Vortex pinning in high-Tc materials via randomly oriented columnar defects, created by GeV proton-induced fission fragments

Extensive work has shown that irradiation with 0.8 GeV protons can produce randomly oriented columnar defects (CD's) in a large number of HTS materials, specifically those cuprates containing Hg, Tl, Pb, Bi, and similar heavy elements. Absorbing the incident proton causes the nucleus of these species to fission, and the recoiling fission fragments create amorphous tracks, i.e., CD's. The superconductive transition temperature Tc decreases linearly with proton fluence and we analyze how the rate depends on the family of superconductors. In a study of Tl-2212 materials, adding defects decreases the equilibrium magnetization Meq(H) significantly in magnitude and changes its field dependence; this result is modeled in terms of vortex pinning. Analysis of the irreversible magnetization and its time dependence shows marked increases in the persistent current density and effective pinning energy, and leads to an estimate for the elementary attempt time for vortex hopping, tau ~ 4x10^(-9) s.Comment: Submitted to Physica C; presentation at ISS-2001. PDF file only, 13 pp. tota

Co-existence of Distinct Prion Types Enables Conformational Evolution of Human PrPSc by Competitive Selection

The unique phenotypic characteristics of mammalian prions are thought to be encoded in the conformation of pathogenic prion proteins (PrPSc). The molecular mechanism responsible for the adaptation, mutation, and evolution of prions observed in cloned cells and upon crossing the species barrier remains unsolved. Using biophysical techniques and conformation-dependent immunoassays in tandem, we isolated two distinct populations of PrPSc particles with different conformational stabilities and aggregate sizes, which frequently co-exist in the most common human prion disease, sporadic Creutzfeldt-Jakob disease (sCJD). The protein misfolding cyclic amplification (PMCA) replicates each of the PrPSc particle types independently, and leads to the competitive selection of those with lower initial conformational stability. In serial propagation with a nonglycosylated mutant PrPC substrate, the dominant PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to its lowest stability. Cumulatively, the data show that sCJD PrPSc is not a single conformational entity, but a dynamic collection of two distinct populations of particles. This implies the co-existence of different prions, whose adaptation and evolution are governed by the selection of progressively less stable, faster replicating PrPSc conformers

Evaluation of a New Criterion for Detecting Prion Disease with Diffusion Magnetic Resonance Imaging

Importance: Early diagnosis is a requirement for future treatment of prion diseases. Magnetic resonance imaging (MRI) with diffusion-weighted images and improved real-Time quaking-induced conversion (RT-QuIC) in cerebrospinal fluid (CSF) have emerged as reliable tests. Objectives: To assess the sensitivity and specificity of diffusion MRI for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) with a new criterion (index test) of at least 1 positive brain region among the cortex of the frontal, parietal, temporal, and occipital lobes; the caudate; the putamen; and the thalamus. Design, Setting, and Participants: This diagnostic study with a prospective and a retrospective arm was performed from January 1, 2003, to October 31, 2018. MRIs were collected from 1387 patients with suspected sCJD consecutively referred to the National Prion Disease Pathology Surveillance Center as part of a consultation service. Intervention: Magnetic resonance imaging. Four neuroradiologists blinded to the diagnosis scored the MRIs of 200 randomly selected patients. One neuroradiologist scored the MRIs of all patients. Main Outcomes and Measures: Sensitivity and specificity of the index test compared with currently used criteria and CSF diagnostic (improved RT-QuIC, 14-3-3, and tau CSF tests). Results: A total of 872 patients matched the inclusion criteria (diffusion MRI and autopsy-confirmed diagnosis), with 619 having sCJD, 102 having other prion diseases, and 151 having nonprion disease. The primary analysis included 200 patients (mean [SD] age, 63.6 [12.9] years; 100 [50.0%] male). Sensitivity of the index test of 4 neuroradiologists was 90% to 95% and superior to sensitivity of current MRI criteria (69%-76%), whereas specificity was 90% to 100% and unchanged. Interrater reliability of the 4 neuroradiologists was high (\u3ba = 0.81), and individual intrarater reliability was excellent (\u3ba 650.87). The sensitivity of the index test of 1 neuroradiologist for 770 patients was 92.1% (95% CI, 89.7%-94.1%) and the specificity was 97.4% (95% CI, 93.4%-99.3%) compared with a sensitivity of 69.8% (95% CI, 66.0%-73.4%; P <.001) and a specificity of 98.0% (95% CI, 94.3%-99.6%; P >.99) according to the current criteria. For 88 patients, index test sensitivity (94.9%; 95% CI, 87.5%-98.6%) and specificity (100%; 95% CI, 66.4%-100%) were similar to those of improved RT-QuIC (86.1% [95% CI, 76.5%-92.8%] and 100% [95% CI, 66.4%-100%], respectively). Lower specificities were found for 14-3-3 and tau CSF tests in 452 patients. Conclusions and Relevance: In this study, the diagnostic performance of diffusion MRI with the new criterion was superior to that of current standard criteria and similar to that of improved RT-QuIC. These results may have important clinical implications because MRI is noninvasive and typically prescribed at disease presentation

Prion disease tempo determined by host-dependent substrate reduction

The symptoms of prion infection can take years or decades to manifest following the initial exposure. Molecular markers of prion disease include accumulation of the misfolded prion protein (PrPSc), which is derived from its cellular precursor (PrPC), as well as downregulation of the PrP-like Shadoo (Sho) glycoprotein. Given the overlapping cellular environments for PrPC and Sho, we inferred that PrPC levels might also be altered as part of a host response during prion infection. Using rodent models, we found that, in addition to changes in PrPC glycosylation and proteolytic processing, net reductions in PrPC occur in a wide range of prion diseases, including sheep scrapie, human Creutzfeldt-Jakob disease, and cervid chronic wasting disease. The reduction in PrPC results in decreased prion replication, as measured by the protein misfolding cyclic amplification technique for generating PrPSc in vitro. While PrPC downregulation is not discernible in animals with unusually short incubation periods and high PrPC expression, slowly evolving prion infections exhibit downregulation of the PrPC substrate required for new PrPSc synthesis and as a receptor for pathogenic signaling. Our data reveal PrPC downregulation as a previously unappreciated element of disease pathogenesis that defines the extensive, presymptomatic period for many prion strain

Domain-specific quantification of prion protein in cerebrospinal fluid by targeted mass spectrometry

Therapies currently in preclinical development for prion disease seek to lower prion protein (PrP) expression in the brain. Trials of such therapies are likely to rely on quantification of PrP in cerebrospinal fluid (CSF) as a pharmacodynamic biomarker and possibly as a trial endpoint. Studies using PrP ELISA kits have shown that CSF PrP is lowered in the symptomatic phase of disease, a potential confounder for reading out the effect of PrP-lowering drugs in symptomatic patients. Because misfolding or proteolytic cleavage could potentially render PrP invisible to ELISA even if its concentration were constant or increasing in disease, we sought to establish an orthogonal method for CSF PrP quantification. We developed a multispecies targeted mass spectrometry method based on multiple reaction monitoring (MRM) of nine PrP tryptic peptides quantified relative to an isotopically labeled recombinant protein standard for human samples, or isotopically labeled synthetic peptides for nonhuman species. Analytical validation experiments showed process replicate coefficients of variation below 15%, good dilution linearity and recovery, and suitable performance for both CSF and brain homogenate and across humans as well as preclinical species of interest. In n = 55 CSF samples from individuals referred to prion surveillance centers with rapidly progressive dementia, all six human PrP peptides, spanning the N- and C-terminal domains of PrP, were uniformly reduced in prion disease cases compared with individuals with nonprion diagnoses. Thus, lowered CSF PrP concentration in prion disease is a genuine result of the disease process and not an artifact of ELISA-based measurement. As a result, dose-finding studies for PrP lowering drugs may need to be conducted in presymptomatic at-risk individuals rather than in symptomatic patients. We provide a targeted mass spectrometry-based method suitable for preclinical quantification of CSF PrP as a tool for drug development