The RUSH2A Study: Dark-Adapted Visual Fields in Patients With Retinal Degeneration Associated With Biallelic Variants in the USH2A Gene

PurposeTo measure visual fields using two-color dark-adapted chromatic perimetry in a subset of participants in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A), a study of USH2A-mediated syndromic (USH2) and autosomal recessive nonsyndromic retinitis pigmentosa, determine percentage retaining rod function, and explore relationships between dark-adapted visual fields (DAVF) and rod function from ERG and full-field stimulus thresholds (FST).MethodsFull-field rod mean sensitivity, number of rod loci, maximum sensitivity, DAVF full-field hill of vision (DAVF V_TOT), and 30° hill of vision (DAVF V₃₀) were measured in one eye for DAVF ancillary study participants (n = 49). Loci where cyan relative to red sensitivity was more than 5 dB on dark-adapted chromatic perimetry were considered rod mediated. Correlation coefficients between the DAVF measures and standard clinical measures were estimated, as were kappa statistics (κ) for agreement between DAVF and other measures of rod function.ResultsOf 49 participants tested with DAVF, 38 (78%) had evidence of rod function, whereas 15 (31%) had measurable rod ERGs. DAVF maximum sensitivity was highly correlated with FST white thresholds (r = −0.80; P < .001). Although not statistically significant, the number of rod loci and DAVF V_TOT were lower in eyes with longer disease duration by 0.82 (95% confidence interval, −1.76, 0.12) loci/year and 0.59 (95% confidence interval, −1.82, 0.64) dB-steradians/year, respectively.ConclusionsRod-mediated function on FST and DAVF is present in many patients with symptomatic USH2A-related retinal degeneration, including some without measurable rod ERGs. RUSH2A longitudinal data will determine how these measures change with disease progression and whether they are useful for longitudinal studies in inherited retinal degenerations.     

Arginase activity in alternatively activated macrophages protects PI3Kp110δ deficient mice from dextran sodium sulfate induced intestinal inflammation

Alternatively activated or M2 macrophages have been reported to protect mice from intestinal inflammation, but the mechanism of protection has not been elucidated. In this study, we demonstrate that mice deficient in the p110δ catalytic subunit activity of class I phosphatidylinositol 3‐kinase (PI3Kp110δ) have increased clinical disease activity and histological damage during dextran sodium sulfate (DSS) induced colitis. Increased disease severity in PI3Kp110δ‐deficient mice is dependent on professional phagocytes and correlates with reduced numbers of arginase I⁺ M2 macrophages in the colon and increased production of inflammatory nitric oxide. We further demonstrate that PI3Kp110δ‐deficient macrophages are defective in their ability to induce arginase I when skewed to an M2 phenotype with IL‐4. Importantly, adoptive transfer of IL‐4‐treated macrophages derived from WT mice, but not those from PI3Kp110δ‐deficient mice, protects mice during DSS‐induced colitis. Moreover, M2 macrophages mediated protection is lost when mice are cotreated with inhibitors that block arginase activity or during adoptive transfer of arginase I deficient M2 macrophages. Taken together, our data demonstrate that arginase I activity is required for M2 macrophages mediated protection during DSS‐induced colitis in PI3Kp110δ‐deficient mice.     

Spin jam induced by quantum fluctuations in a frustrated magnet

Since the discovery of spin glasses in dilute magnetic systems, their study has been largely focused on understanding randomness and defects as the driving mechanism. The same paradigm has also been applied to explain glassy states found in dense frustrated systems. Recently, however, it has been theoretically suggested that different mechanisms, such as quantum fluctuations and topological features, may induce glassy states in defect-free spin systems, far from the conventional dilute limit. Here we report experimental evidence for existence of a glassy state, which we call a spin jam, in the vicinity of the clean limit of a frustrated magnet, which is insensitive to a low concentration of defects. We have studied the effect of impurities on SrCr_9pGa_12-9pO₁₉ [SCGO(p)], a highly frustrated magnet, in which the magnetic Cr³⁺ (s = 3/2) ions form a quasi-2D triangular system of bipyramids. Our experimental data show that as the nonmagnetic Ga³⁺ impurity concentration is changed, there are two distinct phases of glassiness: an exotic glassy state, which we call a spin jam, for the high magnetic concentration region (p > 0.8) and a cluster spin glass for lower magnetic concentration (p < 0.8). This observation indicates that a spin jam is a unique vantage point from which the class of glassy states of dense frustrated magnets can be understood.Understanding glassy states found in dense frustrated magnets has been an intellectual challenge since peculiar low-temperature glassy behaviors were observed experimentally in the quasi-2D SrCr_9pGa_12-9pO₁₉ (SCGO) (1–3) and in the 3D pyrochlore Y₂Mo₂O₇ (4). Immediately following, theoretical investigations (5–9) were performed to see if an intrinsic spin freezing transition is possible in a defect-free situation, aided by quantum fluctuations, as in the order-by-fluctuations phenomenon (10, 11). Quantum fluctuations at T = 0 were shown to select a long-range ordered state in the 2D kagome isotropic antiferromagnet (AFM) (5, 6), later expanded to the isotropic pyroclore and SCGO (9). Anisotropic interactions were also considered as a possible origin of the glassy kagome AFM (7). For an XY pyrochlore AFM, thermal fluctuations were found to induce a conventional Neel order (8). Experimental works were also performed to investigate if the glassy states are extrinsic due to site defects or random couplings or intrinsic to the magnetic lattice (12, 13). The consensus is that the low-temperature spin freezing transitions in SCGO(p) near the clean limit (p ≈ 1) is not driven by site defects (13).The nature of the frozen state in SCGO has been investigated by numerous experimental techniques, including bulk susceptibility (1–3), specific heat (2, 14), muon spin relaxation (μSR) (15), nuclear magnetic resonance (NMR) (13, 16), and elastic and inelastic neutron scattering (17). Observed are spin glassy behaviors, such as field-cooled and zero-field-cooled (FC/ZFC) hysteresis in bulk susceptibility (3), as well as non-spin-glassy behaviors, such as a quadratic behavior of specific heat at low T, C_v ∝ T² (14), linear dependence of the imaginary part of the dynamic susceptibility at low energies, χ″(ω) ∝ ω (17), and a broad but prominent momentum dependence of the elastic neutron scattering intensity (17). The interpretation of the frozen state below T_f is still controversial. One possibility suggested was a spin liquid with unconfined spinons or resonating valence bond state, based on NMR and μSR studies (15, 16). Many-body singlet excitations were also suggested to be responsible for the C_v ∝ T² behavior (14).Recently, some of us presented an alternative scenario involving a spin jam state by considering the effects of quantum fluctuations in the disorder-free quasi-2D ideal SCGO lattice with a simple nearest neighbor (NN) spin interaction Hamiltonian ? = J∑_NNS_i ? S_j (18, 19). The spin jam framework provided a qualitatively coherent understanding of all of the low-temperature behaviors such as that a complex energy landscape is responsible for the frozen state without long-range order (18), and Halperin−Saslow (HS)-like modes for the C_v ∝ T² and χ″(ω) ∝ ω behaviors (5, 18). In this system, which we refer to as the ideal SCGO model (iSCGO), semiclassical magnetic moments (or spins) are arranged in a triangular network of bipyramids and interact uniformly with their NN (18, 19). The microscopic mechanism for the spin jam state is purely quantum mechanical. The system has a continuous and flat manifold of ground states at the mean field level, including locally collinear, coplanar, and noncoplanar spin arrangements. Quantum fluctuations lift the classical ground state degeneracy (order by fluctuations), resulting in a complex rugged energy landscape that has a plethora of local minima consisting of the locally collinear states separated from each other by potential barriers (18). Although the work of ref. 18 dealt with a similar phase space constriction by quantum fluctuations as the aforementioned other theoretical works did, we would like to stress here the difference between the two: Whereas the other works mainly focused on the selection of the long-range-ordered (LRO) energetic ground state, the work of ref. 18 showed that the short-range-ordered (SRO) states that exist at higher energies are long-lived, dominate entropically over the LRO states, and govern the low-T physics.The introduction of nonmagnetic impurities into a topological spin jam state breaks some of the constraints in the system, and possibly allows local transitions between minima, with a time scale dependent on the density of impurities. At a sufficiently high vacancy concentration, the system exits the spin jam state and becomes either paramagnetic or an ordinary spin glass at lower temperatures. Here we try to identify and explore the spin jam regime in an experimentally accessible system. The three most important signatures we seek for the existence of a spin jam state, different from conventional spin glass states, are (i) a linear dependence of the imaginary part of the dynamic susceptibility at low energies, χ″(ω) ∝ ω, (ii) intrinsic short range static spin correlations, and (iii) insensitivity of its physics to nonmagnetic doping near the clean limit. In the rest of the paper, we provide experimental demonstration of these properties.Experimentally, there are, so far, two materials, SrCr_9pGa_12-9pO₁₉ [SCGO(p)] (1–3, 13–17, 20) and qs-ferrites like Ba₂Sn₂ZnGa₃Cr₇O₂₂ (BSZGCO) (21), in which the magnetic Cr³⁺ (3d³) ion surrounded by six oxygen octahedrally, form distorted quasi-2D triangular lattice of bipyramids (20, 21) as shown in Fig. 1A, and thus may realize a spin jam state. We would like to emphasize that these systems are very good insulators (resistivity ρ > ?10¹³?Ω ? cm at 300 K) and the Cr³⁺ (t2g3) ion has no orbital degree of freedom. Furthermore, the neighboring Cr ions share one edge of oxygen octahedral, and thus the direct overlap of the t2g3 orbitals of the neighboring Cr³⁺ ions make the AFM NN Heisenberg exchange interactions dominant and further neighbor interactions negligible (22, 23), as found in Cr₂O₃ (24) and ZnCr₂O₄ (25).Open in a separate windowFig. 1.(A) In SrCr_9pGa_12-9pO₁₉ [SCGO(p)], the magnetic Cr³⁺ (3d³, s = 3/2) ions form the kagome−triangular−kagome trilayer (Top). The blue and red spheres represent kagome and triangular sites, respectively. When viewed from the top of the layers, they form the triangular network of bipyramids (Bottom). (B) The p−T phase diagram of SCGO(p) constructed by bulk susceptibility and elastic neutron scattering measurements on powder samples with various p values. The freezing temperatures, T_f, marked with blue square and black circle symbols are obtained by bulk susceptibility and elastic neutron scattering measurements, respectively. Note that the values of T_f are much lower than the Curie–Weiss temperatures (see Fig. S1). Filled blue squares represent the data obtained from samples whose crystal structural parameters including the Cr/Ga concentrations were refined by neutron diffraction measurements (see Fig. S2 and Fig. S3).     

Protective effect of a marine polyphenol,dieckol against carbon tetrachloride-induced acute liver damage in mouse

In this study, the hepatoprotective effect of dieckol on carbon tetrachloride (CCl₄) induced hepatic damages in ICR mice liver was investigated. Mice were randomly divided into 4 groups such as saline treated (negative control), CCl₄ treated (positive control), CCl₄ + dieckol (5 mg/kg mouse) and CCl₄ + dieckol (25 mg/kg mouse), respectively. The body weights and survival rates of mice, followed by dieckol treatments were significantly increased compared to the positive control. The level of GOT, GPT and MDA in the serum of the dieckol treated groups were reduced dose dependently than the control, significantly. The antioxidant enzymes including CAT, and GSH-px levels were increased significantly compared to the positive control. However, no significant differences were observed on hepatic histophathological analysis in dieckol treated groups dose dependently. Down-regulation of Bax and up-regulation of Bcl-xl protein expressions were observed in liver tissues of the dieckol administered groups. These results suggested that, dieckol can be developed as a therapeutic agent for liver disease by oxidative stress.     

An updated phylogeny of Sordariomycetes based on phylogenetic and molecular clock evidence

The previous phylogenies of Sordariomycetes by M.E. Barr, O.E. Eriksson and D.L. Hawksworth, and T. Lumbsch and S. Huhndorf, were mainly based on morphology and thus were somewhat subjective. Later outlines by T. Lumbsch and S. Huhndorf, and Maharachchikumbura and co-authors, took into account phylogenetic evidence. However, even these phylogenetic driven arrangements for Sordariomycetes, were somewhat subjective, as the arrangements in trees depended on many variables, such as number of taxa, different gene regions and methods used in the analyses. What is needed is extra evidence to help standardize ranking in the fungi. Estimation of divergence times using molecular clock methods has been proposed for providing additional rational for higher ranking of taxa. Thus, in Sordariomycetes, a divergence period (i.e. 200–300 MYA) can be used as criteria to judge when a group of related taxa evolved and what rank they should be given. In this paper, we provide an updated classification of accepted subclasses, orders of Sordariomycetes and use divergence times to provide additional evidence to stabilize ranking of taxa in the class. We point out and discuss discrepancies where the phylogenetic tree conflicts with the molecular clock.     

Semiparametric modeling and analysis of longitudinal method comparison data

Studies comparing two or more methods of measuring a continuous variable are routinely conducted in biomedical disciplines with the primary goal of measuring agreement between the methods. Often, the data are collected by following a cohort of subjects over a period of time. This gives rise to longitudinal method comparison data where there is one observation trajectory for each method on every subject. It is not required that observations from all methods be available at each observation time. The multiple trajectories on the same subjects are dependent. We propose modeling the trajectories nonparametrically through penalized regression splines within the framework of mixed‐effects models. The model also uses random effects of subjects and their interactions to capture dependence in observations from the same subjects. It additionally allows the within‐subject errors of each method to be correlated. It is fit using the method of maximum likelihood. Agreement between the methods is evaluated by performing inference on measures of agreement, such as concordance correlation coefficient and total deviation index, which are functions of parameters of the assumed model. Simulations indicate that the proposed methodology performs reasonably well for 30 or more subjects. Its application is illustrated by analyzing a dataset of percentage body fat measurements. Copyright © 2017 John Wiley & Sons, Ltd.