Chromosomal aneuploidy and specific gene mutations are recognized early hallmarks of many oncogenic processes. However, the net effect of these abnormalities has generally not been explored. We focused on transient myeloproliferative disorder (TMD) in Down syndrome, which is characteristically associated with somatic mutations in GATA1. To better understand functional interplay between trisomy 21 and GATA1 mutations in hematopoiesis, we constructed cellular disease models using human induced pluripotent stem cells (iPSCs) and genome-editing technologies. Comparative analysis of these engineered iPSCs demonstrated that trisomy 21 perturbed hematopoietic development through the enhanced production of early hematopoietic progenitors and the upregulation of mutated GATA1, resulting in the accelerated production of aberrantly differentiated cells. These effects were mediated by dosage alterations of RUNX1, ETS2, and ERG, which are located in a critical 4-Mb region of chromosome 21. Our study provides insight into the genetic synergy that contributes to multi-step leukemogenesis.

In this numerical study, we investigate natural convection in a two-dimensional square-section enclosure vibrating sinusoidally parallel to the applied temperature gradient in a zero-gravity field. The full Navier–Stokes equations are simplified with the Boussinesq approximation and solved by a finite difference method. Whereas the Prandtl number Pr is fixed to 7.1 (except for some test cases with Pr = 7.0, 6.8), the vibrational Rayleigh number Ra based on acceleration amplitude is varied from 1.0 × 104 to 1.0 × 105, and dimensionless angular frequency ω is varied from 1.0 × 100 to 1.0 × 103. In the tested range, time evolutions exhibit synchronous, 1/2-subharmonic and non-periodic responses, and flow patterns are characterized mainly by one- or two-cell structures. Flow-regime diagrams show considerable differences from results in a non-zero-mean-gravity field even at large acceleration amplitudes, and suggest that some parts of non-periodic-response regimes may be related to transitions between flow patterns. The amplitude of fluctuations in spatially averaged kinetic energy density K (equal to the difference between maximum and minimum kinetic energies over a cycle) tends to be large when fluid is stationary everywhere over some interval of time during each period, and has a peak when fluid begins to move continuously throughout one period. Such peaks are caused by impulsively started convection, and are not connected to resonant oscillations in a constant-gravity field.

Within a cohort of ELBW infants, a bubbly/cystic appearance of the lungs in the neonatal period was the strongest determinant of a low FEV1/FVC ratio at school age.

In the present study, we consider the air entrainment into a suction pipe which is vertically inserted down into a suction sump across a mean free-water surface. This configuration is often referred to as the "vertical wet-pit pump", and has many practical advantages in construction, maintenance and operation. In particular, we focus our concern upon the critical submergence depth S c , which is one of the prime and conventional indicators for the air-entrainment occurrence. By a systematic approach, we experimentally investigate the influences of kinetic and geometric parameters upon S c. As the kinetic parameters, we consider the Reynolds number Re and the Weber number We, in addition to the Froude number Fr, on such a basis as Fr is not much larger than unity in many actual cases. As the geometric parameters, we consider back clearance X, sump breadth B and bottom clearance Z. Here, all parameters are non-dimensionalised by the outside diameter D and the intake velocity V i of the suction pipe. As a result, we reveal the effects of such six parameters upon S c. The We effect, namely, the surface-tension effect can be ignored at We > 12. And, the Re effect, namely, the viscous effect becomes negligibly small at Re > 3×10 4. Under such conditions for We and Re, we could consider only the Fr effect, namely, the gravitational effect. Concerning the X/D and B/D effects, S c /D attains the maximum at a certain X/D or B/D. On the other hand, the Z/D effect is monotonic, and becomes small at Z/D > 2.5. Some aspects of these geometric effects can be evaluated by a local-Froude-number effect on the basis of the global relation between S c /D and Fr. And, the other aspects is necessarily considered to be related with the flow structure in the suction sump.

BackgroundOutcomes of prenatal covariate-adjusted outborn very-low-birth-weight infants (VLBWIs) (≤1500 g) remain uncertain.ObjectiveTo compare morbidity and mortality between outborn and inborn VLBWIs.DesignObservational cohort study using inverse-probability-of-treatment weighting.SettingNeonatal Research Network of Japan.PatientsSingleton VLBWIs with no major anomalies admitted to a neonatal intensive care unit from 2012 to 2016.MethodsInverse-probability-of-treatment weighting with propensity scores was used to reduce imbalances in prenatal covariates (gestational age (GA), birth weight, small for GA, sex, maternal age, premature rupture of membranes, chorioamnionitis, preeclampsia, maternal diabetes mellitus, antenatal steroids and caesarean section). The primary outcome was severe intraventricular haemorrhage (IVH). The secondary outcomes were outcomes at resuscitation, other neonatal morbidities and mortality.ResultsThe full cohort comprised 15 842 VLBWIs (668 outborns). The median (IQR) GA and birth weight were 28.9 (26.4–31.0) weeks and 1128 (862–1351) g for outborns and 28.7 (26.3–30.9) weeks and 1042 (758–1295) g for inborns. Outborn VLBWIs had a higher incidence of severe IVH (8.2% vs 4.1%; OR, 3.45; 95% CI 1.16 to 10.3) and pulmonary haemorrhage (3.7% vs 2.8%; OR, 5.21; 95% CI 1.41 to 19.2). There were no significant differences in Apgar scores, oxygen rates at delivery, intubation ratio at delivery, persistent pulmonary hypertension of the newborn, IVH of any grade, periventricular leukomalacia, chronic lung disease, oxygen at discharge, patent ductus arteriosus, retinopathy of prematurity, necrotising enterocolitis, sepsis or mortality.ConclusionOutborn delivery of VLBWIs was associated with an increased risk of severe IVH.

In ELBW survivors, the obstructive pattern of lung function impairment deteriorated from 8 to 12 years of age, independent of the presence of severe BPD or bubbly/cystic appearance in the neonatal period.

A confined jet sometimes causes a self-exited oscillation due to the existence of a downstream target. In this work, the authors study this phenomenon. More specifically, the authors deal with a simple fluidic oscillator; namely, a two-dimensional confined jet into an abruptly-expanding channel with a downstream target of a square cylinder. The authors conduct the velocity measurements by an UVP (ultrasonic velocity profiler). Besides, the flow patterns in the fluidic oscillator are observed by a PIV (particle image velocimetry). As a result, the authors reveal the geometrical effects upon the range of stable jet's oscillation, such as the aspect-ratio effect, the channel-breadth effect, the cylinder-size effect and the cylinder-distance effect, together with the Re effect.

Eukaryotic genomes are organised into complex higher-order structures within the nucleus, and the three-dimensional arrangement of chromosomes is functionally important for global gene regulation. The existence of supernumerary chromosome 21 in Down syndrome may perturb the nuclear architecture at different levels, which is normally optimised to maintain the physiological balance of gene expression. However, it has not been clearly elucidated whether and how aberrant configuration of chromosomes affects gene activities. To investigate the effects of trisomy 21 on nuclear organisation and gene expression, we performed three-dimensional fluorescent imaging analysis of chromosome-edited human induced pluripotent stem cells (iPSCs), which enabled identification of the parental origin of the three copies of chromosome 21. We found that two copies of maternal chromosomes resulting from meiotic nondisjunction had a higher tendency to form an adjacent pair and were located relatively distant from the nuclear membrane, suggesting the conserved interaction between these homologous chromosomes. Transcriptional profiling of parental-origin-specific corrected disomy 21 iPSC lines indicated upregulated expression of the maternal alleles for a group of genes, which was accompanied by a fluctuating expression pattern. These results suggest the unique effects of a pair of maternal chromosomes in trisomy 21, which may contribute to the pathological phenotype.