Serine, but not glycine, supports one-carbon metabolism and proliferation of cancer cells

Previous work has shown that some cancer cells are highly dependent on serine/glycine uptake for proliferation. Although serine and glycine can be interconverted and either might be used for nucleotide synthesis and one-carbon metabolism, we show that exogenous glycine cannot replace serine to support cancer cell proliferation. Cancer cells selectively consumed exogenous serine, which was converted to intracellular glycine and one-carbon units for building nucleotides. Restriction of exogenous glycine or depletion of the glycine cleavage system did not impede proliferation. In the absence of serine, uptake of exogenous glycine was unable to support nucleotide synthesis. Indeed, higher concentrations of glycine inhibited proliferation. Under these conditions, glycine was converted to serine, a reaction that would deplete the one-carbon pool. Providing one-carbon units by adding formate rescued nucleotide synthesis and growth of glycine-fed cells. We conclude that nucleotide synthesis and cancer cell proliferation are supported by serine—rather than glycine—consumption

№ 102. Ордер № 215 на переведення трусу та арешту у Миколи Чехівського від 13 липня 1929 р.

The costs of intermittent renewable energy systems (IRES) and power storage technologies are compared on a level playing field to those of natural gas combined cycle power plants with CO2 capture and storage (NGCC-CCS). To account for technological progress over time, an "experience curve" approach is used to project future levelised costs of electricity (LCOE) based on technology progress ratios and deployment rates in worldwide energy scenarios, together with European energy and technology cost estimates. Under base case assumptions, the LCOE in 2040 for baseload NGCC-CCS plants is estimated to be 71 €2012/MWh. In contrast, the LCOE for electricity generated intermittently from IRES is estimated at 68, 82, and 104 €2012/MWh for concentrated solar power, offshore wind, and photovoltaic systems, respectively. Considering uncertainties in costs, deployment rates and geographical conditions, LCOE ranges for IRES are wider than for NGCC-CCS. We also assess energy storage technologies versus NGCC-CCS as backup options for IRES. Here, for base case assumptions NGCC-CCS with an LCOE of 90 €2012/MWh in 2040 is more costly than pumped hydro storage (PHS) or compressed air and energy storage (CAES) with LCOEs of 57 and 88 €2012/MWh, respectively. Projected costs for battery backup are 78, 149, and 321 €2012/MWh for Zn-Br, ZEBRA, and Li-ion battery systems, respectively. Finally, we compare four stylised low-carbon systems on a common basis (including all ancillary costs for IRES). In the 2040 base case, the system employing only NGCC-CCS has the lowest LCOE and lowest cost of CO2 avoided with CO2 emissions of 45 kg/MWh. A zero CO2 emission system with IRES plus PHS as backup is 42% more expensive in terms of LCOE, and 13% more costly than a system with IRES plus NGCC-CCS backup with emissions of 23 kg CO2/MWh. Sensitivity results and study limitations are fully discussed within the paper

Lessons-learned abroad:Exchanging knowledge, experience and inspiration between Dutch and Portuguese specialized clinical psychologists

Background: A Dutch delegation of 45 clinical psychologists (in training) and science-practitioners visited their colleagues in Lisbon, Portugal as part of their post academic education program. Hospitals, mental healthcare facilities, universities, start-ups and innovation centers were visited. Purpose: Comparing the differences in the organization of healthcare systems and exchanging information to find inspiration for innovations and solutions regarding the challenges within their own countries. Method: An extensive program of working visits covering the entire spectrum relevant to the work of a psychologist: the clinical evidence-based work, the profession and how to organize scientific research and (technological) innovations in the field. Results: There was agreement between the participants from both countries that these topics require constant attention to promote the relevance of psychology in different domains such as (public) healthcare and scientific research. In addition, the importance of uniformity in education and training, examination and implementation of the profession of psychologists in a European context was supported. Conclusion: The exchange paid off: agreement about future international exchanges to inspire young psychologists, exchanging experience in the clinical field and cooperating in international scientific research as positive outcomes

Mild desalination demo pilot: New normalization approach to effectively evaluate electrodialysis reversal technology

AbstractKey performance indicators for characterization of nanofiltration performance are well developed, similar key performance indicators for electrodialysis reversal are however underdeveloped. Under the E4Water project Dow Benelux BV and Evides Industriewater BV operate a pilot facility to compare both technologies for their application to mildly desalinate a variety of brackish water streams. Normalized pressure drop, normalized current efficiency and normalized membrane resistance proved to be a useful tool to interpret process performance and to initiate a cleaning procedure if required. The availability of these normalized key performance indicators enables optimization and process monitoring and control of electrodialysis reversal independent of the continuously changing conditions of the feed water

Resistance to BRAF inhibitors induces glutamine dependency in melanoma cells

BRAF inhibitors can extend progression-free and overall survival in melanoma patients whose tumors harbor mutations in BRAF. However, the majority of patients eventually develop resistance to these drugs. Here we show that BRAF mutant melanoma cells that have developed acquired resistance to BRAF inhibitors display increased oxidative metabolism and increased dependency on mitochondria for survival. Intriguingly, the increased oxidative metabolism is associated with a switch from glucose to glutamine metabolism and an increased dependence on glutamine over glucose for proliferation. We show that the resistant cells are more sensitive to mitochondrial poisons and to inhibitors of glutaminolysis, suggesting that targeting specific metabolic pathways may offer exciting therapeutic opportunities to treat resistant tumors, or to delay emergence of resistance in the first-line setting

Serine one-carbon catabolism with formate overflow

Serine catabolism to glycine and a one-carbon unit has been linked to the anabolic requirements of proliferating mammalian cells. However, genome-scale modeling predicts a catabolic role with one-carbon release as formate. We experimentally prove that in cultured cancer cells and nontransformed fibroblasts, most of the serine-derived one-carbon units are released from cells as formate, and that formate release is dependent on mitochondrial reverse 10-CHO-THF synthetase activity. We also show that in cancer cells, formate release is coupled to mitochondrial complex I activity, whereas in nontransformed fibroblasts, it is partially insensitive to inhibition of complex I activity. We demonstrate that in mice, about 50% of plasma formate is derived from serine and that serine starvation or complex I inhibition reduces formate synthesis in vivo. These observations transform our understanding of one-carbon metabolism and have implications for the treatment of diabetes and cancer with complex I inhibitors

Regulation of histone H3K4 tri-methylation and PAF complex recruitment by the Ccr4-Not complex

Efficient transcription is linked to modification of chromatin. For instance, tri-methylation of lysine 4 on histone H3 (H3K4) strongly correlates with transcriptional activity and is regulated by the Bur1/2 kinase complex. We found that the evolutionarily conserved Ccr4-Not complex is involved in establishing H3K4 tri-methylation in Saccharomyces cerevisiae. We observed synthetic lethal interactions of Ccr4-Not components with BUR1 and BUR2. Further analysis indicated that the genes encoding the Not-proteins are essential for efficient regulation of H3K4me3, but not H3K4me1/2, H3K36me2 or H3K79me2/3 levels. Moreover, regulation of H3K4me3 levels by NOT4 is independent of defects in RNA polymerase II loading. We found NOT4 to be important for ubiquitylation of histone H2B via recruitment of the PAF complex, but not for recruitment or activation of the Bur1/2 complex. These results suggest a mechanism in which the Ccr4-Not complex functions parallel to or downstream of the Bur1/2 kinase to facilitate H3K4me3 via PAF complex recruitment

Mdm2 Induces Mono-Ubiquitination of FOXO4

Background: The Forkhead box O (FOXO) class of transcription factors are involved in the regulation of several cellular responses including cell cycle progression and apoptosis. Furthermore, in model organisms FOXOs act as tumor suppressors and affect aging. Previously, we noted that FOXOs and p53 are remarkably similar within their spectrum of regulatory proteins [1]. For example, the de-ubiquitinating enzyme USP7 removes ubiquitin from both FOXO and p53. However, Skp2 has been identified as E3 ligase for FOXO1, whereas Mdm2 is the prime E3 ligase for p53. Principal Findings/Methodology: Here we provide evidence that Mdm2 acts as an E3 ligase for FOXO as well. In vitro incubation of Mdm2 and FOXO results in ATP-dependent (multi)mono-ubiquitination of FOXO similar to p53. Furthermore, in vivo co-expression of Mdm2 and FOXO induces FOXO mono-ubiquitination and consistent with this result, siRNAmediated depletion of Mdm2 inhibits mono-ubiquitination of FOXO induced by hydrogen peroxide. Regulation of FOXO ubiquitination by Mdm2 is likely to be direct since Mdm2 and FOXO co-immunoprecipitate. In addition, Mdm2-mediated ubiquitination regulates FOXO transcriptional activity. Conclusions/Significance: These data identify Mdm2 as a novel E3 ligase for FOXOs and extend the analogous mode o

SIRT1 mediates FOXA2 breakdown by deacetylation in a nutrient-dependent manner

The Forkhead transcription factor FOXA2 plays a fundamental role in controlling metabolic homeostasis in the liver during fasting. The precise molecular regulation of FOXA2 in response to nutrients is not fully understood. Here, we studied whether FOXA2 could be controlled at a post-translational level by acetylation. By means of LC-MS/MS analyses, we identified five acetylated residues in FOXA2. Sirtuin family member SIRT1 was found to interact with and deacetylate FOXA2, the latter process being dependent on the NAD +-binding catalytic site of SIRT1. Deacetylation by SIRT1 reduced protein stability of FOXA2 by targeting it towards proteasomal degradation, and inhibited transcription from the FOXA2-driven G6pase and CPT1a promoters. While mutation of the five identified acetylated residues weakly affected protein acetylation and stability, mutation of at least seven additional lysine residues was required to abolish acetylation and reduce protein levels of FOXA2. The importance of acetylation of FOXA2 became apparent upon changes in nutrient levels. The interaction of FOXA2 and SIRT1 was strongly reduced upon nutrient withdrawal in cell culture, while enhanced Foxa2 acetylation levels were observed in murine liver in vivo after starvation for 36 hours. Collectively, this study demonstrates that SIRT1 controls the acetylation level of FOXA2 in a nutrient-dependent manner and in times of nutrient shortage the interaction between SIRT1 and FOXA2 is reduced. As a result, FOXA2 is protected from degradation by enhanced acetylation, hence enabling the FOXA2 transcriptional program to be executed to maintain metabolic homeostasis

Circulating adenosine increases during human experimental endotoxemia but blockade of its receptor does not influence the immune response and subsequent organ injury

Contains fulltext : 95720.pdf (publisher's version ) (Open Access)INTRODUCTION: Preclinical studies have shown that the endogenous nucleoside adenosine prevents excessive tissue injury during systemic inflammation. We aimed to study whether endogenous adenosine also limits tissue injury in a human in vivo model of systemic inflammation. In addition, we studied whether subjects with the common 34C > T nonsense variant (rs17602729) of adenosine monophosphate deaminase (AMPD1), which predicts increased adenosine formation, have less inflammation-induced injury. METHODS: In a randomized double-blinded design, healthy male volunteers received 2 ng/kg E. Coli LPS intravenously with (n = 10) or without (n = 10) pretreatment with the adenosine receptor antagonist caffeine (4 mg/kg body weight). In addition, lipopolysaccharide (LPS) was administered to 10 subjects heterozygous for the AMPD1 34C > T variant. RESULTS: The increase in adenosine levels tended to be more pronounced in the subjects heterozygous for the AMPD1 34C > T variant (71 +/- 22%, P=0.04), compared to placebo- (59 +/- 29%, P=0.012) and caffeine-treated (53 +/- 47%, P=0.29) subjects, but this difference between groups did not reach statistical significance. Also the LPS-induced increase in circulating cytokines was similar in the LPS-placebo, LPS-caffeine and LPS-AMPD1-groups. Endotoxemia resulted in an increase in circulating plasma markers of endothelial activation [intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM)], and in subclinical renal injury, measured by increased urinary excretion of tubular injury markers. The LPS-induced increase of these markers did not differ between the three groups. CONCLUSIONS: Human experimental endotoxemia induces an increase in circulating cytokine levels and subclinical endothelial and renal injury. Although the plasma adenosine concentration is elevated during systemic inflammation, co-administration of caffeine or the presence of the 34C > T variant of AMPD1 does not affect the observed subclinical organ damage, suggesting that adenosine does not affect the inflammatory response and subclinical endothelial and renal injury during human experimental endotoxemia. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00513110