Small molecule inhibition of protein depalmitoylation as a new approach towards downregulation of oncogenic Ras signalling

AbstractThe H- and N-Ras GTPases are prominent examples of proteins, whose localizations and signalling capacities are regulated by reversible palmitoylations and depalmitoylations. Recently, the novel small molecule inhibitor palmostatin B has been described to inhibit Ras depalmitoylation and to revert the phenotype of oncogenic HRasG12V transformed cells. This demonstrates that palmostatin B is a tool to investigate the biochemical effects of the inhibition of cellular Ras depalmitoylation on Ras signalling, which is relevant for oncology. Furthermore, it is to be expected that many proteins, of which the signalling capacities depend on reversible palmitoylation, will be discovered in the near future. This stresses the urgent need for further development of small molecule inhibitors of palmitoylation and depalmitoylation in order to study their functions in cellular signalling

Scoping Studies of Dopants for Stabilization of Uranium Nitride Fuel

Uranium nitride (UN) is considered as nuclear reactor fuel because of, among other reasons, its high uranium density and its high thermal conductivity. Its main drawback is that it relatively easily dissolves in hot water, which is particularly problematic when it is used in water-cooled reactors. One possible remedy to this is to add some corrosion inhibitor as dopant to the UN matrix. A number of dopants have been identified that have the potential to inhibit the dissolution process, and their respective merits have been investigated both by neutronic simulations and dissolution experiments. It is concluded that chromium is the most promising candidate

The Autodepalmitoylating activity of APT maintains the spatial organization of Palmitoylated membrane proteins

The localization and signaling of S-palmitoylated peripheral membrane proteins is sustained by an acylation cycle in which acyl protein thioesterases (APTs) depalmitoylate mislocalized palmitoylated proteins on endomembranes. However, the APTs are themselves reversibly S-palmitoylated, which localizes thioesterase activity to the site of the antagonistc palmitoylation activity on the Golgi. Here, we resolve this conundrum by showing that palmitoylation of APTs is labile due to autodepalmitoylation, creating two interconverting thioesterase pools: palmitoylated APT on the Golgi and depalmitoylated APT in the cytoplasm, with distinct functionality. By imaging APT-substrate catalytic intermediates, we show that it is the depalmitoylated soluble APT pool that depalmitoylates substrates on all membranes in the cell, thereby establishing its function as release factor of mislocalized palmitoylated proteins in the acylation cycle. The autodepalmitoylating activity on the Golgi constitutes a homeostatic regulation mechanism of APT levels at the Golgi that ensures robust partitioning of APT substrates between the plasma membrane and the Golgi.Fil: Vartak, Nachiket. Institut Max Planck Fur Molekulare Physiologie; AlemaniaFil: Papke, Bjoern. Institut Max Planck Fur Molekulare Physiologie; AlemaniaFil: Grecco, Hernan Edgardo. Institut Max Planck Fur Molekulare Physiologie; Alemania. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rossmannek, Lisaweta. Institut Max Planck Fur Molekulare Physiologie; AlemaniaFil: Waldmann, Herbert. Institut Max Planck Fur Molekulare Physiologie; AlemaniaFil: Hedberg, Christian. Institut Max Planck Fur Molekulare Physiologie; AlemaniaFil: Bastiaens, Philippe I. H.. Institut Max Planck Fur Molekulare Physiologie; Alemani

Nitride fuel for Gen IV nuclear power systems

Nuclear energy has been a part of the energy mix in many countries for decades. Today in principle all power producing reactors use the same techniqe. Either PWR or BWR fuelled with oxide fuels. This choice of fuel is not self evident and today there are suggestions to change to fuels which may be safer and more economical and also used in e.g. Gen IV nuclear power systems. One such fuel type is the nitrides. The nitrides have a better thermal conductivity than the oxides and a similar melting point and are thus have larger safety margins to melting during operation. In addition they are between 30 and 40% more dense with respect to fissile material. Drawbacks include instability with respect to water and a sometimes complicated fabrication route. The former is not really an issue with Gen IV systems but for use in the present fleet. In this paper we discuss both production and recycling potential of nitride fuels

Нейминг как элемент фирменного стиля

Материалы VII Междунар. межвуз. науч.-техн. конф. студентов, магистрантов и аспирантов,Гомель, 3–4 мая 2007 г

Inter-kingdom Signaling by the Legionella Quorum Sensing Molecule LAI-1 Modulates Cell Migration through an IQGAP1-Cdc42-ARHGEF9-Dependent Pathway

Small molecule signaling promotes the communication between bacteria as well as between bacteria and eukaryotes. The opportunistic pathogenic bacterium Legionella pneumophila employs LAI-1 (3-hydroxypentadecane-4-one) for bacterial cell-cell communication. LAI-1 is produced and detected by the Lqs (Legionella quorum sensing) system, which regulates a variety of processes including natural competence for DNA uptake and pathogen-host cell interactions. In this study, we analyze the role of LAI-1 in inter-kingdom signaling. L. pneumophila lacking the autoinducer synthase LqsA no longer impeded the migration of infected cells, and the defect was complemented by plasmid-borne lqsA. Synthetic LAI-1 dose-dependently inhibited cell migration, without affecting bacterial uptake or cytotoxicity. The forward migration index but not the velocity of LAI-1-treated cells was reduced, and the cell cytoskeleton appeared destabilized. LAI-1-dependent inhibition of cell migration involved the scaffold protein IQGAP1, the small GTPase Cdc42 as well as the Cdc42-specific guanine nucleotide exchange factor ARHGEF9, but not other modulators of Cdc42, or RhoA, Rac1 or Ran GTPase. Upon treatment with LAI-1, Cdc42 was inactivated and IQGAP1 redistributed to the cell cortex regardless of whether Cdc42 was present or not. Furthermore, LAI-1 reversed the inhibition of cell migration by L. pneumophila, suggesting that the compound and the bacteria antagonistically target host signaling pathway(s). Collectively, the results indicate that the L. pneumophila quorum sensing compound LAI-1 modulates migration of eukaryotic cells through a signaling pathway involving IQGAP1, Cdc42 and ARHGEF9

Prophylactic anticoagulation with low molecular weight heparin in COVID-19: cohort studies in Denmark and Sweden

OBJECTIVES: To evaluate safety and effectiveness of prophylactic anticoagulation with low molecular weight heparin (LMWH) in individuals hospitalised for COVID-19. METHODS: Using healthcare records from the capital region of Denmark (March 2020-February 2021) and Karolinska University Hospital in Sweden (February 2020-September 2021), we conducted an observational cohort study comparing clinical outcomes 30 days after admission among individuals hospitalised for COVID-19 starting prophylactic LMWH during the first 48 hours of hospitalisation with outcomes among those not receiving prophylactic anticoagulation. We used inverse probability weighting to adjust for confounders and bias due to missing information. Risk ratios, risk differences and robust 95% confidence intervals (CI) were estimated using binomial regression. Country-specific risk ratios were pooled using random-effects meta-analysis. RESULTS: We included 1692 and 1868 individuals in the Danish and Swedish cohorts. Of these, 771 (46%) and 1167 (62%) received prophylactic LMWH up to 48 hours after admission. The combined mortality in Denmark and Sweden was 12% (N=432) and the pooled risk ratio was 0.89 (CI 0.61-1.29) comparing individuals who received LMWH to those who did not. The relative risk of ICU admission was 1.12 (CI 0.85-1.48), while we observed no increased risk of bleeding (RR 0.60, 0.14-2.59). The relative risk of venous thromboembolism was 0.68 (CI: 0.33-1.38) in Sweden. Less than 5 VTE events were observed among individuals receiving LMWH in Denmark, preventing a meaningful analysis. CONCLUSION: We found no benefit on mortality with prophylactic LMWH and no increased risk of bleeding among COVID-19 patients receiving prophylactic LMWH

Detailed Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds Suggests a Weakened Effect among Elderly

The rs9939609 single-nucleotide polymorphism (SNP) in the fat mass and obesity (FTO) gene has previously been associated with higher BMI levels in children and young adults. In contrast, this association was not found in elderly men. BMI is a measure of overweight in relation to the individuals' height, but offers no insight into the regional body fat composition or distribution.To examine whether the FTO gene is associated with overweight and body composition-related phenotypes rather than BMI, we measured waist circumference, total fat mass, trunk fat mass, leg fat mass, visceral and subcutaneous adipose tissue, and daily energy intake in 985 humans (493 women) at the age of 70 years. In total, 733 SNPs located in the FTO gene were genotyped in order to examine whether rs9939609 alone or the other SNPs, or their combinations, are linked to obesity-related measures in elderly humans.Cross-sectional analysis of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) cohort.Neither a single SNP, such as rs9939609, nor a SNP combination was significantly linked to overweight, body composition-related measures, or daily energy intake in elderly humans. Of note, these observations hold both among men and women.Due to the diversity of measurements included in the study, our findings strengthen the view that the effect of FTO on body composition appears to be less profound in later life compared to younger ages and that this is seemingly independent of gender

Yes, we should! EU priorities for 2019-2024. EPC Challenge Europe Issue 24, April 2019

The European Union (EU) is not alone in its struggle to grapple with the major headaches of our times. The Western world as a whole is affected. Inside the Union, the crises in and of its national societies and democracies have radiated to the EU level. Half of the member states have minority governments. If they are politically weak in their own countries, how can the Union be strong? The EU is, after all, also the sum of its member states

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)