To study the performance of multi-threaded Geant4 for high-energy physics experiments, an application has been developed which generalizes and extends previous work. A highly-complex detector geometry is used for benchmarking on an Intel Xeon Phi coprocessor. In addition, an implementation of parallel I/O based on Intel SCIF and ROOT technologies is incorporated and studied.

The rapid assembly of the massive black holes that power the luminous quasars observed at $z \sim 6-7$ remains a puzzle. Various direct collapse models have been proposed to head-start black hole growth from initial seeds with masses $\sim 10^5\,\rm M_\odot$, which can then reach a billion solar mass while accreting at the Eddington limit. Here we propose an alternative scenario based on radiatively inefficient super-critical accretion of stellar-mass holes embedded in the gaseous circum-nuclear discs (CNDs) expected to exist in the cores of high redshift galaxies. Our sub-pc resolution hydrodynamical simulations show that stellar-mass holes orbiting within the central 100 pc of the CND bind to very high density gas clumps that arise from the fragmentation of the surrounding gas. Owing to the large reservoir of dense cold gas available, a stellar-mass black hole allowed to grow at super-Eddington rates according to the "slim disc" solution can increase its mass by 3 orders of magnitudes within a few million years. These findings are supported by simulations run with two different hydro codes, RAMSES based on the Adaptive Mesh Refinement technique and GIZMO based on a new Lagrangian Godunov-type method, and with similar, but not identical, sub-grid recipes for star formation, supernova feedback, black hole accretion and feedback. The low radiative efficiency of super-critical accretion flows are instrumental to the rapid mass growth of our black holes, as they imply modest radiative heating of the surrounding nuclear environment.

We analyse the output of the hi-res cosmological zoom-in simulation ErisBH to study self-consistently the formation of a strong stellar bar in a Milky Way-type galaxy and its effect on the galactic structure, on the central gas distribution and on star formation. The simulation includes radiative cooling, star formation, SN feedback and a central massive black hole which is undergoing gas accretion and is heating the surroundings via thermal AGN feedback. A large central region in the ErisBH disk becomes bar-unstable after z~1.4, but a clear bar-like structure starts to grow significantly only after z~0.4, possibly triggered by the interaction with a massive satellite. At z~0.1 the bar reaches its maximum radial extent of l~2.2 kpc. As the bar grows, it becomes prone to buckling instability, which we quantify based on the anisotropy of the stellar velocity dispersion. The actual buckling event is observable at z~0.1, resulting in the formation of a boxy-peanut bulge clearly discernible in the edge-on view of the galaxy at z=0. The bar in ErisBH does not dissolve during the formation of the bulge but remains strongly non-axisymmetric down to the resolution limit of ~100 pc at z=0. During its early growth, the bar exerts a strong torque on the gas within its extent and drives gas inflows that enhance the nuclear star formation on sub-kpc scales. Later on the infalling gas is nearly all consumed into stars and, to a lesser extent, accreted onto the central black hole, leaving behind a gas-depleted region within the central ~2 kpc. Observations would more likely identify a prominent, large-scale bar at the stage when the galactic central region has already been quenched. Bar-driven quenching may play an important role in disk-dominated galaxies at all redshift. [Abridged]

Despite the promise of immune checkpoint blockade (ICB) therapy against cancer, challenges associated with low objective response rates and severe systemic side effects still remain and limit its clinical applications. Here, we described a cold atmospheric plasma (CAP)-mediated ICB therapy integrated with microneedles (MN) for the transdermal delivery of ICB. We found that a hollow-structured MN (hMN) patch facilitates the transportation of CAP through the skin, causing tumor cell death. The release of tumor-associated antigens then promotes the maturation of dendritic cells in the tumor-draining lymph nodes, subsequently initiating T cell-mediated immune response. Anti-programmed death-ligand 1 antibody (aPDL1), an immune checkpoint inhibitor, released from the MN patch further augments the antitumor immunity. Our findings indicate that the proposed transdermal combined CAP and ICB therapy can inhibit the tumor growth of both primary tumors and distant tumors, prolonging the survival of tumor-bearing mice.

Ultrafast electronic dynamics are typically studied using pulsed lasers. Here we demonstrate a complementary experimental approach: quantum simulation of ultrafast dynamics using trapped ultracold atoms. Counter-intuitively, this technique emulates some of the fastest processes in atomic physics with some of the slowest, leading to a temporal magnification factor of up to 12 orders of magnitude. In these experiments, time-varying forces on neutral atoms in the ground state of a tunable optical trap emulate the electric fields of a pulsed laser acting on bound charged particles. We demonstrate the correspondence with ultrafast science by a sequence of experiments: nonlinear spectroscopy of a many-body bound state, control of the excitation spectrum by potential shaping, observation of sub-cycle unbinding dynamics during strong few-cycle pulses, and direct measurement of carrier-envelope phase dependence of the response to an ultrafast-equivalent pulse. These results establish cold-atom quantum simulation as a complementary tool for studying ultrafast dynamics.

The use of periodic driving for synthesizing many-body quantum states depends crucially on the existence of a prethermal regime, which exhibits drive-tunable properties while forestalling the effects of heating. This motivates the search for direct experimental probes of the underlying localized nonergodic nature of the wave function in this metastable regime. We report experiments on a many-body Floquet system consisting of atoms in an optical lattice subjected to ultrastrong sign-changing amplitude modulation. Using a double-quench protocol we measure an inverse participation ratio quantifying the degree of prethermal localization as a function of tunable drive parameters and interactions. We obtain a complete prethermal map of the drive-dependent properties of Floquet matter spanning four square decades of parameter space. Following the full time evolution, we observe sequential formation of two prethermal plateaux, interaction-driven ergodicity, and strongly frequency-dependent dynamics of long-time thermalization. The quantitative characterization of the prethermal Floquet matter realized in these experiments, along with the demonstration of control of its properties by variation of drive parameters and interactions, opens a new frontier for probing far-from-equilibrium quantum statistical mechanics and new possibilities for dynamical quantum engineering.

Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC-platelet-aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aβ peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aβ peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques.

Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8⁺ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.