ROLE OF ALTERNATIVE MACROPHAGE ACTIVATION IN MEDIATING FIBROSIS IN \u3ci\u3ePSEUDOMONAS AERUGINOSA\u3c/i\u3e PNEUMONIA

Patients with cystic fibrosis who are infected with the pathogen Pseudomonas aeruginosa have shown favorable responses to the drug azithromycin (AZM). This drug works in an anti-inflammatory capacity, improving clinical outcomes and improving quality of life in this population. The drug has also been shown to affect macrophage polarization by shifting these cells away from an inflammatory phenotype toward an alternatively activated anti-inflammatory phenotype. The full impact of this phenotypic change is not well understood in the context of the response to P. aeruginosa infection, or the overall immune response in cystic fibrosis. To understand how the AZM-polarized macrophage affects other types of cells, we utilized a co-culture in vitro system, with macrophages and fibroblasts incubating together. In this system, we determined that AZM causes upregulation of the pro-fibrotic mediator transforming growth factor-β as well as the extracellular matrix (ECM) protein fibronectin. The mediator of ECM turnover, matrix metalloproteinase (MMP)-9 was upregulated in this system as well. In an in vivo model of P. aeruginosa infection, MMP- 9 and fibronectin were increased in the bronchoalveolar lavage 7 days post-infection in mice that were treated with AZM. This was accompanied by a decrease in damage to the lung tissue, determine by histological examination. To determine if these changes would continue in human subjects with cystic fibrosis, a clinical study was done in this population. Subjects with AZM treatment had decreased TGF-β levels, but no differences in MMP-9 or fibronectin. Interestingly, correlations between certain fibrotic mediators and inflammatory cytokines, specifically interleukin -1β, were different in subjects with AZM treatment compared to subjects without AZM therapy. Together, these data indicate that AZM alters the fibrotic response from the macrophages, as well as the interaction of the inflammatory response and fibrosis development

Characterization of Defects in Ion Transport and Tissue Development in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Knockout Rats

Animal models for cystic fibrosis (CF) have contributed significantly to our understanding of disease pathogenesis. Here we describe development and characterization of the first cystic fibrosis rat, in which the cystic fibrosis transmembrane conductance regulator gene (CFTR) was knocked out using a pair of zinc finger endonucleases (ZFN). The disrupted Cftr gene carries a 16 base pair deletion in exon 3, resulting in loss of CFTR protein expression. Breeding of heterozygous (CFTR+/−) rats resulted in Mendelian distribution of wild-type, heterozygous, and homozygous (CFTR−/−) pups. Nasal potential difference and transepithelial short circuit current measurements established a robust CF bioelectric phenotype, similar in many respects to that seen in CF patients. Young CFTR−/− rats exhibited histological abnormalities in the ileum and increased intracellular mucus in the proximal nasal septa. By six weeks of age, CFTR−/− males lacked the vas deferens bilaterally. Airway surface liquid and periciliary liquid depth were reduced, and submucosal gland size was abnormal in CFTR−/− animals. Use of ZFN based gene disruption successfully generated a CF animal model that recapitulates many aspects of human disease, and may be useful for modeling other CF genotypes, including CFTR processing defects, premature truncation alleles, and channel gating abnormalities

The impact of emotional well-being on long-term recovery and survival in physical illness: a meta-analysis

This meta-analysis synthesized studies on emotional well-being as predictor of the prognosis of physical illness, while in addition evaluating the impact of putative moderators, namely constructs of well-being, health-related outcome, year of publication, follow-up time and methodological quality of the included studies. The search in reference lists and electronic databases (Medline and PsycInfo) identified 17 eligible studies examining the impact of general well-being, positive affect and life satisfaction on recovery and survival in physically ill patients. Meta-analytically combining these studies revealed a Likelihood Ratio of 1.14, indicating a small but significant effect. Higher levels of emotional well-being are beneficial for recovery and survival in physically ill patients. The findings show that emotional well-being predicts long-term prognosis of physical illness. This suggests that enhancement of emotional well-being may improve the prognosis of physical illness, which should be investigated by future research

Reduction of the ATPase inhibitory factor 1 (IF1) leads to visual impairment in vertebrates

In vertebrates, mitochondria are tightly preserved energy producing organelles, which sustain nervous system development and function. The understanding of proteins that regulate their homoeostasis in complex animals is therefore critical and doing so via means of systemic analysis pivotal to inform pathophysiological conditions associated with mitochondrial deficiency. With the goal to decipher the role of the ATPase inhibitory factor 1 (IF1) in brain development, we employed the zebrafish as elected model reporting that the Atpif1a−/− zebrafish mutant, pinotage (pnttq209), which lacks one of the two IF1 paralogous, exhibits visual impairment alongside increased apoptotic bodies and neuroinflammation in both brain and retina. This associates with increased processing of the dynamin-like GTPase optic atrophy 1 (OPA1), whose ablation is a direct cause of inherited optic atrophy. Defects in vision associated with the processing of OPA1 are specular in Atpif1−/− mice thus confirming a regulatory axis, which interlinks IF1 and OPA1 in the definition of mitochondrial fitness and specialised brain functions. This study unveils a functional relay between IF1 and OPA1 in central nervous system besides representing an example of how the zebrafish model could be harnessed to infer the activity of mitochondrial proteins during development

Immortality of the soul as an intuitive idea: towards a psychological explanation of the origins of afterlife beliefs

This study tried to investigate if intuitive ideas about the continuation of the Self after death determine the way people represent the state of being dead, and, in this way, investigate possible psychological origins of afterlife beliefs, which constitute a recurrent cultural phenomenon. A semi-structured interview and a self-report questionnaire were used to obtain information on the experience of imagining oneself as dead and the representation of the dead-I of young adults. he results suggest that (1) there is a tendency to imagine the state of being dead as a continuation of the I, even in the absence of explicit afterlife beliefs; (2) perceptual, emotional, epistemic and desire experiences are associated to the dead-I; (3) the representation of the dead-I seems to be determined by an interaction between cognitive processes related to self-awareness and theory of mind, and the cultural afterlife beliefs explicitly learned. A previous alternative hypothesis, suggesting that simulation constraints were responsible for the emergence of non-reflective afterlife concepts (Bering, 2002, 2006) is not completely supported by our results. he data presented here suggest that immortality of the soul might be an intuitive religious concept, connected to the experience of the Self and to the implicit theorization that the experienced Self is independent from the body. Future studies should focus on the collection of cross-cultural and developmental data

Method for Quantitative Study of Airway Functional Microanatomy Using Micro-Optical Coherence Tomography

We demonstrate the use of a high resolution form of optical coherence tomography, termed micro-OCT (μOCT), for investigating the functional microanatomy of airway epithelia. μOCT captures several key parameters governing the function of the airway surface (airway surface liquid depth, periciliary liquid depth, ciliary function including beat frequency, and mucociliary transport rate) from the same series of images and without exogenous particles or labels, enabling non-invasive study of dynamic phenomena. Additionally, the high resolution of μOCT reveals distinguishable phases of the ciliary stroke pattern and glandular extrusion. Images and functional measurements from primary human bronchial epithelial cell cultures and excised tissue are presented and compared with measurements using existing gold standard methods. Active secretion from mucus glands in tissue, a key parameter of epithelial function, was also observed and quantified

The historical ecology of Pacific herring: : Tracing Alaska Native use of a forage fish

Long-term use of herring by Alaska Natives is not well-documented over space or through time, yet this information can illuminate pre-industrial patterns of herring abundance and distribution. Such information is important to understand the sustained relationships Alaska Native fishers and egg collectors have had with herring. Understanding the genetics of pre-industrial herring may also inform management of the fish and fisheries to insure their survival into the future. In this paper, we attempt a contextualized account of the long-term history of Alaska Native herring fisheries, bringing together archaeological, ethnographic, and ethnohistorical data. We tie these together as background for presenting the preliminary results of the NSF-funded project, The Archaeology of Herring: Reconstructing the Past to Redeem the Future (No. 1203868). We have now tested 84 herring bone samples from 17 archaeological sites in Alaska expanding beyond Speller et al. (2012), having tripled the earlier archaeological dataset. The oldest herring bones identified archaeologically in Alaska are dated to more than 10,000 cal BP. Early Holocene and Middle Holocene sites have also yielded herring bones, although most of the record dates to the last 2400 years. Preservation of genetic information is effectively complete for the last 2400 years, but achievable back to the terminal Pleistocene (68% success rate for samples between 10,500 and 2400 cal BP). This gives considerable confidence to the potential to expand the analyses and develop a richer pattern of biological variability. The resulting data show genetic continuity between archaeological and modern herring populations. The main technical challenge for the future is to extract adequate amounts of nuclear DNA from the ancient samples for identifying more informative DNA markers that can be used to more effectively reveal any population diversity and/or population size changes over time when compared to modern herring

The big impact of small Airway pH

Cystic fibrosis (CF) lung disease, caused by abnormal ion transport because of deficient CFTR (cystic fibrosis transmembrane conductance regulator) function, is characterized by a dehydrated, hyperconcentrated mucus layer, leading to persistent bacterial infection