Temporal changes in brain morphology related to inflammation and schizophrenia: an omnigenic Mendelian randomization study.

BACKGROUND: Over the past several decades, more research focuses have been made on the inflammation/immune hypothesis of schizophrenia. Building upon synaptic plasticity hypothesis, inflammation may contribute the underlying pathophysiology of schizophrenia. Yet, pinpointing the specific inflammatory agents responsible for schizophrenia remains a complex challenge, mainly due to medication and metabolic status. Multiple lines of evidence point to a wide-spread genetic association across genome underlying the phenotypic variations of schizophrenia. METHOD: We collected the latest genome-wide association analysis (GWAS) summary data of schizophrenia, cytokines, and longitudinal change of brain. We utilized the omnigenic model which takes into account all genomic SNPs included in the GWAS of trait, instead of traditional Mendelian randomization (MR) methods. We conducted two round MR to investigate the inflammatory triggers of schizophrenia and the resulting longitudinal changes in the brain. RESULTS: We identified seven inflammation markers linked to schizophrenia onset, which all passed the Bonferroni correction for multiple comparisons (bNGF, GROA(CXCL1), IL-8, M-CSF, MCP-3 (CCL7), TNF-ß, CRP). Moreover, CRP were found to significantly influence the linear rate of brain morphology changes, predominantly in the white matter of the cerebrum and cerebellum. CONCLUSION: With an omnigenic approach, our study sheds light on the immune pathology of schizophrenia. Although these findings need confirmation from future studies employing different methodologies, our work provides substantial evidence that pervasive, low-level neuroinflammation may play a pivotal role in schizophrenia, potentially leading to notable longitudinal changes in brain morphology.

Hydrolysis-Induced Cu2O Networks and the Triggered Peroxidase-Mimic Activity by Cr6+ under Neutral Conditions.

The current small-scale synthesis and relatively large size of Cu2O have limited its practical applications. Herein, we developed a hydrolysis strategy to prepare phase-pure Cu2O networks composed of small granules (ca. 25 nm) on a gram scale. The preparation involves in situ hydrolyzing the Hx[CuxCl2x] complexes prereduced in N,N'-dimethylformamide (DMF). The DMF-soluble Hx[CuxCl2x] complexes are critical for the homogeneous nucleation of CuCl seeds and subsequent hydrolysis, allowing for separate control over the nucleation and growth stages to regulate the formation of Cu2O networks. The novel Cu2O networks possess numerous exposed active sites and hierarchical porosities, conferring high catalytic activity and fast mass transfer capability. The inherent peroxidase-mimic activity of Cu2O is severely inhibited under neutral conditions but can be triggered by Cr6+, enabling the colorimetric assay of Cr6+ with the assistance of the oxidation-induced color change of 3,3',5,5'-tetramethylbenzidine. Through density functional theory calculation, we confirmed that the attachment of Cr6+ on the Cu2O surface reduced the dissociation energy of H2O2, enhancing the enzyme-mimic activity. The colorimetric detection method demonstrated a sensitive and specific assay capability for Cr6+ (LOD = 0.095 µM). Our work offers a straightforward protocol for novel design of metal or metal-based nanomaterials for nanozymes or other applications.

Ultrasensitive and visual detection of Feline herpesvirus type-1 and Feline calicivirus using one-tube dRPA-Cas12a/Cas13a assay.

BACKGROUND: Feline herpesvirus type 1 (FHV) and Feline calicivirus (FCV) are the primary co-infecting pathogens that cause upper respiratory tract disease in cats. However, there are currently no visual detection assays available for on-site testing. Here, we develop an ultrasensitive and visual detection method based on dual recombinase polymerase amplification (dRPA) reaction and the hybrid Cas12a/Cas13a trans-cleavage activities in a one-tube reaction system, referred to as one-tube dRPA-Cas12a/Cas13a assay. RESULTS: The recombinant plasmid DNAs, crRNAs, and RPA oligonucleotides targeting the FCV ORF1 gene and FHV-1 TK gene were meticulously prepared. Subsequently, dual RPA reactions were performed followed by screening of essential reaction components for hybrid CRISPR-Cas12a (targeting the FHV-1 TK gene) and CRISPR-Cas13a (targeting the FCV ORF1 gene) trans-cleavage reaction. As a result, we successfully established an ultra-sensitive and visually detectable method for simultaneous detection of FCV and FHV-1 nucleic acids using dRPA and CRISPR/Cas-powered technology in one-tube reaction system. Visual readouts were displayed using either a fluorescence detector (Fluor-based assay) or lateral flow dipsticks (LDF-based assay). As expected, this optimized assay exhibited high specificity towards only FHV-1 and FCV without cross-reactivity with other feline pathogens while achieving accurate detection for both targets with limit of detection at 2.4 × 10- 1 copies/µL for the FHV-1 TK gene and 5.5 copies/µL for the FCV ORF1 gene, respectively. Furthermore, field detection was conducted using the dRPA-Cas12a/Cas13a assay and the reference real-time PCR methods for 56 clinical samples collected from cats with URTD. Comparatively, the results of Fluor-based assay were in exceptional concordance with the reference real-time PCR methods, resulting in high sensitivity (100% for both FHV-1 and FCV), specificity (100% for both FHV-1 and FCV), as well as consistency (Kappa values were 1.00 for FHV-1 and FCV). However, several discordant results for FHV-1 detection were observed by LDF-based assay, which suggests its prudent use and interpretaion for clinical detection. In spite of this, incorporating dRPA-Cas12a/Cas13a assay and visual readouts will facilitate rapid and accurate detection of FHV-1 and FCV in resource-limited settings. CONCLUSIONS: The one-tube dRPA-Cas12a/Cas13a assay enables simultaneously ultrasensitive and visual detection of FHV-1 and FCV with user-friendly modality, providing unparalleled convenience for FHV-1 and FCV co-infection surveillance and decision-making of URTD management.

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.

The interactions between host genome and gut microbiome increase the risk of psychiatric disorders: Mendelian randomization and biological annotation.

BACKGROUND: The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association studies on human genome and gut microbiome (mbGWAS) have revealed important host-microbiome interactions. However, establishing causal relationships between specific gut microbiome features and psychological conditions remains challenging due to insufficient sample sizes of previous studies of mbGWAS. METHODS: Cross-cohort meta-analysis (via METAL) and multi-trait analysis (via MTAG) were used to enhance the statistical power of mbGWAS for identifying genetic variants and genes. Using two large mbGWAS studies (7,738 and 5,959 participants respectively) and12 disease-specific studies from the Psychiatric Genomics Consortium (PGC), we performed bidirectional two-sample mendelian randomization (MR) analyses between microbial features and psychiatric diseases (up to 500,199 individuals). Additionally, we conducted downstream gene- and gene-set-based analyses to investigate the shared biology linking gut microbiota and psychiatric diseases. RESULTS: METAL and MTAG conducted in mbGWAS could boost power for gene prioritization and MR analysis. Increases in the number of lead SNPs and mapped genes were witnessed in 13/15 species and 5/10 genera after using METAL, and MTAG analysis gained an increase in sample size equivalent to expanding the original samples from 7% to 63%. Following METAL use, we identified a positive association between Bacteroides faecis and ADHD (OR, 1.09; 95 %CI, 1.02-1.16; P = 0.008). Bacteroides eggerthii and Bacteroides thetaiotaomicron were observed to be positively associated with PTSD (OR, 1.11; 95 %CI, 1.03-1.20; P = 0.007; OR, 1.11; 95 %CI, 1.01-1.23; P = 0.03). These findings remained stable across statistical models and sensitivity analyses. No genetic liabilities to psychiatric diseases may alter the abundance of gut microorganisms.Using biological annotation, we identified that those genes contributing to microbiomes (e.g., GRIN2A and RBFOX1) are expressed and enriched in human brain tissues. CONCLUSIONS: Our statistical genetics strategy helps to enhance the power of mbGWAS, and our genetic findings offer new insights into biological pleiotropy and causal relationship between microbiota and psychiatric diseases.

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.

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.

Phenotypic differences among and within extant populations of Chrysanthemum arcticum L. and C. a. subsp. arcticum.

BACKGROUND: Chrysanthemum arcticum, arctic daisy and its two subspecies (Chrysanthemum arcticum subsp. arcticum, Chrysanthemum arcticum subsp. polaré) are the only chrysanthemum species native to North America. A study on species' variation in morphological and diagnostic traits is important to link morphological traits with previously described single nucleotide polymorphism (SNP) markers, particularly when the genomes are sequenced. The purpose of this study was to establish phenotypic differences and soil conditions among wild C. arcticum and C. a. subsp. arcticum populations, when grown in a uniform environment for two years, for potential linkages with our SNP library. Sixteen quantitative morphological traits and five qualitative morphological traits were investigated for 255 individuals from nine C. arcticum populations and 326 individuals from 21 C. a. subsp. arcticum populations. RESULTS: In long-day controlled environment, C. arcticum flowering rate was 0% in Year 1, increased to 2.7% in Year 2, while C. a. subsp. arcticum flowering rate was 98.5% in Year 2. Two distinct clusters, distributed by taxonomic classification, were detected by Principal component analysis (PCoA) for 551 individuals from C. arcticum and C. a. subsp. arcticum. Pearson's correlation coefficient analysis indicated a positive and significant correlation between plant height, flower fresh and dry weights. Flower fresh weights were correlated with Δflower weight, while inflorescence length had showed a negative correlation with leaf number. Soil samples had high Na levels along with heavy metals. Thus, the species are salt-tolerant. CONCLUSION: A high level of salt tolerance (Na) is tolerated by these maritime species which is a unique trait in Chrysanthemum. A new diagnostic trait of inflorescence length was discovered to distinguish among C. arcticum and C. a. subsp. arcticum. Significant flowering differences occurred among the species C. arcticum and C. a. subsp. arcticum under same photoperiodic environment, including flowering rates and visible bud date. This study on the species' variation in morphological and diagnostic traits is of importance to link morphological traits with single nucleotide polymorphism (SNP) markers.

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.

Chemodiversity of Dissolved Organic Matter and Its Molecular Changes Driven by Rhizosphere Activities in Fe Ore Tailings Undergoing Eco-Engineered Pedogenesis.

Dissolved organic matter (DOM) plays an important role in soil structure and biogeochemical function development, which are fundamental for the eco-engineering of tailings-soil formation to underpin sustainable tailings rehabilitation. In the present study, we have characterized the DOM composition and its molecular changes in an alkaline Fe ore tailing primed with organic matter (OM) amendment and plant colonization. The results demonstrated that microbial OM decomposition dramatically increased DOM richness and average molecular weight, as well as its degree of unsaturation, aromaticity, and oxidation in the tailings. Plant colonization drove molecular shifts of DOM by depleting the unsaturated compounds with a high value of nominal oxidation state of carbon (NOSC), such as tannin-like and carboxyl-rich polycyclic-like compounds. This may be partially related to their sequestration by secondary Fe-Si minerals formed from rhizosphere-driven mineral weathering. Furthermore, the molecular shifts of DOM may have also resulted from plant-regulated microbial community changes, which further influenced DOM molecules through microbial-DOM interactions. These findings contribute to the understanding of DOM biogeochemistry and ecofunctionality in the tailings during early pedogenesis driven by OM input and pioneer plant/microbial colonization, providing an important basis for the development of strategies and technologies toward the eco-engineering of tailings-soil formation.

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.

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.

Organic Matter Amendment and Plant Colonization Drive Mineral Weathering, Organic Carbon Sequestration, and Water-Stable Aggregation in Magnetite Fe Ore Tailings.

The formation of water-stable aggregates in finely textured and polymineral magnetite Fe ore tailings is one of the critical processes in eco-engineering tailings into soil-like substrates as a new way to rehabilitate the tailings. Organic matter (OM) amendment and plant colonization are considered to be effective in enhancing water-stable aggregation, but the underlying mechanisms have not yet been elucidated. The present study aimed to characterize detailed changes in physicochemistry, Fe-bearing mineralogy, and organo-mineral interactions in magnetite Fe ore tailings subject to the combined treatments of OM amendment and plant colonization, by employing various microspectroscopic methods, including synchrotron-based X-ray absorption fine structure spectroscopy and nanoscale secondary ion mass spectroscopy. The results indicated that OM amendment and plant colonization neutralized the tailings' alkaline pH and facilitated water-stable aggregate formation. The resultant aggregates were consequences of ligand-promoted bioweathering of primary Fe-bearing minerals (mainly biotite-like minerals) and the formation of secondary Fe-rich mineral gels. Especially, the sequestration of OM (rich in carboxyl, aromatic, and/or carbonyl C) by Fe-rich minerals via ligand-exchange and/or hydrophobic interactions contributed to the aggregation. These findings have uncovered the processes and mechanisms of water-stable aggregate formation driven by OM amendment and plant colonization in alkaline Fe ore tailings, thus providing important basis for eco-engineered pedogenesis in the tailings.

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).

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.

Magnetite recovery from copper tailings increases arsenic distribution in solution phase and uptake in native grass.

Reprocessing magnetite-rich copper (Cu) tailings prompted a concern about arsenic (As) risks in seepage water and revegetated plants at Ernest Henry Cu Mine (EHM) in North Queensland, Australia, due to the closely coupled relationship between iron (Fe) minerals and As mobility. The magnetite removal alone significantly decreased the content of crystalline Fe minerals and the maximum arsenate (As(V)) sorption capacity of the resultant tailings. A glasshouse experiment with native grass Red Flinders (Iseilema Vaginiflorum) was conducted with the reprocessed (low magnetite (LM)) and original (high magnetite (HM)) tailings, which were amended with 5% sugarcane residue (SR) as a basal treatment in combination with 0, 1 and 5% pine-biochar (BC). The organic matter treatments and plant growth stimulated the formation of secondary Fe minerals. The amount of extractable amorphous Fe in the amended and revegetated HM tailings was significantly higher than those in the LM. Arsenic forms in the specifically sorbed and the sorbed by amorphous Fe oxides were significantly increased by the SR amendment in the LM tailings, but which were decreased in the HM, compared to the unamended tailings. Soluble As levels in the porewater of the LM under revegetation were significantly higher (300-1150 µg As L-1) than those (up to 45-90 µg As L-1) in HM tailings in the same treatment, which led to the higher As concentrations in the plants grown in the LM tailings. In particular, root As concentration (62-146 mg kg-1) in the LM tailings was almost a magnitude higher than those (8-17 mg kg-1) in the HM. The present results confirmed the initial expectation that the recovery of magnetite from the Cu tailings significantly elevated the risk of As solubility in the tailings by decreasing As sorption capacity and increasing soluble As levels. Thus, it would be beneficial to retain high contents of magnetite in the top layer (e.g., root zone) of the Cu tailings for managing As risk and revegetation in the future.

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.

The Wnt-ß-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.

Wnt signalling through ß-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-ß-catenin pathway. Expression studies indicated that the Wnt-ß-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-ß-catenin pathway. Loss of function of Lin28 impairs Wnt-ß-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-ß-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-ß-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-ß-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-ß-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-ß-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.

A double-negative feedback loop between Wnt-ß-catenin signaling and HNF4α regulates epithelial-mesenchymal transition in hepatocellular carcinoma.

Wnt-ß-catenin signaling participates in the epithelial-mesenchymal transition (EMT) in a variety of cancers; however, its involvement in hepatocellular carcinoma (HCC) and downstream molecular events is largely undefined. HNF4α is the most prominent and specific factor maintaining the differentiation of hepatic lineage cells and a potential EMT regulator in HCC cells. However, the molecular mechanisms by which HNF4α maintains the differentiated liver epithelium and inhibits EMT have not been completely defined. In this study, we systematically explored the relationship between Wnt-ß-catenin signaling and HNF4α in the EMT process of HCC cells. Our results indicated that HNF4α expression was negatively regulated during Wnt-ß-catenin signaling-induced EMT through Snail and Slug in HCC cells. In contrast, HNF4α was found to directly associate with TCF4 to compete with ß-catenin but facilitate transcription co-repressor activities, thus inhibiting expression of EMT-related Wnt-ß-catenin targets. Moreover, HNF4α may control the switch between the transcriptional and adhesion functions of ß-catenin. Overexpression of HNF4α was found to completely compromise the Wnt-ß-catenin-signaling-induced EMT phenotype. Finally, we determined the regulation pattern between Wnt-ß-catenin signaling and HNF4α in rat tumor models. Our studies have identified a double-negative feedback mechanism controlling Wnt-ß-catenin signaling and HNF4α expression in vitro and in vivo, which sheds new light on the regulation of EMT in HCC. The modulation of these molecular processes may be a method of inhibiting HCC invasion by blocking Wnt-ß-catenin signaling or restoring HNF4α expression to prevent EMT.