Generalized Compactification in Heterotic String Theory

In this thesis, we consider heterotic string vacua based on a warped product of a four-dimensional domain wall and a six-dimensional internal manifold preserving only two supercharges. Thus, they correspond to half-BPS states of heterotic supergravity. The constraints on the internal manifolds with SU(3) structure are derived. They are found to be a generalization of half-flat manifolds with a particular pattern of torsion classes and they include half-flat manifolds and Strominger's complex non-Kahler manifolds as special cases. We also verify that heterotic compactifications on half-flat mirror manifolds are based on this class of solutions. Furthermore, within this context, we construct specific examples based on six-dimensional nearly-Kahler homogeneous manifolds and non-trivial vector bundles thereon. Our solutions are based on three specific group coset spaces satisfying the half-flat torsion class conditions. It is shown how to construct line bundles over these manifolds, compute their properties and build up vector bundles consistent with supersymmetry and the heterotic anomaly cancellation. It turns out that the most interesting solutions are obtained from $SU(3)/U(1)^2$. This space supports a large number of vector bundles leading to consistent heterotic vacua with GUT group and, for some of them, with three chiral families.Comment: D.Phil. thesis, 143pages, twosid

Standard model plethystics

We study the vacuum geometry prescribed by the gauge invariant operators of the minimal supersymmetric standard model via the plethystic program. This is achieved by using several tricks to perform the highly computationally challenging Molien-Weyl integral, from which we extract the Hilbert series, encoding the invariants of the geometry at all degrees. The fully refined Hilbert series is presented as the explicit sum of 1422 rational functions. We found a good choice of weights to unrefine the Hilbert series into a rational function of a single variable, from which we can read off the dimension and the degree of the vacuum moduli space of the minimal supersymmetric standard model gauge invariants. All data in Mathematica format are also presented

Veronese Geometry and the Electroweak Vacuum Moduli Space

We explain the origin of the Veronese surface in the vacuum moduli space geometry of the MSSM electroweak sector. While this result appeared many years ago using techniques of computational algebraic geometry, it has never been demonstrated analytically. Here, we present an analytical derivation of the vacuum geometry of the electroweak theory by understanding how the F- and D-term relations lead to the Veronese surface. We moreover give a detailed description of this geometry, realising an extra branch as a zero-dimensional point when quadratic Higgs lifting deformations are incorporated into the superpotential

Bundles over Nearly-Kahler Homogeneous Spaces in Heterotic String Theory

We construct heterotic vacua based on six-dimensional nearly-Kahler homogeneous manifolds and non-trivial vector bundles thereon. Our examples are based on three specific group coset spaces. It is shown how to construct line bundles over these spaces, compute their properties and build up vector bundles consistent with supersymmetry and anomaly cancelation. It turns out that the most interesting coset is $SU(3)/U(1)^2$. This space supports a large number of vector bundles which lead to consistent heterotic vacua, some of them with three chiral families.Comment: 32 pages, reference adde

G-structures and Domain Walls in Heterotic Theories

We consider heterotic string solutions based on a warped product of a four-dimensional domain wall and a six-dimensional internal manifold, preserving two supercharges. The constraints on the internal manifolds with SU(3) structure are derived. They are found to be generalized half-flat manifolds with a particular pattern of torsion classes and they include half-flat manifolds and Strominger's complex non-Kahler manifolds as special cases. We also verify that previous heterotic compactifications on half-flat mirror manifolds are based on this class of solutions.Comment: 29 pages, reference added, typos correcte

Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development

miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic metabolism with obesity and cancer remains poorly characterized. Herein, we observed that alterations of hepatic miR-22-3p expression with non-alcoholic fatty liver disease (NAFLD) in the context of obesity are not consistent in various human cohorts and animal models in contrast to the well-characterized miR-22-3p downregulation observed in hepatic cancers. To unravel the role of miR-22 in obesity-associated NAFLD, we generated constitutive Mir22 knockout (miR-22KO) mice, which were subsequently rendered obese by feeding with fat-enriched diet. Functional NAFLD- and obesity-associated metabolic parameters were then analyzed. Insights about the role of miR-22 in NAFLD associated with obesity were further obtained through an unbiased proteomic analysis of miR-22KO livers from obese mice. Metabolic processes governed by miR-22 were finally investigated in hepatic transformed cancer cells. Deletion of Mir22 was asymptomatic when mice were bred under standard conditions, except for an onset of glucose intolerance. However, when challenged with a high fat-containing diet, Mir22 deficiency dramatically exacerbated fat mass gain, hepatomegaly, and liver steatosis in mice. Analyses of explanted white adipose tissue revealed increased lipid synthesis, whereas mass spectrometry analysis of the liver proteome indicated that Mir22 deletion promotes hepatic upregulation of key enzymes in glycolysis and lipid uptake. Surprisingly, expression of miR-22-3p in Huh7 hepatic cancer cells triggers, in contrast to our in vivo observations, a clear induction of a Warburg effect with an increased glycolysis and an inhibited mitochondrial respiration. Together, our study indicates that miR-22-3p is a master regulator of the lipid and glucose metabolism with differential effects in specific organs and in transformed hepatic cancer cells, as compared to non-tumoral tissue

Testing R-parity with geometry

We present a complete classification of the vacuum geometries of all renormalizable superpotentials built from the fields of the electroweak sector of the MSSM. In addition to the Severi and affine Calabi-Yau varieties previously found, new vacuum manifolds are identified; we thereby investigate the geometrical implication of theories which display a manifest matter parity (or R-parity) via the distinction between leptonic and Higgs doublets, and of the lepton number assignment of the right-handed neutrino fields. We find that the traditional R-parity assignments of the MSSM more readily accommodate the neutrino see-saw mechanism with non-trivial geometry than those superpotentials that violate R-parity. However there appears to be no geometrical preference for a fundamental Higgs bilinear in the superpotential, with operators that violate lepton number, such as νHH¯, generating vacuum moduli spaces equivalent to those with a fundamental bilinear

HIDEA syndrome is caused by biallelic, pathogenic, rare or founder P4HTM variants impacting the active site or the overall stability of the P4H-TM protein

HIDEA syndrome is caused by biallelic pathogenic variants in P4HTM. The phenotype is characterized by muscular and central hypotonia, hypoventilation including obstructive and central sleep apneas, intellectual disability, dysautonomia, epilepsy, eye abnormalities, and an increased tendency to develop respiratory distress during pneumonia. Here, we report six new patients with HIDEA syndrome caused by five different biallelic P4HTM variants, including three novel variants. We describe two Finnish enriched pathogenic P4HTM variants and demonstrate that these variants are embedded within founder haplotypes. We review the clinical data from all previously published patients with HIDEA and characterize all reported P4HTM pathogenic variants associated with HIDEA in silico. All known pathogenic variants in P4HTM result in either premature stop codons, an intragenic deletion, or amino acid changes that impact the active site or the overall stability of P4H-TM protein. In all cases, normal P4H-TM enzyme function is expected to be lost or severely decreased. This report expands knowledge of the genotypic and phenotypic spectrum of the disease.publishedVersio

Genetic Ablation of MiR-22 Fosters Diet-Induced Obesity and NAFLD Development

miR-22 is one of the most abundant miRNAs in the liver and alterations of its hepatic expression have been associated with the development of hepatic steatosis and insulin resistance, as well as cancer. However, the pathophysiological roles of miR-22-3p in the deregulated hepatic metabolism with obesity and cancer remains poorly characterized. Herein, we observed that alterations of hepatic miR-22-3p expression with non-alcoholic fatty liver disease (NAFLD) in the context of obesity are not consistent in various human cohorts and animal models in contrast to the well-characterized miR-22-3p downregulation observed in hepatic cancers. To unravel the role of miR-22 in obesity-associated NAFLD, we generated constitutive Mir22 knockout (miR-22KO) mice, which were subsequently rendered obese by feeding with fat-enriched diet. Functional NAFLD- and obesity-associated metabolic parameters were then analyzed. Insights about the role of miR-22 in NAFLD associated with obesity were further obtained through an unbiased proteomic analysis of miR-22KO livers from obese mice. Metabolic processes governed by miR-22 were finally investigated in hepatic transformed cancer cells. Deletion of Mir22 was asymptomatic when mice were bred under standard conditions, except for an onset of glucose intolerance. However, when challenged with a high fat-containing diet, Mir22 deficiency dramatically exacerbated fat mass gain, hepatomegaly, and liver steatosis in mice. Analyses of explanted white adipose tissue revealed increased lipid synthesis, whereas mass spectrometry analysis of the liver proteome indicated that Mir22 deletion promotes hepatic upregulation of key enzymes in glycolysis and lipid uptake. Surprisingly, expression of miR-22-3p in Huh7 hepatic cancer cells triggers, in contrast to our in vivo observations, a clear induction of a Warburg effect with an increased glycolysis and an inhibited mitochondrial respiration. Together, our study indicates that miR-22-3p is a master regulator of the lipid and glucose metabolism with differential effects in specific organs and in transformed hepatic cancer cells, as compared to non-tumoral tissue