FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function

Constructive pointfree topology eliminates non-constructive representation theorems from Riesz space theory

In Riesz space theory it is good practice to avoid representation theorems which depend on the axiom of choice. Here we present a general methodology to do this using pointfree topology. To illustrate the technique we show that almost f-algebras are commutative. The proof is obtained relatively straightforward from the proof by Buskes and van Rooij by using the pointfree Stone-Yosida representation theorem by Coquand and Spitters

Dianion diagnostics in DESIREE: High-sensitivity detection of Cn2−\text{C}_{n}^{2-} from a sputter ion source

A sputter ion source with a solid graphite target has been used to produce dianions with a focus on carbon cluster dianions, $\text{C}_{n}^{2-}$, with $n=7-24$. Singly and doubly charged anions from the source were accelerated together to kinetic energies of 10 keV per atomic unit of charge and injected into one of the cryogenic (13 K) ion-beam storage rings of the Double ElectroStatic Ion Ring Experiment facility at Stockholm University. Spontaneous decay of internally hot $\text{C}_{n}^{2-}$ dianions injected into the ring yielded $\text{C}^{-}$ anions with kinetic energies of 20 keV, which were counted with a microchannel plate detector. Mass spectra produced by scanning the magnetic field of a $90^{\circ}$ analyzing magnet on the ion injection line reflect the production of internally hot $\text{C}_{7}^{2-}-\text{C}_{24}^{2-}$ dianions with lifetimes in the range of tens of microseconds to milliseconds. In spite of the high sensitivity of this method, no conclusive evidence of $\text{C}_{6}^{2-}$ was found while there was a clear $\text{C}_{7}^{2-}$ signal with the expect isotopic distribution. An upper limit is deduced for a $\text{C}_{6}^{2-}$ signal that is two orders-of-magnitue smaller than that for $\text{C}_{7}^{2-}$. In addition, $\text{C}_{n}\text{O}^{2-}$ and $\text{CsCu}^{2-}$ dianions were detected.Comment: 6 pages, 6 figure

An algorithmic approach to the existence of ideal objects in commutative algebra

The existence of ideal objects, such as maximal ideals in nonzero rings, plays a crucial role in commutative algebra. These are typically justified using Zorn's lemma, and thus pose a challenge from a computational point of view. Giving a constructive meaning to ideal objects is a problem which dates back to Hilbert's program, and today is still a central theme in the area of dynamical algebra, which focuses on the elimination of ideal objects via syntactic methods. In this paper, we take an alternative approach based on Kreisel's no counterexample interpretation and sequential algorithms. We first give a computational interpretation to an abstract maximality principle in the countable setting via an intuitive, state based algorithm. We then carry out a concrete case study, in which we give an algorithmic account of the result that in any commutative ring, the intersection of all prime ideals is contained in its nilradical

Lessons on Conditional Gene Targeting in Mouse Adipose Tissue

Conditional gene targeting has been extensively used for in vivo analysis of gene function in adipocyte cell biology but often with debate over the tissue specificity and the efficacy of inactivation. To directly compare the specificity and efficacy of different Cre lines in mediating adipocyte specific recombination, transgenic Cre lines driven by the adipocyte protein 2 (aP2) and adiponectin (Adipoq) gene promoters, as well as a tamoxifen-inducible Cre driven by the aP2 gene promoter (iaP2), were bred to the Rosa26R (R26R) reporter. All three Cre lines demonstrated recombination in the brown and white fat pads. Using different floxed loci, the individual Cre lines displayed a range of efficacy to Cre-mediated recombination that ranged from no observable recombination to complete recombination within the fat. The Adipoq-Cre exhibited no observable recombination in any other tissues examined, whereas both aP2-Cre lines resulted in recombination in endothelial cells of the heart and nonendothelial, nonmyocyte cells in the skeletal muscle. In addition, the aP2-Cre line can lead to germline recombination of floxed alleles in ∼2% of spermatozoa. Thus, different “adipocyte-specific” Cre lines display different degrees of efficiency and specificity, illustrating important differences that must be taken into account in their use for studying adipose biology

X-ray image reconstruction from a diffraction pattern alone

A solution to the inversion problem of scattering would offer aberration-free diffraction-limited 3D images without the resolution and depth-of-field limitations of lens-based tomographic systems. Powerful algorithms are increasingly being used to act as lenses to form such images. Current image reconstruction methods, however, require the knowledge of the shape of the object and the low spatial frequencies unavoidably lost in experiments. Diffractive imaging has thus previously been used to increase the resolution of images obtained by other means. We demonstrate experimentally here a new inversion method, which reconstructs the image of the object without the need for any such prior knowledge.Comment: 5 pages, 3 figures, improved figures and captions, changed titl

Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells