Arbuscular Mycorrhizal Fungi Drive Organo-Mineral Association in Iron Ore Tailings: Unravelling Microstructure at the Submicron Scale by Synchrotron-Based FTIR and STXM-NEXAFS.

Arbuscular mycorrhizal (AM) fungi play an important role in organic matter (OM) stabilization in Fe ore tailings for eco-engineered soil formation. However, little has been understood about the AM fungi-derived organic signature and organo-mineral interactions in situ at the submicron scale. In this study, a compartmentalized cultivation system was used to investigate the role of AM fungi in OM formation and stabilization in tailings. Particularly, microspectroscopic analyses including synchrotron-based transmission Fourier transform infrared (FTIR) and scanning transmission X-ray microspectroscopy combined with near-edge X-ray absorption fine structure spectroscopy (STXM-NEXAFS) were employed to characterize the chemical signatures at the AM fungal-mineral and mineral-OM interfaces at the submicron scale. The results indicated that AM fungal mycelia developed well in the tailings and entangled mineral particles for aggregation. AM fungal colonization enhanced N-rich OM stabilization through organo-mineral association. Bulk spectroscopic analysis together with FTIR mapping revealed that fungi-derived lipids, proteins, and carbohydrates were associated with Fe/Si minerals. Furthermore, STXM-NEXAFS analysis revealed that AM fungi-derived aromatic, aliphatic, and carboxylic/amide compounds were heterogeneously distributed and trapped by Fe(II)/Fe(III)-bearing minerals originating from biotite-like minerals weathering. These findings imply that AM fungi can stimulate mineral weathering and provide organic substances to associate with minerals, contributing to OM stabilization and aggregate formation as key processes for eco-engineered soil formation in tailings.

Elemental Sulfur and Organic Matter Amendment Drive Alkaline pH Neutralization and Mineral Weathering in Iron Ore Tailings Through Inducing Sulfur Oxidizing Bacteria.

Mineral weathering and alkaline pH neutralization are prerequisites to the ecoengineering of alkaline Fe-ore tailings into soil-like growth media (i.e., Technosols). These processes can be accelerated by the growth and physiological functions of tolerant sulfur oxidizing bacteria (SOB) in tailings. The present study characterized an indigenous SOB community enriched in the tailings, in response to the addition of elemental sulfur (S0) and organic matter (OM), as well as resultant S0oxidation, pH neutralization, and mineral weathering in a glasshouse experiment. The addition of S0 was found to have stimulated the growth of indigenous SOB, such as acidophilic Alicyclobacillaceae, Bacillaceae, and Hydrogenophilaceae in tailings. The OM amendment favored the growth of heterotrophic/mixotrophic SOB (e.g., class Alphaproteobacteria and Gammaproteobacteria). The resultant S0 oxidation neutralized the alkaline pH and enhanced the weathering of biotite-like minerals and formation of secondary minerals, such as ferrihydrite- and jarosite-like minerals. The improved physicochemical properties and secondary mineral formation facilitated organo-mineral associations that are critical to soil aggregate formation. From these findings, co-amendments of S0 and plant biomass (OM) can be applied to enhance the abundance of the indigenous SOB community in tailings and accelerate mineral weathering and geochemical changes for eco-engineered soil formation, as a sustainable option for rehabilitation of Fe ore tailings.

Ecological engineering of iron ore tailings into useable soils for sustainable rehabilitation.

Ecological engineering of soil formation in tailings is an emerging technology toward sustainable rehabilitation of iron (Fe) ore tailings landscapes worldwide, which requires the formation of well-organized and stable soil aggregates in finely textured tailings. Here, we demonstrate an approach using microbial and rhizosphere processes to progressively drive aggregate formation and development in Fe ore tailings. The aggregates were initially formed through the agglomeration of mineral particles by organic cements derived from microbial decomposition of exogenous organic matter. The aggregate stability was consolidated by colloidal nanosized Fe(III)-Si minerals formed during Fe-bearing primary mineral weathering driven by rhizosphere biogeochemical processes of pioneer plants. From these findings, we proposed a conceptual model for progressive aggregate structure development in the tailings with Fe(III)-Si rich cements as core nuclei. This renewable resource dependent eco-engineering approach opens a sustainable pathway to achieve resilient tailings rehabilitation without resorting to excavating natural soil resources.

Three-Dimensional Coffee-Ring Effect Induced Deposition on Foam Surface for Enhanced Photothermal Conversion.

Uniformly depositing a thin layer of functional constituents on porous foam is attractive to realize their concentrated interfacial application. Here, a simple but robust polyvinyl alcohol (PVA)-mediated evaporation drying strategy to achieve uniform surface deposition on melamine foam (MF) is introduced. Solutes can be accumulated homogeneously to the surface periphery of MF due to the enhanced coffee-ring effect of PVA and its stabilizing effect on various functional constituents, including molecules and colloidal particles. The deposition thickness is positively correlated with the feeding amounts of PVA but seems to be independent of drying temperature. 3D outward capillary flow driven by the combination of contact surface pinning and continual interfacial evaporation induces the forming of core-shell foams. The enhanced interfacial photothermal effect and solar desalination performance using PVA/polypyrrole-coated MF as a Janus solar evaporator are demonstrated.

Microporous melamine-formaldehyde networks loaded on rice husks for dynamic removal of organic micropollutants.

The alteration of agricultural wastes into novel adsorbents can stimulate their scalability in realistic application, showing great economic and environmental advantages. Here, we proposed a strategy to engineer rice husk (RH) with microporous melamine-formaldehyde networks (MFNs) resins and the utilization for dynamic removal of organic micropollutants rapidly and efficiently. was pre-treated to acquire attractive surface and unique hierarchical porosity, endowing with surface functionalization and essential filtering properties. MFNs can be uniformly generated in-situ on the fully exposed cellulose backbones of the pre-treated RH. MFNs granules functionalized RH (RH@MFNs) exhibited high removal efficiencies over 90% within 30 min for the adsorption of hazardous organic compounds (e.g., phenolic and antibiotic micropollutants) in static tests. Experiment results and density functional theory (DFT) simulation revealed that the synergy of hydrogen bonding, π-πinteraction, and micropore preservation dominates the adsorption. Further dynamic adsorption experiments showed that the removal efficiency and equilibrium removal capacity towards bisphenol A by RH@MFNs packed bed up-flow column were 2.6 and 67 times higher than that of raw RH, respectively. The column adsorption fits well with the Thomas model and bed depth service time (BDST) kinetic model. The inherent macropores inside RH and the roughness caused by the spiky structures and mesopores outside RH, as well as the accumulated MFNs granules, can lead to local turbulence of water flow around RH@MFNs, enabling fast and efficient adsorption. This sustainable and cost-effective preparation of RH-based adsorbents sheds light on the rational design of biomass waste adsorbents for realistic wastewater.

Mineral weathering of iron ore tailings primed by Acidithiobacillus ferrooxidans and elemental sulfur under contrasting pH conditions.

The acidophilic sulfur oxidizing bacterium (SOB), Acidithiobacillus ferrooxidans, has been found to stimulate elemental sulfur (S0) oxidation and mineral weathering in alkaline Fe ore tailings. However, A. ferrooxidans growth and activities depend on the pH conditions surrounding their interfaces with minerals. The present study aimed to investigate how pH influences bacterial growth and functions in Fe ore tailings. A simulated aquatic 'homogeneous' incubation system was initially adjusted into acidic (pH 4), neutral (pH 7) and alkaline (pH 9) conditions, which mimicked the microenvironmental conditions of the water-cell-mineral interfaces in the tailings. It was found that A. ferrooxidans grew well and oxidised S0 under the prevailing and initially acidic conditions (pH < 6). These stimulated the weathering of biotite and amphibole-like minerals and the formation of nanosized jarosite and ferrihydrite-like minerals mediated by extracellular polymer substrate (EPS). In contrast, the initially neutral/alkaline pH conditions (i.e., pH > 7) with the presence of the alkaline tailings restricted SOB growth and functions in S0-oxidation and mineral weathering. These findings suggest that it is essential to prime acidic conditions in microenvironments to support SOB growth, activities, and functions toward mineral weathering in tailings, providing critical basis for involving SOB in eco-engineered pedogenesis in tailings.

Research progress of bile biomarkers and their immunoregulatory role in biliary tract cancers.

Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder carcinoma, originate from the biliary epithelium and have a poor prognosis. Surgery is the only choice for cure in the early stage of disease. However, most patients are diagnosed in the advanced stage and lose the chance for surgery. Early diagnosis could significantly improve the prognosis of patients. Bile has complex components and is in direct contact with biliary tract tumors. Bile components are closely related to the occurrence and development of biliary tract tumors and may be applied as biomarkers for BTCs. Meanwhile, arising evidence has confirmed the immunoregulatory role of bile components. In this review, we aim to summarize and discuss the relationship between bile components and biliary tract cancers and their ability as biomarkers for BTCs, highlighting the role of bile components in regulating immune response, and their promising application prospects.

Acidophilic Iron- and Sulfur-Oxidizing Bacteria, Acidithiobacillus ferrooxidans, Drives Alkaline pH Neutralization and Mineral Weathering in Fe Ore Tailings.

The neutralization of strongly alkaline pH conditions and acceleration of mineral weathering in alkaline Fe ore tailings have been identified as key prerequisites for eco-engineering tailings-soil formation for sustainable mine site rehabilitation. Acidithiobacillus ferrooxidans has great potential in neutralizing alkaline pH and accelerating primary mineral weathering in the tailings but little information is available. This study aimed to investigate the colonization of A. ferrooxidans in alkaline Fe ore tailings and its role in elemental sulfur (S0) oxidation, tailings neutralization, and Fe-bearing mineral weathering through a microcosm experiment. The effects of biological S0 oxidation on the weathering of alkaline Fe ore tailings were examined via various microspectroscopic analyses. It is found that (1) the A. ferrooxidans inoculum combined with the S0 amendment rapidly neutralized the alkaline Fe ore tailings; (2) A. ferrooxidans activities induced Fe-bearing primary mineral (e.g., biotite) weathering and secondary mineral (e.g., ferrihydrite and jarosite) formation; and (3) the association between bacterial cells and tailings minerals were likely facilitated by extracellular polymeric substances (EPS). The behavior and biogeochemical functionality of A. ferrooxidans in the tailings provide a fundamental basis for developing microbial-based technologies toward eco-engineering soil formation in Fe ore tailings.

Integrin CD11b Deficiency Aggravates Retinal Microglial Activation and RGCs Degeneration After Acute Optic Nerve Injury.

Neuroinflammation plays a vital role in the process of a variety of retinal ganglion cells (RGCs) degenerative diseases including traumatic optic neuropathy (TON). Retinal microglial activation is believed as a harbinger of TON, and robust microglial activation can aggravate trauma-induced RGCs degeneration, which ultimately leads to RGCs loss. Toll like receptor 4 (TLR4)-triggered inflammation is of great importance in retinal inflammatory response after optic nerve injury. CD11b on macrophage and brain microglia can inhibit TLR4-triggered inflammation. However, the functional role of CD11b in retinal microglia is not well understood. Here, using an optic nerve crush model and CD11b gene deficient mice, we found that CD11b protein expression was mainly on retinal microglia, significantly increased after optic nerve injury, and still maintained at a high level till at least 28 days post crush. Compared with wild type mice, following acute optic nerve injury, CD11b deficient retinae exhibited more exacerbated microglial activation, accelerated RGCs degeneration, less growth associated protein-43 expression, as well as more proinflammatory cytokines such as interleukin-6 and tumor necrosis factor α while less anti-inflammatory factors such as arginase-1 and interleukin-10 production. We conclude that CD11b is essential in regulating retinal microglial activation and neuroinflammatory responses after acute optic nerve injury, which is critical for subsequent RGCs degeneration and loss.

Retinal blood vessel-origin yes-associated protein (YAP) governs astrocytic maturation via leukaemia inhibitory factor (LIF).

OBJECTIVES: To testify that endothelial cells (ECs) induce astrocyte maturation by leukaemia inhibitory factor (LIF) secretion. MATERIALS AND METHODS: In vivo experiments, mice bearing floxed alleles of YAP were crossed with mice expressing a Cre recombinase driven by the endothelial Tek promoter (Tek-Cre) to finally obtain the following three genotypes: YAPf/f , Tek-Cre; YAPf/w , Tek-Cre; and YAPf/f . Retinal vascularization and astrocyte network were evaluated by whole-mount fluorescence and Western blotting. In vitro, experiments were performed in an astrocyte and human microvascular endothelial cell (HMEC-1) coculture model to analyse the mechanisms underlying the effect of endothelial YAP on astrocytes. RESULTS: In vivo, YAPf/f ;Tek-Cre mice showed delayed angiogenesis, sparse vessels and decreased glial fibrillary acidic protein (GFAP)+ astrocytes but aberrant growth of endothelial networks and immature astrocytes (platelet-derived growth factor A, PDGFRA+ astrocytes) overgrowth. In vitro, Yap deletion attenuated the LIF release that delayed the maturation of retinal astrocyte which was consistent with the results of HMEC-1-astrocyte coculture. The effect of YAP overexpression on LIF-LIFR axis in HMEC-1 interferes the GFAP expression of astrocyte. In contrast, LIF protein rescues the astrocytic GFAP expression when EC YAP was inhibited by siRNAs. CONCLUSIONS: We show that EC yes-associated protein (YAP) is not only a critical coactivator of Hippo signalling in retinal vessel development but also plays an essential role in retinal astrocyte maturation by regulating LIF production.

Rhizosphere modifications of iron-rich minerals and forms of heavy metals encapsulated in sulfidic tailings hardpan.

Hardpan caps formed after extensive weathering of the top layer of sulfidic tailings have been advocated to serve as physical barriers separating reactive tailings in depth and root zones above. However, in a hardpan-based root zone reconstructed with the soil cover, roots growing into contact with hardpan surfaces may induce the transformation of Fe-rich minerals and release potentially toxic elements for plant uptake. For evaluating this potential risk, two representative native species, Turpentine bush (Acacia chisholmii, AC) and Red Flinders grass (Iseilema vaginiflorum, RF), of which pre-cultured root mats were interfaced with thin discs of crushed hardpan minerals in the rhizosphere (RHIZO) test. After 35 days, the surface dissolution of hardpan minerals occurred and Fe-rich cement minerals were transformed from ferrihydrite-like minerals to goethite-like and Fe(III)-carboxylic complexes, as revealed by scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS) and synchrotron-based X-ray absorption fine structure spectroscopy (XAFS) analysis. This transformation may result from the functions of root exudates. The transformation of hardpan cement minerals caused the co-dissolution of Cu and Zn initially encapsulated in the cements and their uptake by plants. Nevertheless, only was the minority of the plant Cu and Zn transported into shoots.

Role of p53 in pseudorabies virus replication, pathogenicity, and host immune responses.

As a key cellular transcription factor that plays a central role in cellular responses to a broad range of stress factors, p53 has generally been considered as a host cell restriction factor for various viral infections. However, the defined roles of p53 in pseudorabies virus (PRV) replication, pathogenesis, and host responses remain unclear. In the present study, we initially constructed a p53 overexpressing a porcine kidney epithelial cell line (PK-15) to detect the effect of p53 on PRV replication in vitro. The results show that viral glycoprotein B (gB) gene copies and the titers of virus were significantly higher in p53 overexpressing PK-15 cells than in PK-15 and p53 inhibitor treated p53 overexpressing PK-15 cells. A similar result was also found in the p53 inhibitor PFT-α-treated PK-15 cells. We then examined the effects of p53 on PRV infection in vivo by using p53-knockout (p53-/-) mice. The results show that p53 knockout not only led to significantly reduced rates of mortality but also to reduced viral replication and development of viral encephalitis in the brains of mice following intracranial inoculation. Furthermore, we examined the effect of p53 knockout on the expression of the reported host cell regulators of PRV replication in the brains of mice by using RNA sequencing. The results show that p53 knockout downregulated the interferon (IFN) regulator genes, chemokine genes, and antiviral genes after PRV infection. This finding suggests that p53 positively regulates viral replication and pathogenesis both in vitro and in vivo. These findings offer novel targets of intrinsic host cell immunity for PRV infection.

Geochemical and mineralogical constraints in iron ore tailings limit soil formation for direct phytostabilization.

The present study aimed to characterize key physico-chemical and mineralogical attributes of magnetite iron (Fe) ore tailings to identify potential constraints limiting in situ soil formation and direct phytostabilization. Tailings of different age, together with undisturbed local native soils, were sampled from a magnetite mine in Western Australia. Tailings were extremely alkaline (pH > 9.0), with a lack of water stable aggregate and organic matter, and contained abundant primary minerals including mica (e.g., biotite), with low specific surface area (N2-BET around 1.2 m2 g-1). These conditions remained relatively unchanged after four years' aging under field conditions. Chemical extraction and spectroscopic analysis [e.g., X-ray diffraction (XRD) and synchrotron-based Fe K edge X-ray absorption fine structure spectroscopy (XAFS) analysis] revealed that the aging process decreased biotite-like minerals, but increased hematite and magnetite in the tailings. However, the aged tailings lacked goethite, a compound abundant in natural soils. Examination using backscattered-scanning electron microscope - energy dispersive X-ray spectrometry (BSE-SEM-EDS) revealed that aged tailings contained discrete sharp edged Fe-bearing minerals that did not physically integrate with other minerals (e.g., Si/Al bearing minerals). In contrast, Fe minerals in native soils appeared randomly distributed and closely amassed with Si/Al rich phyllosilicates, with highly eroded edges. The lack of labile organic matter and the persistence of alkaline-saline conditions may have significantly hindered the bioweathering of Fe-minerals and the biogenic formation of secondary Fe-minerals in tailings. However, there is signature that a native pioneer plant, Maireana brevifolia can facilitate the bioweathering of Fe-bearing minerals in tailings. We propose that eco-engineering inputs like organic carbon accumulation, together with the introduction of functional microbes and pioneer plants, should be adopted to accelerate bioweathering of Fe-bearing minerals as a priority for initiating in situ soil formation in the Fe ore tailings.

OVOL2 antagonizes TGF-ß signaling to regulate epithelial to mesenchymal transition during mammary tumor metastasis.

Great progress has been achieved in the study of the role of TGF-ß signaling in triggering epithelial-mesenchymal transition (EMT) in a variety of cancers; however, the regulation of TGF-ß signaling during EMT in mammary tumor metastasis has not been completely defined. In the present study, we demonstrated that OVOL2, a zinc finger transcription factor, inhibits TGF-ß signaling-induced EMT in mouse and human mammary tumor cells, as well as in mouse tumor models. Data from the Oncomine databases indicated a strong negative relationship between OVOL2 expression and breast cancer progression. Moreover, our experiments revealed that OVOL2 inhibits TGF-ß signaling at multiple levels, including inhibiting Smad4 mRNA expression and inducing Smad7 mRNA expression, blocking the binding between Smad4 and target DNA, and interfering with complex formation between Smad4 and Smad2/3. These findings reveal a novel mechanism that controls the TGF-ß signaling output level in vitro and in vivo. The modulation of these molecular processes may represent a strategy for inhibiting breast cancer invasion by restoring OVOL2 expression.

Yes-associated protein/TEA domain family member and hepatocyte nuclear factor 4-alpha (HNF4α) repress reciprocally to regulate hepatocarcinogenesis in rats and mice.

Great progress has been achieved in the study of Hippo signaling in regulating tumorigenesis; however, the downstream molecular events that mediate this process have not been completely defined. Moreover, regulation of Hippo signaling during tumorigenesis in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we systematically investigated the relationship between Yes-associated protein/TEA domain family member (YAP-TEAD) and hepatocyte nuclear factor 4-alpha (HNF4α) in the hepatocarcinogenesis of HCC cells. Our results indicated that HNF4α expression was negatively regulated by YAP1 in HCC cells by a ubiquitin proteasome pathway. By contrast, HNF4α was found to directly associate with TEAD4 to compete with YAP1 for binding to TEAD4, thus inhibiting the transcriptional activity of YAP-TEAD and expression of their target genes. Moreover, overexpression of HNF4α was found to significantly compromise YAP-TEAD-induced HCC cell proliferation and stem cell expansion. Finally, we documented the regulatory mechanism between YAP-TEAD and HNF4α in rat and mouse tumor models, which confirmed our in vitro results. CONCLUSION: There is a double-negative feedback mechanism that controls TEAD-YAP and HNF4α expression in vitro and in vivo, thereby regulating cellular proliferation and differentiation. Given that YAP acts as a dominant oncogene in HCC and plays a crucial role in stem cell homeostasis and tissue regeneration, manipulating the interaction between YAP, TEADs, and HNF4α may provide a new approach for HCC treatment and regenerative medicine. (Hepatology 2017;65:1206-1221).

miR-23a, miR-146a and miR-301a confer predisposition to Vogt-Koyanagi-Harada syndrome but not to Behcet's disease.

Ninety-eight miRNAs are involved in the immune response. However, the genetic roles of these miRNAs remain unclear in Behcet's disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aimed to explore the association and functional roles of copy number variants (CNV) in several miRNAs with BD and VKH syndrome. Genotyping of CNVs was examined by TaqMan PCR. The expression of miR-23a, transfection efficiency and cytokine production were measured by real-time PCR, flow cytometry or ELISA. First, replication and combined studies for miR-23a, miR-146a and miR-301a demonstrated a similar association with VKH syndrome (Combined: P = 5.53 × 10(-8); P = 8.43 × 10(-31); P = 9.23 × 10(-8), respectively). No association of CNVs of the above mentioned miRNAs was observed in BD patients. mRNA expression of miR-23a showed a positive association with its copy numbers. Additionally, individuals with high copy number of miR-23a show an increased production of interleukin-6 (IL-6), but not IL-8 and monocyte chemoattractant protein-1 (MCP-1) by stimulated PBMCs. miR-23a transfected ARPE-19 cells modulated the production of IL-6 and IL-8, but not MCP-1. Our results suggest that CNVs of miR-146a, miR-23a and miR-301a confer susceptibility to VKH syndrome, but not to BD. The contribution of miR-23a to VKH syndrome may be mediated by increasing the production of IL-6.

OVOL2, an Inhibitor of WNT Signaling, Reduces Invasive Activities of Human and Mouse Cancer Cells and Is Down-regulated in Human Colorectal Tumors.

BACKGROUND & AIMS: Activation of WNT signaling promotes the invasive activities of several types of cancer cells, but it is not clear if it regulates the same processes in colorectal cancer (CRC) cells, or what mechanisms are involved. We studied the expression and function of OVOL2, a member of the Ovo family of conserved zinc-finger transcription factors regulated by the WNT signaling pathway, in intestinal tumors of mice and human beings. METHODS: We analyzed the expression of OVOL2 protein and messenger RNA in CRC cell lines and tissue arrays, as well as CRC samples from patients who underwent surgery at Xiamen University in China from 2009 to 2012; clinical information also was collected. CRC cell lines (SW620) were infected with lentivirus expressing OVOL2, analyzed in migration and invasion assays, and injected into nude mice to assess tumor growth and metastasis. Tandem affinity purification was used to purify the OVOL2-containing complex from CRC cells; the complex was analyzed by liquid chromatography, tandem mass spectrometry, and immunoprecipitation experiments. Gene promoter activities were measured in luciferase reporter assays. We analyzed mice with an intestine-specific disruption of Ovol2 (Ovol2(flox/+) transgenic mice), as well as Apc(min/+) mice; these mice were crossed and analyzed. RESULTS: Analysis of data from patients indicated that the levels of OVOL2 messenger RNA were significantly lower in colon carcinomas than adenomas, and decreased significantly as carcinomas progressed from grades 2 to 4. Immunohistochemical analysis of a tissue array of 275 CRC samples showed a negative association between tumor stage and OVOL2 level. Overexpression of OVOL2 in SW620 cells decreased their migration and invasion, reduced markers of the epithelial-to-mesenchymal transition, and suppressed their metastasis as xenograft tumors in nude mice; knockdown of OVOL2 caused LS174T cells to transition from epithelial to mesenchymal phenotypes. OVOL2 bound T-cell factor (TCF)4 and ß-catenin, facilitating recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex; this inhibited expression of epithelial-to-mesenchymal transition-related genes regulated by WNT, such as SLUG, in CRC cell lines. OVOL2 was a downstream target of WNT signaling in LS174T and SW480 cells. The OVOL2 promoter was hypermethylated in late-stage CRC specimens from patients and in SW620 cells; hypermethylation resulted in OVOL2 down-regulation and an inability to inhibit WNT signaling. Disruption of Ovol2 in Apc(min/+) mice increased WNT activity in intestinal tissues and the formation of invasive intestinal tumors. CONCLUSIONS: OVOL2 is a colorectal tumor suppressor that blocks WNT signaling by facilitating the recruitment of histone deacetylase 1 to the TCF4-ß-catenin complex. Strategies to increase levels of OVOL2 might be developed to reduce colorectal tumor progression and metastasis.

FAS Gene Copy Numbers are Associated with Susceptibility to Behçet Disease and VKH Syndrome in Han Chinese.

Previous studies have identified that disturbed apoptosis was involved in the pathogenesis of Behçet disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome. This study aims to investigate whether copy number variations of apoptosis-related genes, including FAS, CASPASE8, CASPASE3, and BCL2, are associated with BD and VKH syndrome in Han Chinese. A two-stage association study was performed in 1,014 BD patients, 1,051 VKH syndrome patients, and 2,076 healthy controls. TaqMan(®) Copy Number Assays and real-time PCR were performed. The first-stage study showed that increased frequency of high FAS copy number (>2) was found in BD (P = 1.05 × 10(-3) ) and VKH syndrome (P = 2.56 × 10(-3) ). Replication and combined study confirmed the association of high copy number (>2) of FAS with BD (P = 3.35 × 10(-8) ) and VKH syndrome (P = 9.77 × 10(-8) ). A significant upregulated mRNA expression of FAS was observed in anti-CD3/CD28 antibodies-stimulated CD4(+) T cells from individuals carrying a high gene copy number (>2) as compared to normal diploid 2 copy number carriers (P = 0.004). Moreover, the mRNA expression of FAS both in active patients with BD and VKH syndrome was significantly higher than that in controls (P = 0.001 and P = 0.007, respectively). Our findings suggest that a high copy number of FAS gene confers risk for BD and VKH syndrome.

Decreased interleukin-37 expression in Vogt-Koyanagi-Harada disease and upregulation following immunosuppressive treatment.

Interleukin-37 (IL-37) is emerging as an important inhibitor of immune response. This study was set up to investigate the expression of IL-37 in Vogt-Koyanagi-Harada (VKH) disease and to explore its possible regulatory role during inflammation. Twenty-four untreated active VKH patients, 10 VKH patients receiving corticosteroids and cyclosporin A (CsA), and 35 healthy controls were included in this study. IL-37 expression in lipopolysaccharides (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from these 3 groups was assayed by real-time polymerase chain reaction (RT-PCR) and flow cytometry. Cytokines in the supernatants of stimulated PBMCs and CD4(+) T cells were assayed by enzyme-linked immunosorbent assay (ELISA). Mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) activation were measured by flow cytometry. VKH patients showed a decreased IL-37 and IL-27 expression and increased IL-1ß, IL-6, and tumor necrosis factor-alpha (TNF-α) levels in PBMC culture supernatants. IL-37 significantly inhibited the production of IL-1ß, IL-6, and TNF-α, but induced IL-27 expression. VKH patients treated with corticosteroids combined with CsA showed a regression of the intraocular inflammation, and treatment was associated with an enhanced IL-37 production. IL-37 did not affect the production of IL-17, interferon-gamma (IFN-γ), or IL-10 from CD4(+) T cells. The present study suggests that a decreased IL-37 expression in VKH patients is associated with a reduced control of the inflammatory response. Treatment of VKH patients with corticosteroids and CsA is associated with an increased expression of IL-37, which suggests that corticosteroids and CsA may partly exert their immunosuppressive effect by upregulating IL-37 production.

FoxO1 gene confers genetic predisposition to acute anterior uveitis with ankylosing spondylitis.

PURPOSE: Recent studies have shown that a decrease of regulatory T (Treg) cells may contribute to the activity of acute anterior uveitis (AAU) and ankylosing spondylitis (AS). A number of immunogenetic factors including IL2RA, miR-27a, miR-182, and FoxO1 are associated with Treg cell function. In this study, we investigated the association between polymorphisms of these genes and AAU with or without AS in a Chinese Han population. METHODS: Using PCR-restricted fragment length polymorphism (RFLP) assay, a two-stage association study was performed in 680 AAU patients with or without AS and 1280 controls. Gene expression was quantified by real-time PCR. RESULTS: In the first stage study, an association analysis of 10 single nucleotide polymorphisms (SNPs) was performed in 230 AAU patients with AS, 240 AAU patients without AS, and 650 controls. The results showed significantly increased frequencies of the FoxO1/rs2297626 AA genotype and A allele in AAU patients with AS (AA genotype: P = 6.23 × 10(-5), odds ratio [OR] = 1.86; A allele: P = 2.17 × 10(-4), OR = 1.53). No significant association of the other 9 SNPs with AAU with or without AS was observed. In the second stage study, an association analysis of FoxO1/rs2297626 was performed in 210 AAU patients with AS and 630 controls. The second stage and combined studies confirmed the association of FoxO1/rs2297626 with AAU with AS (AA genotype: P = 3.45 × 10(-8), OR = 1.85; A allele: P = 1.55 × 10(-7), OR = 1.55). CONCLUSION: This study suggests that FoxO1, but not miR-27a, miR-182, and IL2RA, contributes to the genetic susceptibility of AAU with AS, but none of the tested polymorphisms confer risk to AAU without AS.