Antitumor effect of SIRT1 inhibition in human HCC tumor models in vitro and in vivo

Sirtuins (SIRT1-7) are a highly conserved family of NAD(+)-dependent enzymes that control the activity of histone and nonhistone regulatory proteins. SIRT1 is purposed to promote longevity and to suppress the initiation of some cancers. Nevertheless, SIRT1 is reported to function as a tumor suppressor as well as an oncogenic protein. Our data show that compared with normal liver or surrounding tumor tissue, SIRT1 is strongly overexpressed in human hepatocellular carcinoma (HCC). In addition, human HCC cell lines (Hep3B, HepG2, HuH7, HLE, HLF, HepKK1, skHep1) were screened for the expression of the sirtuin family members and only SIRT1 was consistently overexpressed compared with normal hepatocytes. To determine its effect on HCC growth, SIRT1 activity was inhibited either with lentiviruses expressing short hairpin RNAs or with the small molecule inhibitor, cambinol. Knockdown or inhibition of SIRT1 activity had a cytostatic effect, characterized by an altered morphology, impaired proliferation, an increased expression of differentiation markers, and cellular senescence. In an orthotopic xenograft model, knockdown of SIRT1 resulted in 50% fewer animals developing tumors and cambinol treatment resulted in an overall lower tumor burden. Taken together, our data show that inhibition of SIRT1 in HCC cells impairs their proliferation in vitro and tumor formation in vivo. These data suggest that SIRT1 expression positively influences the growth of HCC and support further studies aimed to block its activity alone or in combination as a novel treatment strategy.

Historical and idealized climate model experiments: an intercomparison of Earth system models of intermediate complexity

Both historical and idealized climate model experiments are performed with a variety of Earth system models of intermediate complexity (EMICs) as part of a community contribution to the Intergovernmental Panel on Climate Change Fifth Assessment Report. Historical simulations start at 850 CE and continue through to 2005. The standard simulations include changes in forcing from solar luminosity, Earth's orbital configuration, CO2, additional greenhouse gases, land use, and sulphate and volcanic aerosols. In spite of very different modelled pre-industrial global surface air temperatures, overall 20th century trends in surface air temperature and carbon uptake are reasonably well simulated when compared to observed trends. Land carbon fluxes show much more variation between models than ocean carbon fluxes, and recent land fluxes appear to be slightly underestimated. It is possible that recent modelled climate trends or climate–carbon feedbacks are overestimated resulting in too much land carbon loss or that carbon uptake due to CO2 and/or nitrogen fertilization is underestimated. Several one thousand year long, idealized, 2 × and 4 × CO2 experiments are used to quantify standard model characteristics, including transient and equilibrium climate sensitivities, and climate–carbon feedbacks. The values from EMICs generally fall within the range given by general circulation models. Seven additional historical simulations, each including a single specified forcing, are used to assess the contributions of different climate forcings to the overall climate and carbon cycle response. The response of surface air temperature is the linear sum of the individual forcings, while the carbon cycle response shows a non-linear interaction between land-use change and CO2 forcings for some models. Finally, the preindustrial portions of the last millennium simulations are used to assess historical model carbon-climate feedbacks. Given the specified forcing, there is a tendency for the EMICs to underestimate the drop in surface air temperature and CO2 between the Medieval Climate Anomaly and the Little Ice Age estimated from palaeoclimate reconstructions. This in turn could be a result of unforced variability within the climate system, uncertainty in the reconstructions of temperature and CO2, errors in the reconstructions of forcing used to drive the models, or the incomplete representation of certain processes within the models. Given the forcing datasets used in this study, the models calculate significant land-use emissions over the pre-industrial period. This implies that land-use emissions might need to be taken into account, when making estimates of climate–carbon feedbacks from palaeoclimate reconstructions.

Family models of independence/interdependence and their intergenerational similarity in Germany, Turkey, and India

Family change theory suggests three ideal-typical family models characterized by different combinations of emotional and material interdependencies in the family. Its major proposition is that in economically developing countries with a collectivistic background a family model of emotional interdependence emerges from a family model of complete interdependence. The current study aims to identify and compare patterns of family-related value orientations related to family change theory across three cultures and two generations. Overall, N = 919 dyads of mothers and their adolescent children from Germany, Turkey, and India participated in the study. Three clusters were identified representing the family models of independence, interdependence, and emotional interdependence, respectively. Especially the identification of an emotionally interdependent value pattern using a person-oriented approach is an important step in the empirical validation of family change theory. The preference for the three family models differed across as well as within cultures and generations according to theoretical predictions. Dyadic analyses pointed to substantial intergenerational similarities and also to differences in family models, reflecting both cultural continuity as well as change in family-related value orientations.

Values of children and family models of adolescents: An eleven-culture study

Starting from Kagitcibasi's (2007) conceptualization of family models, this study compared N = 2961 adolescents' values across eleven cultures and explored whether patterns of values were related to the three proposed family models through cluster analyses. Three clusters with value profiles corresponding to the family models of interdependence, emotional interdependence, and independence were identified on the cultural as well as on the individual level. Furthermore, individual-level clusters corresponded to culture-level clusters in terms of individual cluster membership. The results largely support Kagitcibasi's proposition of changing family models and demonstrate their representation as individual-level value profiles across cultures.

Syntheses, characterization and crystal structures of a new functionalised TTF derivative and its Ni(II) complex

The new ligand 4,5-bis (2-pyridylmethylsulfanyl)-4',5'-bis(cyanoethylthio)tetrathiafulvalene (BPM-BCET-TTF) and its nickel(II) complex have been prepared and crystallographically characterized. The Ni(II) complex shows octahedral geometry around the metal ion with the coordination site occupied by the pyridyl nitrogen atoms, the thioether sulfur atoms of the ligand and cis coordination of the halide ions.

Simultaneous analysis of nuclear and mitochondrial DNA, mRNA and miRNA from backspatter from inside parts of firearms generated by shots at "triple contrast" doped ballistic models

When a firearm projectile hits a biological target a spray of biological material (e.g., blood and tissue fragments) can be propelled from the entrance wound back towards the firearm. This phenomenon has become known as "backspatter" and if caused by contact shots or shots from short distances traces of backspatter may reach, consolidate on, and be recovered from, the inside surfaces of the firearm. Thus, a comprehensive investigation of firearm-related crimes must not only comprise of wound ballistic assessment but also backspatter analysis, and may even take into account potential correlations between these emergences. The aim of the present study was to evaluate and expand the applicability of the "triple contrast" method by probing its compatibility with forensic analysis of nuclear and mitochondrial DNA and the simultaneous investigation of co-extracted mRNA and miRNA from backspatter collected from internal components of different types of firearms after experimental shootings. We demonstrate that "triple contrast" stained biological samples collected from the inside surfaces of firearms are amenable to forensic co-analysis of DNA and RNA and permit sequence analysis of the entire mtDNA displacement-loop, even for "low template" DNA amounts that preclude standard short tandem repeat DNA analysis. Our findings underscore the "triple contrast" method's usefulness as a research tool in experimental forensic ballistics.