Association of Systemic Collagen Type IV Formation with Survival among Patients Undergoing Hemodialysis

Objective

The 7S domain of collagen type IV (P4NP_7S) assessed in plasma represents systemic collagen type IV formation. The objective of the study was to investigate the association of systemic collagen type IV formation with survival among patients undergoing hemodialysis.

Methods

We performed an observational cohort study of 371 hemodialysis patients. Plasma P4NP_7S was analyzed using a specific enzyme-linked immunosorbent assay detecting the amino-terminal propeptide of type IV procollagen. Association between categories of plasma P4NP_7S concentrations and survival was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model.

Results

For hemodialysis patients in the highest category of systemic collagen type IV formation, i.e. plasma P4NP_7S concentrations more than 775 pg/L, an increased risk for death was observed (highest P4NP_7S category vs all other categories, hazard ratio, 1.934; 95% confidence interval, 1.139 to 3.285). Survival analysis showed an increased risk of death in the highest P4NP_7S category compared to the other categories (Chi square 6.903; P = 0.032). Median survival was only 105 days in the highest P4NP_7S category whereas it was 629 days in the medium category, and 905 days in the lowest category. Multivariable-adjusted Cox regression showed increased odds for death with higher age and higher P4NP_7S categories. Systemic collagen type IV formation was associated with plasma concentrations of the collagen IV degradation product C4M (Spearman r = 0.764; P<0.0001) confirming extracellular matrix turnover.

Conclusion

Among hemodialysis patients elevated systemic collagen type IV formation suggesting accelerating systemic fibrosis was associated with increased risk of death.     

Inhibiting AKT Phosphorylation Employing Non-Cytotoxic Anthraquinones Ameliorates TH2 Mediated Allergic Airways Disease and Rhinovirus Exacerbation

Background

Severe asthma is associated with T helper (T_H) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.

Objective

To determine the anti-inflammatory potential of anthraquinones in-vivo.

Methods

BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.

Results

Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of T_H2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.

Conclusion

Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT.     

Patterns of time since last meal revealed by sparse PCA in an observational LC–MS based metabolomics study

In metabolomics studies, liquid chromatography mass spectrometry (LC–MS) provides comprehensive information on biological samples. However, extraction of few relevant metabolites from this large and complex data is cumbersome. To resolve this issue, we have employed sparse principal component analysis (SPCA) to capture the underlying patterns and select relevant metabolites from LC–MS plasma profiles. The study involves a small pilot cohort with 270 subjects where each subject’s time since last meal (TSLM) has been recorded prior to plasma sampling. Our results have demonstrated that both PCA and SPCA can capture the TSLM patterns. Nevertheless, SPCA provides more easily interpretable loadings in terms of selection of relevant metabolites, which are identified as amino acids and lyso-lipids. This study demonstrates the utility of SPCA as a pattern recognition and variable selection tool in metabolomics. Furthermore, amino acids and lyso-lipids are determined as dominating compounds in response to TSLM.     

Sympatric Breeding Auks Shift between Dietary and Spatial Resource Partitioning across the Annual Cycle

When species competing for the same resources coexist, some segregation in the way they utilize those resources is expected. However, little is known about how closely related sympatric breeding species segregate outside the breeding season. We investigated the annual segregation of three closely related seabirds (razorbill Alca torda , common guillemot Uria aalge and Brünnich’s guillemot U . lomvia ) breeding at the same colony in Southwest Greenland. By combining GPS and geolocation (GLS) tracking with dive depth and stable isotope analyses, we compared spatial and dietary resource partitioning. During the breeding season, we found the three species to segregate in diet and/or dive depth, but less in foraging area. During both the post-breeding and pre-breeding periods, the three species had an increased overlap in diet, but were dispersed over a larger spatial scale. Dive depths were similar across the annual cycle, suggesting morphological adaptations fixed by evolution. Prey choice, on the other hand, seemed much more flexible and therefore more likely to be affected by the immediate presence of potential competitors.     

Homeobox Genes in the Rodent Pineal Gland: Roles in Development and Phenotype Maintenance

The pineal gland is a neuroendocrine gland responsible for nocturnal synthesis of melatonin. During early development of the rodent pineal gland from the roof of the diencephalon, homeobox genes of the orthodenticle homeobox (Otx)- and paired box (Pax)-families are expressed and are essential for normal pineal development consistent with the well-established role that homeobox genes play in developmental processes. However, the pineal gland appears to be unusual because strong homeobox gene expression persists in the pineal gland of the adult brain. Accordingly, in addition to developmental functions, homeobox genes appear to be key regulators in postnatal phenotype maintenance in this tissue. In this paper, we review ontogenetic and phylogenetic aspects of pineal development and recent progress in understanding the involvement of homebox genes in rodent pineal development and adult function. A working model is proposed for understanding the sequential action of homeobox genes in controlling development and mature circadian function of the mammalian pinealocyte based on knowledge from detailed developmental and daily gene expression analyses in rats, the pineal phenotypes of homebox gene-deficient mice and studies on development of the retinal photoreceptor; the pinealocyte and retinal photoreceptor share features not seen in other tissues and are likely to have evolved from the same ancestral photodetector cell.     

The Perivascular Phagocyte of the Mouse Pineal Gland: an Antigen‐Presenting Cell

The perivascular space of the rat pineal gland is known to contain phagocytic cells that are immunoreactive for leukocyte antigens, and thus they appear to belong to the macrophage/microglial cell line. These cells also contain MHC class II proteins. We investigated this cell type in the pineal gland of mice. Actively phagocytosing cells with a prominent lysosomal system were found in the pericapillary spaces of the mouse pineal gland following intravenous injection of horseradish peroxidase. The cells also exhibited strong acid phosphatase activity. Perivascular cells were immunopositive for MHC class II protein and for CD68, a marker of monocytes/phagocytes. This study verifies that perivascular phagocytes with antigen‐presenting properties are present in the mouse pineal gland.     

NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes, HLA-DR, HLA-DP and HLA-DQ

Major histocompatibility complex class II (MHCII) molecules play an important role in cell-mediated immunity. They present specific peptides derived from endosomal proteins for recognition by T helper cells. The identification of peptides that bind to MHCII molecules is therefore of great importance for understanding the nature of immune responses and identifying T cell epitopes for the design of new vaccines and immunotherapies. Given the large number of MHC variants, and the costly experimental procedures needed to evaluate individual peptide–MHC interactions, computational predictions have become particularly attractive as first-line methods in epitope discovery. However, only a few so-called pan-specific prediction methods capable of predicting binding to any MHC molecule with known protein sequence are currently available, and all of them are limited to HLA-DR. Here, we present the first pan-specific method capable of predicting peptide binding to any HLA class II molecule with a defined protein sequence. The method employs a strategy common for HLA-DR, HLA-DP and HLA-DQ molecules to define the peptide-binding MHC environment in terms of a pseudo sequence. This strategy allows the inclusion of new molecules even from other species. The method was evaluated in several benchmarks and demonstrates a significant improvement over molecule-specific methods as well as the ability to predict peptide binding of previously uncharacterised MHCII molecules. To the best of our knowledge, the NetMHCIIpan-3.0 method is the first pan-specific predictor covering all HLA class II molecules with known sequences including HLA-DR, HLA-DP, and HLA-DQ. The NetMHCpan-3.0 method is available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0.     

Anther extrusion and plant height are associated with Type I resistance to Fusarium head blight in bread wheat line ‘Shanghai-3/Catbird’

Fusarium head blight (FHB) is a destructive wheat disease of global importance. Resistance breeding depends heavily on the Fhb1 gene. The CIMMYT line Shanghai-3/Catbird (SHA3/CBRD) is a promising source without this gene. A recombinant inbred line (RIL) population from the cross of SHA3/CBRD with the German spring wheat cv. Naxos was evaluated for FHB resistance and related traits in field trials using spray and spawn inoculation in Norway and point inoculation in China. After spray and spawn inoculation, FHB severities were negatively correlated with both anther extrusion (AE) and plant height (PH). The QTL analysis showed that the Rht-B1b dwarfing allele co-localized with a QTL for low AE and increased susceptibility after spawn and spray inoculation. In general, SHA3/CBRD contributed most of the favorable alleles for resistance to severity after spray and spawn inoculation, while Naxos contributed more favorable alleles for reduction in FDK and DON content and resistance to severity after point inoculation. SHA3/CBRD contributed a major resistance QTL close to the centromere on 2DLc affecting FHB severity and DON after all inoculation methods. This QTL was also associated with AE and PH, with high AE and tall alleles contributed by SHA3/CBRD. Several QTL for AE and PH were detected, and low AE or reduced PH was always associated with increased susceptibility after spawn and spray inoculation. Most of the other minor FHB resistance QTL from SHA3/CBRD were associated with AE or PH, while the QTL from Naxos were mostly not. After point inoculation, no other QTL for FHB traits was associated with AE or PH, except the 2DLc QTL which was common across all inoculation methods. Marker-assisted selection based on the 2DLc QTL from SHA3/CBRD combined with phenotypic selection for AE is recommended for resistance breeding based on this valuable source of resistance.