Although North American and European serotypes of porcine reproductive and respiratory syndrome virus (PRRSV) are recognized, only the genome of the European Lelystad strain (LV) has been sequenced completely. Here, the genome of the pathogenic North American PRRSV isolate 16244B has been sequenced and compared with LV. The genomic organization of 16244B was the same as LV but with only 63n4 % nucleotide identity. The 189 nucleotide 5h non-coding region (NCR) of 16244B was distinct from the LV NCR, with good conservation (83 %) only over a 43 base region immediately upstream of open reading frame (ORF) 1a. Major differences were found in the region encoding the non-structural part of the ORF1a polyprotein, which shared only 47 % amino acid identity over 2503 residues of the six non-structural proteins (Nsps) encoded. Nsp2, thought to have a species-specific function, showed the greatest divergence, sharing only 32 % amino acid identity with LV and containing 120 additional amino acids in the central region. Nsps encoded by the 5h-proximal and central regions of ORF1b had from 66 to 75 % amino acid identity ; however, the carboxy-terminal protein CP4 was distinct (42 % identity). The ORF1a-1b frameshift region of 16244B had 98 % nucleotide identity with LV. Consistent with previous reports for North American isolates, the six structural proteins encoded were 58 to 79 % identical to LV proteins. The 3h NCR (150 nucleotides) was 76 % identical between isolates. These genomic differences confirm the presence of distinct North American and European PRRSV genotypes.
We computationally dissected the electronic and geometrical influences of ortho-chlorinated azobenzenes on their photophysical properties. X-ray analysis provided the insight that trans-tetra-ortho-chloro azobenzene is conformationally flexible and thus subject to molecular motions. This allows the photoswitch to adopt a range of red-shifted geometries, which account for the extended n → π* band tails. On the basis of our results, we designed the di-ortho-fluoro di-ortho-chloro (dfdc) azobenzene and provided computational evidence for the superiority of this substitution pattern to tetra-ortho-chloro azobenzene. Thereafter, we synthesized dfdc azobenzene by ortho-chlorination via 2-fold C−H activation and experimentally confirmed its structural and photophysical properties through UV−vis, NMR, and X-ray analyses. The advantages include near-bistable isomers and an increased separation of the n → π* bands between the transand cis-conformations, which allows for the generation of unusually high levels of the cis-isomer by irradiation with green/yellow light as well as red light within the biooptical window.
Medulloblastoma (MB), the most common malignant paediatric brain tumor, is currently treated using a combination of surgery, craniospinal radiotherapy and chemotherapy. Owing to MB stem cells (MBSCs), a subset of MB patients remains untreatable despite standard therapy. CD133 is used to identify MBSCs although its functional role in tumorigenesis has yet to be determined. In this work, we showed enrichment of CD133 in Group 3 MB is associated with increased rate of metastasis and poor clinical outcome. The signal transducers and activators of transcription-3 (STAT3) pathway are selectively activated in CD133+ MBSCs and promote tumorigenesis through regulation of c-MYC, a key genetic driver of Group 3 MB. We screened compound libraries for STAT3 inhibitors and treatment with the selected STAT3 inhibitors resulted in tumor size reduction in vivo. We propose that inhibition of STAT3 signaling in MBSCs may represent a potential therapeutic strategy to treat patients with recurrent MB.
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