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In this paper we characterize the function of Xylosyltransferase 2 (XylT2) in different tissues to investigate the role XylT2 has in the proteoglycan (PG) biochemistry of multiple organs. The results show that in all organs examined there is a widespread and significant decrease in total XylT activity in Xylt2 knock out mice (Xylt2-/-). This decrease results in increased organ weight differences in lung, heart, and spleen. These findings, in addition to our previous findings of increased liver and kidney weight with loss of serum XylT activity, suggest systemic changes in organ function due to loss of XylT2 activity. The Xylt2-/- mice have splenomegaly due to enlargement of the red pulp area and enhanced pulmonary response to bacterial liposaccharide. Tissue glycosaminoglycan composition changes are also found. These results demonstrate a role of XylT2 activity in multiple organs and their PG content. Because the residual XylT activity in the Xylt2-/- is due to xylosyltransferase 1 (XylT1), these studies indicate that both XylT1 and XylT2 have important roles in PG biosynthesis and organ homeostasis.

Background: A surfactant protein-A-derived peptide, which we call SPA4 peptide (amino acids: GDFRYSDGTPVNYTNWYRGE), alleviates lung infection and inflammation. This study investigated the effects of intratracheally administered SPA4 peptide on systemic, lung, and health parameters in an outbred mouse strain, and in an intratracheal lipopolysaccharide (LPS) challenge model., Methods: The outbred CD-1 mice were intratracheally administered with incremental doses of SPA4 peptide (0.625-10 μg/g body weight) once every 24 h, for 3 days. Mice left untreated and those treated with vehicle were included as controls. Mice were euthanized after 24 h of last administration of SPA4 peptide. In order to assess the biological activity of SPA4 peptide, C57BL6 mice were intratracheally challenged with 5 μg LPS/g body weight and treated with 50 μg SPA4 peptide via intratracheal route 1 h post LPS-challenge. Mice were euthanized after 4 h of LPS challenge. Signs of sickness and body weights were regularly monitored. At the time of necropsy, blood and major organs were harvested. Blood gas and electrolytes, serum biochemical profiles and SPA4 peptide-specific immunoglobulin G (IgG) antibody levels, and common lung injury markers (levels of total protein, albumin, and lactate, lactate dehydrogenase activity, and lung wet/dry weight ratios) were determined. Lung, liver, spleen, kidney, heart, and intestine were examined histologically. Differences in measured parameters were analyzed among study groups by analysis of variance test., Results: The results demonstrated no signs of sickness or changes in body weight over 3 days of treatment with various doses of SPA4 peptide. It did not induce any major toxicity or IgG antibody response to SPA4 peptide. The SPA4 peptide treatment also did not affect blood gas, electrolytes, or serum biochemistry. There was no evidence of injury to the tissues and organs. However, the SPA4 peptide suppressed the LPS-induced lung inflammation., Conclusions: These findings provide an initial toxicity profile of SPA4 peptide. Intratracheal administration of escalating doses of SPA4 peptide does not induce any significant toxicity at tissue and organ levels. However, treatment with a dose of 50 μg SPA4 peptide, comparable to 2.5 μg/g body weight, alleviates LPS-induced lung inflammation.

Two-dimensional (2D) materials show great potential for use in battery electrodes and are believed to be particularly promising for high-rate applications. However, there does not seem to be much hard evidence for the superior rate performance of 2D materials compared to non-2D materials. To examine this point, we have analyzed published rate-performance data for a wide range of 2D materials as well as non-2D materials for comparison. For each capacity-rate curve, we extract parameters that quantify performance which can then be analyzed using a simple mechanistic model. Contrary to expectations, by comparing a previously proposed figure of merit, we find 2D-based electrodes to be on average ∼40 times poorer in terms of rate performance than non-2D materials. This is not due to differences in solid-state diffusion times which were similarly distributed for 2D and non-2D materials. In fact, we found the main difference between 2D and non-2D materials is that ion mobility within the electrolyte-filled pores of the electrodes is significantly lower for 2D materials, a situation which we attribute to their high aspect ratios.

IT127 is a dinuclear transition metal complex that contains a Pt(ii) and a Ru(iii) metal center. We have shown that IT127 is significantly more effective in binding the 29-base sarcin ricin loop (SRL) RNA in comparison to Cisplatin, a hallmark anticancer agent. Binding site analysis shows that IT127 prefers purine bases and the GAGA tetraloop region of SRL RNA. Our results with a dihydrofolate reductase (DHFR) model system reveal that IT127 binding to mRNA reduces translation of DHFR enzyme and that the Ru(iii) and Pt(ii) centers in IT127 appear to work in a synergistic manner.

Pulmonary neutrophils are the initial inflammatory cells that are recruited during lung injury and are crucial for innate immunity. However, pathological recruitment of neutrophils results in lung injury. The objective of this study is to determine whether the novel neutrophil chemoattractant, soluble VCAM-1 (sVCAM-1), recruits pathological levels of neutrophils to injury sites and amplifies lung inflammation during acute lung injury. The mice with P2X7 receptor deficiency, or treated with a P2X7 receptor inhibitor or anti-VCAM-1 Abs, were subjected to a clinically relevant two-hit LPS and mechanical ventilation-induced acute lung injury. Neutrophil infiltration and lung inflammation were measured. Neutrophil chemotactic activities were determined by a chemotaxis assay. VCAM-1 shedding and signaling pathways were assessed in isolated lung epithelial cells. Ab neutralization of sVCAM-1 or deficiency or antagonism of P2X7R reduced neutrophil infiltration and proinflammatory cytokine levels. The ligands for sVCAM-1 were increased during acute lung injury. sVCAM-1 had neutrophil chemotactic activities and activated alveolar macrophages. VCAM-1 is released into the alveolar airspace from alveolar epithelial type I cells through P2X7 receptor-mediated activation of the metalloproteinase ADAM-17. In conclusion, sVCAM-1 is a novel chemoattractant for neutrophils and an activator for alveolar macrophages. Targeting sVCAM-1 provides a therapeutic intervention that could block pathological neutrophil recruitment, without interfering with the physiological recruitment of neutrophils, thus avoiding the impairment of host defenses., (Copyright © 2016 by The American Association of Immunologists, Inc.)

The pathogenesis of β-cell dysfunction leading to pancreatic β-cell failure seen in type 2 diabetes mellitus is incompletely understood. Pancreatic tissues were collected from nine control cats and nine diabetic cats and labelled immunohistochemically to examine expression of interleukin (IL)-1β, insulin, islet amyloid polypeptide (IAPP) and 4-hydroxynonenal (4-HNE). Thioflavin-S was used to stain for amyloid. All control cats showed positive labelling for IL-1β and 4-HNE. Diabetic cats showed varying degrees of inflammation and oxidative modification, owing in large part to the very small amount of islet structure remaining in the typical diabetic cat pancreas. Amyloid deposition was identified in 8/9 diabetic cats and 1/9 control cats. In order to validate these findings, paired biopsy samples taken from an additional group of cats enrolled in a study of obesity and hyperglycaemia (sampling at baseline and after 8-16 weeks of obesity and hyperglycaemia) were labelled for IL-1β and 4-HNE. A similar pattern of labelling was identified in the baseline samples to that seen in control cats. A significant increase in IL-1β and 4-HNE expression was seen after a period of hyperglycaemia and obesity. Taken together, these findings suggest that while present in normal cats, markers of inflammation and oxidative modification increase very early during the development of disease. Future studies focusing on these earlier time points are needed to understand the factors that function in protection of the islet β cell and the development of islet pathology in type 2 diabetes mellitus in the cat., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary epithelial injury and extensive inflammation of the pulmonary parenchyma. Systematic analyses of microRNA (miRNA) and mRNA expression profiling in ARDS provide insights into understanding of molecular mechanisms of the pathogenesis of ARDS. The objective of this study was to identify miRNA and mRNA interactions in a rat model of ARDS by combining miRNA and mRNA microarray analyses., Methods: Rat model of ARDS was induced by saline lavage and mechanical ventilation. The expression profiles of both mRNAs and miRNAs in rat ARDS model were performed by microarray analyses. Microarray data were further verified by quantitative RT-PCR. Functional annotation on dys-regulated mRNAs and miRNAs was carried out by bioinformatics analysis., Results: The expression of 27 miRNAs and 37 mRNAs were found to be significantly changed. The selected miRNAs and genes were further verified by quantitative real-time PCR. The down-regulated miRNAs included miR-24, miR-26a, miR-126, and Let-7a, b, c, f. The up-regulated miRNAs were composed of miR-344, miR-346, miR-99a, miR-127, miR-128b, miR-135b, and miR-30a/b. Gene ontology and functional annotation analyses indicated that up-regulated mRNAs, such as Apc, Timp1, and Sod2, were involved in the regulation of apoptosis. Bioinformatics analysis showed the inverse correlation of altered miRNAs with the expression of their predicted target mRNAs. While Sod2 was inversely correlated with Let-7a, b, c, f., Ebf1 and Apc were inversely correlated with miR-24 and miR-26a, respectively. miR-26a, miR-346, miR-135b, miR-30a/b, miR-344, and miR-18a targeted multiple altered mRNAs. Gabrb1, Sod2, Eif2ak1, Fbln5, and Tspan8 were targeted by multiple altered miRNAs., Conclusion: The expressions of miRNAs and mRNAs were altered in a rat model of ARDS. The identified miRNA-mRNA pairs may play critical roles in the pathogenesis of ARDS.

We carried out a critical appraisal and synthesis of the systematic reviews and meta-analyses of remote monitoring for heart failure. A comprehensive literature search identified 65 relevant publications from 3333 citations. Seventeen studies fulfilled the inclusion and exclusion criteria. Seven (41%) systematic reviews pooled results for meta-analysis. Eight (47%) considered all non-invasive remote monitoring strategies. Five (29%) focused on telemonitoring. Four (24%) included both non-invasive and invasive technologies. The reviews were appraised by two independent reviewers for their quality and risk of bias using the AMSTAR tool. According to the AMSTAR criteria, ten (58%) systematic reviews were of poor methodological quality. In the high quality reviews, the relative risk of mortality in patients who received remote monitoring ranged from 0.53 to 0.88. The high quality reviews also reported that remote monitoring reduced the relative risk of all-cause (0.52 to 0.96) and heart failure-related hospitalizations (0.72 to 0.79) and, as a consequence, healthcare costs. However, further research is required before considering widespread implementation of remote monitoring. The subset of the heart failure population that derives the most benefit from intensive monitoring, the best technology, and the optimum duration of monitoring, all need to be identified.

Bronchopulmonary dysplasia (BPD) is a multifactorial chronic lung disease of premature infants. BPD can be attributed to the dysregulation of normal lung development due to ventilation and oxygen toxicity, resulting in pathologic complications of impaired alveolarization and vascularization. MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression posttranscriptionally and are implicated in diverse biological processes and diseases. The objectives of this study are to identify the changed miRNAs and their target genes in neonatal rat lungs in response to hyperoxia exposure. Using miRNA microarray and real-time PCR analyses, we found downregulation of five miRNAs, miR-342, miR-335, miR-150, miR-126*, and miR-151*, and upregulation of two miRNAs, miR-21 and miR-34a. Some of these miRNAs had the highest expression during embryonic and early postnatal development. DNA microarray analysis yielded several genes with conserved binding sites for these altered miRNAs. Glycoprotein nonmetastatic melanoma protein b (GPNMB) was experimentally verified as a target of miR-150. In summary, we identified seven miRNAs that were changed in hyperoxia-exposed neonatal lungs. These results provide a basis for deciphering the mechanisms involved in the spatial and temporal regulation of proteins that contribute to the pathogenesis of BPD.

Alaskan racing sled dogs are a well-established model of exercise-induced gastric disease. The aim of this study was to define the temporal development of microscopical gastric lesions during long distance racing. Two groups of dogs were examined: group I comprised conditioned dogs that were exercising and group II were conditioned dogs not exercising. The gastric mucosa was examined endoscopically and sampled for routine histopathology and microscopical scoring, immunohistochemistry (IHC) and detection of apoptotic epithelial cells. Overall, group I dogs exhibited more significant epithelial lesions, including ulcers, compared with dogs in group II. Group II dogs exhibited the most severe mucosal inflammatory infiltrates. Although the intensity of inflammation differed, the nature of the inflammation was similar between groups, consisting of diffuse lymphocytic infiltration and a unique interface-type infiltrate that obscured the basement membrane zone and was accompanied by intraepithelial infiltration of lymphocytes. IHC confirmed the presence of CD3(+) T and CD79(+) B lymphocytes within the mucosal infiltrates; however, most of the intraepithelial and interface infiltrates were CD3(+) T cells. Spiral-shaped bacterial organisms were seen in the gastric tissues; however, their presence did not correlate with either the severity of epithelial lesions, inflammation or the pattern of interface inflammation. The number of apoptotic epithelial cells was widely variable and not significantly different between groups. These findings confirm previous observations that gastric ulcers develop in conditioned dogs under racing stress. The unique nature of the interface-type gastric inflammation is similar to that of human lymphocytic gastritis and may suggest an immune-mediated mechanism for the changes seen in Alaskan racing sled dogs., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Isolates of baboon alpha-herpesvirus Papiine herpesvirus 2 (HVP2) exhibit one of two distinct phenotypes in mice: extremely neurovirulent or apathogenic. Previous studies implicated the type I interferon (IFN) response as being a major factor in controlling infection by apathogenic isolates. To further investigate the possibility that the host IFN-beta response underlies the pathogenicity of the two HVP2 subtypes, the susceptibility of mice lacking the IFN-beta receptor (IFNAR(-/-)) to infection was examined. Apathogenic isolates of HVP2 (HVP2ap) replicated in IFNAR(-/-) primary mouse dermal fibroblast (PMDF) cultures as well as neurovirulent (HVP2nv) isolates. IFNAR(-/-) mice were also susceptible to lethal infection by HVP2ap isolates. Unlike Balb/c or parental 129 mice, LD(50) and ID(50) values for HVP2ap were the same in IFNAR(-/-) mice indicating that in these mice infection always progressed to death. HVP2ap replicated in the skin at the site of inoculation and invaded dorsal root ganglia as efficiently as HVP2nv in IFNAR(-/-) mice. Since the virion host shutoff (vhs) protein encoded by the UL41 gene of herpes simplex virus has been implicated in circumventing the host IFN-beta response and the phenotype of UL41 deletion mutants of HSV is very similar to that of HVP2ap isolates, the UL41 gene was deleted from HVP2nv (Delta 41) and replaced with the UL41 ORF from HVP2ap (Delta 41C). Like the parental HVP2nv virus, the Delta 41C recombinant replicated efficiently in Balb/c PMDFs and did not induce a strong IFN-beta response. The neuropathogenicity of the Delta 41C recombinant was also the same as the parental HVP2nv virus in Balb/c mice, indicating that the vhs protein does not underlie the different neuropathogenic phenotype of HVP2ap and HVP2nv. In contrast, the Delta 41 deletion virus induced a strong IFN-beta response but was still able to undergo multiple rounds of replication in PMDF cultures, albeit at a slower pace than the parental HVP2nv. This was reflected in vivo as the Delta 41 mutant had an LD(50) equivalent to that of the parental HVP2nv virus although the time to death was longer. These results indicate that while the vhs protein is involved in preventing and/or suppressing an IFN-beta response, it is not responsible for the ability of HVP2nv to overcome IFN-beta induced resistance of uninfected cells and does not underlie the divergent pathogenicity of the two HVP2 subtypes in mice.

Saimiriine herpesvirus 1 (SaHV-1), an alphaherpesvirus enzootic in squirrel monkeys, is genetically related to monkey B virus and human herpes simplex virus (HSV). To study the temporal progression of viral spread and associated lesions, Balb/c mice were inoculated epidermally by scarification with a green fluorescent protein (GFP)-expressing recombinant strain of SaHV-1 and killed sequentially. Pinpoint ulcerative lesions in the inoculated epidermis progressed over a few days to unilateral or bilateral hindlimb paresis or paralysis, urinary and faecal incontinence, abdominal distension, hunched posture and eventual depression warranting euthanasia. Viral replication was present within epidermal keratinocytes, neurons of the dorsal root ganglia and thoracolumbar spinal cord, regional autonomic ganglia, lower urinary tract epithelium and colonic myenteric plexuses, as indicated by histological lesions and GFP expression. Almost all mice inoculated with 10(5) or 10(6) plaque-forming units (PFU) of SaHV-1 developed rapidly progressive disease. Two of eight mice given 10(4)PFU developed disease, but no mice receiving less than 10(4)PFU gave evidence of infection. Mice that showed no clinical signs also failed to develop an antiviral IgG response, indicating absence of active viral infection. For SaHV-1 inoculated epidermally, the ID(50), CNSD(50) and LD(50) values were identical (10(4.38)), indicating that successful infection by this route invariably resulted in lethal CNS (central nervous system) disease. Consistently severe disease in all infected animals, with regionally extensive distribution of viral replication, constituted a marked difference from the disease produced by intramuscular inoculation.

Accidental B virus (Herpesvirus simiae) infection of human beings working with macaques is frequently fatal. However, the pathogenic potential of other similar simian alphaherpesviruses, such as the squirrel monkey virus Herpesvirus saimiri (HVS1), is virtually unknown. As part of an effort to develop a murine model for infections with these agents, Balb/c mice were inoculated intramuscularly in the left hindlimb with 10 to 10(6) plaque forming units (PFU) of HVS1. After observation for clinical signs of infection for 21 days, mice were killed and specimens collected for serology and histopathology. Mice receiving 510(3) PFU of HVS1 exhibited severe, pruritic, ulcerative skin lesions near the site of inoculation and developed unilateral or bilateral hindlimb paralysis with severe muscle atrophy. Histological lesions were characterized by a necrotizing dermatitis and folliculitis. Spinal cord lesions consisted of a non-suppurative myelitis affecting primarily the ipsilateral dorsal horn of the thoracolumbar spinal cord with occasional extension to ventral and contralateral spinal cord regions. Immunohistochemical labelling confirmed the presence of viral antigen within the lesions, and anti-HVS1 IgG concentrations were related to the occurrence of disease. HVS1 infection in some mice extended from the ipsilateral dorsal horn and funiculus into the ventral and contralateral grey and white matter, resulting in bilateral hindlimb paralysis. Thoracolumbar spinal cord lesions resolved without continued spread of the virus to cranial nervous system structures, i.e., cervical spinal cord and brain., (Copyright Harcourt Publishers Ltd.)

Nine of 16 free-ranging coyotes (Canis latrans) from central Oklahoma (USA) had naturally acquired infections of Hepatozoon americanum. Infections were confirmed by recognition of tissue stages closely resembling H. americanum in skeletal and cardiac muscle. At the time coyotes were collected they were infested with a variety of ticks, including adult Gulf Coast ticks (Amblyomma maculatum). We propose that the high prevalence of H. americanum in this small sample of free-ranging coyotes and the ability of these same animals to harbor adult populations of A. maculatum is an important component of the epizootiology of canine hepatozoonosis in North America.