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Background Pediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Melanoma cell adhesion molecule (MCAM) is highly expressed on ES and associated with ES metastasis. NKTR-255 is a polymer-conjugated recombinant human interleukin-15 (IL-15) agonist improving NK cell activity and persistence. Magrolimab (MAG) is a CD47 blockade that reactivates the phagocytic activity of macrophages.Methods Transcriptome profiling coupled with CIBERSORT analyses in both ES mouse xenografts and human patient tumors were performed to identify mechanisms of NK resistance in ES TME. A chimeric antigen receptor (CAR) NK cell targeting MCAM was engineered by CAR mRNA electroporation into ex vivo expanded NK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-MCAM-CAR-NK cell alone or combined with NKTR-255 against ES cells. Interferon-γ and perforin levels were measured by ELISA. The effect of MAG on macrophage phagocytosis of ES cells was evaluated by in vitro phagocytosis assays. Cell-based and patient-derived xenograft (PDX)-based xenograft mouse models of ES were used to investigate the antitumor efficacy of CAR-NK alone and combined with NKTR-255 and MAG in vivo.Results We found that NK cell infiltration and activity were negatively regulated by tumor-associated macrophages (TAM) in ES TME. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity against MCAMhigh but not MCAM-knockout ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in vivo. NKTR-255 and MAG significantly enhanced in vitro CAR-NK cytotoxicity and macrophage phagocytic activity against ES cells, respectively. By combining with NKTR-255 and MAG, the anti-MCAM-CAR-NK cell significantly decreased primary tumor growth and prolonged animal survival in both cell- and PDX-based ES xenograft mouse models.Conclusions Our preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAMhigh malignant metastatic ES.

The nonlinear Schrödinger equation (NLSE) in one spatial dimension has stationary solutions similar to those of the linear Schrödinger equation (LSE) as well as more exotic solutions such as solitary waves and quantum droplets. Here, we present a newly discovered conformal duality which unifies the stationary and time-dependent traveling-wave solutions of the one-dimensional cubic-quintic NLSE, the cubic NLSE and LSE. Any two systems that are classified by the same single number called the cross ratio are related by this symmetry. Notably, the conformal duality can also be adapted in Newtonian mechanics and serves as a powerful tool for investigating physical systems that otherwise cannot be directly accessed in experiments. Further, we show that the conformal symmetry is a valuable resource to substantially improve NLSE parameter estimation from noisy empirical data by introducing an optimization afterburner. The new method therefore has far reaching practical applications for nonlinear physical systems.

Compared with time-independent Hamiltonians, the dynamics of generic quantum Hamiltonians H(t) are complicated by the presence of time ordering in the evolution operator. In the context of digital quantum simulation, this difficulty prevents a direct adaptation of many time-independent simulation algorithms for time-dependent simulation. However, there exists a framework within the theory of dynamical systems that eliminates time ordering by adding a “clock” degree of freedom. In this work, we provide a computational framework, based on this reduction, for encoding time-dependent dynamics as time-independent systems. As a result, we make two advances in digital Hamiltonian simulation. First, we create a time-dependent simulation algorithm based on performing qubitization on the augmented clock system and, in doing so, provide the first qubitization-based approach to time-dependent Hamiltonians that goes beyond Trotterization of the ordered exponential. Second, we define a natural generalization of multiproduct formulas for time-ordered exponentials and then propose and analyze an algorithm based on these formulas. Unlike other algorithms of similar accuracy, the multiproduct approach achieves commutator scaling, meaning that this method outperforms existing methods for physically local time-dependent Hamiltonians with sufficient smoothness. Our work reduces the disparity between time-dependent and time-independent simulation and indicates a step toward optimal quantum simulation of time-dependent Hamiltonians.

We present a systematic ab initio study of clustering in hot dilute nuclear matter using nuclear lattice effective field theory with an SU(4)-symmetric interaction. We introduce a method called light-cluster distillation to determine the abundances of dimers, trimers, and alpha clusters as a function of density and temperature. Our lattice results are compared with an ideal gas model composed of free nucleons and clusters. Excellent agreement is found at very low density, while deviations from ideal gas abundances appear at increasing density due to cluster-nucleon and cluster-cluster interactions. In addition to determining the composition of hot dilute nuclear matter as a function of density and temperature, the lattice calculations also serve as benchmarks for virial expansion calculations, statistical models, and transport models of fragmentation and clustering in nucleus-nucleus collisions.

Abstract The carbon atom provides the backbone for the complex organic chemistry composing the building blocks of life. The physics of the carbon nucleus in its predominant isotope, 12C, is similarly full of multifaceted complexity. Here we provide a model-independent density map of the geometry of the nuclear states of 12C using the ab initio framework of nuclear lattice effective field theory. We find that the well-known but enigmatic Hoyle state is composed of a “bent-arm” or obtuse triangular arrangement of alpha clusters. We identify all of the low-lying nuclear states of 12C as having an intrinsic shape composed of three alpha clusters forming either an equilateral triangle or an obtuse triangle. The states with the equilateral triangle formation also have a dual description in terms of particle-hole excitations in the mean-field picture.

Solving the generalized eigenvalue problem is a useful method for finding energy eigenstates of large quantum systems. It uses projection onto a set of basis states which are typically not orthogonal. One needs to invert a matrix whose entries are inner products of the basis states, and the process is unfortunately susceptible to even small errors. The problem is especially bad when matrix elements are evaluated using stochastic methods and have significant error bars. In this work, we introduce the trimmed sampling algorithm in order to solve this problem. Using the framework of Bayesian inference, we sample prior probability distributions determined by uncertainty estimates of the various matrix elements and likelihood functions composed of physics-informed constraints. The result is a probability distribution for the eigenvectors and observables which automatically comes with a reliable estimate of the error and performs far better than standard regularization methods. The method should have immediate use for a wide range of applications involving classical and quantum computing calculations of large quantum systems.

Abstract We investigate the phase shifts of low-energy α-α scattering under variations of the fundamental parameters of the Standard Model, namely the light quark mass, the electromagnetic fine-structure constant as well as the QCD θ-angle. As a first step, we recalculate α-α scattering in our Universe utilizing various improvements in the adiabatic projection method, which leads to an improved, parameter-free prediction of the S- and D-wave phase shifts for laboratory energies below 10 MeV. We find that positive shifts in the pion mass have a small effect on the S-wave phase shift, whereas lowering the pion mass adds some repulsion in the two-alpha system. The effect on the D-wave phase shift turns out to be more pronounced as signaled by the D-wave resonance parameters. Variations of the fine-structure constant have almost no effect on the low-energy α-α phase shifts. We further show that up-to-and-including next-to-leading order in the chiral expansion, variations of these phase shifts with respect to the QCD θ-angle can be expressed in terms of the θ-dependent pion mass.

Emulators that can bypass computationally expensive scientific calculations with high accuracy and speed can enable new studies of fundamental science as well as more potential applications. In this work we discuss solving a system of constraint equations efficiently using a self-learning emulator. A self-learning emulator is an active learning protocol that can be used with any emulator that faithfully reproduces the exact solution at selected training points. The key ingredient is a fast estimate of the emulator error that becomes progressively more accurate as the emulator is improved, and the accuracy of the error estimate can be corrected using machine learning. We illustrate with three examples. The first uses cubic spline interpolation to find the solution of a transcendental equation with variable coefficients. The second example compares a spline emulator and a reduced basis method emulator to find solutions of a parametrized differential equation. The third example uses eigenvector continuation to find the eigenvectors and eigenvalues of a large Hamiltonian matrix that depends on several control parameters.

Background The prognosis of patients with relapsed or progressive B cell (CD20+) non-Hodgkin’s lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity.Methods We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20+ BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD/SCID/IL2rγnull (NSG) mice. We also investigated the cytokines/chemokines/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays.Results N-820 significantly enhanced the expression of NK activating receptors (p

In the current era of noisy quantum devices, there is a need for quantum algorithms that are efficient and robust against noise. Towards this end, we introduce the projected cooling algorithm for quantum computation. The projected cooling algorithm is able to construct the localized ground state of any Hamiltonian with a translationally-invariant kinetic energy and interactions that vanish at large distances. The term “localized” refers to localization in position space. The method can be viewed as the quantum analog of evaporative cooling. We start with an initial state with support over a compact region of a large volume. We then drive the excited quantum states to disperse and measure the remaining portion of the wave function left behind. For the nontrivial examples we consider here, the improvement over other methods is substantial. The only additional resource required is performing the operations in a volume significantly larger than the size of the localized state. These characteristics make the projected cooling algorithm a promising tool for calculations of self-bound systems such as atomic nuclei.

We review several recent results on lattice simulations by the Nuclear Lattice Effective Field Theory Collaboration. In the first part we discuss the implementation of nuclear forces on the lattice using chiral effective field theory. The new development we highlight is the use of non-local lattice operators to achieve a simpler spin channel decomposition, in contrast with previous studies that considered only local interactions. In the second part, we present evidence that nuclear physics is close to a quantum phase transition. This development is also linked to the study of the differences between local and non-local interactions. In the final part we further explore the link between the nuclear forces and nuclear structure. We consider the simplest possible nuclear interaction which can accurately reproduce the ground state energies of neutron matter, light nuclei, and medium-mass nuclei. We discuss what these recent developments say about the emergence of nuclear structure from nuclear forces and the road ahead for nuclear lattice simulations.

The main objective of this article is to raise questions regarding the complex interactions between local and creative economies. To do so, a review of the literature dealing with the creative economy from a geographical perspective is carried out, with emphasis on authors such as Richard Florida, Amaral Filho, Ana Fani Carlos and Milton Santos. Special attention is given to approaches that address the issues of mode of production, trajectories and other characteristics associated with the identity of the place that affect the development of creative economies. Also treated are those approaches that deal with the many ventures associated with the creative economy and how labour relations manifest themselves in geographic space. Also noteworthy are the studies of Economic Geography that seek to understand the relations between creative economy and society based on principles that emphasize the importance of local. Finally, given the importance of factors such as the structure and spatial dynamics of networks, territoriality and locality, the relevance of studies that address the creative economy from a geographic perspective is explored, especially by its capacity to explain how the different realities or manifestations of this type of economy reflect in inequalities and conditions that at the same time characterize the place and mark the differences between the localities.

We derive the finite-volume correction to the binding energy of an N-particle quantum bound state in a cubic periodic volume. Our results are applicable to bound states with arbitrary composition and total angular momentum, and in any number of spatial dimensions. The only assumptions are that the interactions have finite range. The finite-volume correction is a sum of contributions from all possible breakup channels. In the case where the separation is into two bound clusters, our result gives the leading volume dependence up to exponentially small corrections. If the separation is into three or more clusters, there is a power-law factor that is beyond the scope of this work, however our result again determines the leading exponential dependence. We also present two independent methods that use finite-volume data to determine asymptotic normalization coefficients. The coefficients are useful to determine low-energy capture reactions into weakly bound states relevant for nuclear astrophysics. Using the techniques introduced here, one can even extract the infinite-volume energy limit using data from a single-volume calculation. The derived relations are tested using several exactly solvable systems and numerical examples. We anticipate immediate applications to lattice calculations of hadronic, nuclear, and cold atomic systems. Keywords: Finite-volume correction, Bound states, Lattice field theory

We consider two-component fermions with short-range interactions and large scattering length. This system has universal properties that are realized in several different fields of physics. In the limit of large fermion–fermion scattering length aff and zero-range interaction, all properties of the system scale proportionally with aff. For the case with shallow bound dimers, we calculate the dimer–dimer scattering phase shifts using lattice effective field theory. We extract the universal dimer–dimer scattering length add/aff=0.618(30) and effective range rdd/aff=−0.431(48). This result for the effective range is the first calculation with quantified and controlled systematic errors. We also benchmark our methods by computing the fermion–dimer scattering parameters and testing some predictions of conformal scaling of irrelevant operators near the unitarity limit.

How does nuclear binding emerge from first principles? Our current best understanding of nuclear forces is based on a systematic low-energy expansion called chiral effective field theory. However, recent ab initio calculations of nuclear structure have found that not all chiral effective field theory interactions give accurate predictions with increasing nuclear density. In this letter we address the reason for this problem and the first steps toward a solution. Using nuclear lattice simulations, we deduce the minimal nuclear interaction that can reproduce the ground state properties of light nuclei, medium-mass nuclei, and neutron matter simultaneously with no more than a few percent error in the energies and charge radii. We find that only four parameters are needed. With these four parameters one can accurately describe neutron matter up to saturation density and the ground state properties of nuclei up to calcium. Given the absence of sign oscillations in these lattice Monte Carlo simulations and the mild scaling of computational effort scaling with nucleon number, this work provides a pathway to high-quality simulations in the future with as many as one or two hundred nucleons.

We introduce a general and accurate method for determining lattice phase shifts and mixing angles, which is applicable to arbitrary, non-cubic lattices. Our method combines angular momentum projection, spherical wall boundaries and an adjustable auxiliary potential. This allows us to construct radial lattice wave functions and to determine phase shifts at arbitrary energies. For coupled partial waves, we use a complex-valued auxiliary potential that breaks time-reversal invariance. We benchmark our method using a system of two spin-1/2 particles interacting through a finite-range potential with a strong tensor component. We are able to extract phase shifts and mixing angles for all angular momenta and energies, with precision greater than that of extant methods. We discuss a wide range of applications from nuclear lattice simulations to optical lattice experiments.

We investigate the impact of the QCD vacuum at nonzero θ on the properties of light nuclei, Big Bang nucleosynthesis, and stellar nucleosynthesis. Our analysis starts with a calculation of the θ-dependence of the neutron-proton mass difference and neutron decay using chiral perturbation theory. We then discuss the θ-dependence of the nucleon-nucleon interaction using a one-boson-exchange model and compute the properties of the two-nucleon system. Using the universal properties of four-component fermions at large scattering length, we then deduce the binding energies of the three-nucleon and four-nucleon systems. Based on these results, we discuss the implications for primordial abundances of light nuclei, the production of nuclei in stellar environments, and implications for an anthropic view of the universe.

Genetically modified pigs have been considered favorable resources in xenotransplantation. Microinjection of randomly integrating transgenes into zygotes, somatic cell nuclear transfer, homologous recombination, zinc finger nucleases, transcription activator-like effector nucleases, and most recently, clustered regularly interspaced short palindromic repeats-cas9 (CRISPR/Cas9) are the techniques that have been used to generate these animals. Here, we provide an overview of the CRISPR approaches that have been used to modify genes which are vital in improving xenograft survival rate, including cytidine monophosphate-N-acetylneuraminic acid hydroxylase, B1,4N-acetylgalactosaminyltransferase, isoglobotrihexosylceramide synthase, class I MHC, von Willebrand factor, C3, and porcine endogenous retroviruses. In addition, we will mention the importance of potential candidate genes which could be targeted using CRISPR/Cas9.

We investigate Nuclear Lattice Effective Field Theory for the two-body system for several lattice spacings at lowest order in the pionless as well as in the pionful theory. We discuss issues of regularizations and predictions for the effective range expansion. In the pionless case, a simple Gaussian smearing allows to demonstrate lattice spacing independence over a wide range of lattice spacings. We show that regularization methods known from the continuum formulation are necessary as well as feasible for the pionful approach.