Analyzing Risk and Performance Using the Multi-Factor Concept

In this paper, we present a new model to analyze the risk and the expected level of firm performance. This model is based on the multi-factor approach to risk, in which unexpected performance is explained through sensitivities to unexpected changes of risk factors. Instead of using the multi-factor approach for the analysis of security portfolios, it is used to analyze performance measures of firms. In this paper the multi-factor approach is not only used to analyze risk, but also to analyze the expected level of performance. Furthermore, it is analyzed how instruments, as for instance projects, can be used to change the risk and the expected level of performance. An illustrative application in the field of finance is presented, although the model can also be applied in other areas

Adenine versus Guanine Quartets in Aqueous Solution. Dispersion-Corrected DFT Study on the Differences in π-Stacking and Hydrogen-Bonding Behavior

We have investigated the performance of the dispersion-corrected density functionals (BLYP-D, BP86-D and PBE-D) and the widely used B3LYP functional for describing the hydrogen bonds and the stacking interactions in DNA base dimers. For the gas-phase situation, the bonding energies have been compared to the best ab initio results available in the literature. All dispersion-corrected functionals reproduce well the ab initio results, whereas B3LYP fails completely for the stacked systems. The use of the proper functional leads us to find minima for the adenine quartets, which are energetically and structurally very different from the

Kinase and channel activity of TRPM6 are co-ordinated by a dimerization motif and pocket interaction

Contains fulltext : 138516.pdf (publisher's version ) (Open Access)Mutations in the gene that encodes the atypical channel-kinase TRPM6 (transient receptor potential melastatin 6) cause HSH (hypomagnesaemia with secondary hypocalcaemia), a disorder characterized by defective intestinal Mg2+ transport and impaired renal Mg2+ reabsorption. TRPM6, together with its homologue TRPM7, are unique proteins as they combine an ion channel domain with a C-terminally fused protein kinase domain. How TRPM6 channel and kinase activity are linked is unknown. Previous structural analysis revealed that TRPM7 possesses a non-catalytic dimerization motif preceding the kinase domain. This interacts with a dimerization pocket lying within the kinase domain. In the present study, we provide evidence that the dimerization motif in TRPM6 plays a critical role in regulating kinase activity as well as ion channel activity. We identify mutations within the TRPM6 dimerization motif (Leu1718 and Leu1721) or dimerization pocket (L1743A, Q1832K, A1836N, L1840A and L1919Q) that abolish dimerization and establish that these mutations inhibit protein kinase activity. We also demonstrate that kinase activity of a dimerization motif mutant can be restored by addition of a peptide encompassing the dimerization motif. Moreover, we observe that mutations that disrupt the dimerization motif and dimerization pocket interaction greatly diminish TRPM6 ion channel activity, in a manner that is independent of kinase activity. Finally, we analyse the impact on kinase activity of ten disease-causing missense mutations that lie outwith the protein kinase domain of TRPM6. This revealed that one mutation lying nearby the dimerization motif (S1754N), found previously to inhibit channel activity, abolished kinase activity. These results provide the first evidence that there is structural co-ordination between channel and kinase activity, which is mediated by the dimerization motif and pocket interaction. We discuss that modulation of this interaction could comprise a major regulatory mechanism by which TRPM6 function is controlled

Decomposition analysis of per capita emissions : a tool for assessing consumption changes and technology changes within scenarios

Recent studies show that behaviour changes can provide an essential contribution to achieving the Paris climate targets. Existing climate change mitigation scenarios primarily focus on technological change and underrepresent the possible contribution of behaviour change. This paper presents and applies a methodology to decompose the factors contributing to changes in per capita emissions in scenarios. With this approach, we determine the relative contribution to total emissions from changes in activity, the way activities are carried out, the intensity of activities, as well as fuel choice. The decomposition tool breaks down per capita emissions loosely following the Kaya Identity, allowing a comparison between the contributions of technology and consumption changes among regions and between various scenarios. We illustrate the use of the tool by applying it to three previously-published scenarios; a baseline scenario, a scenario with a selection of behaviour changes, and a 2 degrees C scenario with the same selection of behaviour changes. Within these scenarios, we explore the contribution of technology and consumption changes to total emission changes in the transport and residential sector, for a selection of both developed and developing regions. In doing so, the tool helps identify where specifically (i.e. via consumption or technology factors) different measures play a role in mitigating emissions and expose opportunities for improved representation of behaviour changes in integrated assessment models. This research shows the value of the decomposition tool and how the approach could be flexibly replicated for different global models based on available variables and aims. The application of the tool to previously-published scenarios shows substantial differences in consumption and technology changes from CO2 price and behaviour changes, in transport and residential per capita emissions and between developing and developed regions. Furthermore, the tool's application can highlight opportunities for future scenario development of a more nuanced and heterogeneous representation of behaviour and lifestyle changes in global models.Peer reviewe

New damage curves and multimodel analysis suggest lower optimal temperature

Economic analyses of global climate change have been criticized for their poor representation of climate change damages. Here we develop and apply aggregate damage functions in three economic Integrated Assessment Models (IAMs) with different degrees of complexity. The damage functions encompass a wide but still incomplete set of climate change impacts based on physical impact models. We show that with medium estimates for damage functions, global damages are in the range of 10% to 12% of GDP by 2100 in a baseline scenario with 3 °C temperature change, and about 2% in a well-below 2 °C scenario. These damages are much higher than previous estimates in benefit-cost studies, resulting in optimal temperatures below 2 °C with central estimates of damages and discount rates. Moreover, we find a benefit-cost ratio of 1.5 to 3.9, even without considering damages that could not be accounted for, such as biodiversity losses, health and tipping points

Experimental mitochondria-targeted DNA methylation identifies GpC methylation, not CpG methylation, as potential regulator of mitochondrial gene expression

Like the nucleus, mitochondria contain their own DNA and recent reports provide accumulating evidence that also the mitochondrial DNA (mtDNA) is subjective to DNA methylation. This evidence includes the demonstration of mitochondria-localised DNA methyltransferases and demethylases, and the detection of mtDNA methylation as well as hydroxymethylation. Importantly, differential mtDNA methylation has been linked to aging and diseases, including cancer and diabetes. However, functionality of mtDNA methylation has not been demonstrated. Therefore, we targeted DNA methylating enzymes (modifying cytosine in the CpG or GpC context) to the mtDNA. Unexpectedly, mtDNA gene expression remained unchanged upon induction of CpG mtDNA methylation, whereas induction of C-methylation in the GpC context decreased mtDNA gene expression. Intriguingly, in the latter case, the three mtDNA promoters were differentially affected in each cell line, while cellular function seemed undisturbed. In conclusion, this is the first study which directly addresses the potential functionality of mtDNA methylation. Giving the important role of mitochondria in health and disease, unravelling the impact of mtDNA methylation adds to our understanding of the role of mitochondria in physiological and pathophysiological processes

Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure

Not just differential gene expression but also differential gene regulation in immune cells account for individual differences in the immune response. Authors show here by single-cell RNA-sequencing of peripheral blood mononuclear cells from a large cohort of genetically diverse individuals that gene expression and regulatory changes in these cells depend on the context of and interactions between cell types, genetics, type of pathogen and time after exposure. The host's gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host's genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease

Labour productivity and profitability in the Dutch flower trade

This paper makes an attempt to illustrate the use of econometric models as frame of reference for diagnosing small firm performance. For this purpose, two models are developed explaining differences in labour productivity and profitability among Dutch flower exporters. In addition, we show how these models can be used for inter-firm performance comparisons