Energy Density Functionals From the Strong-Coupling Limit Applied to the Anions of the He Isoelectronic Series

Anions and radicals are important for many applications including environmental chemistry, semiconductors, and charge transfer, but are poorly described by the available approximate energy density functionals. Here we test an approximate exchange-correlation functional based on the exact strong-coupling limit of the Hohenberg-Kohn functional on the prototypical case of the He isoelectronic series with varying nuclear charge $Z<2$, which includes weakly bound negative ions and a quantum phase transition at a critical value of $Z$, representing a big challenge for density functional theory. We use accurate wavefunction calculations to validate our results, comparing energies and Kohn-Sham potentials, thus also providing useful reference data close to and at the quantum phase transition. We show that our functional is able to bind H$^-$ and to capture in general the physics of loosely bound anions, with a tendency to strongly overbind that can be proven mathematically. We also include corrections based on the uniform electron gas which improve the results.Comment: Accepted for the JCP Special Topic Issue "Advances in DFT Methodology

Density functional theory for strongly-correlated bosonic and fermionic ultracold dipolar and ionic gases

We introduce a density functional formalism to study the ground-state properties of strongly-correlated dipolar and ionic ultracold bosonic and fermionic gases, based on the self-consistent combination of the weak and the strong coupling limits. Contrary to conventional density functional approaches, our formalism does not require a previous calculation of the interacting homogeneous gas, and it is thus very suitable to treat systems with tunable long-range interactions. Due to its asymptotic exactness in the regime of strong correlation, the formalism works for systems in which standard mean-field theories fail.Comment: 5 pages, 2 figure

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with beta-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of beta-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from beta-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of beta-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis

Modulation of Myelopoiesis Progenitors Is an Integral Component of Trained Immunity

Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery

HIF-driven SF3B1 induces KHK-C to enforce fructolysis and heart disease.

Fructose is a major component of dietary sugar and its overconsumption exacerbates key pathological features of metabolic syndrome. The central fructose-metabolising enzyme is ketohexokinase (KHK), which exists in two isoforms: KHK-A and KHK-C, generated through mutually exclusive alternative splicing of KHK pre-mRNAs. KHK-C displays superior affinity for fructose compared with KHK-A and is produced primarily in the liver, thus restricting fructose metabolism almost exclusively to this organ. Here we show that myocardial hypoxia actuates fructose metabolism in human and mouse models of pathological cardiac hypertrophy through hypoxia-inducible factor 1α (HIF1α) activation of SF3B1 and SF3B1-mediated splice switching of KHK-A to KHK-C. Heart-specific depletion of SF3B1 or genetic ablation of Khk, but not Khk-A alone, in mice, suppresses pathological stress-induced fructose metabolism, growth and contractile dysfunction, thus defining signalling components and molecular underpinnings of a fructose metabolism regulatory system crucial for pathological growth

Energy densities in the strong-interaction limit of density functional theory

We discuss energy densities in the strong-interaction limit of density functional theory, deriving an exact expression within the definition (gauge) of the electrostatic potential of the exchange-correlation hole. Exact results for small atoms and small model quantum dots are compared with available approximations defined in the same gauge. The idea of a local interpolation along the adiabatic connection is discussed, comparing the energy densities of the Kohn-Sham, the physical, and the strong-interacting systems. We also use our results to analyze the local version of the Lieb-Oxford bound, widely used in the construction of approximate exchange-correlation functionals.Comment: 12 page

Labeling of Fatty Acid Ligands with the Strong Electrophilic Metal Fragment [99mTc(N)(PNP)]2+ (PNP=Diphosphane Ligand)

The electrophilic metal fragment [99mTc(N)(PNP)]2+ (PNP ) diphosphane ligand) has been employed for the labeling of fatty acid chains of different lengths. To provide a site-specific group for the attachment of the metallic moiety, the fatty acid derivatives were functionalized by appending a bis-mercapto or, alternatively, a dithiocarbamato π-donor chelating systems to one terminus of the carbon chain to yield both dianionic and monoanionic bifunctional ligands (L). The resulting complexes, [99mTc(N)(PNP)(L)]0/+, exhibited the usual asymmetrical structure in which a TctN group was surrounded by two different bidentate chelating ligands. Dianionic ligands gave rise to neutral complexes, while monoanionic ligands afforded monocationic species. Biodistribution studies were carried out in rats. An isolated perfused rat heart model was employed to assess how strucural changes in the radiolabeled fatty acid compound affect the myocardial first pass extraction. Results showed that only monocationic complexes accumulated in myocardium to a significant extent. Conversely, neutral complexes were not efficiently retained into the heart region and rapidly washed out. In isolated perfused rat heart experiments, monocationic complexes exhibited a behavior similar to that of the monocationic flow tracers 99mTc-MIBI and 99mTc-DBODC with almost identical extraction values, a result that could be attributed to the presence of the monopositive charge. Instead, a slightly lower myocardial extraction was found for neutral complexes. Comparison of the observed kinetic behavior of neutral complexes in the isolated perfused rat heart model with that of the myocardial metabolic tracer [123I]IPPA revealed that the introduction of the metallic moiety partially hampers recognition of the labeled fatty acids by cardiac enzymes, and consequently, their behavior did not completely reflect myocardial metabolism

SF3B1 promotes tumor malignancy through splicing-independent co-activation of HIF1α

Heterozygous mutations in the splicing factor SF3B1 are frequently occurring in various cancers and drive tumor progression through the activation of cryptic splice sites in multiple genes. Recent studies moreover demonstrate a positive correlation between expression levels of wildtype SF3B1 and tumor malignancy, although the underlying mechanisms for this phenomenon remain elusive. Here, we report that SF3B1 acts as a coactivator for hypoxia-inducible factor (HIF)1α through a splicing-independent mechanism. By directly interacting with HIF1α, SF3B1 augments HIF1α-HIF1β heterodimer binding to hypoxia response elements, and facilitates full transcriptional response of HIF target genes. We further validate the relevance of this mechanism for tumor progression, and show that monoallelic deletion of Sf3b1 impedes pancreatic cancer formation via HIF signaling. Altogether our work demonstrates a pivotal role of SF3B1 in the adaptation to hypoxia, suggesting a causal link between high SF3B1 levels and cancer aggressiveness