Derivative Discontinuity in the Strong-Interaction Limit of Density-Functional Theory

We generalize the exact strong-interaction limit of the exchange-correlation energy of Kohn-Sham density functional theory to open systems with fluctuating particle numbers. When used in the self-consistent Kohn-Sham procedure on strongly interacting systems, this functional yields exact features crucial for important applications such as quantum transport. In particular, the steplike structure of the highest-occupied Kohn-Sham eigenvalue is very well captured, with accurate quantitative agreement with exact many-body chemical potentials. While it can be shown that a sharp derivative discontinuity is present only in the infinitely strongly correlated limit, at finite correlation regimes we observe a slightly smoothened discontinuity, with qualitative and quantitative features that improve with increasing correlation. From the fundamental point of view, our results obtain the derivative discontinuity without making the assumptions used in its standard derivation, offering independent support for its existence. © 2013 American Physical Society

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

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

Density Functional Theory for Strongly-Interacting Electrons

Although Kohn-Sham (KS) density functional theory (DFT) is an exact theory, able in principle to describe any interacting N-electron system in terms of the non-interacting Kohn-Sham model, in practice only approximate expressions for the exchange-correlation term are available. For decades, a large number of such approximations have been developed, proving enormously successful and accurate for applications in many different fields. However, there still remain important sit- uations, of both fundamental and practical interest, for which all the commonly employed exchange-correlation functionals fail to provide an accurate description. The paradigm of such scenarios are those systems in which the electronic correla- tion plays the most important role. In this chapter, we show how the knowledge on the strong-interaction limit of DFT, recently formulated within the so-called strictly-correlated-electrons (SCE) formalism, can be imported into the Kohn-Sham approach and used to build approximations for the exchange-correlation energy that are able to reproduce key features of the strongly-correlated regime. We report results of the first applications of this "KS SCE'' DFT approach on quasi-one-dimensional systems, showing its very good accuracy in the limits of both vanishing and infinite correlation. In the last part of the chapter, we propose a generalization of the approach for its application to more general systems

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

Inhibition of the Hypoxia-Inducible Factor 1α-Induced Cardiospecific HERNA1 Enhance-Templated RNA Protects From Heart Disease.

Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive. We performed chromatin immunoprecipitation-coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA ( HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN-BoxB tethering-based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress-induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell-derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy. HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks-enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca <sup>2+</sup> -sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase-related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival. HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation