Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells.

Rett syndrome may be treated by reactivating the silent copy of Mecp2 from the inactive X chromosome in female cells. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model based on a dual bioluminescent and fluorescent reporter to assess the level of reactivation of Mecp2 and the inactive X chromosome by treating neural stem cells with 5-azacytidine and Xist knockdown. We show that reactivation of Mecp2 and other X-linked genes correlates with CpG density, with distance from escapees, and, very strongly, with the presence of short interspersed nuclear elements. In addition, X-linked genes reactivated in neural stem cells overlap substantially with early reactivating genes by induced pluripotent stem cell reprogramming of fibroblasts or neuronal progenitors, indicating that X chromosome reactivation follows similar paths regardless of the technique or cell type used.

Planned Cesarean or planned vaginal delivery for twins: secondary analysis of randomized controlled trial.

OBJECTIVE: To evaluate whether there is a differential benefit of planned Cesarean delivery (CD) over planned vaginal delivery (VD) in women with a twin pregnancy and the first twin in cephalic presentation, depending on prespecified baseline maternal and pregnancy characteristics, and/or gestational age (GA) at delivery. METHODS: This was a secondary analysis of the Twin Birth Study, which included 2804 women with a twin pregnancy and the first twin (Twin A) in cephalic presentation between 32 + 0 and 38 + 6 weeks' gestation at 106 centers in 25 countries. Women were assigned randomly to either planned CD or planned VD. The main outcome measure was composite adverse perinatal outcome, defined as the occurrence of perinatal mortality or serious neonatal morbidity in at least one twin. The baseline maternal and pregnancy characteristics (markers) considered were maternal age, parity, history of CD, use of antenatal corticosteroids, estimated fetal weight (EFW) of Twin A, EFW of Twin B, > 25% difference in EFW between the twins, presentation of Twin B, chorionicity on ultrasound, method of conception, complications of pregnancy, ruptured membranes at randomization and GA at randomization. Separate logistic regression models were developed for each marker in order to model composite adverse perinatal outcome as a function of the specific marker, planned delivery mode and the interaction between these two terms. In addition, multivariable logistic regression analysis with backward variable elimination was performed separately in each arm of the trial. The association between planned mode of delivery and composite adverse perinatal outcome, according to GA at delivery, was assessed using logistic regression analysis. RESULTS: Of the 2804 women initially randomized, 1391 were included in each study arm. None of the studied baseline markers was associated with a differential benefit of planned CD over planned VD in the rate of composite adverse perinatal outcome. GA at delivery was associated differentially with composite adverse perinatal outcome in the treatment arms (P for interaction < 0.001). Among pregnancies delivered at 32 + 0 to 36 + 6 weeks, there was a trend towards a lower rate of composite adverse perinatal outcome in those in the planned-VD group compared with those in planned-CD group (29 (2.2%) vs 48 (3.6%) cases; odds ratio (OR) 0.62 (95% CI, 0.37-1.03)). In pregnancies delivered at or after 37 + 0 weeks, planned VD was associated with a significantly higher rate of composite adverse perinatal outcome, as compared with planned CD (23 (1.5%) vs 10 (0.7%) cases; OR, 2.25 (95% CI, 1.06-4.77)). CONCLUSION: The perinatal outcome of twin pregnancies with the first twin in cephalic presentation may differ depending on GA at delivery and planned mode of delivery. At 32-37 weeks, planned VD seems to be favorable, while, from around 37 weeks onwards, planned CD might be safer. The absolute risks of adverse perinatal outcomes at term are low and must be weighed against the increased maternal risks associated with planned CD. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Heterogeneous mass distribution of the rubble-pile asteroid (101955) Bennu.

The gravity field of a small body provides insight into its internal mass distribution. We used two approaches to measure the gravity field of the rubble-pile asteroid (101955) Bennu: (i) tracking and modeling the spacecraft in orbit about the asteroid and (ii) tracking and modeling pebble-sized particles naturally ejected from Bennu's surface into sustained orbits. These approaches yield statistically consistent results up to degree and order 3, with the particle-based field being statistically significant up to degree and order 9. Comparisons with a constant-density shape model show that Bennu has a heterogeneous mass distribution. These deviations can be modeled with lower densities at Bennu's equatorial bulge and center. The lower-density equator is consistent with recent migration and redistribution of material. The lower-density center is consistent with a past period of rapid rotation, either from a previous Yarkovsky-O'Keefe-Radzievskii-Paddack cycle or arising during Bennu's accretion following the disruption of its parent body.

COVID-19 during pregnancy: non-reassuring fetal heart rate, placental pathology and coagulopathy.

We report a case of a pregnant woman with COVID-19 who developed coagulopathy in the absence of severe clinical symptoms. A polymerase chain reaction test of a vaginal swab was positive for SARS-CoV-2 RNA, suggesting a possibility of perinatal transmission. Cesarean delivery was performed because of a non-reassuring fetal heart rate; the placenta showed increased perivillous fibrin deposition and intervillositis. Moreover, placental infection with SARS-CoV-2 was demonstrated by placental immunostaining. The findings suggest a possible relationship between placental fibrin deposition and chronic and acute intervillositis, non-reassuring fetal heart rate and coagulopathy in pregnant women with COVID-19. © 2020 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.

Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

Planning the mode of delivery for twin pregnancies: A web-based questionnaire.

Using orthogonal design, we created a questionnaire containing 16 cases of twin pregnancies. For each case, respondents indicated whether they would plan a vaginal delivery (VD) or a caesarean section (CS). We assessed the association between each variable (maternal age, parity, mode of conception, gestational age, chorionicity, body mass index, foetal growth, foetal presentation and wish for additional children) and the planned mode of delivery. A VD was planned mostly for vertex presentation of twin A (vertex-vertex vs. non-vertex-vertex, odds ratio [OR]: 0.002, 95% confidence interval [CI]: 0.001-0.003, p < 0.001). For vertex- non-vertex (vs. vertex-vertex) presentation, chances on planning a VD decreased threefold (OR: 0.29, 95% CI: 0.018-0.46, p < 0.001), although the majority of respondents would still plan a VD. In multiparous (vs. nulliparous) women, VD was chosen more often (OR: 3.24, 95% CI: 2.50-4.18, p < 0.001).Vertex presentation of twin A and multiparity were the main reasons for planning a VD.

Small-scale density variations in the lunar crust revealed by GRAIL.

Data from the Gravity Recovery and Interior Laboratory (GRAIL) mission have revealed that ~98% of the power of the gravity signal of the Moon at high spherical harmonic degrees correlates with the topography. The remaining 2% of the signal, which cannot be explained by topography, contains information about density variations within the crust. These high-degree Bouguer gravity anomalies are likely caused by small-scale (10's of km) shallow density variations. Here we use gravity inversions to model the small-scale three-dimensional variations in the density of the lunar crust. Inversion results from three non-descript areas yield shallow density variations in the range of 100-200 kg/m3. Three end-member scenarios of variations in porosity, intrusions into the crust, and variations in bulk crustal composition were tested as possible sources of the density variations. We find that the density anomalies can be caused entirely by changes in porosity. Characteristics of density anomalies in the South Pole-Aitken basin also support porosity as a primary source of these variations. Mafic intrusions into the crust could explain many, but not all of the anomalies. Additionally, variations in crustal composition revealed by spectral data could only explain a small fraction of the density anomalies. Nevertheless, all three sources of density variations likely contribute. Collectively, results from this study of GRAIL gravity data, combined with other studies of remote sensing data and lunar samples, show that the lunar crust exhibits variations in density by ±10% over scales ranging from centimeters to 100's of kilometers.

MicroRNA-193b-3p acts as a tumor suppressor by targeting the MYB oncogene in T-cell acute lymphoblastic leukemia.

The MYB oncogene is a leucine zipper transcription factor essential for normal and malignant hematopoiesis. In T-cell acute lymphoblastic leukemia (T-ALL), elevated MYB levels can arise directly through T-cell receptor-mediated MYB translocations, genomic MYB duplications or enhanced TAL1 complex binding at the MYB locus or indirectly through the TAL1/miR-223/FBXW7 regulatory axis. In this study, we used an unbiased MYB 3'untranslated region-microRNA (miRNA) library screen and identified 33 putative MYB-targeting miRNAs. Subsequently, transcriptome data from two independent T-ALL cohorts and different subsets of normal T-cells were used to select miRNAs with relevance in the context of normal and malignant T-cell transformation. Hereby, miR-193b-3p was identified as a novel bona fide tumor-suppressor miRNA that targets MYB during malignant T-cell transformation thereby offering an entry point for efficient MYB targeting-oriented therapies for human T-ALL.

Immunohistological Description of Nongestational Ovarian Choriocarcinoma in Two Female Mice With Conditional Loss of Trp53 Driven by the Tie2 Promoter.

Nongestational ovarian choriocarcinoma (NGCO) is a tumor of germ cell origin seldom described in nonhuman species. Few spontaneous cases are reported in macaques and mice, with the B6C3F1 strain overrepresented. This report describes 2 cases of ovarian choriocarcinoma in nulliparous female mice with conditional loss of Trp53 under the Tie2 promoter. The mouse line was maintained on a mixed genetic background including Crl: CD1(ICR) and 129X1/SvJ strains. In both cases, affected ovary was partially replaced by blood-filled lacunae lined by neoplastic trophoblast-like giant cells. Immunohistochemically, neoplastic cells expressed folate-binding protein and prolactin and were invariably negative for p53. To the authors' knowledge, this is the first report characterizing this entity in a genetically engineered mouse (GEM) line. Considering that germ cells (the cell population from which NGCO originates) constitutively express Tie2 receptor, it can be speculated that Tie2-driven deletion of Trp53 may have played a role in the development of these tumors.

Second-trimester cervical length as risk indicator for Cesarean delivery in women with twin pregnancy.

OBJECTIVE: To determine whether second-trimester cervical length (CL) in women with a twin pregnancy is associated with the risk of emergency Cesarean section. METHODS: This was a secondary analysis of two randomized trials conducted in 57 hospitals in The Netherlands. We assessed the univariable association between risk indicators, including second-trimester CL in quartiles, and emergency Cesarean delivery using a logistic regression model. For multivariable analysis, we assessed whether adjustment for other risk indicators altered the associations found in univariable (unadjusted) analysis. Separate analyses were performed for suspected fetal distress and failure to progress in labor as indications for Cesarean section. RESULTS: In total, 311 women with a twin pregnancy attempted vaginal delivery after 34 weeks' gestation. Emergency Cesarean delivery was performed in 111 (36%) women, of which 67 (60%) were performed owing to arrest of labor. There was no relationship between second-trimester CL and Cesarean delivery (adjusted odds ratio (aOR): 0.97 for CL 26(th) -50(th) percentiles; 0.71 for CL 51(st) - 75(th) percentiles; and 0.92 for CL > 75(th) percentile, using CL ≤ 25(th) percentile as reference). In multivariable analysis, the only variables associated with emergency Cesarean delivery were maternal age (aOR, 1.07 (95% CI, 1.00-1.13)), body mass index (BMI) (aOR, 3.99 (95% CI, 1.07-14.9) for BMI 20-23 kg/m(2) ; 5.04 (95% CI, 1.34-19.03) for BMI 24-28 kg/m(2) ; and 3.1 (95% CI, 0.65-14.78) for BMI > 28 kg/m(2) ) and induction of labor (aOR, 1.92 (95% CI, 1.05-3.5)). CONCLUSION: In nulliparous women with a twin pregnancy, second-trimester CL is not associated with risk of emergency Cesarean delivery.

p53 promotes VEGF expression and angiogenesis in the absence of an intact p21-Rb pathway.

There is growing evidence that the p53 tumour suppressor downregulates vascular endothelial growth factor (VEGF) expression, although the underlying mechanisms remain unclear and controversial. Here we provide insights from in vitro experiments and in vivo xenotransplantation assays that highlight a dual role for p53 in regulating VEGF during hypoxia. Unexpectedly, and for the first time, we demonstrate that p53 rapidly induces VEGF transcription upon hypoxia exposure by binding, in an HIF-1α-dependent manner, to a highly conserved and functional p53-binding site within the VEGF promoter. However, during sustained hypoxia, p53 indirectly downregulates VEGF expression via the retinoblastoma (Rb) pathway in a p21-dependent manner, which is distinct from its role in cell-cycle regulation. Our findings have important implications for cancer therapy, especially for tumours that harbour wild-type TP53 and a dysfunctional Rb pathway.

Tissue-wide overexpression of alpha-T-catenin results in aberrant trophoblast invasion but does not cause embryonic mortality in mice.

Transcriptional activation of CTNNA3, encoding αT-catenin, by the Y153H mutated form of the human STOX1 transcription factor was proposed to be responsible for altered fetal trophoblast invasion into the maternal endometrium during placentation in pre-eclampsia. Here we have generated a mouse model to investigate the in vivo effects of ectopic αT-catenin expression on trophoblast invasion. Histological analysis was used to determine the invasive capacities of trophoblasts from transgenic embryos, as well as proliferation rates of spongiotrophoblasts in the junctional zone. Augmented expression of αT-catenin reduced the number of invading trophoblasts but did not cause embryonic mortality. The, αT-catenin positive cells could still invade into the decidual layer and migrated as deeply as wild-type trophoblasts. Furthermore, the junctional zone is enlarged in placentas of mice overexpressing αT-catenin due to hyperproliferation of the residing spongiotrophoblasts, suggesting a pivotal role of αT-catenin levels in the control of the proliferative versus invasive state of trophoblasts during placentation. Our study provides, for the first time, in vivo data on the effects of increased levels of αT-catenin in the placenta.

Predicting the wetting dynamics of a two-liquid system.

We propose a new theoretical model of dynamic wetting for systems comprising two immiscible liquids, in which one liquid displaces another from the surface of a solid. Such systems are important in many industrial processes and the natural world. The new model is an extension of the molecular-kinetic theory of wetting and offers a way to predict the dynamics of a two-liquid system from the individual wetting dynamics of its parent liquids. We also present the results of large-scale molecular dynamics simulations for one- and two-liquid systems and show them to be in good agreement with the new model. Finally, we show that the new model is consistent with the limited data currently available from experiment.

Can we predict the spreading of a two-liquid system from the spreading of the corresponding liquid-air systems?

We present new data obtained from the spreading of a series of oil droplets, on top of a hydrophobic grafted silicon substrate, in air and immersed in water. We follow the contact angle and radius dynamics of hexane, dodecane, hexadecane, dibutyl phthalate, and squalane from the first milliseconds to approximately 1 s. Analysis of the images allows us to make several hundred contact angle and droplet radius measurements with great accuracy. The G-Dyna (Seveno et al. Langmuir 2010, 25, 13034) software is then used to fit the data with one of the wetting theories, the molecular-kinetic theory (MKT) (Blake et al. J. Colloid Interface Sci.1969, 30, 421), which takes into account the dissipation at the three-phase zone at the contact line. This theory allows us to extract the coefficient of friction of the contact line, which expresses the relationship between the driving force, that is, the unbalanced Young force, and the contact-line velocity V. It is first shown that the MKT is appropriate to describe the experimental data and then that the contact-line friction is a linear function of the viscosity as theoretically predicted. This is checked for oil-air and oil-water systems. A linear relation between the contact-line friction measured in oil-water systems and the contact-line frictions of the parent single liquid system seems plausible. To the best of our knowledge, this is the first trial to establish a link between the dynamics of wetting in liquid-liquid and in liquid-air systems.

Lunar global shape and polar topography derived from Kaguya-LALT laser altimetry.

A global lunar topographic map with a spatial resolution of finer than 0.5 degree has been derived using data from the laser altimeter (LALT) on board the Japanese lunar explorer Selenological and Engineering Explorer (SELENE or Kaguya). In comparison with the previous Unified Lunar Control Network (ULCN 2005) model, the new map reveals unbiased lunar topography for scales finer than a few hundred kilometers. Spherical harmonic analysis of global topographic data for the Moon, Earth, Mars, and Venus suggests that isostatic compensation is the prevailing lithospheric support mechanism at large scales. However, simple rigid support is suggested to dominate for the Moon, Venus, and Mars for smaller scales, which may indicate a drier lithosphere than on Earth, especially for the Moon and Venus.

alphaT-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell-cell adhesion.

Cadherins are major cell-cell adhesion proteins whose cytoplasmic domains bind to catenin proteins. Strong intercellular adhesion depends on linkage of the cadherin/catenin complex to the actin cytoskeleton via alpha-catenin. To date, it is not clear how different cell types achieve the variable strength of cell-cell adhesion clearly needed in a multicellular organism. Here, we report the cloning and molecular characterization of alphaT(testis)-catenin, a novel human cDNA encoding a protein with homology to both human alphaE(epithelial)-catenin and alphaN(neural)-catenin. Although originally discovered in testis, alphaT-catenin is expressed in other tissues, the highest levels being observed in heart. Immunohistochemical analysis showed human alphaT-catenin localization at intercalated discs of cardiomyocytes and in peritubular myoid cells of testis. In cells transfected with alphaT-catenin cDNA, interaction with beta-catenin was demonstrated by co-immunoprecipitation. Transfection of alpha-catenin-deficient colon carcinoma cells recruited E-cadherin and beta-catenin to cell-cell contacts and functional cadherin-mediated cell-cell adhesion was restored in this way. Moreover, compaction of these cells was at least as prominent as in the case of cells expressing endogenous alphaE-catenin. We propose that alphaT-catenin is necessary for the formation of stretch-resistant cell-cell adhesion complexes, in particular, muscle cells.

Evaluation of the effects of mivacurium chloride on hemodynamics and left ventricular function in patients with coronary artery disease undergoing abdominal aortic surgery.

OBJECTIVE: To determine the effects of two doses of mivacurium chloride on hemodynamics and left ventricular function in patients with documented coronary artery disease undergoing aortic surgery. DESIGN: A prospective study with the dose of mivacurium determined by randomization. SETTING: Induction area at a university hospital. PARTICIPANTS: Twenty consecutive patients undergoing aortic surgery with clinically and/or angiographically documented coronary artery disease. INTERVENTIONS: Intravenous administration of mivacurium chloride. MEASUREMENTS AND MAIN RESULTS: Induction of anesthesia was performed with midazolam and fentanyl. Two different doses of mivacurium chloride, 0.15 mg/kg (n = 10) and 0.2 mg/kg (n = 10; 2 and 2.5 ED95; respectively), were administered as a single bolus injection over a 60-second period in the absence of any surgical stimulation. In addition to standard hemodynamic monitoring, pulmonary artery catheterization and transesophageal echocardiography were used. The occurrence of myocardial ischemia was monitored using both a computerized three-lead ST-segment analysis system and the echocardiographic assessment of regional wall motion. No change in heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac output, and global left ventricular function was noted after administration of mivacurium with the two doses studied. No ST-segment change or new segmental wall motion abnormality was noted in either group. CONCLUSION: Mivacurium chloride, when injected over a 60-second period, preserves global and regional myocardial function in patients with documented coronary artery disease undergoing noncardiac surgery.