Investigation of the Enteric Pathogenic Potential of Oral Campylobacter concisus Strains Isolated from Patients with Inflammatory Bowel Disease

BACKGROUND: Campylobacter concisus, a bacterium colonizing the human oral cavity, has been shown to be associated with inflammatory bowel disease (IBD). This study investigated if patients with IBD are colonized with specific oral C. concisus strains that have potential to cause enteric diseases. METHODOLOGY: Seventy oral and enteric C. concisus isolates obtained from eight patients with IBD and six controls were examined for housekeeping genes by multilocus sequence typing (MLST), Caco2 cell invasion by gentamicin-protection-assay, protein analysis by mass spectrometry and SDS-PAGE, and morphology by scanning electron microscopy. The whole genome sequenced C. concisus strain 13826 which was isolated from an individual with bloody diarrhea was included in MLST analysis. PRINCIPAL FINDINGS: MLST analysis showed that 87.5% of individuals whose C. concisus belonged to Cluster I had inflammatory enteric diseases (six IBD and one with bloody diarrhea), which was significantly higher than that in the remaining individuals (28.6%) (P<0.05). Enteric invasive C. concisus (EICC) oral strain was detected in 50% of patients with IBD and none of the controls. All EICC strains were in Cluster 1. The C. concisus strain colonizing intestinal tissues of patient No. 1 was closely related to the oral C. concisus strain from patient No. 6 and had gene recombination with the patient's own oral C. concisus. The oral and intestinal C. concisus strains of patient No. 3 were the same strain. Some individuals were colonized with multiple oral C. concisus strains that have undergone natural recombination. CONCLUSIONS: This study provides the first evidence that patients with IBD are colonized with specific oral C. concisus strains, with some being EICC strains. C. concisus colonizing intestinal tissues of patients with IBD at least in some instances results from an endogenous colonization of the patient's oral C. concisus and that C. concisus strains undergo natural recombination

Tumor-Like Stem Cells Derived from Human Keloid Are Governed by the Inflammatory Niche Driven by IL-17/IL-6 Axis

Alterations in the stem cell niche are likely to contribute to tumorigenesis; however, the concept of niche promoted benign tumor growth remains to be explored. Here we use keloid, an exuberant fibroproliferative dermal growth unique to human skin, as a model to characterize benign tumor-like stem cells and delineate the role of their "pathological" niche in the development of the benign tumor.Subclonal assay, flow cytometric and multipotent differentiation analyses demonstrate that keloid contains a new population of stem cells, named keloid derived precursor cells (KPCs), which exhibit clonogenicity, self-renewal, distinct embryonic and mesenchymal stem cell surface markers, and multipotent differentiation. KPCs display elevated telomerase activity and an inherently upregulated proliferation capability as compared to their peripheral normal skin counterparts. A robust elevation of IL-6 and IL-17 expression in keloid is confirmed by cytokine array, western blot and ELISA analyses. The altered biological functions are tightly regulated by the inflammatory niche mediated by an autocrine/paracrine cytokine IL-17/IL-6 axis. Utilizing KPCs transplanted subcutaneously in immunocompromised mice we generate for the first time a human keloid-like tumor model that is driven by the in vivo inflammatory niche and allows testing of the anti-tumor therapeutic effect of antibodies targeting distinct niche components, specifically IL-6 and IL-17.These findings support our hypothesis that the altered niche in keloids, predominantly inflammatory, contributes to the acquirement of a benign tumor-like stem cell phenotype of KPCs characterized by the uncontrolled self-renewal and increased proliferation, supporting the rationale for in vivo modification of the "pathological" stem cell niche as a novel therapy for keloid and other mesenchymal benign tumors

Pharmacologic stem cell based intervention as a new approach to osteoporosis treatment in rodents

Background: Osteoporosis is the most prevalent skeletal disorder, characterized by a low bone mineral density (BMD) and bone structural deterioration, leading to bone fragility fractures. Accelerated bone resorption by osteoclasts has been established as a principal mechanism in osteoporosis. However, recent experimental evidences suggest that inappropriate apoptosis of osteoblasts/osteocytes accounts for, at least in part, the imbalance in bone remodeling as occurs in osteoporosis. The aim of this study is to examine whether aspirin, which has been reported as an effective drug improving bone mineral density in human epidemiology studies, regulates the balance between bone resorption and bone formation at stem cell levels. Methods and Findings: We found that T cell-mediated bone marrow mesenchymal stem cell (BMMSC) impairment plays a crucial role in ovariectomized-induced osteoporosis. Ex vivo mechanistic studies revealed that T cell-mediated BMMSC impairment was mainly attributed to the apoptosis of BMMSCs via the Fas/Fas ligand pathway. To explore potential of using pharmacologic stem cell based intervention as an approach for osteoporosis treatment, we selected ovariectomy (OVX)- induced ostoeporosis mouse model to examine feasibility and mechanism of aspirin-mediated therapy for osteoporosis. We found that aspirin can inhibit T cell activation and Fas ligand induced BMMSC apoptosis in vitro. Further, we revealed that aspirin increases osteogenesis of BMMSCs by aiming at telomerase activity and inhibits osteoclast activity in OVX mice, leading to ameliorating bone density. Conclusion: Our findings have revealed a novel osteoporosis mechanism in which activated T cells induce BMMSC apoptosis via Fas/Fas ligand pathway and suggested that pharmacologic stem cell based intervention by aspirin may be a new alternative in osteoporosis treatment including activated osteoblasts and inhibited osteoclasts.Takayoshi Yamaza, Yasuo Miura, Yanming Bi, Yongzhong Liu, Kentaro Akiyama, Wataru Sonoyama, Voymesh Patel, Silvio Gutkind, Marian Young, Stan Gronthos, Anh Le, Cun-Yu Wang, WanJun Chen and Songtao Sh

Ligand Binding Strength Explains the Distribution of Iron in the North Atlantic Ocean

Observations of dissolved iron (dFe) in the subtropical North Atlantic revealed remarkable features: While the near-surface dFe concentration is low despite receiving high dust deposition, the subsurface dFe concentration is high. We test several hypotheses that might explain this feature in an ocean biogeochemistry model with a refined Fe cycling scheme. These hypotheses invoke a stronger lithogenic scavenging rate, rapid biological uptake, and a weaker binding between Fe and a ubiquitous, refractory ligand. While the standard model overestimates the surface dFe concentration, a 10-time stronger biological uptake run causes a slight reduction in the model surface dFe. A tenfold decrease in the binding strength of the refractory ligand, suggested by recent observations, starts reproducing the observed dFe pattern, with a potential impact for the global nutrient distribution. An extreme value for the lithogenic scavenging rate can also match the model dFe with observations, but this process is still poorly constrained

Formation and Maintenance of the GEOTRACES Subsurface‐Dissolved Iron Maxima in an Ocean Biogeochemistry Model

Recent GEOTRACES transects revealed basin-scale patterns of dissolved iron in the global oceans, providing a unique opportunity to test numerical models and to improve our understanding of the iron cycling. Subsurface maxima of dissolved iron in the upper ocean thermocline are observed in various transects, which can play an important role in regulating marine productivity due to their proximity to the surface euphotic layer. An ocean biogeochemistry model with refined parameterizations of iron cycling is used to examine the mechanisms controlling the formation and maintenance of these subsurface maxima. The model includes the representation of three iron sources including dust deposition, continental shelves, and hydrothermal vents. Two classes of organic ligands are parameterized based on the dissolved organic matter and apparent oxygen utilization. Parameterizations of particle-dependent scavenging and desorption are included. Although the model still struggles in fully capturing the observed dissolved iron distribution, it starts reproducing some major features, especially in the main thermocline. A suite of numerical sensitivity experiments suggests that the release of scavenged iron associated with sinking organic particles forms the subsurface-dissolved iron maxima in high-dust regions of the Indian and Atlantic Oceans. In low-dust regions of the Pacific basin, the subsurface-dissolved iron extrema are sustained by inputs from the continental shelves or hydrothermal vents. In all cases, subsurface ligands produced by the remineralization of organic particles retain the dissolved iron and play a central role in the maintenance of the subsurface maxima in our model. Thus, the parameterization of subsurface ligands has a far-reaching impact on the representation of global iron cycling and biological productivity in ocean biogeochemistry models