Distinct E2F-Mediated Transcriptional Mechanisms in Cell Proliferation, Endoreplication and Apoptosis

E2F and DP family proteins are evolutionally conserved transcription factors among higher eukaryotes. E2F and DP proteins typically form a heterodimeric complex, which controls cell proliferation by regulating expression of growth-related genes. In addition, E2F family proteins have roles in various cellular events that require the expression of context-specific genes. E2F proteins use distinct mechanisms to regulate context-specific genes in different circumstances. The primary goal of this chapter is to compare three distinct mechanisms of mammalian E2F-mediated transcriptional regulation that control cell proliferation, endoreplication and apoptosis. Briefly, E2F7 and E2F8 control endoreplication by suppressing the expression of their target genes. They do not require DP or pRb. In control of apoptosis, E2F1 regulates the expression of the tumor suppressor gene Arf by binding to a non-canonical E2F binding site, within the Arf promoter, in a DP-independent manner. Furthermore, we examine the functions of E2F and DP in Drosophila melanogaster (fruit fly) to identify those mechanisms of E2F-mediated transcriptional regulation that have been evolutionarily conserved. The detailed mechanisms of how E2F protein regulates the expression of context-specific target genes will be instrumental in understanding how a single family of transcription factor regulates diverse pleiotropic cellular processes in an organism

Three Super-Earths Orbiting HD 7924

We report the discovery of two super-Earth mass planets orbiting the nearby K0.5 dwarf HD 7924 which was previously known to host one small planet. The new companions have masses of 7.9 and 6.4 M$_\oplus$, and orbital periods of 15.3 and 24.5 days. We perform a joint analysis of high-precision radial velocity data from Keck/HIRES and the new Automated Planet Finder Telescope (APF) to robustly detect three total planets in the system. We refine the ephemeris of the previously known planet using five years of new Keck data and high-cadence observations over the last 1.3 years with the APF. With this new ephemeris, we show that a previous transit search for the inner-most planet would have covered 70% of the predicted ingress or egress times. Photometric data collected over the last eight years using the Automated Photometric Telescope shows no evidence for transits of any of the planets, which would be detectable if the planets transit and their compositions are hydrogen-dominated. We detect a long-period signal that we interpret as the stellar magnetic activity cycle since it is strongly correlated with the Ca II H and K activity index. We also detect two additional short-period signals that we attribute to rotationally-modulated starspots and a one month alias. The high-cadence APF data help to distinguish between the true orbital periods and aliases caused by the window function of the Keck data. The planets orbiting HD 7924 are a local example of the compact, multi-planet systems that the Kepler Mission found in great abundance.Comment: Accepted to ApJ on 4/7/201

6-exo-trig Michael addition-lactonizations for catalytic enantioselective chromenone synthesis

The authors thank the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1, RMNP) for funding.The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged. ADS thanks the Royal Society for a Wolfson Research Merit AwardThe catalytic enantioselective 6-exo-trig Michael addition-lactonization of enone-acid substrates to form cis-chromenones with high diastereo- and enantiocontrol was developed using the commercially available isothiourea tetramisole. An acidic workup proved necessary to minimize product epimerization and maximize product er, providing cis-chromenones in excellent yield, and with excellent diastereo- and enantioselectivity.Publisher PDFPeer reviewe

The Key Role of E2F in Tumor Suppression through Specific Regulation of Tumor Suppressor Genes in Response to Oncogenic Changes

E2F, the principal target of the tumor suppressor pRB, plays crucial roles in tumor suppression. Upon dysfunction of pRB, E2F activates tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, resulting in the induction of apoptosis and tumor suppression. The E2F activity that activates the tumor suppressor genes is detected only in cancer cells and not in normal growing cells. The E2F activity can drive selective suicide gene expression and induce apoptosis specifically in cancer cells. Thus, the E2F activity provides a beneficial tool to specifically target cancer cells in cancer treatment

Recent structural evolution of early-type galaxies : size growth from z=1 to z=0

Strong size and internal density evolution of early-type galaxies between z similar to 2 and the present has been reported by several authors. Here we analyze samples of nearby and distant (z similar to 1) galaxies with dynamically measured masses in order to confirm the previous, model-dependent results and constrain the uncertainties that may play a role. Velocity dispersion (sigma) measurements are taken from the literature for 50 morphologically selected 0.8 < z < 1.2 field and cluster early-type galaxies with typical masses M-dyn = 2 x 10(11) M-circle dot. Sizes (R-eff) are determined with Advanced Camera for Surveys imaging. We compare the distant sample with a large sample of nearby (0.04 < z < 0.08) early-type galaxies extracted from the Sloan Digital Sky Survey for which we determine sizes, masses, and densities in a consistent manner, using simulations to quantify systematic differences between the size measurements of nearby and distant galaxies. We find a highly significant difference between the sigma-R-eff distributions of the nearby and distant samples, regardless of sample selection effects. The implied evolution in R-eff at fixed mass between z = 1 and the present is a factor of 1.97 +/- 0.15. This is in qualitative agreement with semianalytic models; however, the observed evolution is much faster than the predicted evolution. Our results reinforce and are quantitatively consistent with previous, photometric studies that found size evolution of up to a factor of 5 since z similar to 2. A combination of structural evolution of individual galaxies through the accretion of companions and the continuous formation of early-type galaxies through increasingly gas-poor mergers is one plausible explanation of the observations

Neurophysiology

Contains a report on a research project

Sarcopenia is a Significant Predictor of Mortality After Abdominal Aortic Aneurysm Repair

Aims Repair of abdominal aortic aneurysms (AAA) decreases the incidence of rupture and death. In cancer patients, sarcopenia has been associated with increased surgical complications and mortality. The impact of sarcopenia on survival after AAA repair has yet to be described. Methods and Results Patient demographic, laboratory, body composition measurements and survival data were obtained from patients undergoing AAA repair at the Indiana University medical campus over a 5-year period. Univariate and multivariate analyses were performed to identify factors associated with overall survival. Overall, 58.2% presented with sarcopenia. Sarcopenic patients were older (71.8±8.3 versus 66.8±8.1 years; p<0.001), had lower body mass index (BMI) (26.3±5.2 versus 31.5±5.9 kg/m2; p<0.001), higher rates of myosteatosis (84.4% versus 52.%; p<0.001), greater AAA diameter (60.6±14.0 versus 57.8±11.7 mm; p=0.016), higher Charlson Comorbidity Index (CCI) (32.3% versus 25.1% ≥6; p=0.034), and increased rates of rupture (8.2% versus 3.8%; p=0.047). Sarcopenic and nonsarcopenic patients had no difference in 30-day morbidity (8.5% versus 8.5%; p=0.991) or mortality (3.7% versus 0.9%; p=0.07). Univariate analysis demonstrated age, sarcopenia, myosteatosis, CCI, and BMI to be associated with long-term survival. There was no correlation between BMI and sarcopenia. Both sarcopenia and myosteatosis resulted in decreased one-, three-, and five-year survivals compared to their counterparts. On multivariate analysis sarcopenia is independently associated with survival, conferring a 1.6-fold increase in death (p=0.04). The combination of sarcopenia plus myosteatosis doubled the risk of death compared to sarcopenia alone. Conclusions This is the first study to demonstrate that over half of all patients undergoing AAA repair are sarcopenic, a condition associated with increased mortality. Sarcopenia with myosteatosis is associated with double the mortality of sarcopenia alone. CT scan, but not BMI, accurately identifies sarcopenia and myosteatosis. Defining the mechanisms through which sarcopenia contributes to late death after AAA repair is critical to developing novel interventions that may improve survival in this high risk population

Joint MiRNA/mRNA expression profiling reveals rhanges consistent with development of dysfunctional corpus luteum after weight gain

<div><p>Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (<i>Chlorocebus aethiops</i>) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7–9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.</p></div

Neurophysiology

Contains research objectives.National Science FoundationIlluminating Engineering Society Research FundTeagle FoundationBell Telephone Laboratories, Incorporate