Colonist, 1889-02-15

The Colonist began on 6 March 1886, changing its name to The Newfoundland Colonist after 18 July 1891. Having printed local and international news Monday to Saturday for six years, the paper came to an abrupt end when its offices were destroyed in The Great Fire of 8 July 1892.Title variations recorded in Alternative Title, as needed

Concordant Signaling Pathways Produced by Pesticide Exposure in Mice Correspond to Pathways Identified in Human Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disease in which the etiology of 90 percent of the patients is unknown. Pesticide exposure is a major risk factor for PD, and paraquat (PQ), pyridaben (PY) and maneb (MN) are amongst the most widely used pesticides. We studied mRNA expression using transcriptome sequencing (RNA-Seq) in the ventral midbrain (VMB) and striatum (STR) of PQ, PY and paraquat+maneb (MNPQ) treated mice, followed by pathway analysis. We found concordance of signaling pathways between the three pesticide models in both the VMB and STR as well as concordance in these two brain areas. The concordant signaling pathways with relevance to PD pathogenesis were e.g. axonal guidance signaling, Wnt/β-catenin signaling, as well as pathways not previously linked to PD, e.g. basal cell carcinoma, human embryonic stem cell pluripotency and role of macrophages, fibroblasts and endothelial cells in rheumatoid arthritis. Human PD pathways previously identified by expression analysis, concordant with VMB pathways identified in our study were axonal guidance signaling, Wnt/β-catenin signaling, IL-6 signaling, ephrin receptor signaling, TGF-β signaling, PPAR signaling and G-protein coupled receptor signaling. Human PD pathways concordant with the STR pathways in our study were Wnt/β-catenin signaling, axonal guidance signaling and G-protein coupled receptor signaling. Peroxisome proliferator activated receptor delta (Ppard) and G-Protein Coupled Receptors (GPCRs) were common genes in VMB and STR identified by network analysis. In conclusion, the pesticides PQ, PY and MNPQ elicit common signaling pathways in the VMB and STR in mice, which are concordant with known signaling pathways identified in human PD, suggesting that these pathways contribute to the pathogenesis of idiopathic PD. The analysis of these networks and pathways may therefore lead to improved understanding of disease pathogenesis, and potential novel therapeutic targets

Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway

Background: reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN. Methods: to test whether EGFR pathway activity was predictive of increased sensitivity to reovirus, correlative analyses between reoviral IC50 by MTT assay and EGFR levels by western blot and FACS were conducted. Inhibition or stimulation of EGFR signalling were analysed for their effect on reoviral oncolysis by MTT assay, and viral growth by TCID50 assay. We next analysed the effects of inhibiting signalling downstream of Ras, by specific inhibitors of p38MAPK, PI3-K or MEK, on reoviral killing examined by MTT assay. The role of PKR in reoviral killing was also determined by blockade of PKR using 2-aminopurine and assaying for cell survival by MTT assay. The apoptotic response of SCCHN to reovirus was examined by western blot analysis of caspase 3 cleavage. Results: correlative analyses between reoviral sensitivity and EGFR levels revealed no association. Intermediate sub-viral and core particles showed the same infectivity/cytotoxicity as intact reovirus. Therefore, sensitivity was not determined by cell entry. In 4 cell lines, oncolysis and viral growth were both unaffected by inhibition or stimulation of EGFR signalling. Inhibition of signalling downstream of Ras did not abrogate reoviral oncolysis and, in addition, modulation of PKR using 2-aminopurine did not alter reovirus sensitivity in resistant cell lines. Caspase 3 cleavage was not detected in infected cells and oncolysis was observed in pan-caspase inhibited cells. Conclusions: in summary, reovirus is potently oncolytic in a broad panel of SCCHN cell lines. Attempts to define sensitivity/resistance by analysis of the EGFR/Ras/MAPK pathway have failed to provide a clear predictive biomarker of response. Further analysis of material from in vitro and clinical studies is ongoing in an attempt to shed further light on this issue

Uncovering an undisclosed diagnosis: a glucose‐6‐phosphate dehydrogenase deficiency diagnosis in a critically ill adult

Abstract Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency affects over 400 million people worldwide. The most common variant of G6PD deficiency in the United States is the A‐variant, which is present amongst African‐Americans. Most people with this variant, however, do not experience severe hemolysis unless under extreme circumstances. Here, we present the case of a 44‐year‐old African‐American male who under circumstances of multiple admissions for critical illness eventually presented with a masked diagnosis of G6PD deficiency

Comparative evaluation of phosphorus losses from subsurface and naturally drained agricultural fields in the Pike River watershed of Quebec, Canada

Phosphorus (P) is the limiting nutrient responsible for the development of algal blooms in freshwater bodies, adversely impacting the water quality of downstream lakes and rivers. Since agriculture is a major non-point source of P in southern Quebec, this study was carried out to investigate P transport under subsurface and naturally drained agricultural fields with two common soil types (clay loam and sandy loam). Monitoring stations were installed at four sites (A, B, C and D) in the Pike River watershed of southern Quebec. Sites A-B had subsurface drainage whereas sites C-D were naturally drained. In addition, sites A-C had clay loam soils whereas sites B-D had sandy loam soils. Analysis of data acquired over two hydrologic years (2004-2006) revealed that site A discharged 1.8 times more water than site B, 4 times more than site C and 3 times more than site D. The presence of subsurface drainage in sandy loam soils had a significant beneficial effect in minimizing surface runoff and total phosphorus (TP) losses from the field, but the contrary was observed in clay loam soils. This was attributed to the finding that P speciation as particulate phosphorus (PP) and dissolved phosphorus (DP) remained relatively independent of the hydrologic transport pathway, and was a strong function of soil texture. While 80% of TP occurred as PP at both clay loam sites, only 20% occurred as PP at both sandy loam sites. Moreover, P transport pathways in artificially drained soils were greatly influenced by the prevailing preferential and macropore flow conditions.Non-point source pollution Nutrient transport Surface runoff Subsurface drainage Water quality monitoring

Optimal Multistage Interference Cancellation for CDMA Systems

This paper proposes an optimal multistage interference cancellation scheme for a multiuser DS/CDMA system with linear or nonlinear modulation. The proposed canceler is optimal in terms of minimizing the energy of the dierence between true and reconstructed interference due to each user. Solutions for the special cases of BPSK and M-ary orthogonal modulation are derived using the general solution and ecient architectures are proposed for implementation. A novel blind channel estimation strategy based on an adaptive ltering approach that yields unbiased channel estimates and low estimation variance is also proposed. Simulation results indicate that the proposed scheme achieves substantial capacity gains with very little additional computational complexity compared to the conventional multistage canceler

Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion

Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells’ metabolism is characterized by low respiration and fragmented mitochondria, a metabolic phenotype that may not support secondary outgrowth after adhesion. Here, we investigated how adhesion affects cellular respiration and substrate utilization of spheroids mimicking early stages of secondary metastasis. Using different glucose and oxygen levels, we investigated cellular metabolism at early time points of adherence (24 h and less) comparing slow and fast-developing disease models. We found that adhesion over time showed changes in cellular energy metabolism and substrate utilization, with a switch in the utilization of mostly glutamine to glucose but no changes in fatty acid oxidation. Interestingly, low glucose levels had less of an impact on cellular metabolism than hypoxia. A resilience to culture conditions and the capacity to utilize a broader spectrum of substrates more efficiently distinguished the highly aggressive cells from the cells representing slow-developing disease, suggesting a flexible metabolism contributes to the stem-like properties. These results indicate that adhesion to secondary sites initiates a metabolic switch in the oxidation of substrates that could support outgrowth and successful metastasis