KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.This work was supported by the Wellcome Trust (098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical Research Centre (ISF, IB and SOR), and European Research Council (ISF). This study makes use of data generated by the UK10K Consortium (WT091310). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2

Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics

The assessment of oocyte quality in human in vitro fertilization (IVF) is getting increasing attention from embryologists. Oocyte selection and the identification of the best oocytes, in fact, would help to limit embryo overproduction and to improve the results of oocyte cryostorage programs. Follicular fluid (FF) is easily available during oocyte pick-up and theorically represents an optimal source on non-invasive biochemical predictors of oocyte quality. Unfortunately, however, the studies aiming to find a good molecular predictor of oocyte quality in FF were not able to identify substances that could be used as reliable markers of oocyte competence to fertilization, embryo development and pregnancy. In the last years, a well definite trend toward passing from the research of single molecular markers to more complex techniques that study all metabolites of FF has been observed. The metabolomic approach is a powerful tool to study biochemical predictors of oocyte quality in FF, but its application in this area is still at the beginning. This review provides an overview of the current knowledge about the biochemical predictors of oocyte quality in FF, describing both the results coming from studies on single biochemical markers and those deriving from the most recent studies of metabolomic

THE ROLE OF Mg (3P^{3}P) ATOMS IN THE Mg+NO2Mg + NO_{2} REACTION

$^{1}$D. J Benard, W. D. Slafer and P. H. Lee, Chem. Phys. Lett-43, 69 (1976). This work was performed under the auspices of the U.S. Department of Energy under contract No. H-7405-Eng-48. ""Author Institution: Lawrence Livermore Laboratory, University of CaliforniaThe addition of CO to the $Mg + N_{2}O$ reaction has previously been $reported^{1}$ to enhance the resulting MgO chemiluminescence and to increase the intensity of the forbidden. Mg atom $(^{3}P_{1}\rightarrow\ ^{1}S_{O})$ transition at 457.1 nm. This work examines the role of metastable Mg ($^{3}p$) atoms, produced directly in a low voltage discharge, in the $Mg + N_{2}O$ reaction. Although the metastables are efficiently quenched by the addition of $N_{2}O$, preliminary experiments Indicate the Mg ($^{3}p$) is not the key reactant leading to MgO $(B^{1}\Sigma - X^{1}\Sigma)$ chemilumiescence in the $Mg + N_{2}O$ reaction

VIBRATIONAL POPULATION DISTRIBUTIONS OF THE GROUND STATE OF BARIUM OXIDE

Author Institution: Quantum Institute, University of CaliforniaThe vibrational population distributions of ground state BaO formed by the reactions $Ba + O_{2}$ and $Ba + N_{2}O$ at 0.3 to 10 Torr have been measured. A scanning rhodamine 6G cw dye laser is used to pump $X^{1}\Sigma(\nu^{\prime\prime}) \rightarrow A^{1}\Sigma(\nu ^{\prime})$ transitions from sequential ground state vibrationa1 levels $(\nu^{\prime\prime}_{i})$, while a 3 nm resolution monochromator detects only the photo-luminescence originating from this $A^{1}\Sigma(\nu ^{\prime})$ in a band outside the dye laser region. Shown below are the relative populations, determined from laser induced fluorescence intensities, of the $\nu ^{\prime} = 0$ through $\nu ^{\prime} = 7$ vibrational levels of $BaO X^{1}\Sigma$ formed in the $Ba + 0_{2}$ reaction at 0.3 Torr. [FIGURE] Similar data for the $Ba + N_{2}O$ reaction suggest that a population inversion may exist between $BaO\ \ A^{1}\Sigma(\nu^{\prime} = 1)^{1}$ and $X^{1}\Sigma(\nu^{\prime\prime}= 7)$ at 16 Torr

Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model

<p>Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (<i>p</i> < .00001). These results indicate that inhalation delivery increases topotecan exposure of lung tissue and improves its efficacy against lung cancer while also lowering the effective dose and maximum systemic concentration that is responsible for its dose-limiting toxicity.</p