Pathogenicity of anti-ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease in which anti-ADAMTS13 autoantibodies cause severe enzyme deficiency. ADAMTS13 deficiency causes the loss of regulation of von Willebrand factor multimeric size and platelet-tethering function, which results in the formation of disseminated microvascular platelet microthrombi. Precisely how anti-ADAMTS13 autoantibodies, or antibody subsets, cause ADAMTS13 deficiency (ADAMTS13 activity generally < 10%) has not been formally investigated. METHODS: We analysed 92 acquired TTP episodes at presentation, through treatment and remission/relapse using epitope mapping and functional analyses to understand the pathogenic mechanisms of anti-ADAMTS13 IgG. RESULTS: 89/92 of TTP episodes had IgG recognising the ADAMTS13 N-terminal domains. The central spacer domain was the only N-terminal antigenic target detected. 38/92 TTP episodes had autoantibodies recognising the N-terminal domains alone; 54/92 TTP episodes also had antibodies against the ADAMTS13 C-terminal domains (TSP2-8 and/or CUB domains). Changes in autoantibody specificity were detected in 9/16 patients at relapse, suggesting a continued development of the disease. Functional analyses on IgG from 43 patients revealed inhibitory IgG were limited to anti-spacer domain antibodies. However, 15/43 patients had autoantibodies with no detectable inhibitory action and as many as 32/43 patients had autoantibodies with inhibitory function that was insufficient to account for the severe deficiency state, suggesting that in many patients there is an alternative pathogenic mechanism. We therefore analysed plasma ADAMTS13 antigen levels in 91 acquired TTP presentation samples. We demonstrated markedly reduced ADAMTS13 antigen levels in all presentation samples, median 6% normal (range 0-47%), with 84/91 patients having < 25% ADAMTS13 antigen. ADAMTS13 antigen in the lowest quartile at first presentation was associated with increased mortality (odds ratio 5.7). CONCLUSIONS: Anti-spacer domain autoantibodies are the major inhibitory antibodies in acquired TTP. However, depletion of ADAMTS13 antigen (rather than enzyme inhibition) is a dominant pathogenic mechanism. ADAMTS13 antigen levels at presentation have prognostic significance. Taken together, our results provide new insights into the pathophysiology of acquired TTP

Biometric security based on ECG

Recently the electrocardiogram (ECG) has been proposed as a novel biometric. This paper aims to construct a reliable ECG verification system, in terms of privacy protection. To this end, an improved expression to estimate the capacity in the autocorrelation (AC) of the ECG is derived, which not only gives an upper bound for the number of identifiable subjects using ECG, but also helps to determine the number of independent features needed for verification. This capacity derivation, to our best knowledge, is new and can be easily extended to other biometrics. In addition, we apply the Quantization Index Modulation (QIM) scheme to the verification system for template protection. Based on our database, we found that, the capacity in the AC of ECG is approximately 20 bits information contained in the 23 independent features. We have also shown that compared to unprotected systems, the QIM scheme greatly enhances privacy protection of ECG templates without significant sacrificing of the identification performance

Using surface waves recorded by a large mesh of three-element arrays to detect and locate disparate seismic sources

Author Posting. © The Authors, 2018. This article is posted here by permission of The Royal Astronomical Society for personal use, not for redistribution. The definitive version was published in Geophysical Journal International 215 (2018): 942–958, doi:10.1093/gji/ggy316.Surface waves recorded by global arrays have proven useful for locating tectonic earthquakes and in detecting slip events depleted in high frequency, such as glacial quakes. We develop a novel method using an aggregation of small- to continental-scale arrays to detect and locate seismic sources with Rayleigh waves at 20–50 s period. The proposed method is a hybrid approach including first dividing a large aperture aggregate array into Delaunay triangular subarrays for beamforming, and then using the resolved surface wave propagation directions and arrival times from the subarrays as data to formulate an inverse problem to locate the seismic sources and their origin times. The approach harnesses surface wave coherence and maximizes resolution of detections by combining measurements from stations spanning the whole U.S. continent. We tested the method with earthquakes, glacial quakes and landslides. The results show that the method can effectively resolve earthquakes as small as ∼M3 and exotic slip events in Greenland. We find that the resolution of the locations is non-uniform with respect to azimuth, and decays with increasing distance between the source and the array when no calibration events are available. The approach has a few advantages: the method is insensitive to seismic event type, it does not require a velocity model to locate seismic sources, and it is computationally efficient. The method can be adapted to real-time applications and can help in identifying new classes of seismic sources.WF is currently supported by the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution, with funding provided by the Weston Howland Jr. Postdoctoral Scholarship. This work was supported by National Science Foundation grant EAR-1358520 at Scripps Institution of Oceanography, UC San Diego

Ground State and Magnetization Process of the Mixture of Bond-Alternating and Uniform S=1/2 Antiferromagnetic Heisenberg Chains

The mixture of bond-alternating and uniform S=1/2 antiferromagnetic Heisenberg chains is investigated by the density matrix renormalization group method. The ground state magnetization curve is calculated and the exchange parameters are determined by fitting to the experimentally measured magnetization curve of \CuCl$_{2x}$Br$_{2(1-x)}$($\gamma$-pic)$_2$. The low field behavior of the magnetization curve and low temperature behavior of the magnetic susceptibility are found to be sensitive to whether the bond-alternation pattern (parity) is fixed all over the sample or randomly distributed. The both quantities are compatible with the numerical results for the random parity model.Comment: 5 pages, 7 figures. Final and enlarged version accepted for publication in J. Phys. Soc. Jp

Autoimmune diseases and new-onset atrial fibrillation:a UK Biobank study

AimsThe underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF.Methods and resultsParticipants from the population-based UK Biobank were screened for rheumatic fever, gastrointestinal autoimmune diseases, autoimmune diseases targeting the musculoskeletal system and connective tissues, and neurological autoimmune diseases. Between 2006 and 2022, participants were followed for incident AF. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations. 494 072 participants free from AF were included (median age 58.0 years, 54.8% women). After a median of 12.8 years, 27 194 (5.5%) participants were diagnosed with new-onset AF. Rheumatic fever without heart involvement (HR, 95% CI: 1.47, 1.26–1.72), Crohn’s disease (1.23, 1.05–1.45), ulcerative colitis (1.17, 1.06–1.31), rheumatoid arthritis (1.39, 1.28–1.51), polyarteritis nodosa (1.82, 1.04–3.09), systemic lupus erythematosus (1.82, 1.41–2.35), and systemic sclerosis (2.32, 1.57–3.44) were associated with a larger AF risk. In sex-stratified analyses, rheumatic fever without heart involvement, multiple sclerosis, Crohn’s disease, seropositive rheumatoid arthritis, psoriatic and enteropathic arthropathies, systemic sclerosis and ankylosing spondylitis were associated with larger AF risk in women, whereas only men showed a larger AF risk associated with ulcerative colitis.ConclusionsVarious autoimmune diseases are associated with new-onset AF, more distinct in women. Our findings elaborate on the pathophysiological differences in autoimmunity and AF risk between men and women

6D Effective Action of Heterotic Compactification on K3 with nontrivial Gauge Bundles

We compute the six-dimensional effective action of the heterotic string compactified on K3 for the standard embedding and for a class of backgrounds with line bundles and appropriate Yang-Mills fluxes. We compute the couplings of the charged scalars and the bundle moduli as functions of the geometrical K3 moduli from a Kaluza-Klein analysis. We derive the D-term potential and show that in the flux backgrounds U(1) vector multiplets become massive by a Stuckelberg mechanism.Comment: 41 pages, typos corrected, references adde

Antiferromagnetic Heisenberg chains with bond alternation and quenched disorder

We consider S=1/2 antiferromagnetic Heisenberg chains with alternating bonds and quenched disorder, which represents a theoretical model of the compound CuCl_{2x}Br_{2(1-x)}(\gamma-{pic})_2. Using a numerical implementation of the strong disorder renormalization group method we study the low-energy properties of the system as a function of the concentration, x, and the type of correlations in the disorder. For perfect correlation of disorder the system is in the random dimer (Griffiths) phase having a concentration dependent dynamical exponent. For weak or vanishing disorder correlations the system is in the random singlet phase, in which the dynamical exponent is formally infinity. We discuss consequences of our results for the experimentally measured low-temperature susceptibility of CuCl_{2x}Br_{2(1-x)}(\gamma-{pic})_2

Simultaneous Nano‐ and Microscale Control of Nanofibrous Microspheres Self‐Assembled from Star‐Shaped Polymers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/112291/1/adma201501329-sup-0001-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/112291/2/adma201501329.pd

An inhomogeneous toy-model of the quantum gravity with explicitly evolvable observables

An inhomogeneous (1+1)-dimensional model of the quantum gravity is considered. It is found, that this model corresponds to a string propagating against some curved background space. The quantization scheme including the Wheeler-DeWitt equation and the "particle on a sphere" type of the gauge condition is suggested. In the quantization scheme considered, the "problem of time" is solved by building of the quasi-Heisenberg operators acting in a space of solutions of the Wheeler-DeWitt equation and the normalization of the wave function corresponds to the Klein-Gordon type. To analyze the physical consequences of the scheme, a (1+1)-dimensional background space is considered for which a classical solution is found and quantized. The obtained estimations show the way to solution of the cosmological constant problem, which consists in compensation of the zero-point oscillations of the matter fields by the quantum oscillations of the scale factor. Along with such a compensation, a slow global evolution of a background corresponding to an universe expansion exists.Comment: 18 page

N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes

Background: Pregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes.Methods: Female mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed.Results: Our data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment.Conclusions: Treatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes. © 2014 Moazzen et al.; licensee BioMed Central Ltd