Functional expression of NF1 tumor suppressor protein: association with keratin intermediate filaments during the early development of human epidermis

BACKGROUND: NF1 refers to type 1 neurofibromatosis syndrome, which has been linked with mutations of the large NF1 gene. NF1 tumor suppressor protein, neurofibromin, has been shown to regulate ras: the NF1 protein contains a GTPase activating protein (GAP) related domain which functions as p21rasGAP. Our studies have previously demonstrated that the NF1 protein forms a high affinity association with cytokeratin 14 during the formation of desmosomes and hemidesmosomes in cultured keratinocytes. METHODS: The expression of NF1 protein was studied in developing human epidermis using western transfer analysis, indirect immunofluorescence, confocal laser scanning microscopy, immunoelectron microscopy, and in situ hybridization. RESULTS: The expression of NF1 protein was noted to be highly elevated in the periderm at 8 weeks estimated gestational age (EGA) and in the basal cells at 8–14 weeks EGA. During this period, NF1 protein was associated with cytokeratin filaments terminating to desmosomes and hemidesmosomes. NF1 protein did not display colocalization with α-tubulin or actin of the cytoskeleton, or with adherens junction proteins. CONCLUSIONS: These results depict an early fetal period when the NF1 tumor suppressor is abundantly expressed in epidermis and associated with cytokeratin filaments. This period is characterized by the initiation of differentiation of the basal cells, maturation of the basement membrane zone as well as accentuated formation of selected cellular junctions. NF1 tumor suppressor may function in the regulation of epidermal histogenesis via controlling the organization of the keratin cytoskeleton during the assembly of desmosomes and hemidesmosomes

Aflatoxin B1 Degradation by Stenotrophomonas Maltophilia and Other Microbes Selected Using Coumarin Medium#

Aflatoxin B1 (AFB1) is one of the most harmful mycotoxins in animal production and food industry. A safe, effective and environmentally sound detoxification method is needed for controlling this toxin. In this study, 65 samples were screened from various sources with vast microbial populations using a newly developed medium containing coumarin as the sole carbon source. Twenty five single-colony bacterial isolates showing AFB1 reduction activity in a liquid culture medium were selected from the screen. Isolate 35-3, obtained from tapir feces and identified to be Stenotrophomonas maltophilia, reduced AFB1 by 82.5% after incubation in the liquid medium at 37 °C for 72 h. The culture supernatant of isolate 35-3 was able to degrade AFB1 effectively, whereas the viable cells and cell extracts were far less effective. Factors influencing AFB1 degradation by the culture supernatant were investigated. Activity was reduced to 60.8% and 63.5% at 20 °C and 30 °C, respectively, from 78.7% at 37 °C. The highest degradation rate was 84.8% at pH 8 and the lowest was only 14.3% at pH 4.0. Ions Mg2+ and Cu2+ were activators for AFB1 degradation, however ion Zn2+ was a strong inhibitor. Treatments with proteinase K, proteinase K plus SDS and heating significantly reduced or eradicated the degradation activity of the culture supernatant. The results indicated that the degradation of AFB1 by S. maltophilia 35-3 was enzymatic and could have a great potential in industrial applications

Analysis of polycyclic aromatic hydrocarbons in atmospheric particulate samples by microwaveassisted extraction and liquid chromatography

A methodology based on microwave-assisted extraction (MAE) and LC with fluorescence detection (FLD) was investigated for the efficient determination of 15 polycyclic aromatic hydrocarbons (PAHs) regarded as priority pollutants by the US Environmental Protection Agency and dibenzo(a,l)pyrene in atmospheric particulate samples. PAHs were successfully extracted from real outdoor particulate matter (PM) samples with recoveries ranging from 81.4±8.8 to 112.0±1.1%, for all the compounds except for naphthalene (62.3±18.0%) and anthracene (67.3±5.7%), under the optimum MAE conditions (30.0 mL of ACN for 20 min at 110ºC). No clean-up steps were necessary prior to LC analysis. LOQs ranging from 0.0054 ng/m3 for benzo( a)anthracene to 0.089 ng/m3 for naphthalene were reached. The validated MAE methodology was applied to the determination of PAHs from a set of real world PM samples collected in Oporto (north of Portugal). The sum of particulate-bound PAHs in outdoor PM ranged from 2.5 and 28 ng/m3.http://recipp.ipp.pt/handle/10400.22/289

How does risk flow in the credit default swap market?

We develop a framework to analyse the credit default swap (CDS) market as a network of risk transfers among counterparties. From a theoretical perspective, we introduce the notion of flow-of-risk and provide sufficient conditions for a bow-tie network architecture to endogenously emerge as a result of intermediation. This architecture shows three distinct sets of counterparties: (i) Ultimate Risk Sellers (URS), (ii) Dealers (indirectly connected to each other), (iii) Ultimate Risk Buyers (URB). We show that the probability of widespread distress due to counterparty risk is higher in a bow-tie architecture than in more fragmented network structures. Empirically, we analyse a unique global dataset of bilateral CDS exposures on major sovereign and financial reference entities in 2011–2014. We find the presence of a bow-tie network architecture consistently across both reference entities and time, and that the flow-of-risk originates from a large number of URSs (e.g. hedge funds) and ends up in a few leading URBs, most of which are non-banks (in particular asset managers). Finally, the analysis of the CDS portfolio composition of the URBs shows a high level of concentration: in particular, the top URBs often show large exposures to potentially correlated reference entities

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE-Glycated hemoglobin (HbA(1c)), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA(1c). We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA(1c) levels.RESEARCH DESIGN AND METHODS-We studied associations with HbA(1c) in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA(1c) loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening.RESULTS-Ten loci reached genome-wide significant association with HbA(1c), including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 x 10(-26)), HFE (rs1800562/P = 2.6 x 10(-20)), TMPRSS6 (rs855791/P = 2.7 x 10(-14)), ANK1 (rs4737009/P = 6.1 x 10(-12)), SPTA1 (rs2779116/P = 2.8 x 10(-9)) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 x 10(-9)), and four known HbA(1c) loci: HK1 (rs16926246/P = 3.1 x 10(-54)), MTNR1B (rs1387153/P = 4.0 X 10(-11)), GCK (rs1799884/P = 1.5 x 10(-20)) and G6PC2/ABCB11 (rs552976/P = 8.2 x 10(-18)). We show that associations with HbA(1c) are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (%HbA(1c)) difference between the extreme 10% tails of the risk score, and would reclassify similar to 2% of a general white population screened for diabetes with HbA(1c).CONCLUSIONS-GWAS identified 10 genetic loci reproducibly associated with HbA(1c). Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA(1c) levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA(1c) Diabetes 59: 3229-3239, 201