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Background: The relationship between Insulin-like growth factor 2 (IGF2) methylation in the P3 promoter region and birth outcomes in a hypobaric-hypoxia environment has never been investigated. This study examined the association and compared birth outcomes and IGF2 methylation in this region by ethnicity and altitude. Methods: Four hundred and six (406) mother and newborn pairs in the Tibetan Plateau were enrolled in a birth cohort study. Data were collected through interviews using structural questionnaires or extracted from medical records. Pyrosequencing was performed for IGF2 methylation in the P3 promoter region in maternal peripheral and umbilical cord blood. Birth outcomes and IGF2 methylation were compared among three groups: Han in high altitude (HHA, n=164, 2000-3500m), Tibetan in high altitude (THA, n=42, 2000-3500m), and Tibetan in ultra-high altitude (TUHA, n=200, 3500m and higher). Results: TUHA seemed to have a higher prevalence of macrosomia (7.5%) than both THA (0.0.%) and HHA (2.4%) and a lower IGF2 methylation level in maternal blood than THA (P=0.008). No difference in the IGF2 methylation levels was found between THA and HHA. The IGF2 methylation levels in maternal peripheral blood were associated with a reduced risk of macrosomia (RR= 0.726, 95% CL [0.528,0.998], P=0.049) among all mother and newborn pairs. Conclusions: Increased altitude appears to be associated with decreased maternal IGF2 methylation levels in the P3 promoter region, and maternal IGF2 methylation levels in this region was associated with reduced risk of macrosomia in newborns in the hypobaric hypoxic Tibetan Plateau environment. Keywords Macrosomia; IGF2; DNA methylation; high altitude; Tibet Plateau

DYRK1A, a ubiquitously expressed kinase, is linked to the dominant intellectual developmental disorder, microcephaly and Down syndrome in humans. It regulates numerous cellular processes such cell cycle, vesicle trafficking and microtubule assembly. DYRK1A is a critical regulator of organ growth, however, how it regulates organ growth is not fully understood. Here we show that knockdown ofDYRK1Aresults in reduced cell size, which is dependent on mTORC1. Using proteomic approaches, we found that DYRK1A interacts with the Tuberous sclerosis complex (TSC) proteins, namely TSC1 and TSC2, which negatively regulate mTORC1 activation. Further, we show that DYRK1A phosphorylates TSC2 at T1462, a modification that is known to inhibit TSC activity and promote mTORC1 activity. We also found that the reduced cell growth upon knockdown of DYRK1A can be rescued by overexpression of RHEB, an activator of mTORC1. Our findings suggest that DYRK1A inhibits TSC complex activity through an inhibitory phosphorylation on TSC2 and thereby promotes mTORC1 activity. Further, usingDrosophilaneuromuscular junction as model, we show that themnb, the fly homologues ofDYRK1A, is rescued by RHEB overexpression suggesting a conserved role ofDYRK1Ain TORC1 regulation.

Background/Aims: Circulation long non-coding RNAs (lncRNAs) have emerged recently as major players in tumor biology and might be applied for cancer diagnosis, prognosis, or potential therapeutic targets. In this study, we aimed to explore whether the circulation lncRNA could predict the tumorigenesis of surgical squamous cervical cancer (CC). Methods: In this study, we applied the lncRNA microarray to screen the potential biomarker for CC. Real-time quantitate polymerase chain reaction was conducted for further validation in a larger sample size. The multi-stage validation and risk score formula analysis were used to examine the sensitivity and specificity. Results: We discovered 4 lncRNAs including HOTAIR, PVT1, XLOC_000303, and AL592284.1, which were upregulated in CC comparing with the cancer-free controls. Further, the receiver operating characteristic curve (ROC) analysis by risk score formula revealed the combined 4 factors with a high diagnostic ability with the area under ROC curve value of 0.875 and 0.958 in training set and validation set respectively. We finally confirmed the stable detection of the 4 lncRNAs by 5 cycles of freezing and thawing. Conclusion: HOTAIR, PVT1, XLOC_000303, and AL592284.1 might be the potential biomarkers for predicting the tumorigenesis of CC in the future.