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Flores, C. A.

Publications and source records attributed to Flores, C. A..

2 recordsLinked to original sources

Mental Health, Schooling Attainment and Polygenic Scores: Are There Significant Gene-Environment Associations?

It is well-established that (1) there is a large genetic component to mental health, and (2) higher schooling attainment is associated with better mental health. Given these two observations, we test the hypothesis that schooling may attenuate the genetic predisposition to poor mental health. Specifically, we estimate associations between a polygenic score (PGS) for depressive symptoms, schooling attainment and gene-environment (GxE) interactions with mental health (depressive symptoms and depression), in two distinct United States datasets at different adult ages-29 years old in the National Longitudinal Study of Adolescent Health (Add Health) and 54 years old in the Wisconsin Longitudinal Study (WLS). OLS results indicate that the association of the PGS with mental health is similar in Add Health and the WLS, but the association of schooling attainment is much larger in Add Health than in the WLS. There is some suggestive evidence that the association of the PGS with mental health is lower for more-schooled older individuals in the WLS, but there is no evidence of any significant GxE associations in Add Health. Quantile regression estimates also show that in the WLS the GxE associations are statistically significant only in the upper parts of the conditional depressive symptoms score distribution. We assess the robustness of the OLS results to omitted variable bias by using the siblings samples in both datasets to estimate sibling fixed-effect regressions. The sibling fixed-effect results must be qualified, in part due to low statistical power. However, the sibling fixed-effect estimates show that college education is associated with fewer depressive symptoms in both datasets.

genomics

MCT4 is a high affinity transporter capable of exporting lactate in high-lactate environments

MCT4 is an H+-coupled transporter expressed in metastatic cancer cells, macrophages, and other highly glycolytic cells, where it extrudes excess lactate generated by the Warburg phenomenon or by hypoxia. Intriguingly, its reported Km for lactate, obtained with pH-sensitive probes, is more than an order of magnitude higher than physiological lactate. Here we examined MCT4-rich MDA-MB-231 cells using the FRET sensor Laconic and found a median Km for lactate uptake of only 1.7 mM, while parallel estimation in the same cells with a pH probe gave a Km of 27 mM. The median Km of MCT4 for lactate was 0.7 mM in MCT4-expressing HEK293 cells and 1.2 mM in human macrophages, suggesting that high substrate affinity is a robust property of the transporter. Probed with the FRET sensor Pyronic, MCT4 showed a Km for pyruvate of only 4.2 mM in MDA-MB-231 cells, as opposed to > 150 mM reported previously. We conclude that prior estimates of MCT4 affinity based on pH probes were severely biased by the confounding action of pH regulatory mechanisms. Numerical simulation showed that MCT4, but not MCT1 or MCT2, endows cells with the capability of lactate extrusion in high lactate environments. The revised kinetic properties and novel transport assays may help in developing small-molecule MCT4 blockers for research and therapy.

physiology