Microarray analysis of E9.5 reduced folate carrier (RFC1; Slc19a1) knockout embryos reveals altered expression of genes in the cubilin-megalin multiligand endocytic receptor complex

<p>Abstract</p> <p>Background</p> <p>The reduced folate carrier (<it>RFC1</it>) is an integral membrane protein and facilitative anion exchanger that mediates delivery of 5-methyltetrahydrofolate into mammalian cells. Adequate maternal-fetal transport of folate is necessary for normal embryogenesis. Targeted inactivation of the murine <it>RFC1 </it>gene results in post-implantation embryolethality, but daily folic acid supplementation of pregnant dams prolongs survival of homozygous embryos until mid-gestation. At E10.5 <it>RFC1</it>^-/-embryos are developmentally delayed relative to wildtype littermates, have multiple malformations, including neural tube defects, and die due to failure of chorioallantoic fusion. The mesoderm is sparse and disorganized, and there is a marked absence of erythrocytes in yolk sac blood islands. The identification of alterations in gene expression and signaling pathways involved in the observed dysmorphology following inactivation of RFC1-mediated folate transport are the focus of this investigation.</p> <p>Results</p> <p>Affymetrix microarray analysis of the relative gene expression profiles in whole E9.5 <it>RFC1</it>^-/-vs. <it>RFC1</it>^+/+embryos identified 200 known genes that were differentially expressed. Major ontology groups included transcription factors (13.04%), and genes involved in transport functions (ion, lipid, carbohydrate) (11.37%). Genes that code for receptors, ligands and interacting proteins in the cubilin-megalin multiligand endocytic receptor complex accounted for 9.36% of the total, followed closely by several genes involved in hematopoiesis (8.03%). The most highly significant gene network identified by Ingenuity™ Pathway analysis included 12 genes in the cubilin-megalin multiligand endocytic receptor complex. Altered expression of these genes was validated by quantitative RT-PCR, and immunohistochemical analysis demonstrated that megalin protein expression disappeared from the visceral yolk sac of <it>RFC1</it>^-/-embryos, while cubilin protein was widely misexpressed.</p> <p>Conclusion</p> <p>Inactivation of <it>RFC1 </it>impacts the expression of several ligands and interacting proteins in the cubilin-amnionless-megalin complex that are involved in the maternal-fetal transport of folate and other nutrients, lipids and morphogens such as sonic hedgehog (Shh) and retinoids that play critical roles in normal embryogenesis.</p

On the next-to-leading-order correction to the effective action in N=2 gauge theories

I attempt to analyse the next-to-leading-order non-holomorphic contribution to the Wilsonian low-energy effective action in the four-dimensional N=2 gauge theories with matter, from the manifestly N=2 supersymmeric point of view, by using the harmonic superspace. The perturbative one-loop correction is found to be in agreement with the N=1 superfield calculations of de Wit, Grisaru and Rocek. The previously unknown coefficient in front of this non-holomorphic correction is calculated. A special attention is devoted to the N=2 superconformal gauge theories, whose one-loop non-holomorphic contribution is likely to be exact, even non-perturbatively. This leading (one-loop) non-holomorphic contribution to the LEEA of the N=2 superconformally invariant gauge field theories is calculated, and it does not vanish, similarly to the case of the N=4 super-Yang-Mills theory.Comment: 15 pages, LaTeX; changes in the abstract and in sect.

Grand Unification with Three Generations in Free Fermionic String Models

We examine the problem of constructing three generation free fermionic string models with grand unified gauge groups. We attempt the construction of $G\times G$ models, where $G$ is a grand unified group realized at level 1. This structure allows those Higgs representations to appear which are necessary to break the symmetry down to the standard model gauge group. For $G=SO(10)$, we find only models with an even number of generations. However, for $G=SU(5)$ we find a number of 3 generation models.Comment: 22 pages, latex. References added to original versio

Nonperturbative Renormalization Group Equation and Beta Function in N=2 SUSY Yang-Mills

We obtain the exact beta function for $N=2$ SUSY $SU(2)$ Yang-Mills theory and prove the nonperturbative Renormalization Group Equation $$\partial_\Lambda{\cal F}(a,\Lambda)= {\Lambda\over \Lambda_0}\partial_{\Lambda_0}{\cal F}(a_0,\Lambda_0) e^{-2\int_{\tau_0}^\tau {dx \beta^{-1}(x)}}.$$Comment: LaTex, 10 pg. Expanded introduction, references added, to appear in Phys. Rev. Let

A Classification of 3-Family Grand Unification in String Theory I. The SO(10) and E_6 Models

We give a classification of 3-family SO(10) and E_6 grand unification in string theory within the framework of conformal field theory and asymmetric orbifolds. We argue that the construction of such models in the heterotic string theory requires certain Z_6 asymmetric orbifolds that include a Z_3 outer-automorphism, the latter yielding a level-3 current algebra for the grand unification gauge group SO(10) or E_6. We then classify all such Z_6 asymmetric orbifolds that result in models with a non-abelian hidden sector. All models classified in this paper have only one adjoint (but no other higher representation) Higgs field in the grand unified gauge group. In addition, all of them are completely anomaly free. There are two types of such 3-family models. The first type consists of the unique SO(10) model with SU(2) X SU(2) X SU(2) as its hidden sector (which is not asymptotically-free at the string scale). This SO(10) model has 4 left-handed and 1 right-handed 16s. The second type is described by a moduli space containing 17 models (distinguished by their massless spectra). All these models have an SU(2) hidden sector, and 5 left-handed and 2 right-handed families in the grand unified gauge group. One of these models is the unique E_6 model with an asymptotically-free SU(2) hidden sector. The others are SO(10) models, 8 of them with an asymptotically free hidden sector at the string scale.Comment: 35 pages, Revtex 3.0, one eps figure (to appear in Phys. Rev. D

N=2 SYM Action as a BRST Exact Term, Topological Yang Mills and Instantons

By constructing a nilpotent extended BRST operator \bs that involves the N=2 global supersymmetry transformations of one chirality, we show that the standard N=2 off-shell Super Yang Mills Action can be represented as an exact BRST term \bs \Psi, if the gauge fermion $\Psi$ is allowed to depend on the inverse powers of supersymmetry ghosts. By using this nonanalytical structure of the gauge fermion (via inverse powers of supersymmetry ghosts), we give field redefinitions in terms of composite fields of supersymmetry ghosts and N=2 fields and we show that Witten's topological Yang Mills theory can be obtained from the ordinary Euclidean N=2 Super Yang Mills theory directly by using such field redefinitions. In other words, TYM theory is obtained as a change of variables (without twisting). As a consequence it is found that physical and topological interpretations of N=2 SYM are intertwined together due to the requirement of analyticity of global SUSY ghosts. Moreover, when after an instanton inspired truncation of the model is used, we show that the given field redefinitions yield the Baulieu-Singer formulation of Topological Yang Mills.Comment: Latex, 1+15 pages. Published versio

Realizing Higher-Level Gauge Symmetries in String Theory: New Embeddings for String GUTs

We consider the methods by which higher-level and non-simply laced gauge symmetries can be realized in free-field heterotic string theory. We show that all such realizations have a common underlying feature, namely a dimensional truncation of the charge lattice, and we identify such dimensional truncations with certain irregular embeddings of higher-level and non-simply laced gauge groups within level-one simply-laced gauge groups. This identification allows us to formulate a direct mapping between a given subgroup embedding, and the sorts of GSO constraints that are necessary in order to realize the embedding in string theory. This also allows us to determine a number of useful constraints that generally affect string GUT model-building. For example, most string GUT realizations of higher-level gauge symmetries G_k employ the so-called diagonal embeddings G_k\subset G\times G \times...\times G. We find that there exist interesting alternative embeddings by which such groups can be realized at higher levels, and we derive a complete list of all possibilities for the GUT groups SU(5), SU(6), SO(10), and E_6 at levels k=2,3,4 (and in some cases up to k=7). We find that these new embeddings are always more efficient and require less central charge than the diagonal embeddings which have traditionally been employed. As a byproduct, we also prove that it is impossible to realize SO(10) at levels k>4. This implies, in particular, that free-field heterotic string models can never give a massless 126 representation of SO(10).Comment: 69 pages, LaTeX, 5 figures (Encapsulated PostScript). Revised to match published versio

SU(2) Yang-Mills Theory with extended Supersymmetry in a Background Magnetic Field

The vacuum structure of N=2 (and N=4) SUSY Yang-Mills theory is analyzed in detail by considering the effective potential for constant background scalar- magnetic fields within different approximations. We compare the one-loop approximation with- or without instanton improved effective coupling with the one-loop result in the dual desription. For N=2 we find that non-perturbative monopole degrees of freedom remove the non-trivial minima present in the (improved) one-loop potential in the strong-coupling regime. The combination of Yang-Mills and dual desription leads to a self-consistent effective potential over the full range of background fields.Comment: 15 pages, Revtex, 3 figures, References added, section two shortened, some minor remarks and corrections adde