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BackgroundNorovirus GII.4 is the predominant genotype circulating worldwide over the last decade causing 80% of all norovirus outbreaks with new GII.4 variants reported in parallel with periodic epidemic waves of norovirus outbreaks. The circulating new GII.4 variants and the epidemiology of norovirus outbreaks in Alberta, Canada have not been described. Our hypothesis is that the periodic epidemic norovirus outbreak activity in Alberta was driven by new GII.4 variants evolving by genetic drift.Methodology/Principal FindingsThe Alberta Provincial Public Health Laboratory performed norovirus testing using RT-PCR for suspected norovirus outbreaks in the province and the northern Territories between 2000 and 2008. At least one norovirus strain from 707 out of 1,057 (66.9%) confirmed norovirus outbreaks were successfully sequenced. Phylogenetic analysis was performed using BioNumerics and 617 (91.1%) outbreaks were characterized as caused by GII.4 with 598 assigned as novel variants including: GII.4-1996, GII.4-2002, GII.4-2004, GII.4-2006a, GII.4-2006b, GII.4-2008a and GII.4-2008b. Defining July to June of the following year as the yearly observation period, there was clear biannual pattern of low and high outbreak activity in Alberta. Within this biannual pattern, high outbreak activity followed the emergence of novel GII.4 variants. The two variants that emerged in 2006 had wider geographic distribution and resulted in higher outbreak activity compared to other variants. The outbreak settings were analyzed. Community-based group residence was the most common for both GII.4 variants and non-GII.4 variants. GII.4 variants were more commonly associated with outbreaks in acute care hospitals while outbreaks associated non-GII.4 variants were more commonly seen in school and community social events settings (p<0.01).Conclusions/SignificanceThe emergence of new norovirus GII.4 variants resulted in an increased norovirus outbreak activity in the following season in a unique biannual pattern in Alberta over an eight year period. The association between antigenic drift of GII.4 strains and epidemic norovirus outbreak activity could be due to changes in host immunity, viral receptor binding efficiency or virulence factors in the new variants. Early detection of novel GII.4 variants provides vital information that could be used to forecast the norovirus outbreak burden, enhance public health preparedness and allocate appropriate resources for outbreak management.

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The clonal osteoblast-like cell line MC3T3-E1 undergoes time-dependent morphological changes leading to the formation of bone nodules in vitro. Serial analysis of gene expression was used to identify genes expressed in MC3T3-E1 cells, including known osteoblast markers, structural and matrix proteins, transcription factors, cell-cycle regulators, and housekeeping genes. Relative changes in the expression of 92 representative transcripts were determined by arrayed cDNA hybridization. Complex probes were derived from MC3T3-E1 cells during the proliferation, differentiation, and matrix mineralization stages, and from cells grown with all- trans-retinoic acid (RA), a potent bone morphogen. We found that the relative expression of 68 of these genes was higher during differentiation than in the earlier proliferative phase. In the mineralization phase, all but 16 cDNAs had lower normalized hybridization intensity ratios as compared with the differentiation phase. cDNAs for vimentin (Vim), presenilin 2 (Psen2), guanine nucleotide binding protein alpha stimulating (Gnas), gap-junction membrane channel protein beta 1 (Gjb1), fibroblast growth factor receptor 1 (Fgfr1), eukaryotic translation elongation factor 2 (Eef2), and calponin 2 (Cnn2) had higher normalized hybridization intensities in both differentiation and mineralization than in proliferation. RA treatment during the differentiation phase appeared to reduce the expression of the 92 genes examined, as 62 cDNAs had lower hybridization intensities with complex cDNA probes derived from RA-treated cells than with the probe from untreated cells. Several cDNAs representing genes with previously unrecognized RA responsiveness were identified by this comparison, including the receptor for bone morphogenetic proteins 2 and 4 (Bmp2/Bmp4) and hemoglobin Y.