Computational fluid dynamic simulations of maternal circulation : wall shear stress in the human placenta and its biological implications

Introduction In the human placenta the maternal blood circulates in the intervillous space (IVS). The syncytiotrophoblast (STB) is in direct contact with maternal blood. The wall shear stress (WSS) exerted by the maternal blood flow on the STB has not been evaluated. Our objective was to determine the physiological WSS exerted on the surface of the STB during the third trimester of pregnancy. Material and Methods To gain insight into the shear stress levels that the STB is expected to experience in vivo, we have formulated three different computational models of varying levels of complexity that reflect different physical representations of the IVS. Computations of the flow fields in all models were performed using the CFD module of the finite element code COMSOL Multi-physics 4.4. The mean velocity of maternal blood in the IVS during the third trimester was measured in vivo with dynamic MRI (0.94 +/- 0.14 mm.s(-1)). To investigate if the in silico results are consistent with physiological observations, we studied the cytoadhesion of human parasitized (Plasmodium falciparum) erythrocytes to primary human STB cultures, in flow conditions with different WSS values. Results The WSS applied to the STB is highly heterogeneous in the IVS. The estimated average values are relatively low (0.5 +/- 0.2 to 2.3 +/- 1.1 dyn.cm(-2)). The increase of WSS from 0.15 to 5 dyn.cm(-2) was associated with a significant decrease of infected erythrocyte cytoadhesion. No cytoadhesion of infected erythrocytes was observed above 5 dyn.cm(-2) applied for one hour. Conclusion Our study provides for the first time a WSS estimation in the maternal placental circulation. In spite of high maternal blood flow rates, the average WSS applied at the surface of the chorionic villi is low (<5 dyn.cm(-2)). These results provide the basis for future physiologicallyrelevant in vitro studies of the biological effects of WSS on the STB

Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism

Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production

Lucy's Flat Feet: The Relationship between the Ankle and Rearfoot Arching in Early Hominins

BACKGROUND. In the Plio-Pleistocene, the hominin foot evolved from a grasping appendage to a stiff, propulsive lever. Central to this transition was the development of the longitudinal arch, a structure that helps store elastic energy and stiffen the foot during bipedal locomotion. Direct evidence for arch evolution, however, has been somewhat elusive given the failure of soft-tissue to fossilize. Paleoanthropologists have relied on footprints and bony correlates of arch development, though little consensus has emerged as to when the arch evolved. METHODOLOGY/PRINCIPAL FINDINGS. Here, we present evidence from radiographs of modern humans (n=261) that the set of the distal tibia in the sagittal plane, henceforth referred to as the tibial arch angle, is related to rearfoot arching. Non-human primates have a posteriorly directed tibial arch angle, while most humans have an anteriorly directed tibial arch angle. Those humans with a posteriorly directed tibial arch angle (8%) have significantly lower talocalcaneal and talar declination angles, both measures of an asymptomatic flatfoot. Application of these results to the hominin fossil record reveals that a well developed rearfoot arch had evolved in Australopithecus afarensis. However, as in humans today, Australopithecus populations exhibited individual variation in foot morphology and arch development, and "Lucy" (A.L. 288-1), a 3.18 Myr-old female Australopithecus, likely possessed asymptomatic flat feet. Additional distal tibiae from the Plio-Pleistocene show variation in tibial arch angles, including two early Homo tibiae that also have slightly posteriorly directed tibial arch angles. CONCLUSIONS/SIGNIFICANCE. This study finds that the rearfoot arch was present in the genus Australopithecus. However, the female Australopithecus afarensis "Lucy" has an ankle morphology consistent with non-pathological flat-footedness. This study suggests that, as in humans today, there was variation in arch development in Plio-Pleistocene hominins.Leakey Foundatio

The evolution of the upright posture and gait—a review and a new synthesis

During the last century, approximately 30 hypotheses have been constructed to explain the evolution of the human upright posture and locomotion. The most important and recent ones are discussed here. Meanwhile, it has been established that all main hypotheses published until the last decade of the past century are outdated, at least with respect to some of their main ideas: Firstly, they were focused on only one cause for the evolution of bipedality, whereas the evolutionary process was much more complex. Secondly, they were all placed into a savannah scenario. During the 1990s, the fossil record allowed the reconstruction of emerging bipedalism more precisely in a forested habitat (e.g., as reported by Clarke and Tobias (Science 269:521–524, 1995) and WoldeGabriel et al. (Nature 412:175–178, 2001)). Moreover, the fossil remains revealed increasing evidence that this part of human evolution took place in a more humid environment than previously assumed. The Amphibian Generalist Theory, presented first in the year 2000, suggests that bipedalism began in a wooded habitat. The forests were not far from a shore, where our early ancestor, along with its arboreal habits, walked and waded in shallow water finding rich food with little investment. In contrast to all other theories, wading behaviour not only triggers an upright posture, but also forces the individual to maintain this position and to walk bipedally. So far, this is the only scenario suitable to overcome the considerable anatomical and functional threshold from quadrupedalism to bipedalism. This is consistent with paleoanthropological findings and with functional anatomy as well as with energetic calculations, and not least, with evolutionary psychology. The new synthesis presented here is able to harmonise many of the hitherto competing theories

Vein of Galen aneurysmal malformation (VGAM) in the fetus: retrospective analysis of perinatal prognostic indicators in a two-center series of 49 cases

Objective: Vein of Galen aneurysmal malformation (VGAM) is a rare fetal anomaly, the neurological outcome of which can be good with appropriate perinatal management. However, most fetal series are too small to allow reliable statistical assessment of potential prognostic indicators. Our aim was to assess, in a two-center series of 49 cases, the prognostic value of several prenatal variables, in order to identify possible prenatal indicators of poor outcome, in terms of mortality and cerebral disability. Methods: This was a retrospective study involving 49 cases of VGAM diagnosed prenatally and managed at two centers over a 17-year period (1999–2015). All cases had undergone detailed prenatal cerebral and cardiac assessment by grayscale ultrasound, color and pulsed-wave Doppler and magnetic resonance imaging (MRI). Ultrasound and MRI examination reports and images were reviewed and outcome information was obtained from medical reports. Volume of the VGAM (on ultrasound and MRI) was calculated and development of straight-sinus dilatation, ventriculomegaly and other major brain abnormalities was noted. Cardiothoracic ratio, tricuspid regurgitation and reversed blood flow across the aortic isthmus were evaluated on fetal echocardiography. Major brain lesions were considered by definition to be associated with poor outcome in all cases. Pregnancy and fetoneonatal outcome were known in all cases. Fetoneonatal outcome and brain damage were considered as dependent variables in the statistical evaluation. Poor outcome was defined as death, late termination of pregnancy due to association with related severe brain anomalies or severe neurological impairment. Results: At a mean follow-up time of 20 (range, 0–72) months, 36.7% of the whole series and 52.9% of the cases which did not undergo late termination were alive and free of adverse sequelae. Five (10.2%) cases showed progression of the lesion between diagnosis and delivery. On univariate analysis, dilatation of the straight sinus, VGAM volume ≥ 20 000 mm3 and tricuspid regurgitation were all significantly related to poor outcome. However, on logistic regression analysis, the only variables associated significantly with poor outcome were tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3. The former was also the only variable associated with brain damage. Conclusions: Major brain lesions, tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3 are the only prenatal variables associated with poor outcome in fetal VGAM. Prenatal multidisciplinary counseling should be based on these variables. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd

England and France in the Sixteenth Century

This article summarises the main developments in Anglo-French relations in the context of Tudor foreign policy. It reviews the historiography of the subject, highlighting the main developments in twentieth century research. It argues that this research demonstrates that it was in the sixteenth century, under the later Valois monarchs and the first Bourbon king of France that Franco-English relations changed significantly. From being openly hostile they became more ambivalent in the true meaning of the word. Under Henry VIII and Elizabeth I the two nations began to create a still-difficult but sometimes more productive relationship with each other. This set the broad pattern for relations up to and beyond the Entente-Cordiale of 1904

2D realistic modeling of a human placentone and simulation of maternal circulation in the IVS.

<p>A: (1) Digitization, binarization and vectorization of a vertical cross-section from the chorionic plate (blue line = fetal side) to the basal plate (pink line = maternal side) of a third-trimester normal human placenta. (2) Correction of the placental collapse; the coordinates (x_A;y_A) of the center of gravity for each solid element were determined, and the ordinate (y) of each center of gravity was then multiplied by 2. (3) Reconstruction of a placentone with 4 vertical corrected sections assembled by axial symmetry. B: Velocity plots for the 4 inlet velocities (50, 100, 200 and 300 mm.s^-1). C: Mean wall shear stress (WSS) (dyn.cm^-2) in the IVS as a function of the inlet velocity. D: For an abscissa (x = 1), WSS (dyn.cm-²) as a function of y (heigh in the IVS).</p

Experimental device for applying increasing levels of wall shear stress to the human syncytiotrophoblast in primary culture.

<p>A: Human syncytiotrophoblasts were obtained by spontaneous fusion of villous cytotrophoblasts (VT) after 48 hours of culture. VT and STBs were fixed and immunostained for desmoplakin (DPK, 5 μg.mL^-1, <i>green</i>), and nuclei were counterstained with 4’,6-diamidino-2-phenylindole (DAPI, <i>blue</i>). B: STBs were exposed to steady unidirectional laminar shear stress with the culture medium containing human erythrocytes infected by <i>Plasmodium falciparum</i> (hematocrit: 1%, parasitemia: 2%) for one hour. Channel slides (sticky-slides Luer I 0.4, Luer I 0.6, Luer I 0.8, Ibidi^® GmbH Martinsreid, Germany) with increasing heights (h = 400/600/800 μm), arranged in series and connected to a pump system (Ibidi^® GmbH Martinsreid, Germany) generating flow rates of 0.45 mL.min^-1 and 3.8 mL.min^-1, were used to apply a increasing levels of wall shear stress (0.15, 0.30, 0.60, 1.2, 2.4 and 5 dyn.cm^-2). C: Infections with the human malaria parasite <i>Plasmodium falciparum</i> during pregnancy lead to cytoadhesion of parasitized erythrocytes in the intervillous space. Cytoadherence is conferred by the specific interaction of the parasite-encoded adhesin VAR2CSA with chondroitin-4-sulfate A (CSA) present on human syncytiotrophoblast proteoglycans.</p

Dynamic placental MRI.

<p>A: Placenta (green line), uterus (blue line), fetus (pink line). The intraplacental progression of the contrast-enhanced maternal blood in the IVS was measured (yellow arrows) every Δt in a perpendicular direction between the basal plate and the chorionic plate. B-G: Progression of the gadolinium is measured every 4.8s, from the first MRI picture with gadolinium in the placenta (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0147262#pone.0147262.g006" target="_blank">Fig 6D</a>) in order to avoid calculating the velocity of the maternal blood in the central cavity (CC) of the placentone. The mean flow velocity of maternal blood measured in the IVS is 0.94±0.14 mm.s^-1.</p