Modular Oxime Formation by a trans-AT Polyketide Synthase.

Modular trans-acyltransferase polyketide synthases (trans-AT PKSs) are enzymatic assembly lines that biosynthesize complex polyketide natural products. Relative to their better studied cis-AT counterparts, the trans-AT PKSs introduce remarkable chemical diversity into their polyketide products. A notable example is the lobatamide A PKS, which incorporates a methylated oxime. Here we demonstrate biochemically that this functionality is installed on-line by an unusual oxygenase-containing bimodule. Furthermore, analysis of the oxygenase crystal structure coupled with site-directed mutagenesis allows us to propose a model for catalysis, as well as identifying key protein-protein interactions that support this chemistry. Overall, our work adds oxime-forming machinery to the biomolecular toolbox available for trans-AT PKS engineering, opening the way to introducing such masked aldehyde functionalities into diverse polyketides.

Circulating tumor DNA is detectable in canine histiocytic sarcoma, oral malignant melanoma, and multicentric lymphoma.

Circulating tumor DNA (ctDNA) has become an attractive biomarker in human oncology, and its use may be informative in canine cancer. Thus, we used droplet digital PCR or PCR for antigen receptor rearrangement, to explore tumor-specific point mutations, copy number alterations, and chromosomal rearrangements in the plasma of cancer-affected dogs. We detected ctDNA in 21/23 (91.3%) of histiocytic sarcoma (HS), 2/8 (25%) of oral melanoma, and 12/13 (92.3%) of lymphoma cases. The utility of ctDNA in diagnosing HS was explored in 133 dogs, including 49 with HS, and the screening of recurrent PTPN11 mutations in plasma had a specificity of 98.8% and a sensitivity between 42.8 and 77% according to the clinical presentation of HS. Sensitivity was greater in visceral forms and especially related to pulmonary location. Follow-up of four dogs by targeting lymphoma-specific antigen receptor rearrangement in plasma showed that minimal residual disease detection was concordant with clinical evaluation and treatment response. Thus, our study shows that ctDNA is detectable in the plasma of cancer-affected dogs and is a promising biomarker for diagnosis and clinical follow-up. ctDNA detection appears to be useful in comparative oncology research due to growing interest in the study of natural canine tumors and exploration of new therapies.

Does residential mobility during pregnancy induce exposure misclassification for air pollution?

BACKGROUND: Prenatal exposure to outdoor air pollution has been shown to have health effects in many studies; low birth weight, preterm delivery, small for gestational age, and stillbirth are the most often cited. However, exposure of pregnant women is difficult to quantify, especially with regard to their mobility, which is rarely taken into account in epidemiological studies. This study aimed to assess the impact of mobility of pregnant women living in Paris, France, on their exposure estimates to nitrogen dioxide (NO2). METHODS: A total of 486 pregnant women were recruited in 5 maternity hospitals in Paris between January and April 2016. A questionnaire was used to collect mothers' characteristics (demography, education, etc.) and to assess their daily mobility during pregnancy (time spent at work, commuting time and mode used to move from residential to occupational places). Daily NO2 concentrations were estimated based on the combination of annual average concentrations modeled at the census block scale and daily concentrations measured from fixed monitoring stations. Different models were used to compare the exposure of pregnant women in residential and occupational places, also taking into account travel time and travel mode. The socioeconomic profile of the census blocks was characterized using a multi-component index. RESULTS: During the first trimester of pregnancy, women living in the least deprived census blocks were exposed to higher concentrations of NO2 than those living in the most deprived ones. Occupational mobility had a small impact on exposure levels (average increase after taking account of mobility: + 0.52 µg/m3) which was not related to the socioeconomic profile of the women. The commuting mode made a greater difference (+ 1.46 µg/m3 on average), in particular among women living in the most deprived census blocks. CONCLUSIONS: Our study illustrates that air pollution exposure can be underestimated when ignoring occupational mobility and commuting mode of pregnant women. This effect might be differential according to the neighborhood deprivation profile.