting–rejoining enzyme protelomerase. Protelomerase resolves a concatenated dimer of chromosomes as the last step of chromosome replication, converting a palindromic DNA sequence at the junctions between chromosomes into covalently closed hairpins. The mechanism by which protelomerase transforms a duplex DNA substrate into the hairpin telomeres remains largely unknown. We report here a series of crystal structures of the protelomerase TelA bound to DNA that represent distinct stages along the reaction pathway. The structures suggest that TelA converts a linear duplex substrate into hairpin turns via a transient strand-refolding intermediate that involves DNA-base flipping and wobble base-pairs. The extremely compact di-nucleotide hairpin structure of the product is fully stabilized by TelA prior to strand ligation, which drives the reaction to completion. The enzyme-catalyzed, multistep strand refolding is a novel mechanism in DNA rearrangement reactions.</p> </div

The strand-refolding intermediate.

<p>(A) The open DNA conformation observed in the phosphotyrosine complexes stabilized by stacking of the flipped-out bases, G-T wobble base-pairs, and water-mediated hydrogen bonds. The protein and DNA molecules are colored as in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001472#pbio-1001472-g004" target="_blank">Figure 4A</a>. (B) Schematic diagram of the strand-refolding intermediate DNA conformation. The 5′ bases Thy1, Cyt2, and Ade3 are flexible. Thy1 in our crystal structures is either missing or replaced by cytosine to block ligation and trap the phosphotyrosine bond. (C) Simulated annealing omit Fo-Fc electron density contoured at 3.0 σ for the G-T wobble pair. (D) 5′-overhang conformation observed in the phosphotyrosine complexes (the refolding intermediate) trapped using two different types of suicide DNA substrates. The structure obtained with the nicked suicide substrate (DNAb/DNAc) is shown in yellow, while that obtained with a mismatch-based suicide substrate (DNAd) is shown in purple. The tri-nucleotide stretch Thy4, Gua5, and Ade6 is superimposable with an r.m.s.d. of 0.78 Å. The deviation comes mostly from the phosphate backbone atoms. (E) Comparison of the DNA structures between the refolding intermediate (yellow) and the hairpin telomere product (alternate conformations shown in black and grey). The superposition is based on the double-stranded stem region of the DNAs.</p

Structure of the hairpin telomere bound to TelA.

<p>(A) The compact di-nucleotide hairpin DNA product. All bases except two at the apex (Ade3 and Thy4) form Watson–Crick base-pairs. The DNA strand near the tip of the hairpin loop adopts two alternative conformations as indicated by the red arrows. The two protein subunits and two DNA molecules in the TelA–DNA complex are all colored differently (yellow/green for DNA, and grey/cyan for protein) to highlight <i>cis</i> versus <i>trans</i> interactions made by TelA. (B) Schematic diagram of the hairpin DNA conformation. The red dots represent the scissile phosphates. (C and D) Simulated annealing composite omit 2Fo-Fc densities for the wild-type TelA–hairpin DNA complex (C) and the R255A unligated hairpin complex (D). Electron densities within 2.0 Å from the DNA or active site protein atoms are shown, contoured at 1.5 σ (blue) or 7.0 σ (red) above the mean levels. (E) Two hairpin ends in alternative conformations are packed tightly across the 2-fold axis, interacting with one another as well as with Arg205. Van der Waals radii for Arg205 and Thy4 are shown by dots.</p

Overall structure of the TelA dimer bound to hairpin telomeres.

<p>Molecular surface is shown for one of the molecules in the TelA dimer, whereas the other molecule is shown by ribbons. The view in (A) is perpendicular to and that in (B) is parallel to the 2-fold axis relating the two TelA molecules. The two hairpin DNAs in alternative conformations are shown, as in <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001472#pbio-1001472-g004" target="_blank">Figure 4E</a>.</p

X-ray data collection, phasing, and refinement statistics.

<p>Statistics for the highest resolution shell are shown in parentheses.</p