Evidence for a “Pathogenic Triumvirate” in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Autosomal recessive polycystic kidney disease (ARPKD) is a severe monogenic disorder that occurs due to mutations in the PKHD1 gene. Congenital hepatic fibrosis (CHF) associated with ARPKD is characterized by the presence of hepatic cysts derived from dilated bile ducts and a robust, pericystic fibrosis. Cyst growth, due to cyst wall epithelial cell hyperproliferation and fluid secretion, is thought to be the driving force behind disease progression. Liver fibrosis is a wound healing response in which collagen accumulates in the liver due to an imbalance between extracellular matrix synthesis and degradation. Whereas both hyperproliferation and pericystic fibrosis are hallmarks of CHF/ARPKD, whether or not these two processes influence one another remains unclear. Additionally, recent studies demonstrate that inflammation is a common feature of CHF/ARPKD. Therefore, we propose a “pathogenic triumvirate” consisting of hyperproliferation of cyst wall growth, pericystic fibrosis, and inflammation which drives CHF/ARPKD progression. This review will summarize what is known regarding the mechanisms of cyst growth, fibrosis, and inflammation in CHF/ARPKD. Further, we will discuss the potential advantage of identifying a core pathogenic feature in CHF/ARPKD to aid in the development of novel therapeutic approaches. If a core pathogenic feature does not exist, then developing multimodality therapeutic approaches to target each member of the “pathogenic triumvirate” individually may be a better strategy to manage this debilitating disease

Delayed development of systemic immunity in preterm pigs as a model for preterm infants

Preterm neonates are highly sensitive to systemic infections in early life but little is known about systemic immune development following preterm birth. We hypothesized that preterm neonates have immature systemic immunity with distinct developmental trajectory for the first several weeks of life, relative to those born at near-term or term. Using pigs as a model, we characterized blood leukocyte subsets, antimicrobial activities and TLR-mediated cytokine production during the first weeks after preterm birth. Relative to near-term and term pigs, newborn preterm pigs had low blood leukocyte counts, poor neutrophil phagocytic rate, and limited cytokine responses to TLR1/2/5/7/9 and NOD1/2 agonists. The preterm systemic responses remained immature during the first postnatal week, but thereafter showed increased blood leukocyte numbers, NK cell proportion, neutrophil phagocytic rate and TLR2-mediated IL-6 and TNF-α production. These immune parameters remained different between preterm and near-term pigs at 2–3 weeks, even when adjusted for post-conceptional age. Our data suggest that systemic immunity follows a distinct developmental trajectory following preterm birth that may be influenced by postnatal age, complications of prematurity and environmental factors. Consequently, the immediate postnatal period may represent a window of opportunity to improve innate immunity in preterm neonates by medical, antimicrobial or dietary interventions

A complete DNA sequence map of the ovine Major Histocompatibility Complex

<p>Abstract</p> <p>Background</p> <p>The ovine Major Histocompatibility Complex (MHC) harbors clusters of genes involved in overall resistance/susceptibility of an animal to infectious pathogens. However, only a limited number of ovine MHC genes have been identified and no adequate sequence information is available, as compared to those of swine and bovine. We previously constructed a BAC clone-based physical map that covers entire class I, class II and class III region of ovine MHC. Here we describe the assembling of a complete DNA sequence map for the ovine MHC by shotgun sequencing of 26 overlapping BAC clones.</p> <p>Results</p> <p>DNA shotgun sequencing generated approximately 8-fold genome equivalent data that were successfully assembled into a finished sequence map of the ovine MHC. The sequence map spans approximately 2,434,000 nucleotides in length, covering almost all of the MHC loci currently known in the sheep and cattle. Gene annotation resulted in the identification of 177 protein-coding genes/ORFs, among which 145 were not previously reported in the sheep, and 10 were ovine species specific, absent in cattle or other mammals. A comparative sequence analyses among human, sheep and cattle revealed a high conservation in the MHC structure and loci order except for the class II, which were divided into IIa and IIb subregions in the sheep and cattle, separated by a large piece of non-MHC autosome of approximately 18.5 Mb. In addition, a total of 18 non-protein-coding microRNAs were predicted in the ovine MHC region for the first time.</p> <p>Conclusion</p> <p>An ovine MHC DNA sequence map was successfully assembled by shotgun sequencing of 26 overlapping BAC clone. This makes the sheep the second ruminant species for which the complete MHC sequence information is available for evolution and functional studies, following that of the bovine. The results of the comparative analysis support a hypothesis that an inversion of the ancestral chromosome containing the MHC has shaped the MHC structures of ruminants, as we currently observed in the sheep and cattle. Identification of relative large numbers of microRNAs in the ovine MHC region helps to provide evidence that microRNAs are actively involved in the regulation of MHC gene expression and function.</p

Protective effects of transforming growth factor β2 in intestinal epithelial cells by regulation of proteins associated with stress and endotoxin responses

Transforming growth factor (TGF)-β2 is an important anti-inflammatory protein in milk and colostrum. TGF-β2 supplementation appears to reduce gut inflammatory diseases in early life, such as necrotizing enterocolitis (NEC) in young mice. However, the molecular mechanisms by which TGF-β2 protects immature intestinal epithelial cells (IECs) remain to be more clearly elucidated before interventions in infants can be considered. Porcine IECs PsIc1 were treated with TGF-β2 and/or lipopolysaccharide (LPS), and changes in the cellular proteome were subsequently analyzed using two-dimensional gel electrophoresis-MS and LC-MS-based proteomics. TGF-β2 alone induced the differential expression of 13 proteins and the majority of the identified proteins were associated with stress responses, TGF-β and Toll-like receptor 4 signaling cascades. In particular, a series of heat shock proteins had similar differential trends as previously shown in the intestine of NEC-resistant preterm pigs and young mice. Furthermore, LC-MS-based proteomics and Western blot analyses revealed 20 differentially expressed proteins following treatment with TGF-β2 in LPS-challenged IECs. Thirteen of these proteins were associated with stress response pathways, among which five proteins were altered by LPS and restored by TGF-β2, whereas six were differentially expressed only by TGF-β2 in LPS-challenged IECs. Based on previously reported biological functions, these patterns indicate the anti-stress and anti-inflammatory effects of TGF-β2 in IECs. We conclude that TGF-β2 of dietary or endogenous origin may regulate the IEC responses against LPS stimuli, thereby supporting cellular homeostasis and innate immunity in response to bacterial colonization, and the first enteral feeding in early life

Catalyst performance of novel Pt/Mg(Ga)(Al)O catalysts for alkane dehydrogenation

a b s t r a c t The dehydrogenation of ethane and propane using a Pt catalyst supported on a novel Mg(Ga)(Al)O mixed oxide support was investigated. Catalyst performance is strongly dependent on Ga content in the support, a peak in activity for both ethane and propane dehydrogenation occurs at Ga/Pt = 1.4-5.4, and selectivity is a monotonic function of Ga/Pt, reaching nearly 100% at Ga/Pt = 5.4. The addition of hydrogen to the feed resulted in a peak in activity with respect to H 2 /alkane. The increase in dehydrogenation rate with H 2 addition is attributed to H-atom-assisted dehydrogenation of alkyl species formed upon dissociative adsorption of the reactant alkane. Beyond the peak in activity with H 2 addition, a further increase in H 2 feed concentration contribute to alkene hydrogenation, thereby reducing the net rate of dehydrogenation. Hydrogen addition to the feed, however, had relatively little effect on alkene selectivity, which remained near 100%. The presence of Ga also suppressed coke formation. Interestingly, less coke was formed during propane dehydrogenation than ethane dehydrogenation, and no correlation was found between coke formation and catalyst deactivation. Thus, the extent of deactivation was lower for ethane than propane dehydrogenation, whereas the amount of coke deposited was higher in the former case. Since the amount of carbon deposited as coke is higher than the amount of exposed Pt, it is concluded that most of the coke resides on the support, and that only a small amount resides on the Pt particles. The higher level of deactivation seen during propane versus ethane dehydrogenation is attributed to a higher coverage of Pt by coke precursors derived from propane than ethane

Milk Diets Influence Doxorubicin-Induced Intestinal Toxicity in Piglets

Chemotherapy-induced gastrointestinal (GI) toxicity is a common adverse effect of cancer treatment. We used preweaned piglets as models to test our hypothesis that the immunomodulatory and GI trophic effects of bovine colostrum would reduce the severity of GI complications associated with doxorubicin (DOX) treatment. Five-day-old pigs were administered DOX (1 × 100 mg/m2) or an equivalent volume of saline (SAL) and either fed formula (DOX-Form, n = 9, or SAL-Form, n = 7) or bovine colostrum (DOX-Colos, n = 9, or SAL-Colos, n = 7). Pigs were euthanized 5 days after initiation of chemotherapy to assess markers of small intestinal function and inflammation. All DOX-treated animals developed diarrhea, growth deficits, and leukopenia. However, the intestines of DOX-Colos pigs had lower intestinal permeability, longer intestinal villi with higher activities of brush border enzymes, and lower tissue IL-8 levels compared with DOX-Form (all P &lt; 0.05). DOX-Form pigs, but not DOX-Colos pigs, had significantly higher plasma C-reactive protein, compared with SAL-Form. Plasma citrulline was not affected by DOX treatment or diet. Thus a single dose of DOX induces intestinal toxicity in preweaned pigs and may lead to a systemic inflammatory response. The toxicity is affected by type of enteral nutrition with more pronounced GI toxicity when formula is fed compared with bovine colostrum. The results indicate that bovine colostrum may be a beneficial supplementary diet for children subjected to chemotherapy and subsequent intestinal toxicity. </jats:p

An Improvement of Shotgun Proteomics Analysis by Adding Next-Generation Sequencing Transcriptome Data in Orange

BACKGROUND: Shotgun proteomics data analysis usually relies on database search. Because commonly employed protein sequence databases of most species do not contain sufficient protein information, the application of shotgun proteomics to the research of protein sequence profile remains a big challenge, especially to the species whose genome has not been sequenced yet. METHODOLOGY/PRINCIPAL FINDINGS: In this paper, we present a workflow with integrated database to partly address this problem. First, we downloaded the homologous species database. Next, we identified the transcriptome of the sample, created a protein sequence database based on the transcriptome data, and integtrated it with homologous species database. Lastly, we developed a workflow for identifying peptides simultaneously from shotgun proteomics data. CONCLUSIONS/SIGNIFICANCE: We used datasets from orange leaves samples to demonstrate our workflow. The results showed that the integrated database had great advantage on orange shotgun proteomics data analysis compared to the homologous species database, an 18.5% increase in number of proteins identification

A Quick Summary of IMERG Versions and Features

This talk will summarize the shifts in IMERG (Integrated Multi-satellitE Retrievals for GPM (Global Precipitation Measurement)) from Version 03 to 04 in early Spring 2016, and to Version 05 in late Summer 2017. For example, Version 04 replaced approximate pre-launch calibrations with GPM Core Observatory-based calibrations, while Version 05 introduced improved estimates for the primary GPM instrument products (DPR, GMI, and Combined Instrument). In Version 04 the IR estimates were routinely calibrated to the passive microwave estimates. As analysis showed that the Combined Instrument estimates (the IMERG calibration standard) tend to be biased high over land and low over ocean at higher latitudes, in Version 04 we climatologically calibrated IMERG to the Global Precipitation Climatology Project (GPCP) monthly Satellite-Gauge product, except in low- and mid-latitude ocean regions. This calibration leaves the relative time series intact, and only adjusts the mean of the entire series. In Version 05 the primary GPM instrument products have reduced biases, but calibration to GPCP continues to be necessary to achieve the most realistic estimates. Finally, retrospective processing back into the TRMM (Tropical Rainfall Measuring Mission) era is expected in early 2018, after which the legacy TMPA (TRMM Multi-satellite Precipitation Analysis) dataset will be retired

Heading for 20 Years of Quasi-Global Precipitation with the New Version 06 IMERG

The U.S. Global Precipitation Measurement mission (GPM) science team is developing a long-term dataset based on intercalibrated estimates from the international constellation of precipitation-relevant satellites and other data. The Integrated Multi-satellitE Retrievals for GPM (IMERG) merged precipitation product (IMERG) is computed at the half hour, 0.1 x 0.1 resolution globally in three "Runs"Early, Late, and Final (4 hours, 14 hours, and 3.5 months after observation time, respectively). GPM is well into computing the new Version 06, which will be the first time IMERG covers the last two decades and routinely provides morphed estimates in polar regions where the surface is snow- and ice-free.A few salient features of the IMERG algorithm will be summarized, then representative examples of IMERG products will be shown. This starts with basic results, such as animations of maps, then extends to preliminary analyses of dataset characteristics. For example, the diurnal cycle demonstrates improvements over V05