Default Risk Premia and Asset Returns

We identify a common default risk premia (DRP) factor in the risk-adjusted excess returns on pure default-contingent claims. Asset pricing tests using almost 50 corporate bond portfolios sorted on rating, maturity or industry suggest that the DRP factor is priced in the corporate bond market. For index put option portfolios sorted on maturity and moneyness, both average returns and DRP beta estimates become more negative with decreasing time to maturity. There is little to no evidence of the DRP factor being priced in equity markets. Most of the variation in DRP is explained by the portion DRP^{JtD} due to common jump-to-default risk premia. A theoretical framework where DRP^{JtD} is part of the pricing kernel supports our empirical findings.

Direct activation of NADPH oxidase 2 by 2-deoxyribose-1-phosphate triggers nuclear factor kappa B-dependent angiogenesis.

AbstractAims: Deoxyribose-1-phosphate (dRP) is a proangiogenic paracrine stimulus released by cancer cells, platelets, and macrophages and acting on endothelial cells. The objective of this study was to clarify how dRP stimulates angiogenic responses in human endothelial cells.Results: Live cell imaging, electron paramagnetic resonance, pull-down of dRP-interacting proteins, followed by immunoblotting, gene silencing of different NADPH oxidases (NOXs), and their regulatory cosubunits by small interfering RNA (siRNA) transfection, and experiments with inhibitors of the sugar transporter glucose transporter 1 (GLUT1) were utilized to demonstrate that dRP acts intracellularly by directly activating the endothelial NOX2 complex, but not NOX4. Increased reactive oxygen species generation in response to NOX2 activity leads to redox-dependent activation of the transcription factor nuclear factor kappa B (NF-κB), which, in turn, induces vascular endothelial growth factor receptor 2 (VEGFR2) upregulation. Using endothelial tube formation assays, gene silencing by siRNA, and antibody-based receptor inhibition, we demonstrate that the activation of NF-κB and VEGFR2 is necessary for the angiogenic responses elicited by dRP. The upregulation of VEGFR2 and NOX2-dependent stimulation of angiogenesis by dRP were confirmed in excisional wound and Matrigel plug vascularization assays in vivo using NOX2−/− mice.Innovation: For the first time, we demonstrate that dRP acts intracellularly and stimulates superoxide anion generation by direct binding and activation of the NOX2 enzymatic complex.Conclusions: This study describes a novel molecular mechanism underlying the proangiogenic activity of dRP, which involves the sequential activation of NOX2 and NF-κB and upregulation of VEGFR2. Antioxid. Redox Signal. 28, 110–130

In Silico Derivation of HLA-Specific Alloreactivity Potential from Whole Exome Sequencing of Stem Cell Transplant Donors and Recipients: Understanding the Quantitative Immuno-biology of Allogeneic Transplantation

Donor T cell mediated graft vs. host effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the HLA in each donor-recipient pair (DRP) undergoing stem cell transplantation (SCT). Whole exome sequencing has demonstrated extensive nucleotide sequence variation in HLA-matched DRP. Non-synonymous single nucleotide polymorphisms (nsSNPs) in the GVH direction (polymorphisms present in recipient and absent in donor) were identified in 4 HLA-matched related and 5 unrelated DRP. The nucleotide sequence flanking each SNP was obtained utilizing the ANNOVAR software package. All possible nonameric-peptides encoded by the non-synonymous SNP were then interrogated in-silico for their likelihood to be presented by the HLA class I molecules in individual DRP, using the Immune-Epitope Database (IEDB) SMM algorithm. The IEDB-SMM algorithm predicted a median 18,396 peptides/DRP which bound HLA with an IC50 of <500nM, and 2254 peptides/DRP with an IC50 of <50nM. Unrelated donors generally had higher numbers of peptides presented by the HLA. A similarly large library of presented peptides was identified when the data was interrogated using the Net MHCPan algorithm. These peptides were uniformly distributed in the various organ systems. The bioinformatic algorithm presented here demonstrates that there may be a high level of minor histocompatibility antigen variation in HLA-matched individuals, constituting an HLA-specific alloreactivity potential. These data provide a possible explanation for how relatively minor adjustments in GVHD prophylaxis yield relatively similar outcomes in HLA matched and mismatched SCT recipients.Comment: Abstract: 235, Words: 6422, Figures: 7, Tables: 3, Supplementary figures: 2, Supplementary tables:

Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins

Objective—We explored mechanisms that alter mitochondrial structure and function in pulmonary endothelial cells (PEC) function after hyperoxia. Approach and Results—Mitochondrial structures of PECs exposed to hyperoxia or normoxia were visualized and mitochondrial fragmentation quantified. Expression of pro-fission or fusion proteins or autophagy-related proteins were assessed by Western blot. Mitochondrial oxidative state was determined using mito-roGFP. Tetramethylrhodamine methyl ester estimated mitochondrial polarization in treatment groups. The role of mitochondrially derived reactive oxygen species in mt-fragmentation was investigated with mito-TEMPOL and mitochondrial DNA (mtDNA) damage studied by using ENDO III (mt-tat-endonuclease III), a protein that repairs mDNA damage. Drp-1 (dynamin-related protein 1) was overexpressed or silenced to test the role of this protein in cell survival or transwell resistance. Hyperoxia increased fragmentation of PEC mitochondria in a time-dependent manner through 48 hours of exposure. Hyperoxic PECs exhibited increased phosphorylation of Drp-1 (serine 616), decreases in Mfn1 (mitofusion protein 1), but increases in OPA-1 (optic atrophy 1). Pro-autophagy proteins p62 (LC3 adapter–binding protein SQSTM1/p62), PINK-1 (PTEN-induced putative kinase 1), and LC3B (microtubule-associated protein 1A/1B-light chain 3) were increased. Returning cells to normoxia for 24 hours reversed the increased mt-fragmentation and changes in expression of pro-fission proteins. Hyperoxia-induced changes in mitochondrial structure or cell survival were mitigated by antioxidants mito-TEMPOL, Drp-1 silencing, or inhibition or protection by the mitochondrial endonuclease ENDO III. Hyperoxia induced oxidation and mitochondrial depolarization and impaired transwell resistance. Decrease in resistance was mitigated by mito-TEMPOL or ENDO III and reproduced by overexpression of Drp-1. Conclusions—Because hyperoxia evoked mt-fragmentation, cell survival and transwell resistance are prevented by ENDO III and mito-TEMPOL and Drp-1 silencing, and these data link hyperoxia-induced mt-DNA damage, Drp-1 expression, mt-fragmentation, and PEC dysfunction

Environmental aspects of soil phosphorus testing

peer-reviewedSoil phosphorus testing in Ireland uses Morgan’s reagent from samples taken to 10 cm depth for agronomic recommendations. However, its suitability as an environmental indicator has been questioned in terms of sample depth and extraction solution. Seven grassland sites were sampled to depths of 2, 5 and 10 cm and extracted for Morgan’s P, the standard agronomic test, as well as iron-oxide impregnated paper strip P (FeOP), calcium chloride extractable P (CaCl2-P) and water soluble P (WSP), all proposed as environmental soil tests. Extractable soil P decreased with increasing sample depth, as did variances in each test, such that, 2 cm samples had highest concentrations and variances. The current standard sample depth (10 cm) was linearly related to corresponding data from samples taken to 2 and 5 cm, indicating that surface soil P can be consistently estimated from the current standard depth. When soil tests were compared with dissolved reactive P (DRP) in overland flow collected from two field sites, certain soil tests were better indicators of P loss than others. The relative difference in Morgan’s P values at the standard sample depth (10 cm) was reflected in the relative difference in P loss between the two sites. Average values of DRP collected from two sites ranged from 0.032 to 0.067 mg/l at the low P site and 0.261 to 0.620 at the high P site. Average DRP values from the high P site and maximum DRP values from the low P site were simulated using water-soluble P extraction at water to soil ratios 5 to 250 l/kg. In this study, Morgan’s P to 10 cm gave a good indication of the relative difference in DRP loss between the two sites

Factors affecting phosphate concentrations in surface and subsurface runoff from steep East Coast hill country : a thesis presented in partial fulfilment of the requirements for the degree of Masters of Applied Science, Department of Soil Science, Massey University

Eutrophication is a problem receiving much attention within New Zealand and throughout the rest of the world. Problems associated with eutrophication cause major financial, aesthetic and recreational costs to not only commercial and recreational water users but to society in general. The major nutrient of concern in relation to eutrophication is phosphorus (P) as it is often considered to be the limiting factor. The two major areas from which P enters waterways are point sources and non-point sources. Point sources are relatively easy to identify and quantify. Non-point sources however, are less easy to quantify due to the size of areas from which P is sourced and the number of varying factors which can affect the amount of P which is lost to water-ways. This study investigated P concentrations in surface runoff and subsurface flow from steep east coast hill country. Factors studied included aspect, soil P status, season and fertiliser addition. The study was carried out on grazed pasture farmlets, in which there were 'High P' and 'Low P' fertiliser regimes. Each regime had north and south facing aspects. Four sites were used in the study. High P North (HPN), High P South (HPS), Low P North (LPN) and Low P South (LPS). Simulated rainfall was applied to the sites and surface runoff samples were collected and analysed for dissolved reactive phosphate concentration (DRP). Superphosphate fertiliser was then applied at 20 kg P ha-1 to each site and the runoff procedure was repeated 7 weeks and 14 weeks the lower P soil test values on the south-facing slopes. A water extractable P test provided a better correlation with runoff DRP concentrations for individual runoff events than the Olsen P test. Both tests however, provided poor correlations when all of the Runs were combined. This was due largely to the large increase in DRP concentrations in surface runoff in Run 3 with no corresponding increase in soil tests. There was no apparent relationship between fertiliser regime i.e. soil P status, and the concentration of DRP in subsurface runoff. In Run 3 however, there was a marked increase in subsurface DRP concentration for both sites which was consistent with the surface runoff results and supported the theory of soil moisture playing a major role in determining the DRP concentration in water. The study suggests that the greatest risk of P loss from soil to surface waters will be from northerly aspects with high fertiliser histories during the summer months when soil moisture levels are low

New Modularity of DAP-Kinases: Alternative Splicing of the DRP-1 Gene Produces a ZIPk-Like Isoform

DRP-1 and ZIPk are two members of the Death Associated Protein Ser/Thr Kinase (DAP-kinase) family, which function in different settings of cell death including autophagy. DAP kinases are very similar in their catalytic domains but differ substantially in their extra-catalytic domains. This difference is crucial for the significantly different modes of regulation and function among DAP kinases. Here we report the identification of a novel alternatively spliced kinase isoform of the DRP-1 gene, termed DRP-1β. The alternative splicing event replaces the whole extra catalytic domain of DRP-1 with a single coding exon that is closely related to the sequence of the extra catalytic domain of ZIPk. As a consequence, DRP-1β lacks the calmodulin regulatory domain of DRP-1, and instead contains a leucine zipper-like motif similar to the protein binding region of ZIPk. Several functional assays proved that this new isoform retained the biochemical and cellular properties that are common to DRP-1 and ZIPk, including myosin light chain phosphorylation, and activation of membrane blebbing and autophagy. In addition, DRP-1β also acquired binding to the ATF4 transcription factor, a feature characteristic of ZIPk but not DRP-1. Thus, a splicing event of the DRP-1 produces a ZIPk like isoform. DRP-1β is highly conserved in evolution, present in all known vertebrate DRP-1 loci. We detected the corresponding mRNA and protein in embryonic mouse brains and in human embryonic stem cells thus confirming the in vivo utilization of this isoform. The discovery of module conservation within the DAPk family members illustrates a parsimonious way to increase the functional complexity within protein families. It also provides crucial data for modeling the expansion and evolution of DAP kinase proteins within vertebrates, suggesting that DRP-1 and ZIPk most likely evolved from their ancient ancestor gene DAPk by two gene duplication events that occurred close to the emergence of vertebrates