Lipids promote survival, proliferation, and maintenance of differentiation of rat liver sinusoidal endothelial cells in vitro

Primary rat liver sinusoidal endothelial cells (LSEC) are difficult to maintain in a differentiated state in culture for scientific studies or technological applications. Relatively little is known about molecular regulatory processes that affect LSEC differentiation because of this inability to maintain cellular viability and proper phenotypic characteristics for extended times in vitro, given that LSEC typically undergo death and detachment around 48–72 h even when treated with VEGF. We demonstrate that particular lipid supplements added to serum-free, VEGF-containing medium increase primary rat liver LSEC viability and maintain differentiation. Addition of a defined lipid combination, or even oleic acid (OA) alone, promotes LSEC survival beyond 72 h and proliferation to confluency. Moreover, assessment of LSEC cultures for endocytic function, CD32b surface expression, and exhibition of fenestrae showed that these differentiation characteristics were maintained when lipids were included in the medium. With respect to the underlying regulatory pathways, we found lipid supplement-enhanced phosphatidylinositol 3-kinase and MAPK signaling to be critical for ensuring LSEC function in a temporally dependent manner. Inhibition of Akt activity before 72 h prevents growth of SEC, whereas MEK inhibition past 72 h prevents survival and proliferation. Our findings indicate that OA and lipids modulate Akt/PKB signaling early in culture to mediate survival, followed by a switch to a dependence on ERK signaling pathways to maintain viability and induce proliferation after 72 h. We conclude that free fatty acids can support maintenance of liver LSEC cultures in vitro; key regulatory pathways involved include early Akt signaling followed by ERK signaling.National Science Foundation (U.S.) (Grant EFRI-0735997)National Institutes of Health (U.S.) (Grant R01 GM069668

Evolution of strigolactone receptors by gradual neofunctionalization of KAI2 paralogues

Background: Strigolactones (SLs) are a class of plant hormones that control many aspects of plant growth. The SL signalling mechanism is homologous to that of karrikins (KARs), smoke-derived compounds that stimulate seed germination. In angiosperms, the SL receptor is an a/p hydrolase known as DWARF14 (D14); its close homologue, KARRIKIN INSENSITIVE2 (KAI2), functions as a KAR receptor, and likely recognizes an uncharacterized, endogenous signal (‘KL’). Previous phylogenetic analyses have suggested that the KAI2 lineage is ancestral in land plants, and that canonical D14-type SL receptors only arose in seed plants; this is paradoxical, however, as nonvascular plants synthesize and respond to SLs. Results: We have used a combination of phylogenetic and structural approaches to re-assess the evolution of the D14/KAI2 family in land plants. We analyzed 339 members of the D14/KAI2 family from land plants and charophyte algae. Our phylogenetic analyses show that the divergence between the eu-KAI2 lineage and the DDK (D14/DLK2/KAI2) lineage that includes D14 occurred very early in land plant evolution. We show that eu-KAI2 proteins are highly conserved, and have unique features not found in DDK proteins. Conversely, we show that DDK proteins show considerable sequence and structural variation to each other, and lack clearly definable characteristics. We use homology modelling to show that the earliest members of the DDK lineage structurally resemble KAI2, and that SL receptors in non-seed plants likely do not have D14-like structure. We also show that certain groups of DDK proteins lack the otherwise conserved MAX2-interface, and may thus function independently of MAX2, which we show is highly conserved throughout land plant evolution. Conclusions: Our results suggest D14-like structure is not required for SL perception, and that SL perception has relatively relaxed structural requirements compared to KAI2-mediated signalling. We suggest that SL perception gradually evolved by neo-functionalization within the DDK lineage, and that the transition from KAI2-like to D14-like protein may have been driven by interactions with protein partners, rather than being required for SL perception per se

Yang-Mills instantons and dyons on homogeneous G_2-manifolds

We consider Lie G-valued Yang-Mills fields on the space R x G/H, where G/H is a compact nearly K"ahler six-dimensional homogeneous space, and the manifold R x G/H carries a G_2-structure. After imposing a general G-invariance condition, Yang-Mills theory with torsion on R x G/H is reduced to Newtonian mechanics of a particle moving in R^6, R^4 or R^2 under the influence of an inverted double-well-type potential for the cases G/H = SU(3)/U(1)xU(1), Sp(2)/Sp(1)xU(1) or G_2/SU(3), respectively. We analyze all critical points and present analytical and numerical kink- and bounce-type solutions, which yield G-invariant instanton configurations on those cosets. Periodic solutions on S^1 x G/H and dyons on iR x G/H are also given.Comment: 1+26 pages, 14 figures, 6 miniplot

New Gauged Linear Sigma Models for 8D HyperKahler Manifolds and Calabi-Yau Crystals

We propose two kinds of gauged linear sigma models whose moduli spaces are real eight-dimensional hyperKahler and Calabi-Yau manifolds, respectively. Here, hyperKahler manifolds have sp(2) holonomy in general and are dual to Type IIB (p,q)5-brane configurations. On the other hand, Calabi-Yau fourfolds are toric varieties expressed as quotient spaces. Our model involving fourfolds is different from the usual one which is directly related to a symplectic quotient procedure. Remarkable features in newly-found three-dimensional Chern-Simons-matter theories appear here as well, such as dynamical Fayet-Iliopoulos parameters, one dualized photon and its residual discrete gauge symmetry.Comment: 20 pages, 1 figure; v2: minor changes and references added; v3: statements improved, newer than JHEP versio

Contact Manifolds, Contact Instantons, and Twistor Geometry

Recently, Kallen and Zabzine computed the partition function of a twisted supersymmetric Yang-Mills theory on the five-dimensional sphere using localisation techniques. Key to their construction is a five-dimensional generalisation of the instanton equation to which they refer as the contact instanton equation. Subject of this article is the twistor construction of this equation when formulated on K-contact manifolds and the discussion of its integrability properties. We also present certain extensions to higher dimensions and supersymmetric generalisations.Comment: v3: 28 pages, clarifications and references added, version to appear in JHE

D-instantons and Closed String Tachyons in Misner Space

We investigate closed string tachyon condensation in Misner space, a toy model for big bang universe. In Misner space, we are able to condense tachyonic modes of closed strings in the twisted sectors, which is supposed to remove the big bang singularity. In order to examine this, we utilize D-instanton as a probe. First, we study general properties of D-instanton by constructing boundary state and effective action. Then, resorting to these, we are able to show that tachyon condensation actually deforms the geometry such that the singularity becomes milder.Comment: 24 pages, 1 figure, minor change

Crohn\u27s disease-associated ATG16L1 T300A genotype is associated with improved survival in gastric cancer

BACKGROUND: A non-synonymous single nucleotide polymorphism of the ATG16L1 gene, T300A, is a major Crohn\u27s disease (CD) susceptibility allele, and is known to be associated with increased apoptosis induction in the small intestinal crypt base in CD subjects and mouse models. We hypothesized that ATG16L1 T300A genotype also correlates with increased tumor apoptosis and therefore could lead to superior clinical outcome in cancer subjects. METHODS: T300A genotyping by Taqman assay was performed for gastric carcinoma subjects who underwent resection from two academic medical centers. Transcriptomic analysis was performed by RNA-seq on formalin-fixed paraffin-embedded cancerous tissue. Tumor apoptosis and autophagy were determined by cleaved caspase-3 and p62 immunohistochemistry, respectively. The subjects\u27 genotypes were correlated with demographics, various histopathologic features, transcriptome, and clinical outcome. FINDINGS: Of the 220 genotyped subjects, 163 (74%) subjects carried the T300A allele(s), including 55 (25%) homozygous and 108 (49%) heterozygous subjects. The T300A/T300A subjects had superior overall survival than the other groups. Their tumors were associated with increased CD-like lymphoid aggregates and increased tumor apoptosis without concurrent increase in tumor mitosis or defective autophagy. Transcriptomic analysis showed upregulation of WNT/β-catenin signaling and downregulation of PPAR, EGFR, and inflammatory chemokine pathways in tumors of T300A/T300A subjects. INTERPRETATION: Gastric carcinoma of subjects with the T300A/T300A genotype is associated with repressed EGFR and PPAR pathways, increased tumor apoptosis, and improved overall survival. Genotyping gastric cancer subjects may provide additional insight for clinical stratification

Nonabelian Faddeev-Niemi Decomposition of the SU(3) Yang-Mills Theory

Faddeev and Niemi (FN) have introduced an abelian gauge theory which simulates dynamical abelianization in Yang-Mills theory (YM). It contains both YM instantons and Wu-Yang monopoles and appears to be able to describe the confining phase. Motivated by the meson degeneracy problem in dynamical abelianization models, in this note we present a generalization of the FN theory. We first generalize the Cho connection to dynamical symmetry breaking pattern SU(N+1) -> U(N), and subsequently try to complete the Faddeev-Niemi decomposition by keeping the missing degrees of freedom. While it is not possible to write an on-shell complete FN decomposition, in the case of SU(3) theory of physical interest we find an off-shell complete decomposition for SU(3) -> U(2) which amounts to partial gauge fixing, generalizing naturally the result found by Faddeev and Niemi for the abelian scenario SU(N+1) -> U(1)^N. We discuss general topological aspects of these breakings, demonstrating for example that the FN knot solitons never exist when the unbroken gauge symmetry is nonabelian, and recovering the usual no-go theorems for colored dyons.Comment: Latex 30 page