West Nile virus (WNV) is the most widely distributed of the encephalitic flaviviruses and is a major cause of encephalitis, with isolates obtained from all continents, apart from Antarctica. Subsequent to its divergence from the other members of the Japanese encephalitis virus complex, presumably in Africa, WNV has diverged into individual lineages that mostly correspond with geographic distribution. Here we elucidate the phylogeography and evolutionary history of isolates from lineage 1 of WNV. Interestingly, there are many examples of the same amino acid having evolved independently on multiple occasions. In Africa, WNV exists in an endemic cycle, whereas it is epidemic in Europe, being reintroduced regularly from Africa either directly (in western Europe) or via the Middle East (in eastern Europe). Significantly, introduction into other geographic areas has occurred on one occasion only in each region, leading to subsequent establishment and expansion of the virus in these areas. Only one endemic genotype each is present in India and Australia, suggesting that WNV was successfully introduced into these locations once only. Each introduction occurred many centuries ago, probably due to trade and exploration during the 19th century. Likewise, in the Americas, WNV was successfully introduced in 1999 and subsequently became endemic across most temperate regions of North America (NA). In contrast to previous suggestions, an isolate from the epidemic in Israel in 1998 was not the direct progenitor of the NA epidemic; rather, both epidemics originated from the same (unknown) location.
An encephalitis outbreak among horses was caused by a pathogenic variant of Kunjin virus.
Recent reports of a novel group of flaviviruses that replicate only in mosquitoes and appear to spread through insect populations via vertical transmission have emerged from around the globe. To date, there is no information on the presence or prevalence of these insect-specific flaviviruses (ISFs) in Australian mosquito species. To assess whether such viruses occur locally, we used reverse transcription-polymerase chain reaction (RT-PCR) and flavivirus universal primers that are specific to the NS5 gene to detect these viruses in mosquito pools collected from the Northern Territory. Of 94 pools of mosquitoes, 13 were RT-PCR positive, and of these, 6 flavivirus isolates were obtained by inoculation of mosquito cell culture. Sequence analysis of the NS5 gene revealed that these isolates are genetically and phylogenetically similar to ISFs reported from other parts of the world. The entire coding region of one isolate (designated 56) was sequenced and shown to have approximately 63.7% nucleotide identity and 66.6% amino acid identity with its closest known relative (Nakiwogo virus) indicating that the prototype Australian ISF represents a new species. All isolates were obtained from Coquillettidia xanthogaster mosquitoes. The new virus is tentatively named Palm Creek virus (PCV) after its place of isolation. We also demonstrated that prior infection of cultured mosquito cells with PCV suppressed subsequent replication of the medically significant West Nile and Murray Valley encephalitis viruses by 10–43 fold (1 to 1.63 log) at 48 hr post-infection, suggesting that superinfection exclusion can occur between ISFs and vertebrate-infecting flaviviruses despite their high level of genetic diversity. We also generated several monoclonal antibodies (mAbs) that are specific to the NS1 protein of PCV, and these represent the first ISF-specific mAbs reported to date.
Peroxisome proliferator-activated receptor (PPAR) alpha is a ligand-activated transcription factor that has been linked with rodent hepatocarcinogenesis. It has been suggested that PPARalpha mRNA expression levels are an important determinant of rodent hepatic tumorigenicity. Previous work in rat mammary gland epithelial cells showed significantly increased PPARalpha mRNA expression in carcinomas, suggesting the possible role of this isoform in rodent mammary gland carcinogenesis. In this study we sought to determine whether PPARalpha is expressed and dynamically regulated in human breast cancer MCF-7 and MDA-MB-231 cells. Having established the presence of PPARalpha in both cell types, we then examined the consequence of PPARalpha activation, by its ligands Wy-14,643 and clofibrate, on proliferation. With real-time reverse transcriptase-polymerase chain reaction, we showed that PPARalpha mRNA was dynamically regulated in MDA-MB-231 cells and that PPARalpha activation significantly increased proliferation of the cell line. In contrast, PPARalpha expression in MCF-7 cells did not change with proliferation during culture and was present at significantly lower levels than in MDA-MB-231 cells. However, PPARalpha ligand activation still significantly increased the proliferation of MCF-7 cells. The promotion of proliferation in breast cancer cell lines following PPARalpha activation was in stark contrast to the effects of PPARgamma-activating ligands that decrease proliferation in human breast cancer cells. Our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. Hence, this pathway may be significant in mammary gland tumorigenesis.
Previous studies of North American isolates of West Nile virus (WNV) during 1999–2005 suggested that the virus had reached genetic homeostasis in North America. However, genomic sequencing of WNV isolates from Harris County, Texas, during 2002–2009 suggests that this is not the case. Three new genetic groups have been identified in Texas since 2005. Spread of the southwestern US genotype (SW/WN03) from the Arizona/Colorado/northern Mexico region to California, Illinois, New Mexico, New York, North Dakota, and the Texas Gulf Coast demonstrates continued evolution of WNV. Thus, WNV continues to evolve in North America, as demonstrated by selection of this new genotype. Continued surveillance of the virus is essential as it continues to evolve in the New World.
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