A unique tau conformation generated by an acetylation-mimic substitution modulates P301S-dependent tau pathology and hyperphosphorylation.

Abnormal intracellular accumulation of aggregated tau is a hallmark feature of Alzheimer's disease and other tauopathies. Pathological tau can undergo a range of post-translational modifications (PTMs) that are implicated as triggers of disease pathology. Recent studies now indicate that tau acetylation, in particular, controls both microtubule binding and tau aggregation, thereby acting as a central regulator of tau's biochemical properties and providing avenues to exploit for potential therapies. Here, using cell-based assays and tau transgenic mice harboring an acetylation-mimic mutation at residue Lys-280 (K280Q), we evaluated whether this substitution modifies the neurodegenerative disease pathology associated with the aggregate-prone tau P301S variant. Strikingly, the addition of a K280Q-substituted variant altered P301S-mediated tau conformation and reduced tau hyperphosphorylation. We further evaluated neurodegeneration markers in K280Q acetylation-mimic mice and observed reduced neuroinflammation as well as restored levels of N-methyl-d-aspartate receptors and post-synaptic markers compared with the parental mice. Thus, substituting a single lysine residue in the context of a P301S disease-linked mutation produces a unique tau species that abrogates some of the cardinal features of tauopathy. The findings of our study indicate that a complex tau PTM code likely regulates tau pathogenesis, highlighting the potential utility of manipulating and detoxifying tau strains through site-specific tau-targeting approaches.

Curvature of Radial Electric Field Aggravates Edge Magnetohydrodynamics Mode in Toroidally Confined Plasmas.

We show that the radial electric field (E_{r}) plays a dual role in edge magnetohydrodynamics (MHD) activity. While E_{r} shear (first spatial derivative of E_{r}) dephases radial velocity and displacement, and so is stabilizing, a new finding here is that E_{r} curvature (second spatial derivative of E_{r}) tends to synchronize the radial velocity and displacement, and so destabilizes MHD. As a highlighted result, we analytically demonstrate that E_{r} curvature can destabilize an otherwise stable kink mode, and so form a joint vortex-kink mode. The synergetic effects of E_{r} shear and E_{r} curvature in edge MHD extend the familiar E×B shearing paradigm. This theory thus explains the experimental findings that a deeper E×B well may aggravate edge MHD, and so trigger the formation of the edge harmonic oscillation. A simple criterion linking E_{r} structure and the edge MHD activity is derived.

Tracing the Pathway from Drift-Wave Turbulence with Broken Symmetry to the Production of Sheared Axial Mean Flow.

This study traces the emergence of sheared axial flow from collisional drift-wave turbulence with broken symmetry in a linear plasma device-the controlled shear decorrelation experiment. As the density profile steepens, the axial Reynolds stress develops and drives a radially sheared axial flow that is parallel to the magnetic field. Results show that the nondiffusive piece of the Reynolds stress is driven by the density gradient, results from spectral asymmetry of the turbulence, and, thus, is dynamical in origin. Taken together, these findings constitute the first simultaneous demonstration of the causal link between the density gradient, turbulence, and stress with broken spectral symmetry and the mean axial flow.

Zonal Flow Patterns: How Toroidal Coupling Induces Phase Jumps and Shear Layers.

A new, frequency modulation mechanism for zonal flow pattern formation is presented. The model predicts the probability distribution function of the flow strength as well as the evolution of the characteristic spatial scale. Magnetic toroidicity-induced global phase dynamics is shown to determine the spatial structure of the flow. A key result is the observation that global phase patterning can lead to zonal flow formation in the absence of turbulence inhomogeneity.

Synchronization of Geodesic Acoustic Modes and Magnetic Fluctuations in Toroidal Plasmas.

The synchronization of geodesic acoustic modes (GAMs) and magnetic fluctuations is identified in the edge plasmas of the HL-2A tokamak. Mesoscale electric fluctuations (MSEFs) having components of a dominant GAM, and m/n=6/2 potential fluctuations are found at the same frequency as that of the magnetic fluctuations of m/n=6/2 (m and n are poloidal and toroidal mode numbers, respectively). The temporal evolutions of the MSEFs and the magnetic fluctuations clearly show the frequency entrainment and the phase lock between the GAM and the m/n=6/2 magnetic fluctuations. The results indicate that GAMs and magnetic fluctuations can transfer energy through nonlinear synchronization. Such nonlinear synchronization may also contribute to low-frequency zonal flow formation, reduction of turbulence level, and thus confinement regime transitions.

From phase locking to phase slips: a mechanism for a quiescent H mode.

We demonstrate that E×B shear, V_{E×B}^{'}, governs the dynamics of the cross phase of the peeling-ballooning-(PB-)mode-driven heat flux, and so determines the evolution from the edge-localized (ELMy) H mode to the quiescent (Q) H mode. A physics-based scaling of the critical E×B shearing rate (V_{E×B,cr}^{'}) for accessing the QH mode is predicted. The ELMy H mode to the QH-mode evolution is shown to follow from the conversion from a phase locked state to a phase slip state. In the phase locked state, PB modes are pumped continuously, so bursts occur. In the slip state, the PB activity is a coherent oscillation. Stronger E×B shearing implies a higher phase slip frequency. This finding predicts a new state of cross phase dynamics and shows a new way to understand the physics mechanism for ELMy to the QH-mode evolution.

Finding the elusive E×B staircase in magnetized plasmas.

Turbulence in hot magnetized plasmas is shown to generate permeable localized transport barriers that globally organize into the so-called "ExB staircase" [G. Dif-Pradalier et al., Phys. Rev. E, 82, 025401(R) (2010)]. Its domain of existence and dependence with key plasma parameters is discussed theoretically. Based on these predictions, staircases are observed experimentally in the Tore Supra tokamak by means of high-resolution fast-sweeping X-mode reflectometry. This observation strongly emphasizes the critical role of mesoscale self-organization in plasma turbulence and may have far-reaching consequences for turbulent transport models and their validation.

Staircase resiliency in a fluctuating cellular array.

Inhomogeneous mixing by stationary convective cells set in a fixed array is a particularly simple route to layering. Layered profile structures, or staircases, have been observed in many systems, including drift-wave turbulence in magnetic confinement devices. The simplest type of staircase occurs in passive-scalar advection, due to the existence and interplay of two disparate timescales, the cell turn-over (τ_{H}), and the cell diffusion (τ_{D}) time. In this simple system, we study the resiliency of the staircase structure in the presence of global transverse shear and weak vortex scattering. The fixed cellular array is then generalized to a fluctuating vortex array in a series of numerical experiments. The focus is on regimes of low-modest effective Reynolds numbers, as found in magnetic fusion devices. By systematically perturbing the elements of the vortex array, we learn that staircases form and are resilient (although steps become less regular, due to cell mergers) over a broad range of Reynolds numbers. The criteria for resiliency are (a) τ_{D}≫τ_{H} and (b) a sufficiently high profile curvature (κ≥1.5). We learn that scalar concentration travels along regions of shear, thus staircase barriers form first, and scalar concentration "homogenizes" in vortices later. The scattering of vortices induces a lower effective speed of scalar concentration front propagation. The paths are those of the least time. We observe that if background diffusion is kept fixed, the cell geometric properties can be used to derive an approximation for the effective diffusivity of the scalar. The effective diffusivity of the fluctuating vortex array does not deviate significantly from that of the fixed cellular array.

Clinical, epidemiological, and molecular investigation of Kyasanur forest disease from Karnataka state, India during 2018-2019.

BACKGROUND: In this study, we carried out an investigation of Kyasanur Forest Disease (KFD) suspected human cases reported in Karnataka state, India from December 2018 to June 2019. METHODS: The clinical samples of KFD suspected cases (n = 1955) from 14 districts of Karnataka were tested for KFD using real-time RT-PCR and IgM ELISA. Further, the KFD-negative samples were tested for IgM antibodies against dengue and chikungunya viruses. Monkey samples (n = 276) and tick pools (n = 11582) were also screened using real-time RT-PCR. KFD-positive samples were further analysed using next-generation sequencing along with clinico-epidemiological analysis. RESULTS: Of all, 173 (8.8%) cases tested positive for KFD either by real-time RT-PCR (n = 124), IgM ELISA (n = 53) or both tests (n = 4) from seven districts. Among KFD-negative cases, IgM antibody positivity was observed for dengue (2.6%), chikungunya (5.8%), dengue and chikungunya coinfection (3.7%). KFD cases peaked in January 2019 with fever, conjunctivitis, and myalgia as the predominant symptoms and a mortality of 4.6%. Among confirmed cases, 41% received a single dose and 20% received two doses of the KFD vaccine. Of the seven districts with KFDV positivity, Shivamogga and Hassan districts reported KFD viral RNA positivity in humans, monkeys, and ticks. Sequencing analysis of 2019 cases demonstrated a difference of less than 1.5% amino acid compared to prototype KFDV. CONCLUSION: Although the KFD has been endemic in many districts of Karnataka state, our study confirms the presence of KFDV for the first time in two new districts, i.e. Hassan and Mysore. A comparative analysis of KFDV infection among the KFD-vaccinated and non-vaccinated populations demonstrated an insignificant difference.

Gyrokinetic theory of turbulent acceleration of parallel rotation in tokamak plasmas.

A mechanism for turbulent acceleration of parallel rotation is discovered using gyrokinetic theory. This new turbulent acceleration term cannot be written as a divergence of parallel Reynolds stress. Therefore, turbulent acceleration acts as a local source or sink of parallel rotation. The physics of turbulent acceleration is intrinsically different from the Reynolds stress. For symmetry breaking by positive intensity gradient, a positive turbulent acceleration, i.e., cocurrent rotation, is predicted. The turbulent acceleration is independent of mean rotation and mean rotation gradient, and so constitutes a new candidate for the origin of spontaneous rotation. A quasilinear estimate for ion temperature gradient turbulence shows that the turbulent acceleration of parallel rotation is explicitly linked to the ion temperature gradient scale length and temperature ratio Ti0/Te0. Methods for testing the effects of turbulent parallel acceleration by gyrokinetic simulation and experiment are proposed.

How the propagation of heat-flux modulations triggers E × B flow pattern formation.

We propose a novel mechanism to describe E×B flow pattern formation based upon the dynamics of propagation of heat-flux modulations. The E × B flows of interest are staircases, which are quasiregular patterns of strong, localized shear layers and profile corrugations interspersed between regions of avalanching. An analogy of staircase formation to jam formation in traffic flow is used to develop an extended model of heat avalanche dynamics. The extension includes a flux response time, during which the instantaneous heat flux relaxes to the mean heat flux, determined by symmetry constraints. The response time introduced here is the counterpart of the drivers' response time in traffic, during which drivers adjust their speed to match the background traffic flow. The finite response time causes the growth of mesoscale temperature perturbations, which evolve to form profile corrugations. The length scale associated with the maximum growth rate scales as Δ(2) ~ (v(thi)/λT(i))ρ(i)sqrt[χ(neo)τ], where λT(i) is a typical heat pulse speed, χ(neo) is the neoclassical thermal diffusivity, and τ is the response time of the heat flux. The connection between the scale length Δ(2) and the staircase interstep scale is discussed.

Physics of stimulated L→H transitions.

We report on model studies of stimulated L→H transitions. These studies use a novel reduced mesoscale model. Studies reveal that L→H transitions can be triggered by particle injection into a subcritical state (i.e., P

Effects of magnetic shear on toroidal rotation in tokamak plasmas with lower hybrid current drive.

Application of lower hybrid (LH) current drive in tokamak plasmas can induce both co- and countercurrent directed changes in toroidal rotation, depending on the core q profile. For discharges with q(0) <1, rotation increments in the countercurrent direction are observed. If the LH-driven current is sufficient to suppress sawteeth and increase q(0) above unity, the core toroidal rotation change is in the cocurrent direction. This change in sign of the rotation increment is consistent with a change in sign of the residual stress (the divergence of which constitutes an intrinsic torque that drives the flow) through its dependence on magnetic shear.

Generation of momentum transport in weakly turbulent ß-plane magnetohydrodynamics.

Magnetohydrodynamic turbulence on a ß plane with an in-plane mean field, a system which serves as a simple model for the solar tachocline, is investigated analytically and computationally. We first derive two useful analytic constraints: We express the mean turbulent cross-helicity in terms of the mean turbulent magnetic energy, and then show that (for weak turbulence) the time-averaged momentum transport in the system can be expressed in terms of the cross-helicity spectrum. We then complete a closure of the system using weak turbulence theory, appropriately extended to a system with multiple interacting eigenmodes. We use this closure to perturbatively solve for the spectra at lowest order in the Rossby parameter ß and thereby show that the momentum transport in the system is O(ß^{2}), thus quantifying the transition away from Alfvénized turbulence. Finally, we verify our theoretical results by performing direct numerical simulations of the system over a broad range of ß.

Proton-helium spectral anomaly as a signature of cosmic ray accelerator.

The much-anticipated proof of cosmic ray (CR) acceleration in supernova remnants must hinge on the full consistency of acceleration theory with the observations; direct proof is impossible because of CR-orbit scrambling. Recent observations indicate deviations between helium and proton CR rigidity spectra inconsistent with the theory. By considering an initial (injection) phase of the diffusive shock acceleration, where elemental similarity does not apply, we demonstrate that the spectral difference is, in fact, a unique signature of the acceleration mechanism. Collisionless shocks inject more He(2+) when they are stronger and so produce harder He(2+) spectra. The injection bias is due to Alfvén waves driven by the more abundant protons, so the He(2+) ions are harder to trap by these waves. By fitting the p/He ratio to the PAMELA data, we bolster the diffusive shock acceleration case for resolving the century-old mystery of CR origin.

Frequency-resolved nonlinear turbulent energy transfer into zonal flows in strongly heated L-mode plasmas in the HL-2A tokamak.

The absolute rate of nonlinear energy transfer among broadband turbulence, low-frequency zonal flows (ZFs) and geodesic acoustic modes (GAMs) was measured for the first time in fusion-grade plasmas using two independent methods across a range of heating powers. The results show that turbulent kinetic energy from intermediate frequencies (20-80 kHz) was transferred into ZFs and GAMs, as well as into fluctuations at higher frequencies (>80 kHz). As the heating power was increased, the energy transfer from turbulence into GAMs and the GAM amplitudes increased, peaked and then decreased, while the energy transfer into the ZFs and the ZFs themselves increased monotonically with heating power. Thus there exists a competition between ZFs and GAMs for the transfer of turbulent energy, and the transfer into ZFs becomes dominant as the heating power is increased. The poloidal-radial Reynolds stress and the mean radial electric field profiles were also measured at different heating powers and found to be consistent with the energy transfer measurement. The results suggest that ZFs play an important role in the low-to-high (L-H) plasma confinement transition.

The prevalence of detrusor overactivity amongst patients with symptoms of overactive bladder: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: Overactive bladder (OAB) is a symptom-based condition consisting of urgency, with or without incontinence, usually with frequency and nocturia. There are many potential causes of OAB, yet many patients are prescribed anticholinergic medications empirically. This study aimed to determine what proportion of patients presenting for urogynecologic assessment with symptoms of OAB had urodynamic detrusor overactivity (DO). METHODS: Retrospective chart review was performed for 220 consecutive patient referrals. Demographic data, physical exam information, and urodynamic results were collected. The t test and Fisher's exact test were used for statistical analyses. RESULTS: The prevalence of DO was 11.8 % in this population. Urogenital atrophy and incomplete emptying were more common. Patients with DO were older and more often menopausal than those without DO. Significant prolapse was a common finding amongst patients with OAB symptoms. CONCLUSIONS: Patients with symptoms of OAB should undergo pelvic examination and assessment of post-void residuals before being initiated on anticholinergic medication.

Change in prevalence of post-traumatic stress disorder in the two years following trauma: a meta-analytic study.

Background: Understanding the course of post-traumatic stress disorder (PTSD) and the factors that impact this is essential to inform decisions about when and for whom screening and intervention are likely to be beneficial. Objective: To provide meta-analytic evidence of the course of recovery from PTSD in the first year following trauma, and the factors that influence that recovery. Method: We conducted a meta-analysis of observational studies of adult PTSD prevalence which included at least two assessments within the first 12 months following trauma exposure, examining prevalence statistics through to 2 years post-trauma. We examined trauma intentionality (intentional or non-intentional), PTSD assessment method (clinician or self-report), sample sex distribution, and age as moderators of PTSD prevalence over time. Results: We identified 78 eligible studies including 16,484 participants. Pooled prevalence statistics indicated that over a quarter of individuals presented with PTSD at 1 month post-trauma, with this proportion reducing by a third between 1 and 3 months. Beyond 3 months, any prevalence changes were detected over longer intervals and were small in magnitude. Intentional trauma, younger age, and female sex were associated with higher PTSD prevalence at 1 month. In addition, higher proportions of females, intentional trauma exposure, and higher baseline PTSD prevalence were each associated with larger reductions in prevalence over time. Conclusions: Recovery from PTSD following acute trauma exposure primarily occurs in the first 3 months post-trauma. Screening measures and intervention approaches offered at 3 months may better target persistent symptoms than those conducted prior to this point. HIGHLIGHTS: PTSD rates in the immediate aftermath of trauma exposure decline from 27% at 1 month to 18% at 3 months post-trauma, showing significant spontaneous recovery.Problems appear to stabilize after 3 months.Screening/intervention for PTSD at 3 months post-trauma is indicated.

Spatiotemporal structure of the interaction between turbulence and flows at the L-H transition in a toroidal plasma.

The spatiotemporal behavior of the interaction between turbulence and flows has been studied close to the L-H transition threshold conditions in the edge region (ρ≥0.7) of TJ-II plasmas. The temporal dynamics of the interaction displays an oscillatory behavior with a characteristic predator-prey relationship. The spatial evolution of this turbulence-flow oscillation pattern has been measured, showing both radial outward and inward propagation velocities of the turbulence-flow front. The results indicate that the edge shear flow linked to the L-H transition can behave either as a slowing-down, damping mechanism of outward propagating turbulent-flow oscillating structures, or as a source of inward propagating turbulence-flow events.

Trapped electron mode turbulence driven intrinsic rotation in Tokamak plasmas.

Progress from global gyrokinetic simulations in understanding the origin of intrinsic rotation in toroidal plasmas is reported. The turbulence-driven intrinsic torque associated with nonlinear residual stress generation due to zonal flow shear induced asymmetry in the parallel wave number spectrum is shown to scale close to linearly with plasma gradients and the inverse of the plasma current, qualitatively reproducing experimental empirical scalings of intrinsic rotation. The origin of current scaling is found to be enhanced k(∥) symmetry breaking induced by the increased radial variation of the safety factor as the current decreases. The intrinsic torque is proportional to the pressure gradient because both turbulence intensity and zonal flow shear, which are two key ingredients for driving residual stress, increase with turbulence drive, which is R/L(T(e)) and R/L(n(e)) for the trapped electron mode.