Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature termination codons (PTCs). SMG-1-mediated Upf1 phosphorylation takes place in the decay inducing complex (DECID), which contains a ribosome, release factors, Upf1, SMG-1, an exon junction complex (EJC) and a PTC-mRNA. However, the significance and the consequence of Upf1 phosphorylation remain to be clarified. Here, we demonstrate that SMG-6 binds to a newly identified phosphorylation site in Upf1 at N-terminal threonine 28, whereas the SMG-5:SMG-7 complex binds to phosphorylated serine 1096 of Upf1. In addition, the binding of the SMG-5:SMG-7 complex to Upf1 resulted in the dissociation of the ribosome and release factors from the DECID complex. Importantly, the simultaneous binding of both the SMG-5:SMG-7 complex and SMG-6 to phospho-Upf1 are required for both NMD and Upf1 dissociation from mRNA. Thus, the SMG-1-mediated phosphorylation of Upf1 creates a binding platforms for the SMG-5:SMG-7 complex and for SMG-6, and triggers sequential remodeling of the mRNA surveillance complex for NMD induction and recycling of the ribosome, release factors and NMD factors.

ObjectiveTo verify whether body mass index (BMI) classification proposed by the Institute of Medicine (IOM) is valid in Japanese women.MethodA study was conducted in 97,157 women with singleton pregnancies registered in the Japan Society of Obstetrics and Gynecology (JSOG) Successive Pregnancy Birth Registry System between January 2013 and December 2013, to examine pregnancy outcomes in four groups stratified by pre-pregnancy BMI category according to the 2009 criteria recommended by the Institute of Medicine (IOM). The groups comprised 17,724 underweight women with BMI <18.5, 69,126 normal weight women with BMI 18.5–24.9, 7,502 overweight women with BMI 25–29.9, and 2,805 obese women with BMI ≥30. The pregnancy outcomes were also compared among subgroups stratified by a gestational weight gain below, within, and above the optimal weight gain.ResultsThe higher the pre-pregnancy BMI, the higher the incidences of pregnancy-induced hypertension, gestational diabetes mellitus, macrosomia, cesarean delivery, postpartum hemorrhage, and post-term birth, but the lower the incidence of small for gestational age (SGA). In all pre-pregnancy BMI category groups, excess gestational weight gain was associated with a higher frequency of large for gestational age and macrosomia; poor weight gain correlated with a higher frequency of SGA, preterm birth, preterm premature rupture of membranes, and spontaneous preterm birth; and optimal weight gain within the recommended range was associated with a better outcome.ConclusionThe BMI classification by the IOM was demonstrated to be valid in Japanese women.

Blood coagulation factor VII ( fVII) is physiologically synthesized in the liver and released into the blood. Binding of fVII to tissue factor (TF) at sites of vascular injury triggers coagulation and hemostasis. TF/fVIIa complex formation on the surface of cancer cells plays important roles in cancer biology. Although fVII is synthesized by hepatocellular carcinoma, it remained unclear how TF/fVIIa complex formation and promigratory signaling can occur for most other cancers in extravascular locations. Here, we show by reverse transcription-PCR analysis that nonhepatic cancer cell lines constitutively express fVII mRNA and that endogenously synthesized fVIIa triggers coagulation activation on these cells. fVIIa expression in cancer cells is inducible under hypoxic conditions and hypoxia-inducible factor-2A bound the promoter region of the FVII gene in chromatin immunoprecipitation analyses. Constitutive fVII expression in an ovarian cancer cell line enhanced both migration and invasion. Enhanced motility was blocked by anti-TF antibodies, factor Xa inhibition, and anti-protease-activated receptor-1 antibody treatment, confirming that TF/fVIIa stimulated migration by triggering cell signaling. This study shows that ectopic synthesis of fVII by cancer cells is sufficient to support proinvasive factor Xa-mediated protease-activated receptor-1 signaling and that this pathway is inducible under hypoxia.

Pregnancies in women with adenomyosis were associated with a higher preterm delivery rate and more frequent occurrences of fetal growth restriction and fetal malpresentation, such that both pregnancy and delivery outcomes were poor.