RESUMEN
Coordinated animal locomotion depends on the development of functional proprioceptors. While early cell-fate determination processes are well characterized, little is known about the terminal differentiation of cells within the proprioceptive lineage and the genetic networks that control them. In this work we describe a gene regulatory network consisting of three transcription factors-Prospero (Pros), D-Pax2, and Delilah (Dei)-that dictates two alternative differentiation programs within the proprioceptive lineage in Drosophila. We show that D-Pax2 and Pros control the differentiation of cap versus scolopale cells in the chordotonal organ lineage by, respectively, activating and repressing the transcription of dei. Normally, D-Pax2 activates the expression of dei in the cap cell but is unable to do so in the scolopale cell where Pros is co-expressed. We further show that D-Pax2 and Pros exert their effects on dei transcription via a 262 bp chordotonal-specific enhancer in which two D-Pax2- and three Pros-binding sites were identified experimentally. When this enhancer was removed from the fly genome, the cap- and ligament-specific expression of dei was lost, resulting in loss of chordotonal organ functionality and defective larval locomotion. Thus, coordinated larval locomotion depends on the activity of a dei enhancer that integrates both activating and repressive inputs for the generation of a functional proprioceptive organ.
Asunto(s)
Drosophila melanogaster/genética , Redes Reguladoras de Genes/genética , Células Receptoras Sensoriales , Factores de Transcripción/genética , Animales , Animales Modificados Genéticamente , Diferenciación Celular , Drosophila melanogaster/crecimiento & desarrollo , Genes de Insecto , Larva/genética , Locomoción/genética , Propiocepción/genéticaRESUMEN
RESEARCH QUESTION: To study gestational hypertensive disorders in oocyte donation pregnancies compared with other modes of conception at very advanced maternal age. DESIGN: A historical cohort study of all women aged 45-47 years who gave birth to singletons at a tertiary medical centre between March 2011 and May 2018, at 24 weeks' gestation or later. Pregnancy outcomes were compared between donor oocyte (IVF-OD), IVF using autologous oocytes (IVF-A) and naturally conceived pregnancies. A multivariate logistic regression was used to evaluate the association between the mode of conception and gestational hypertensive disorders. RESULTS: The final analysis included 159, 68 and 73 patients in the IVF-OD, IVF-A and natural conception groups, respectively. The rate of gestational hypertensive disorders was significantly higher among those who conceived by IVF compared with those who conceived naturally but did not differ between the two IVF groups (27.0% for IVF-OD, 19.1% for IVF-A, Pâ¯=â¯0.204; 5.5% for natural conception, P < 0.001 and Pâ¯=â¯0.013 compared with IVF-OD and IVF-A, respectively). The results remained similar in a multivariate logistic regression analysis. The rate of Caesarean deliveries was significantly higher in the IVF-OD and IVF-A groups compared with the natural conception group (83.6%, 70.6% and 37.0%, respectively, P < 0.001), but other pregnancy outcomes did not differ between the groups. CONCLUSIONS: IVF pregnancies in the late fifth decade of life were associated with significantly higher rates of gestational hypertensive disorders compared with naturally conceived pregnancies. No difference existed between the two IVF groups. These results may highlight the impact of IVF itself on gestational hypertensive disorders at very advanced maternal age.
Asunto(s)
Cesárea , Fertilización In Vitro , Fertilización , Hipertensión Inducida en el Embarazo/epidemiología , Femenino , Humanos , Incidencia , Edad Materna , Persona de Mediana Edad , Donación de Oocito , Embarazo , Resultado del EmbarazoRESUMEN
BACKGROUND: Pregnancies in the fifth and sixth decades of life have been increasing, but current data are limited regarding the outcomes of twin compared with singleton pregnancies in this age group and to twin pregnancies at younger age. OBJECTIVE: To compare obstetrical and neonatal outcomes of IVF conceived pregnancies, in twin gestations of women who were ≥45 years old at delivery to singletons at similar age and twin gestations at the age of <35 years, and to assess if the complications are mainly influenced by the very advanced maternal age or by the multifetal pregnancy. STUDY DESIGN: A retrospective cohort study from a single tertiary medical center of women aged ≥45 at delivery between March 2011 and January 2018 and women aged <35 at delivery with twin pregnancies that conceived by IVF. Exclusion criteria were spontaneous pregnancies or pregnancies after ovulation induction, monochorionic twin pregnancies, higher order multiple gestations, or women that underwent fetal reduction. Pregnancy, delivery, postpartum and neonatal outcomes were compared between singleton and twin pregnancies. Multivariate logistic regression was used to evaluate the association between twin pregnancies and adverse outcomes. RESULTS: Out of 67,355 deliveries, 612 were of women ≥45 years old, of whom 492 women conceived via IVF (395 singleton and 97 twin pregnancies). Of those, 60 women were ≥50 years old, 49 of them carried singleton and 11 carried twin pregnancies. Baseline characteristics were similar between groups. Women at the fifth and sixth decades with twins had significantly higher rates of preeclampsia (32.0% vs. 10.9%, p < 0.001), gestational diabetes mellitus (35.4% vs. 23.8%, p = 0.020), preterm deliveries <32 weeks of gestation (8.2% vs. 1.3%, p = 0.001), and fetal growth restriction (18.6% vs. 7.6%, p = 0.001) compared with singleton pregnancies at similar maternal age. After multivariate analysis adjusting for confounders, the odds ratio for the composite of preeclampsia, gestational hypertension, intrauterine fetal growth restriction, and placental abruption was 3.19 for twin compared with singleton pregnancies and 1.73 for gestational diabetes mellitus. Pregnancy complications among older women with twins were also significantly higher when compared with younger women with twins (<35 years old). Women in the fifth and sixth decades with twins had higher rates of cesarean deliveries (91.8% vs. 56.4%, p<0.001), gestational hypertension, preeclampsia, and gestational diabetes mellitus (10.3% vs. 4.2%., p=0.016; 32.0% vs. 6.2%, p<0.001; 35.1% vs. 8.1%, p<0.001, respectively) than the younger group carrying twins. CONCLUSIONS: Twin pregnancies in the fifth and sixth decades carry significantly higher complications rate compared with singleton pregnancies at the same age and twin pregnancies at younger age.
Asunto(s)
Fertilización In Vitro , Edad Materna , Resultado del Embarazo , Embarazo Gemelar , Gemelos , Femenino , Humanos , Recién Nacido , Persona de Mediana Edad , Embarazo , Complicaciones del Embarazo , Embarazo de Alto Riesgo , Estudios RetrospectivosRESUMEN
The proprioceptive chordotonal organs (ChO) of a fly larva respond to mechanical stimuli generated by muscle contractions and consequent deformations of the cuticle. The ability of the ChO to sense the relative displacement of its epidermal attachment sites likely depends on the correct mechanical properties of the accessory (cap and ligament) and attachment cells that connect the sensory unit (neuron and scolopale cell) to the cuticle. The genetic programs dictating the development of ChO cells with unique morphologies and mechanical properties are largely unknown. Here we describe an RNAi screen that focused on the ChO's accessory and attachment cells and was performed in 2nd instar larvae to allow for phenotypic analysis of ChOs that had already experienced mechanical stresses during larval growth. Nearly one thousand strains carrying RNAi constructs targeting more than 500 candidate genes were screened for their effects on ChO morphogenesis. The screen identified 31 candidate genes whose knockdown within the ChO lineage disrupted various aspects of cell fate determination, cell differentiation, cellular morphogenesis and cell-cell attachment. Most interestingly, one phenotypic group consisted of genes that affected the response of specific ChO cell types to developmental organ stretching, leading to abnormal pattern of cell elongation. The 'cell elongation' group included the transcription factors Delilah and Stripe, implicating them for the first time in regulating the response of ChO cells to developmental stretching forces. Other genes found to affect the pattern of ChO cell elongation, such as αTub85E, ß1Tub56D, Tbce, CCT8, mys, Rac1 and shot, represent putative effectors that link between cell-fate determinants and the realization of cell-specific mechanical properties.