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Despite the fact that most cancer cells display high glycolytic activity, cancer cells selectively express the less active M2 isoform of pyruvate kinase (PKM2). Here we demonstrate that PKM2 expression makes a critical regulatory contribution to the serine synthetic pathway. In the absence of serine, an allosteric activator of PKM2, glycolytic efflux to lactate is significantly reduced in PKM2-expressing cells. This inhibition of PKM2 results in the accumulation of glycolytic intermediates that feed into serine synthesis. As a consequence, PKM2-expressing cells can maintain mammalian target of rapamycin complex 1 activity and proliferate in serine-depleted medium, but PKM1-expressing cells cannot. Cellular detection of serine depletion depends on general control nonderepressible 2 kinase-activating transcription factor 4 (GCN2-ATF4) pathway activation and results in increased expression of enzymes required for serine synthesis from the accumulating glycolytic precursors. These findings suggest that tumor cells use serine-dependent regulation of PKM2 and GCN2 to modulate the flux of glycolytic intermediates in support of cell proliferation.

Mutation of isocitrate dehydrogenase 1 (IDH1) is shown to induce DNA hypermethylation and to remodel the epigenome to resemble that of gliomas with the CpG island methylator phenotype. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology 1 , 2 , 3 . Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 ( IDH1 ), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.

Cancer-associated IDH mutants that produce 2-hydroxyglutarate are shown to prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. Cancer induction by isocitrate dehydrogenase mutation Mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 have been identified in gliomas, the most common form of brain tumour, and in other cancers including leukaemias. The mutated enzymes produce 2-hydroxyglutarate (2HG), which is a potential oncometabolite. Three papers in this issue of Nature examine the mechanisms through which IDH mutations promote cancers. Lu et al . show that 2HG-producing IDH mutants can prevent the histone demethylation that is required for progenitor cells to differentiate, potentially contributing to tumour-cell accumulation. Turcan et al . show that IDH1 mutation in primary human astrocytes induces DNA hypermethylation and reshapes the methylome to resemble that of the CIMP phenotype, a common feature of gliomas and other solid tumours. Koivunen et al . show that the ( R )-enantiomer of 2HG (but not the ( S )-enantiomer) can stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of hypoxia-inducible factor (HIF), which in turn can enhance cell proliferation. These papers establish a framework for understanding gliomagenesis and highlight the interplay between genomic and epigenomic changes in human cancers. Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 have been identified in gliomas, acute myeloid leukaemias (AML) and chondrosarcomas, and share a novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate 1 , 2 , 3 , 4 , 5 , 6 . Here we report that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells. In tumour samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells, and this was associated with increased histone methylation. To test whether the ability of IDH mutants to promote histone methylation contributes to a block in cell differentiation in non-transformed cells, we tested the effect of neomorphic IDH mutants on adipocyte differentiation in vitro . Introduction of either mutant IDH or cell-permeable 2HG was associated with repression of the inducible expression of lineage-specific differentiation genes and a block to differentiation. This correlated with a significant increase in repressive histone methylation marks without observable changes in promoter DNA methylation. Gliomas were found to have elevated levels of similar histone repressive marks. Stable transfection of a 2HG-producing mutant IDH into immortalized astrocytes resulted in progressive accumulation of histone methylation. Of the marks examined, increased H3K9 methylation reproducibly preceded a rise in DNA methylation as cells were passaged in culture. Furthermore, we found that the 2HG-inhibitable H3K9 demethylase KDM4C was induced during adipocyte differentiation, and that RNA-interference suppression of KDM4C was sufficient to block differentiation. Together these data demonstrate that 2HG can inhibit histone demethylation and that inhibition of histone demethylation can be sufficient to block the differentiation of non-transformed cells.

Citrate is a critical metabolite required to support both mitochondrial bioenergetics and cytosolic macromolecular synthesis. When cells proliferate under normoxic conditions, glucose provides the acetyl-CoA that condenses with oxaloacetate to support citrate production. Tricarboxylic acid (TCA) cycle anaplerosis is maintained primarily by glutamine. Here we report that some hypoxic cells are able to maintain cell proliferation despite a profound reduction in glucose-dependent citrate production. In these hypoxic cells, glutamine becomes a major source of citrate. Glutamine-derived α-ketoglutarate is reductively carboxylated by the NADPH-linked mitochondrial isocitrate dehydrogenase (IDH2) to form isocitrate, which can then be isomerized to citrate. The increased IDH2-dependent carboxylation of glutamine-derived α-ketoglutarate in hypoxia is associated with a concomitant increased synthesis of 2-hydroxyglutarate (2HG) in cells with wild-type IDH1 and IDH2. When either starved of glutamine or rendered IDH2-deficient by RNAi, hypoxic cells are unable to proliferate. The reductive carboxylation of glutamine is part of the metabolic reprogramming associated with hypoxia-inducible factor 1 (HIF1), as constitutive activation of HIF1 recapitulates the preferential reductive metabolism of glutamine-derived α-ketoglutarate even in normoxic conditions. These data support a role for glutamine carboxylation in maintaining citrate synthesis and cell growth under hypoxic conditions.

The growing prevalence of livestock as an alternative or complementary livelihood strategy has become a growing threat to wildlife and forest ecosystems in China. To achieve the dual objectives of biodiversity conservation and rural development requires cooperation and coordination from local communities. However, relatively little is known about the prevalence of these social attitudes in rural China, nor the extent to which cooperation and coordination could be leveraged for the enhanced natural resource management. In this study, we used a series of experimental games to study the propensity for cooperation in the management of common property resources among rural communities in national panda nature reserves in Gansu and Sichuan provinces. We also explored how variations in socioeconomic factors may explain differences in participants' voluntary contribution patterns. Our results show that expected cooperation among peers was a major determinant of voluntary cooperation under the provision point mechanism but not the voluntary contribution mechanism. The risk in the collective returns reduced the chance for voluntary cooperation while the private risk did not show a significant effect. Other socioeconomic factors contributed little to the voluntary cooperation behaviors. Our study suggests that alleviating uncertainty of rural resident's income could enhance collective action in endangered species conservation. A cooperative with support from the government to lower the potential risk in returns could be effective in managing the livestock number and promote sustainable livelihoods around protected areas.

Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are a common feature of a major subset of primary human brain cancers. These mutations occur at a single amino acid residue of the IDH1 active site, resulting in loss of the enzyme’s ability to catalyse conversion of isocitrate to α-ketoglutarate. However, only a single copy of the gene is mutated in tumours, raising the possibility that the mutations do not result in a simple loss of function. Here we show that cancer-associated IDH1 mutations result in a new ability of the enzyme to catalyse the NADPH-dependent reduction of α-ketoglutarate to R (-)-2-hydroxyglutarate (2HG). Structural studies demonstrate that when arginine 132 is mutated to histidine, residues in the active site are shifted to produce structural changes consistent with reduced oxidative decarboxylation of isocitrate and acquisition of the ability to convert α-ketoglutarate to 2HG. Excess accumulation of 2HG has been shown to lead to an elevated risk of malignant brain tumours in patients with inborn errors of 2HG metabolism. Similarly, in human malignant gliomas harbouring IDH1 mutations, we find markedly elevated levels of 2HG. These data demonstrate that the IDH1 mutations result in production of the onco-metabolite 2HG, and indicate that the excess 2HG which accumulates in vivo contributes to the formation and malignant progression of gliomas. Role of 2-hydroxyglutarate in cancer A high percentage of human glioblastomas has been found to harbour mutations in the metabolic enzyme cytosolic isocitrate dehydrogenase 1 (IDH1). The predominant R132H mutation is now shown to act as a gain-of-function mutation, enabling IDH1 to convert α-ketoglutarate to 2-hydroxyglutarate (2-HG). Human glioblastoma samples with IDH1 mutations indeed contain elevated levels of 2-HG. Future work will be directed at understanding the mechanisms by which 2-HG can contribute to tumorigenesis. Mutations in the enzyme cytosolic isocitrate dehydrogenase 1 (IDH1) are commonly found in glioblastomas, a major subset of primary human brain cancers. However, only a single copy of the gene is mutated, suggesting that the mutation does not result in a simple loss of function. Here, IDH1 mutations are shown to act in a gain-of-function manner, resulting in a new ability of the enzyme to catalyse α-ketoglutarate to R (-)-2-hydroxyglutarate, an onco-metabolite.

Although cyclophilins are attractive targets for probing biology and therapeutic intervention, no subtype-selective cyclophilin inhibitors have been described. We discovered novel cyclophilin inhibitors from the in vitro selection of a DNA-templated library of 256,000 drug-like macrocycles for cyclophilin D (CypD) affinity. Iterated macrocycle engineering guided by ten X-ray co-crystal structures yielded potent and selective inhibitors (half maximal inhibitory concentration (IC50) = 10 nM) that bind the active site of CypD and also make novel interactions with non-conserved residues in the S2 pocket, an adjacent exo-site. The resulting macrocycles inhibit CypD activity with 21- to >10,000-fold selectivity over other cyclophilins and inhibit mitochondrial permeability transition pore opening in isolated mitochondria. We further exploited S2 pocket interactions to develop the first cyclophilin E (CypE)-selective inhibitor, which forms a reversible covalent bond with a CypE S2 pocket lysine, and exhibits 30- to >4,000-fold selectivity over other cyclophilins. These findings reveal a strategy to generate isoform-selective small-molecule cyclophilin modulators, advancing their suitability as targets for biological investigation and therapeutic development.DNA-templated compound library screening and structure-guided hit optimization resulted in the identification of selective macrocyclic inhibitors of cyclophilin isoforms CypD and CypE.

Consumer preference for environmentally-friendly beverage packaging was investigated. Consumers are willing to pay a premium for post-consumer recycled materials. Environmental information and green identity labels have synergistic effect on consumer willingness to pay. Product unit size seems irrelevant in most consumer decisions. This study examined whether urban Chinese consumers with stronger environmental values have higher valuations for plastic beverage bottles that are made of post-consumer recycled material (rPET) or that come in large sizes that use plastic more efficiently. It also assesses the effectiveness of environmental information provision and green identity labeling in increasing consumer willingness to pay for environmentally-friendly packaging. The results suggest that urban Chinese consumers are willing to pay a premium for rPET bottles, indicating that there is a potential market for rPET food and beverage packaging in China that calls for manufacturing guidelines, safety standards, or regulations. Providing environmental information and attaching green identity labels increases consumer valuations of rPET bottles, with their joint use exerting the largest effect. Pro-environmental consumers are more responsive to environmental information and green identity labeling and thus are willing to pay a higher premium for rPET bottles. However, in terms of choosing large bottles as a means to reduce plastic use in product packaging, consumers were found to be indifferent about plastic bottle sizes even after receiving environmental information. It is suggested that the inconvenience of carrying or storing large bottles might have offset their perceived environmental benefits.

The advent of cheap smartphones in rural areas across the globe presents an opportunity to change the mode with which researchers engage hard-to-reach populations. In particular, smartphones allow researchers to connect with respondents more frequently than standard household surveys, opening a new window into important short-term variability in key measures of household and community wellbeing. In this paper, we present early results from a pilot study in rural Bangladesh using a 'microtasks for micropayments' model to collect a range of community and household living standards data using Android smartphones. We find that more frequent task repetition with shorter recall periods leads to more inclusive reporting, improved capture of intra-seasonal variability, and earlier signals of events such as illness. Payments in the form of mobile talk time and data provide a positive development externality in the form of expanded access to mobile internet and social networks. Taken to scale, programs such as this have potential to transform data collection in rural areas, providing near-real-time windows into the development of markets, the spread of illnesses, or the diffusion of ideas and innovations.