Molecular basis for gene-specific transactivation by nuclear receptors

AbstractNuclear receptors (NRs) are key transcriptional regulators of metazoan physiology and metabolism. Different NRs bind to similar or even identical core response elements; however, they regulate transcription in a highly receptor- and gene-specific manner. These differences in gene activation can most likely be accounted for by mechanisms involving receptor-specific interactions with DNA as well as receptor-specific interactions with protein complexes binding to adjacent and distant DNA sequences. Here, we review key molecular aspects of transactivation by NRs with special emphasis on the recent advances in the molecular mechanisms responsible for receptor- and gene-specific transcriptional activation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease

Oceanic heat advection to the Arctic in the last Millennium

EGU2011-8738 At present, the Arctic is responding faster to global warming than most other areas on earth, as indicated by rising air temperatures, melting glaciers and ice sheets and a decline of the sea ice cover. As part of the meridional overturning circulation which connects all ocean basins and influences global climate, northward flowing Atlantic Water is the major means of heat and salt advection towards the Arctic where it strongly affects the sea ice distribution. Records of its natural variability are critical for the understanding of feedback mechanisms and the future of the Arctic climate system, but continuous historical records reach back only ca. 150 years. To reconstruct the history of temperature variations in the Fram Strait Branch of the Atlantic Current we analyzed a marine sediment core from the western Svalbard margin. In multidecadal resolution the Atlantic Water temperature record derived from planktic foraminifer associations and Mg/Ca measurements shows variations corresponding to the well-known climatic periods of the last millennium (Medieval Climate Anomaly, Little Ice Age, Modern/Industrial Period). We find that prior to the beginning of atmospheric CO2 rise at ca. 1850 A.D. average summer temperatures in the uppermost Atlantic Water entering the Arctic Ocean were in the range of 3-4.5°C. Within the 20th century, however, temperatures rose by ca. 2°C and eventually reached the modern level of ca. 6°C. Such values are unprecedented in the 1000 years before and are presumably linked to the Arctic Amplification of global warming. Taking into account the ongoing rise of global temperatures, further warming of inflowing Atlantic Water is expected to have a profound influence on sea ice and air temperatures in the Arctic

The large‐scale freshwater cycle of the Arctic

This paper synthesizes our understanding of the Arctic\u27s large‐scale freshwater cycle. It combines terrestrial and oceanic observations with insights gained from the ERA‐40 reanalysis and land surface and ice‐ocean models. Annual mean freshwater input to the Arctic Ocean is dominated by river discharge (38%), inflow through Bering Strait (30%), and net precipitation (24%). Total freshwater export from the Arctic Ocean to the North Atlantic is dominated by transports through the Canadian Arctic Archipelago (35%) and via Fram Strait as liquid (26%) and sea ice (25%). All terms are computed relative to a reference salinity of 34.8. Compared to earlier estimates, our budget features larger import of freshwater through Bering Strait and larger liquid phase export through Fram Strait. While there is no reason to expect a steady state, error analysis indicates that the difference between annual mean oceanic inflows and outflows (∼8% of the total inflow) is indistinguishable from zero. Freshwater in the Arctic Ocean has a mean residence time of about a decade. This is understood in that annual freshwater input, while large (∼8500 km3), is an order of magnitude smaller than oceanic freshwater storage of ∼84,000 km3. Freshwater in the atmosphere, as water vapor, has a residence time of about a week. Seasonality in Arctic Ocean freshwater storage is nevertheless highly uncertain, reflecting both sparse hydrographic data and insufficient information on sea ice volume. Uncertainties mask seasonal storage changes forced by freshwater fluxes. Of flux terms with sufficient data for analysis, Fram Strait ice outflow shows the largest interannual variability

Formal Verification of an Iterative Low-Power x86 Floating-Point Multiplier with Redundant Feedback

We present the formal verification of a low-power x86 floating-point multiplier. The multiplier operates iteratively and feeds back intermediate results in redundant representation. It supports x87 and SSE instructions in various precisions and can block the issuing of new instructions. The design has been optimized for low-power operation and has not been constrained by the formal verification effort. Additional improvements for the implementation were identified through formal verification. The formal verification of the design also incorporates the implementation of clock-gating and control logic. The core of the verification effort was based on ACL2 theorem proving. Additionally, model checking has been used to verify some properties of the floating-point scheduler that are relevant for the correct operation of the unit.Comment: In Proceedings ACL2 2011, arXiv:1110.447

Distributions of nuclear fuel-reprocessing tracers in the Arctic Ocean: Indications of Russian river influence

Radionuclide sampling in 1986 and 1993 in the Canada Basin, and in 1993 in the Amundsen Basin and on the adjacent Laptev shelf, provides new insights into the origin, timing, pathways, and mechanisms for dispersal of non-fallout radioactive tracers in the Arctic Ocean. First, samples from the Beaufort Sea shelf, slope, and adjacent basin show a four-fold increase in 129I concentrations from 1986 to 1993. Second, anthropogenic non-fallout radionuclide concentrations in the Beaufort Sea increase with proximity to slope boundary currents. Third, there is evidence for riverine contributions of anthropogenic radionuclides to surface waters of the Amundsen Basin and the Laptev continental shelf. This evidence includes high surface water burdens of 237Np and 129I, with the maximum in anthropogenic 129I found in the least saline and most 18O-depleted waters, consistent with an origin in high-latitude runoff. Additionally, the 237Np/129I atom ratios in the Laptev Sea and Amundsen Basin in 1993 were significantly lower than observed elsewhere in the Arctic Ocean and can be reasonably explained by 129I added during transit of the Russian shelves. The 240Pu/239Pu ratios in the water column were mostly near 0.18, consistent both with stratospheric bomb fallout and with the discharged-weighted mean Sellafield ratio during 1966-1985. In the least saline water samples collected at the most shallow Laptev shelf station, however, the Pu ratios were lower, consistent with a non-European nuclear fuel reprocessing source. There are clear secondary maxima in 237Np and 129I near 1000 m in the Amundsen Basin, likely associated with the Barents Sea branch of Atlantic water. Finally, the 129I/salinity and 129I/δ18O relationships in the Amundsen and Canada Basins at middepths are indistinguishable, suggesting effective horizontal dispersion

Qualitative assessment of attitudes and knowledge on preterm birth in Malawi and within country framework of care

BACKGROUND: The overarching goal of this study was to qualitatively assess baseline knowledge and perceptions regarding preterm birth (PTB) and oral health in an at-risk, low resource setting surrounding Lilongwe, Malawi. The aims were to determine what is understood regarding normal length of gestation and how gestational age is estimated, to identify common language for preterm birth, and to assess what is understood as options for PTB management. As prior qualitative research had largely focused on patient or client-based focused groups, we primarily focused on groups comprised of community health workers (CHWs) and providers. METHODS: A qualitative study using focus-group discussions, incidence narrative, and informant interviews amongst voluntary participants. Six focus groups were comprised of CHWs, patient couples, midwives, and clinical officers (n = 33) at two rural health centers referring to Kamuzu Central Hospital. Semi-structured questions facilitated discussion of PTB and oral health (inclusive of periodontal disease), including definitions, perception, causation, management, and accepted interventions. RESULTS: Every participant knew of women who had experienced “a baby born too soon”, or preterm birth. All participants recognized both an etiology conceptualization and disease framework for preterm birth, distinguished PTB from miscarriage and macerated stillbirth, and articulated a willingness to engage in studies aimed at prevention or management. Identified gaps included: (1) discordance in the definition of PTB (i.e., 28–34 weeks or less than the 8(th) month, but with a corresponding fetal weight ranging 500 to 2300 grams); (2) utility and regional availability of antenatal steroids for prevention of preterm infant morbidity and mortality; (3) need for antenatal referral for at-risk women, or with symptoms of preterm birth. There was no evident preference for route of progesterone for the prevention of recurrent PTB. CONCLUSIONS: Qualitative research was useful in (1) identifying gaps in knowledge in urban and rural Malawi, and (2) informing the development of educational materials and implementation of programs or trials ultimately aimed at reducing PTB. As a result of this qualitative work, implementation planning was focused on the gaps in knowledge, dissemination of knowledge (to both patients and providers), and practical solutions to barriers in known efficacious therapies

Preterm Premature Rupture of Membranes in Human Immunodeficiency Virus-Infected Women: A Novel Case Series

Objective. To evaluate the management and outcomes of a series of human immunodeficiency virus-(HIV-) infected women whose pregnancies were complicated by preterm premature rupture of membranes (PPROM). Study design. We conducted a retrospective chart review of all women with confirmed HIV infection who had a pregnancy complicated by PPROM remote from term. PPROM remote from term was defined as rupture of membranes prior to 32-week gestation. Collective cases from two centers (Hennepin County Medical Center and The University of Alabama at Birmingham) were reviewed and data on management and outcomes were abstracted. Results. Of the HIV-positive women, we identified 291 pregnancies having occurred in the study interval from two institutions. Of these pregnancies, 7 (2.4%) developed PPROM remote from term with subsequent delivery from 25- to 32-week gestation. Vertical HIV transmission was noted in 2 of 6 children whose long-term followup status was confirmed (33%) of these cases. However, both of these cases occurred in women with either no antepartum/intrapartum antiviral therapy or where only zidovudine monotherapy was used. Importantly, in spite of expectant management, no cases of vertical HIV transmission occurred in women who were receiving either multidrug or highly active antiviral therapy (HAART) at the time of PPROM and who had a cesarean delivery in cases where the predelivery viral load > 1000 copies/mL. Conclusion. Our limited observations raise the question as to whether in the current era of multidrug therapy immediate delivery should be undertaken in HIV+ pregnancies complicated by PPROM at an early gestational age. This case series further suggests that in those pregnancies that lend themselves to expectant management, such a strategy may be considered appropriate

In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model

OBJECTIVE: Data from animal models show that in utero exposure to a maternal high-fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring. STUDY DESIGN: WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure. RESULTS: We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora. CONCLUSION: We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age