Leakage of waves from coronal loops by wave tunneling

To better understand the decay of vertically polarised fast kink modes of coronal loops by the mechanism of wave tunneling, simulations are performed of fast kink modes in straight flux slabs which have Alfvén speed profiles which include a tunneling region. The decay rates are found to be determined by the mode number of the trapped mode and the thickness of the tunneling region. Two analytical models are suggested to explain the observed decay. The first is a extension of the work of Roberts (1981, Sol. Phys., 69, 39) to include a finite thickness tunneling region, and the second is a simpler model which yields an analytical solution for the relationship between decay rate, period and the thickness of the tunneling region. The decay rates for these straight slabs are found to be slower than in observations and those found in a previous paper on the subject by Brady & Arber (2005, A&A, 438, 733) using curved flux slabs. It is found that the difference between the straight slabs used here and the curved slabs used in Brady & Arber (2005, A&A, 438, 733) can be represented as a geometric correction to the decay rate

Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy.

T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level

Stem cell models of Alzheimer's disease: progress and challenges.

A major challenge to our understanding of the molecular mechanisms of Alzheimer's disease (AD) has been the lack of physiologically relevant in vitro models which capture the precise patient genome, in the cell type of interest, with physiological expression levels of the gene(s) of interest. Induced pluripotent stem cell (iPSC) technology, together with advances in 2D and 3D neuronal differentiation, offers a unique opportunity to overcome this challenge and generate a limitless supply of human neurons for in vitro studies. iPSC-neuron models have been widely employed to model AD and we discuss in this review the progress that has been made to date using patient-derived neurons to recapitulate key aspects of AD pathology and how these models have contributed to a deeper understanding of AD molecular mechanisms, as well as addressing the key challenges posed by using this technology and what progress is being made to overcome these. Finally, we highlight future directions for the use of iPSC-neurons in AD research and highlight the potential value of this technology to neurodegenerative research in the coming years

The triggering of MHD instabilities through photospheric footpoint motions

The results of 3D numerical simulations modelling the twisting of a coronal loop due to photospheric vortex motions are presented. The simulations are carried out using an initial purely axial field and an initial equilibrium configuration with twist, . The non-linear and resistive evolutions of the instability are followed. The magnetic field is twisted by the boundary motions into a loop which initially has boundary layers near the photospheric boundaries as has been suggested by previous work. The boundary motions increase the twist in the loop until it becomes unstable. For both cases the boundary twisting triggers the kink instability. In both cases a helical current structure wraps itself around the kinked central current. This current scales linearly with grid resolution indicating current sheet formation. For the cases studied 35-40% of the free magnetic energy is released. This is sufficient to explain the energy released in a compact loop flare

Off-the-Shelf Allogeneic T Cell Therapies for Cancer: Opportunities and Challenges Using Naturally Occurring "Universal" Donor T Cells.

Chimeric antigen receptor (CAR) engineered T cell therapies individually prepared for each patient with autologous T cells have recently changed clinical practice in the management of B cell malignancies. Even though CARs used to redirect polyclonal T cells to the tumor are not HLA restricted, CAR T cells are also characterized by their endogenous T cell receptor (TCR) repertoire. Tumor-antigen targeted TCR-based T cell therapies in clinical trials are thus far using "conventional" αβ-TCRs that recognize antigens presented as peptides in the context of the major histocompatibility complex. Thus, both CAR- and TCR-based adoptive T cell therapies (ACTs) are dictated by compatibility of the highly polymorphic HLA molecules between donors and recipients in order to avoid graft-versus-host disease and rejection. The development of third-party healthy donor derived well-characterized off-the-shelf cell therapy products that are readily available and broadly applicable is an intensive area of research. While genome engineering provides the tools to generate "universal" donor cells that can be redirected to cancers, we will focus our attention on third-party off-the-shelf strategies with T cells that are characterized by unique natural features and do not require genome editing for safe administration. Specifically, we will discuss the use of virus-specific T cells, lipid-restricted (CD1) T cells, MR1-restricted T cells, and γδ-TCR T cells. CD1- and MR1-restricted T cells are not HLA-restricted and have the potential to serve as a unique source of universal TCR sequences to be broadly applicable in TCR-based ACT as their targets are presented by the monomorphic CD1 or MR1 molecules on a wide variety of tumor types. For each cell type, we will summarize the stage of preclinical and clinical development and discuss opportunities and challenges to deliver off-the-shelf targeted cellular therapies against cancer

Nonlinear wave propagation and reconnection at magnetic X-points in the Hall MHD regime

The highly dynamical, complex nature of the solar atmosphere naturally implies the presence of waves in a topologically varied magnetic environment. Here, the interaction of waves with topological features such as null points is inevitable and potentially important for energetics. The low resistivity of the solar coronal plasma implies that non-MHD effects should be considered in studies of magnetic energy release in this environment. This paper investigates the role of the Hall term in the propagation and dissipation of waves, their interaction with 2D magnetic X-points and the nature of the resulting reconnection. A Lagrangian remap shock-capturing code (Lare2d) is used to study the evolution of an initial fast magnetoacoustic wave annulus for a range of values of the ion skin depth in resistive Hall MHD. A magnetic null-point finding algorithm is also used to locate and track the evolution of the multiple null-points that are formed in the system. Depending on the ratio of ion skin depth to system size, our model demonstrates that Hall effects can play a key role in the wave-null interaction. In particular, the initial fast-wave pulse now consists of whistler and ion-cyclotron components; the dispersive nature of the whistler wave leads to (i) earlier interaction with the null, (ii) the creation of multiple additional, transient nulls and, hence, an increased number of energy release sites. In the Hall regime, the relevant timescales (such as the onset of reconnection and the period of the oscillatory relaxation) of the system are reduced significantly, and the reconnection rate is enhanced.Comment: 13 pages, 10 figure

Suppression of energetic electron transport in flares by double layers

During flares and coronal mass ejections, energetic electrons from coronal sources typically have very long lifetimes compared to the transit times across the systems, suggesting confinement in the source region. Particle-in-cell simulations are carried out to explore the mechanisms of energetic electron transport from the corona to the chromosphere and possible confinement. We set up an initial system of pre-accelerated hot electrons in contact with ambient cold electrons along the local magnetic field, and let it evolve over time. Suppression of transport by a nonlinear, highly localized electrostatic electric field (in the form of a double layer) is observed after a short phase of free-streaming by hot electrons. The double layer (DL) emerges at the contact of the two electron populations. It is driven by an ion-electron streaming instability due to the drift of the back-streaming return current electrons interacting with the ions. The DL grows over time and supports a significant drop in temperature and hence reduces heat flux between the two regions that is sustained for the duration of the simulation. This study shows transport suppression begins when the energetic electrons start to propagate away from a coronal acceleration site. It also implies confinement of energetic electrons with kinetic energies less than the electrostatic energy of the DL for the DL lifetime, which is much longer than the electron transit time through the source region

Numerical simulations of kink instability in line-tied coronal loops

The results from numerical simulations carried out using a new shock-capturing, Lagrangian-remap, 3D MHD code, Lare3d are presented. We study the evolution of the m=1 kink mode instability in a photospherically line-tied coronal loop that has no net axial current. During the non-linear evolution of the kink instability, large current concentrations develop in the neighbourhood of the infinite length mode rational surface. We investigate whether this strong current saturates at a finite value or whether scaling indicates current sheet formation. In particular, we consider the effect of the shear, defined by where is the fieldline twist of the loop, on the current concentration. We also include a non-uniform resistivity in the simulations and observe the amount of free magnetic energy released by magnetic reconnection

Transgenic CD8αβ co-receptor rescues endogenous TCR function in TCR-transgenic virus-specific T cells.

Genetically engineered virus-specific T cells (VSTs) are a platform for adoptive cell therapy after allogeneic hematopoietic stem cell transplantation. However, redirection to a tumor-associated antigen by the introduction of a transgenic T-cell receptor (TCR) reduces anti-viral activity, thereby impeding the possibility of preventing or treating two distinct complications-malignant relapse and viral infection-with a single cell therapy product. Availability of CD8αβ co-receptor molecules can significantly impact class I restricted T-cell activation, and thus, we interrogated whether transgenic CD8αβ improves anti-viral activity mediated by native VSTs with or without a co-expressed transgenic TCR (TCR8). Our existing clinical VST manufacturing platform was adapted and validated to engineer TCR+ or TCR8+ VSTs targeting cytomegalovirus and Epstein-Barr virus. Simultaneous anti-viral and anti-tumor function of engineered VSTs was assessed in vitro and in vivo. We used pentamer staining, interferon (IFN)-γ enzyme-linked immunospot (ELISpot), intracellular cytokine staining (ICS), cytotoxicity assays, co-cultures, and cytokine secretion assays for the in vitro characterization. The in vivo anti-tumor function was assessed in a leukemia xenograft mouse model. Both transgenic CD8αβ alone and TCR8 had significant impact on the anti-viral function of engineered VSTs, and TCR8+ VSTs had comparable anti-viral activity as non-engineered VSTs as determined by IFN-γ ELISpot, ICS and cytotoxicity assays. TCR8-engineered VSTs had improved anti-tumor function and greater effector cytokine production in vitro, as well as enhanced anti-tumor function against leukemia xenografts in mice. Incorporation of transgenic CD8αβ into vectors for TCR-targetable antigens preserves anti-viral activity of TCR transgenic VSTs while simultaneously supporting tumor-directed activity mediated by a transgenic TCR. Our approach may provide clinical benefit in preventing and treating viral infections and malignant relapse post-transplant