Association between Food Intake, Clinical and Metabolic Markers and DNA Damage in Older Subjects

Abstract The use of DNA damage as marker of oxidative stress, metabolic dysfunction and age-related diseases is debated. The present study aimed at assessing the level of DNA damage (evaluated as DNA strand-breaks, endogenous and oxidatively-induced DNA damage) in a group of older subjects with intestinal permeability enrolled within the MaPLE (Gut and Blood Microbiomics for Studying the Effect of a Polyphenol-Rich Dietary Pattern on Intestinal Permeability in the Elderly) intervention trial, to evaluate its association with clinical, metabolic and dietary markers. DNA damage in peripheral blood mononuclear cells was assessed by the comet assay in 49 older subjects participating in the study. Clinical and metabolic markers, markers of inflammation, vascular function and intestinal permeability were determined in serum. Food intake was estimated by weighted food diaries. On the whole, a trend towards higher levels of DNA damage was observed in men compared to women (p = 0.071). A positive association between DNA damage and clinical/metabolic markers (e.g., uric acid, lipid profile) and an inverse association with dietary markers (e.g., vitamin C, E, B6, folates) were found and differed based on sex. By considering the importance of DNA stability during aging, the results obtained on sex differences and the potential role of dietary and metabolic factors on DNA damage underline the need for further investigations in a larger group of older adults to confirm the associations found and to promote preventive strategies

A New Name for Pneumocystis from Humans and New Perspectives on the Host-Pathogen Relationship

The disease known as Pneumocystis carinii pneumonia (PCP) is a major cause of illness and death in persons with impaired immune systems. While the genus Pneumocystis has been known to science for nearly a century, understanding of its members remained rudimentary until DNA analysis showed its extensive diversity. Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. In recognition of its genetic and functional distinctness, the organism that causes human PCP is now named Pneumocystis jiroveci Frenkel 1999. Changing the organism’s name does not preclude the use of the acronym PCP because it can be read “Pneumocystis pneumonia.” DNA varies in samples of P. jiroveci, a feature that allows reexamination of the relationships between host and pathogen. Instead of lifelong latency, transient colonization may be the rule

Evidence of the Red-Queen hypothesis from accelerated rates of evolution of genes involved in biotic interactions in Pneumocystis

[EN] Pneumocystis species are ascomycete fungi adapted to live inside the lungs of mammals. These ascomycetes show extensive stenoxenism, meaning that each species of Pneumocystis infects a single species of host. Here, we study the effect exerted by natural selection on gene evolution in the genomes of three Pneumocystis species. We show that genes involved in host interaction evolve under positive selection. In the first place, we found strong evidence of episodic diversifying selection in Major surface glycoproteins (Msg). These proteins are located on the surface of Pneumocystis and are used for host attachment and probably for immune system evasion. Consistent with their function as antigens, most sites under diversifying selection in Msg code for residues with large relative surface accessibility areas. We also found evidence of positive selection in part of the cell machinery used to export Msg to the cell surface. Specifically, we found that genes participating in glycosylphosphatidylinositol (GPI) biosynthesis show an increased rate of nonsynonymous substitutions (dN) versus synonymous substitutions (dS). GPI is a molecule synthesized in the endoplasmic reticulum that is used to anchor proteins to membranes. We interpret the aforementioned findings as evidence of selective pressure exerted by the host immune system on Pneumocystis species, shaping the evolution of Msg and several proteins involved in GPI biosynthesis. We suggest that genome evolution in Pneumocystis is well described by the Red-Queen hypothesis whereby genes relevant for biotic interactions show accelerated rates of evolution.L.D. wishes to thank Eugenia Flores and Ana Fayos for support provided. This project has received funding from the Marie Curie International Research Staff Exchange Scheme within the 7th European Community Framework Program under grant agreement No 612583-DEANN. Part of this work was done during an internship of L.D. as invited professor at the Universidad de Valencia. Support from CONACYT (grant 454938) is gratefully acknowledged. This work was supported by grants to A.M. from the Spanish Ministry of Science and Competitivity (projects SAF 2012-31187, SAF2013-49788-EXP, SAF2015-65878-R), Carlos III Institute of Health (projects PIE14/00045, AC 15/00022 and AC15/00042), Generalitat Valenciana (project PrometeoII/2014/065) and cofinanced by FEDER.Delaye, L.; Ruiz Ruiz, S.; Calderon, E.; Tarazona Campos, S.; Conesa, A.; Moya, A. (2018). Evidence of the Red-Queen hypothesis from accelerated rates of evolution of genes involved in biotic interactions in Pneumocystis. Genome Biology and Evolution. 10(6):1596-1606. https://doi.org/10.1093/gbe/evy116S15961606106Aliouat-Denis, C.-M., Chabé, M., Demanche, C., Aliouat, E. M., Viscogliosi, E., Guillot, J., … Dei-Cas, E. (2008). Pneumocystis species, co-evolution and pathogenic power. 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Pneumocystis cell wall β-glucan stimulates calcium-dependent signaling of IL-8 secretion by human airway epithelial cells

<p>Abstract</p> <p>Background</p> <p>Respiratory failure secondary to alveolar inflammation during <it>Pneumocystis </it>pneumonia is a major cause of death in immunocompromised patients. Neutrophil infiltration in the lung of patients with <it>Pneumocystis </it>infection predicts severity of the infection and death. Several previous studies indicate that airway epithelial cells release the neutrophil chemoattractant proteins, MIP-2 (rodents) and IL-8 (humans), in response to <it>Pneumocystis </it>and purified <it>Pneumocystis </it>cell wall β-glucans (PCBG) through the NF-κB-dependent pathway. However, little is known about the molecular mechanisms that are involved in the activation of airway epithelium cells by PCBG resulting in the secretion of IL-8.</p> <p>Method</p> <p>To address this, we have studied the activation of different calcium-dependent mitogen-activated protein kinases (MAPKs) in 1HAEo^-cells, a human airway epithelial cell line.</p> <p>Results</p> <p>Our data provide evidence that PCBG induces phosphorylation of the MAPKs, ERK, and p38, the activation of NF-κB and the subsequently secretion of IL-8 in a calcium-dependent manner. Further, we evaluated the role of glycosphingolipids as possible receptors for β-glucans in human airway epithelial cells. Preincubation of the cells with D-<it>threo</it>-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) a potent inhibitor of the glycosphingolipids synthesis, prior to PCBG stimulation, significantly decreased IL-8 production.</p> <p>Conclusion</p> <p>These data indicate that PCBG activates calcium dependent MAPK signaling resulting in the release of IL-8 in a process that requires glycosphingolipid for optimal signaling.</p

Pneumocystis murina colonization in immunocompetent surfactant protein A deficient mice following environmental exposure

<p>Abstract</p> <p>Background</p> <p><it>Pneumocystis spp</it>. are opportunistic pathogens that cause pneumonia in immunocompromised humans and animals. <it>Pneumocystis </it>colonization has also been detected in immunocompetent hosts and may exacerbate other pulmonary diseases. Surfactant protein A (SP-A) is an innate host defense molecule and plays a role in the host response to <it>Pneumocystis</it>.</p> <p>Methods</p> <p>To analyze the role of SP-A in protecting the immunocompetent host from <it>Pneumocystis </it>colonization, the susceptibility of immunocompetent mice deficient in SP-A (KO) and wild-type (WT) mice to <it>P. murina </it>colonization was analyzed by reverse-transcriptase quantitative PCR (qPCR) and serum antibodies were measured by enzyme-linked immunosorbent assay (ELISA).</p> <p>Results</p> <p>Detection of <it>P. murina </it>specific serum antibodies in immunocompetent WT and KO mice indicated that the both strains of mice had been exposed to <it>P. murina </it>within the animal facility. However, P. <it>murina </it>mRNA was only detected by qPCR in the lungs of the KO mice. The incidence and level of the mRNA expression peaked at 8–10 weeks and declined to undetectable levels by 16–18 weeks. When the mice were immunosuppressed, <it>P. murina </it>cyst forms were also only detected in KO mice. <it>P. murina </it>mRNA was detected in <it>SCID </it>mice that had been exposed to KO mice, demonstrating that the immunocompetent KO mice are capable of transmitting the infection to immunodeficient mice. The pulmonary cellular response appeared to be responsible for the clearance of the colonization. More CD4+ and CD8+ T-cells were recovered from the lungs of immunocompetent KO mice than from WT mice, and the colonization in KO mice depleted CD4+ cells was not cleared.</p> <p>Conclusion</p> <p>These data support an important role for SP-A in protecting the immunocompetent host from <it>P. murina </it>colonization, and provide a model to study <it>Pneumocystis </it>colonization acquired via environmental exposure in humans. The results also illustrate the difficulties in keeping mice from exposure to <it>P. murina </it>even when housed under barrier conditions.</p

Violations of betweenness and choice shifts in groups

In decision theory, the betweenness axiom postulates that a decision maker who chooses an alternative A over another alternative B must also choose any probability mixture of A and B over B itself and can never choose a probability mixture of A and B over A itself. The betweenness axiom is a weaker version of the independence axiom of expected utility theory. Numerous empirical studies documented systematic violations of the betweenness axiom in revealed individual choice under uncertainty. This paper shows that these systematic violations can be linked to another behavioral regularity\u2014choice shifts in a group decision making. Choice shifts are observed if an individual faces the same decision problem but makes a different choice when deciding alone and in a group

Comparing the MRI-based Goutallier Classification to an experimental quantitative MR spectroscopic fat measurement of the supraspinatus muscle

Background The Goutallier Classification is a semi quantitative classification system to determine the amount of fatty degeneration in rotator cuff muscles. Although initially proposed for axial computer tomography scans it is currently applied to magnet-resonance-imaging-scans. The role for its clinical use is controversial, as the reliability of the classification has been shown to be inconsistent. The purpose of this study was to compare the semi quantitative MRI-based Goutallier Classification applied by 5 different raters to experimental MR spectroscopic quantitative fat measurement in order to determine the correlation between this classification system and the true extent of fatty degeneration shown by spectroscopy. Methods MRI-scans of 42 patients with rotator cuff tears were examined by 5 shoulder surgeons and were graduated according to the MRI-based Goutallier Classification proposed by Fuchs et al. Additionally the fat/water ratio was measured with MR spectroscopy using the experimental SPLASH technique. The semi quantitative grading according to the Goutallier Classification was statistically correlated with the quantitative measured fat/water ratio using Spearman’s rank correlation. Results Statistical analysis of the data revealed only fair correlation of the Goutallier Classification system and the quantitative fat/water ratio with R = 0.35 (p < 0.05). By dichotomizing the scale the correlation was 0.72. The interobserver and intraobserver reliabilities were substantial with R = 0.62 and R = 0.74 (p < 0.01). Conclusion The correlation between the semi quantitative MRI based Goutallier Classification system and MR spectroscopic fat measurement is weak. As an adequate estimation of fatty degeneration based on standard MRI may not be possible, quantitative methods need to be considered in order to increase diagnostic safety and thus provide patients with ideal care in regard to the amount of fatty degeneration. Spectroscopic MR measurement may increase the accuracy of the Goutallier classification and thus improve the prediction of clinical results after rotator cuff repair. However, these techniques are currently only available in an experimental setting

Prostate cancer stem cells and nanotechnology: a focus on Wnt signaling

Prostate cancer is the most common cancer among men worldwide. However, current treatments for prostate cancer patients in advanced stage often fail because of relapse. Prostate cancer stem cells (PCSCs) are resistant to most standard therapies, and are considered to be a major mechanism of cancer metastasis and recurrence. In this review, we summarized current understanding of PCSCs and their self-renewal signaling pathways with a specific focus on Wnt signaling. Although multiple Wnt inhibitors have been developed to target PCSCs, their application is still limited by inefficient delivery and toxicity in vivo. Recently, nanotechnology has opened a new avenue for cancer drug delivery, which significantly increases specificity and reduces toxicity. These nanotechnology-based drug delivery methods showed great potential in targeting PCSCs. Here, we summarized current advancement of nanotechnology-based therapeutic strategies for targeting PCSCs and highlighted the challenges and perspectives in designing future therapies to eliminate PCSCs