What drives diesel fuel prices?

Historically, gasoline has commanded a premium over diesel, but that changed in mid-to-late 2007, when diesel rose above gasoline. In 2007 and 2008, however, gasoline traded higher than diesel only 21.1 percent of the time. This deviation from historic norms raises an interesting question--what drives diesel prices? As with virtually all petroleum-derived products, the story begins with oil prices. Seasonal patterns also play a significant role. Demand for a range of oil-based products changes with the weather, and prices fluctuate as refiners adjust their output mix. Government regulations are another source of price variability. Earlier this decade, new standards aimed at reducing diesel fuel's sulfur content required further processing that increased refinery costs and prices for consumers. Finally, short-term changes in supply and demand--including imports--factor into pricing on a day-to-day basis. Our model suggests that spot diesel should rise 25 cents a gallon over the next six months and 41 cents a gallon over the next 18 months.Petroleum products - Prices ; Petroleum industry and trade ; Energy consumption ; Econometric models

G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.

Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide.Research in the S.P.J. laboratory is funded by Cancer Research UK Program Grant C6/A18796 and the European Research Council (DDREAM) grant 268536-DDRREAM. Core infrastructure funding was provided by Cancer Research UK Grant C6946/ A14492 and Wellcome Trust Grant WT092096. S.P.J. receives a salary from the University of Cambridge, supplemented by Cancer Research UK. P.A. was financially supported by CRUK grant C6/ A11224 and ERC grant DDREAM.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.canlet.2016.07.00

Ubiquitin regulates dissociation of DNA repair factors from chromatin.

This is the final version of the article. It first appeared from Impact Journals via http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=441

A flow cytometry-based method to simplify the analysis and quantification of protein association to chromatin in mammalian cells.

Protein accumulation on chromatin has traditionally been studied using immunofluorescence microscopy or biochemical cellular fractionation followed by western immunoblot analysis. As a way to improve the reproducibility of this kind of analysis, to make it easier to quantify and to allow a streamlined application in high-throughput screens, we recently combined a classical immunofluorescence microscopy detection technique with flow cytometry. In addition to the features described above, and by combining it with detection of both DNA content and DNA replication, this method allows unequivocal and direct assignment of cell cycle distribution of protein association to chromatin without the need for cell culture synchronization. Furthermore, it is relatively quick (takes no more than a working day from sample collection to quantification), requires less starting material compared with standard biochemical fractionation methods and overcomes the need for flat, adherent cell types that are required for immunofluorescence microscopy.Research in our laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A11224), the European Research Council and the European Community Seventh Framework Programme (grant agreement no. HEALTH¬‐F2¬‐2010¬‐259893 (DDResponse)). Core funding is provided by Cancer Research UK (C6946/A14492) and the Wellcome Trust (WT092096). J.V.F. is funded by Cancer Research UK programme grant C6/A11224 and the Ataxia Telangiectasia Society. S.P.J. receives his salary from the University of Cambridge, supplemented by CRUK.This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/nprot.2015.06

Ubiquitylation, neddylation and the DNA damage response.

Failure of accurate DNA damage sensing and repair mechanisms manifests as a variety of human diseases, including neurodegenerative disorders, immunodeficiency, infertility and cancer. The accuracy and efficiency of DNA damage detection and repair, collectively termed the DNA damage response (DDR), requires the recruitment and subsequent post-translational modification (PTM) of a complex network of proteins. Ubiquitin and the ubiquitin-like protein (UBL) SUMO have established roles in regulating the cellular response to DNA double-strand breaks (DSBs). A role for other UBLs, such as NEDD8, is also now emerging. This article provides an overview of the DDR, discusses our current understanding of the process and function of PTM by ubiquitin and NEDD8, and reviews the literature surrounding the role of ubiquitylation and neddylation in DNA repair processes, focusing particularly on DNA DSB repair.J.S.B. is funded by the Wellcome Trust Clinical Fellowship (grant no. 094794/Z/10/Z). Research in the Jackson laboratory is funded by Cancer Research UK programme grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDResponse). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge UK, supplemented by CRUK.This is the final published version. It first appeared at http://rsob.royalsocietypublishing.org/content/5/4/150018

Phospho-dependent interactions between NBS1 and MDC1 mediate chromatin retention of the MRN complex at sites of DNA damage

Mammalian cells respond to DNA double-strand breaks (DSBs) by recruiting DNA repair and cell-cycle checkpoint proteins to such sites. Central to these DNA damage response (DDR) events is the DNA damage mediator protein MDC1. MDC1 interacts with several DDR proteins, including the MRE11–RAD50–NBS1 (MRN) complex. Here, we show that MDC1 is phosphorylated on a cluster of conserved repeat motifs by casein kinase 2 (CK2). Moreover, we establish that this phosphorylation of MDC1 promotes direct, phosphorylation-dependent interactions with NBS1 in a manner that requires the closely apposed FHA and twin BRCT domains in the amino terminus of NBS1. Finally, we show that these CK2-targeted motifs in MDC1 are required to mediate NBS1 association with chromatin-flanking sites of unrepaired DSBs. These findings provide a molecular explanation for the MDC1–MRN interaction and yield insights into how MDC1 coordinates the focal assembly and activation of several DDR factors in response to DNA damage

DNA damage signaling in response to double-strand breaks during mitosis

Dividing cells can sense DNA damage and initiate a primary response, but repair isn’t completed until the cells enter G1

When two is not enough: a CtIP tetramer is required for DNA repair by Homologous Recombination.

Homologous recombination (HR) is central to the repair of double-strand DNA breaks that occur in S/G2 phases of the cell cycle. HR relies on the CtIP protein (Ctp1 in fission yeast, Sae2 in budding yeast) for resection of DNA ends, a key step in generating the 3'-DNA overhangs that are required for the HR strand-exchange reaction. Although much has been learned about the biological importance of CtIP in DNA repair, our mechanistic insight into its molecular functions remains incomplete. It has been recently discovered that CtIP and Ctp1 share a conserved tetrameric architecture that is mediated by their N-terminal domains and is critical for their function in HR. The specific arrangement of protein chains in the CtIP/Ctp1 tetramer indicates that an ability to bridge DNA ends might be an important feature of CtIP/Ctp1 function, establishing an intriguing similarity with the known ability of the MRE11-RAD50-NBS1 complex to link DNA ends. Although the exact mechanism of action remains to be elucidated, the remarkable evolutionary conservation of CtIP/Ctp1 tetramerisation clearly points to its crucial role in HR.This is the author accepted manuscript. The final version is available from Taylor & Francis via http://dx.doi.org/10.1080/19491034.2015.1086050