Resveratrol-Mediated Gold-Nanoceria Synthesis as Green Nanomedicine for Phytotherapy of Hepatocellular Carcinoma

In the present study, resveratrol was used to prepare complexes of cerium and nanoceria, also coated with gold (CeO2@Au core-shells) to improve the surface interactions in physiological conditions.The CeO2@Au core-shells were characterized using powder X-ray diffraction (PXRD), Fourier transforms infrared spectroscopy (FTIR), transmission electron microscope (TEM) analysis, dynamic light scattering (DLS) and ζ potential.The experiment was led to the successful synthesis of nanosized CeO2@Au core-shells, although agglomeration of particles caused the distribution of the larger particles. The TEM analysis demonstrated the particles sizes ranged from 20 nm to 170 nm. Moreover, the PXRD analysis showed that both nanoceria and gold with the same crystal systems and space groups. To investigate the anticancer activity of the CeO2@Au core-shells, the cytotoxicity of the nanoparticles was investigated against liver cancerous cell lines (HepG2).The results indicated biosynthesized NCs have significant cellular toxicity properties against HepG2 and could be utilized in hepatocarcinoma therapy. Furthe

Detection of a Cis eQTL Controlling BMCO1 Gene Expression Leads to the Identification of a QTG for Chicken Breast Meat Color

Classical quantitative trait loci (QTL) analysis and gene expression QTL (eQTL) were combined to identify the causal gene (or QTG) underlying a highly significant QTL controlling the variation of breast meat color in a F2 cross between divergent high-growth (HG) and low-growth (LG) chicken lines. Within this meat quality QTL, BCMO1 (Accession number GenBank: AJ271386), encoding the β-carotene 15, 15′-monooxygenase, a key enzyme in the conversion of β-carotene into colorless retinal, was a good functional candidate. Analysis of the abundance of BCMO1 mRNA in breast muscle of the HG x LG F2 population allowed for the identification of a strong cis eQTL. Moreover, reevaluation of the color QTL taking BCMO1 mRNA levels as a covariate indicated that BCMO1 mRNA levels entirely explained the variations in meat color. Two fully-linked single nucleotide polymorphisms (SNP) located within the proximal promoter of BCMO1 gene were identified. Haplotype substitution resulted in a marked difference in BCMO1 promoter activity in vitro. The association study in the F2 population revealed a three-fold difference in BCMO1 expression leading to a difference of 1 standard deviation in yellow color between the homozygous birds at this haplotype. This difference in meat yellow color was fully consistent with the difference in carotenoid content (i.e. lutein and zeaxanthin) evidenced between the two alternative haplotypes. A significant association between the haplotype, the level of BCMO1 expression and the yellow color of the meat was also recovered in an unrelated commercial broiler population. The mutation could be of economic importance for poultry production by making possible a gene-assisted selection for color, a determining aspect of meat quality. Moreover, this natural genetic diversity constitutes a new model for the study of β-carotene metabolism which may act upon diverse biological processes as precursor of the vitamin A

Identification of QTL controlling meat quality traits in an F2 cross between two chicken lines selected for either low or high growth rate

Meat technological traits (i.e. meat pH, water retention and color) are important considerations for improving further processing of chicken meat. These quality traits were originally characterized in experimental lines selected for high (HG) and low (LG) growth. Presently, quantitative trait loci (QTL) for these traits were analyzed in an F2 population issued from the HG × LG cross. A total of 698 animals in 50 full-sib families were genotyped for 108 microsatellite markers covering 21 linkage groups. The HG and LG birds exhibit large differences in body weight and abdominal fat content. Several meat quality traits [pH at 15 min post-slaughter (pH15) and ultimate pH (pHu), breast color-redness (BCo-R) and breast color-yellowness (BCo-Y)] were lower in HG chickens. In contrast, meat color-lightness (BCo-L) was higher in HG chickens, whereas meat drip loss (DL) was similar in both lines. HG birds were more active on the shackle line. Association analyses were performed using maximum-likelihood interval mapping in QTLMAP. Five genome-wide significant QTLs were revealed: two for pH15 on GGA1 and GGA2, one for DL on GGA1, one for BCo-R and one for BCo-Y both on GGA11. In addition, four suggestive QTLs were identified by QTLMAP for BCo-Y, pHu, pH15 and DL on GGA1, GGA4, GGA12 and GGA14, respectively. The QTL effects, averaged on heterozygous families, ranged from 12 to 31% of the phenotypic variance. Further analyses with QTLExpress confirmed the two genome-wide QTLs for meat color on GGA11, failed to identify the genome-wide QTL for pH15 on GGA2, and revealed only suggestive QTLs for pH15 and DL on GGA1. However, QTLExpress qualified the QTL for pHu on GGA4 as genome-wide. The present study identified genome-wide significant QTLs for all meat technological traits presently assessed in these chickens, except for meat lightness. This study highlights the effects of divergent selection for growth rate on some behavioral traits, muscle biochemistry and ultimately meat quality traits. Several QTL regions were identified that are worthy of further characterization. Some QTLs may in fact co-localize, suggesting pleiotropic effects for some chromosomal regions.https://doi.org/10.1186/1471-2164-8-15

NHLRC2 variants identified in patients with fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) : characterisation of a novel cerebropulmonary disease

A novel multi-organ disease that is fatal in early childhood was identified in three patients from two non-consanguineous families. These children were born asymptomatic but at the age of 2 months they manifested progressive multi-organ symptoms resembling no previously known disease. The main clinical features included progressive cerebropulmonary symptoms, malabsorption, progressive growth failure, recurrent infections, chronic haemolytic anaemia and transient liver dysfunction. In the affected children, neuropathology revealed increased angiomatosis-like leptomeningeal, cortical and superficial white matter vascularisation and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and previously undescribed granuloma-like lesions were observed in the lungs. Hepatomegaly, steatosis and collagen accumulation were detected in the liver. A whole-exome sequencing of the two unrelated families with the affected children revealed the transmission of two heterozygous variants in the NHL repeat-containing protein 2 (NHLRC2); an amino acid substitution p.Asp148Tyr and a frameshift 2-bp deletion p.Arg201GlyfsTer6. NHLRC2 is highly conserved and expressed in multiple organs and its function is unknown. It contains a thioredoxin-like domain; however, an insulin turbidity assay on human recombinant NHLRC2 showed no thioredoxin activity. In patient-derived fibroblasts, NHLRC2 levels were low, and only p.Asp148Tyr was expressed. Therefore, the allele with the frameshift deletion is likely non-functional. Development of the Nhlrc2 null mouse strain stalled before the morula stage. Morpholino knockdown of nhlrc2 in zebrafish embryos affected the integrity of cells in the midbrain region. This is the first description of a fatal, early-onset disease; we have named it FINCA disease based on the combination of pathological features that include fibrosis, neurodegeneration, and cerebral angiomatosis.Peer reviewe

Publisher Correction: A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients

The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'

A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene.

BACKGROUND: Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. METHODS: Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. RESULTS: In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7-19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. CONCLUSIONS: This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families

Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities

<p>Whole-exome sequencing (WES) represents a significant breakthrough in the field of human genetics. This technology has largely contributed to the identification of new disease-causing genes and is now entering clinical laboratories. WES represents a powerful tool for diagnosis and could reduce the ‘diagnostic odyssey’ for many patients. In this review, we present a technical overview of WES analysis, variants annotation and interpretation in a clinical setting. We evaluate the usefulness of clinical WES in different clinical indications, such as rare diseases, cancer and complex diseases. Finally, we discuss the efficacy of WES as a diagnostic tool and the impact on patient management.</p