Perspectives: using polymer modeling to understand the formation and function of nuclear compartments.

Compartmentalization is a ubiquitous feature of cellular function. In the nucleus, early observations revealed a non-random spatial organization of the genome with a large-scale segregation between transcriptionally active-euchromatin-and silenced-heterochromatin-parts of the genome. Recent advances in genome-wide mapping and imaging techniques have strikingly improved the resolution at which nuclear genome folding can be analyzed and have revealed a multiscale spatial compartmentalization with increasing evidences that such compartment may indeed result from and participate to genome function. Understanding the underlying mechanisms of genome folding and in particular the link to gene regulation requires a cross-disciplinary approach that combines the new high-resolution techniques with computational modeling of chromatin and chromosomes. In this perspective article, we first present how the copolymer theoretical framework can account for the genome compartmentalization. We then suggest, in a second part, that compartments may act as a "nanoreactor," increasing the robustness of either activation or repression by enhancing the local concentration of regulators. We conclude with the need to develop a new framework, namely the "living chromatin" model that will allow to explicitly investigate the coupling between spatial compartmentalization and gene regulation.

Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study.

OBJECTIVE: To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm. METHODS: This was a retrospective, multicenter study, including 11 French hospitals, of data from the period between April 2012 and December 2015. In total, 720 fetuses were analyzed by rapid aneuploidy test and the fetuses identified as euploid underwent CMA. CNVs detected were evaluated for clinical significance and classified into five groups: pathogenic CNVs; benign CNVs; CNVs predisposing to neurodevelopmental disorders; variants of uncertain significance (VOUS); and CNVs not related to the phenotype (i.e. incidental findings). RESULTS: In 121 (16.8%) fetuses, an aneuploidy involving chromosome 13, 18 or 21 was detected by rapid aneuploidy test and the remaining 599 fetuses were euploid. Among these, 53 (8.8%) had a CNV detected by CMA: 16/599 (2.7%) were considered to be pathogenic, including 11/599 (1.8%) that were cryptic (not visible by karyotyping); 7/599 (1.2%) were CNVs predisposing to neurodevelopmental disorders; and 8/599 (1.3%) were VOUS. Additionally, there was one (0.2%) CNV that was unrelated to the reason for referral diagnosis (i.e. an incidental finding) and the remaining 21 were benign CNVs, without clinical consequence. Interestingly, we identified five genomic imbalances of the 1q21.1 or 15q11.2 regions known to be associated with congenital heart defects. CONCLUSION: Our study demonstrates the benefit of CMA in the etiological diagnosis of fetuses with isolated increased NT. It is worth noting that most (69%) of the detected pathogenic CNVs were cryptic. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Tunneling splittings from path-integral molecular dynamics using a Langevin thermostat.

We report an improved method for the calculation of tunneling splittings between degenerate configurations in molecules and clusters using path-integral molecular dynamics (PIMD). Starting from an expression involving a ratio of thermodynamic density matrices at the bottom of the symmetric wells, we use thermodynamic integration with molecular dynamics simulations and a Langevin thermostat to compute the splittings stochastically. The thermodynamic integration is performed by sampling along the semiclassical instanton path, which provides an efficient reaction coordinate as well as being physically well-motivated. This approach allows us to carry out PIMD calculations of the multi-well tunneling splitting pattern in the water dimer and to refine previous PIMD calculations for one-dimensional models and malonaldehyde. The large (acceptor) splitting in the water dimer agrees to within 20% of benchmark variational results, and the smaller splittings agree to within 10%.

NOTCH2 related disorders: Description and review of the fetal presentation.

Signs of skeletal dysplasias are relatively common in fetuses with abnormal ultrasound (US) findings. The diversity of congenital skeletal disorders, the possibility of late-onset severe phenotypes and overlapping syndromes can be a challenge in the way of diagnosis, even if prenatal high-throuput sequencing allows for a better diagnosis, prognosis and genetic counseling. Hajdu-Cheney spectrum pathologies are rarely described in prenatal, and the signs associated remain poorly known, and do not include specific postnatal signs as acro-osteolysis and premature osteoporosis. We hereby report a couple for whom a medical termination of pregnancy was performed because a severe polymalformative syndrome associating severely short limbs with bowed long bones, severe cardiopathy, hyperechogenic kidneys and dysmorphism. After fetopathological and radiological examinations, Exome Sequencing (ES) was performed and revealed a de novo truncating mutation in the last exon of NOTCH2, responsible for Hajdu-Cheney or Serpentine Fibula Polycystic Kidney syndromes.

Revisiting polymer statistical physics to account for the presence of long-range-correlated structural disorder in 2D DNA chains.

We elaborate on a generalization of the 2D wormlike chain (WLC) model that accounts for the presence of long-range correlations (LRC) in the intrinsic curvature distribution of eukaryotic DNA. This model predicts some decrease of the DNA persistence length resulting from some large-scale intrinsic curvature induced by sequence-dependent persistent random distribution of local bending sites. When assisting exact analytical calculations by numerical DNA simulations, we show that the conjugated contributions of i) the thermal curvature fluctuations characterized by the "dynamic" persistence length ℓ(p)(d) = 2A, where A is the elastic bending modulus, and ii) the intrinsic LRC curvature disorder of amplitude σ(o) and Hurst exponent H > 1/2, characterized by a "static" persistence length ℓ(p)(H) = A(1/2H)σ(o)(-1/H) Γ(1/2H + 1), can be described by a continuum of generalized WLC (GWLC) models parametrized by the LRC exponent H. We use perturbation analysis to investigate the two limiting cases of weak static disorder (w(H) << 1 and weak dynamical fluctuations (1/w (H) << 1), where w(H) = l(p)(d)/l(p)(H) is a dimensionless parameter. From a quantitative point of view, our study demonstrates that even for a small value of the LRC (H approximately equal 0.6-0.8) static disorder amplitude σ(o) ~ 10(-2), as previously reported for genomic DNA, the decrease of the persistence length from the WLC prediction l(p)(d) can be very significant, up to twofold. The implications of these results on the first steps of compaction of DNA in eukaryotic cells are discussed.

[Significations of extremely elevated C-reactive protein: about 91 cases in a French hospital center]. / Significations d'une protéine C-réactive supérieure à 500mg/l: à propos de 91 prélèvements dans un centre hospitalier brestois.

This report is devoted to 91 extremely elevated protein C-reactive levels. Patients characteristics, etiologies of inflammation, comorbidities and microbiology are subjected to wide variations. Mortality is high (37 % and 51 %, 30 and 90 days later).

Contribution of three-dimensional ultrasonography in depicting perineal features in cloacal malformation.

Cloacal anomaly is a rare malformation with an incidence of 1 in 50,000 births. The definitive prenatal diagnosis of cloacal dysgenesis sequence is difficult. The use of three-dimensional (3-D) ultrasonography helps to describe the perineum and change diagnosis. In our case report, a large median genital structure was visualized, which was initially considered a penis-like structure, but the 3-D technique showed an enlarged bud. The urethral meatus was at the tip of this smooth structure. The lack of anal structure was clearly demonstrated.

Early regulation of brain aromatase (cyp19a1b) by estrogen receptors during zebrafish development.

Early expression of estrogen receptors (esr) and their role in regulating early expression of cyp19a1b encoding brain aromatase were examined in the brain of zebrafish. Using in toto hybridization and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), a significant increase in the expression of esr1, esr2a, and esr2b was observed between 24 and 48 hours postfertilization (hpf). In toto hybridization demonstrated that esr2a and esr2b, but not esr1, are found in the hypothalamus. Using real-time RT-PCR, an increase in cyp19a1b mRNAs occurs between 24 and 48 hpf, indicating that expression of cyp19a1b is temporally correlated with that of esr. This increase is blocked by the pure anti-estrogen ICI182,780. Furthermore, E2 treatment of cyp19a1b-GFP (green fluorescent protein) transgenic embryos results in appearance of GFP expression in the brain as early as 25 hpf. These results indicate that basal expression of cyp19a1b expression in the brain of developing zebrafish most likely relies upon expression of esr that are fully functional before 25 hpf.

Thermodynamics of intragenic nucleosome ordering.

The nucleosome ordering observed in vivo along yeast genes is described by a thermodynamical model of nonuniform fluid of 1D hard rods confined by two excluding energy barriers at gene extremities. For interbarrier distances L less than or approximately equal to 1.5 kbp, nucleosomes equilibrate into a crystal-like configuration with a nucleosome repeat length (NRL) L/n approximately 165 bp, where n is the number of regularly positioned nucleosomes. We also observe "bistable" genes with a fuzzy chromatin resulting from a statistical mixing of two crystal states, one with an expanded chromatin (NRL approximately L/n) and the other with a compact one (NRL approximately L/(n+1)). By means of single nucleosome switching, bistable genes may drastically alter their expression level as suggested by their higher transcriptional plasticity. These results enlighten the role of the intragenic chromatin on gene expression regulation.

[Biological signifiance of 410 microcytosis]. / Signification biologique de 410 microcytoses de découverte fortuite chez des adultes jeunes.

We have detected 410 microcytosis among biological tests of military people. These microcytosis are principally coumpounded by haemoglobin's abnormalities (minor thalassemia, sickle cell diseases, E haemoglobin cases and cases of C haemoglobin) and cases of iron deficiency, usually among women.

[Drepanocytosis with alpha and beta(o) thalassemia: a case report]. / Drépanocytose beta(o) thalassémique associée à une alpha thalassémie: à propos d'un cas.

We describe the case of a Sickle Cell Trait associated with alpha and beta(o) thalassemia at an young man without clinical abnormality. Capillary electrophoresis showed S haemoglobin at 67%, F haemoglobin at 29%, A2 haemoglobin at 4% and an absence of A haemoglobin. Accurate diagnosis was found by techniques of molecular biology.

[Evaluation of two automated methods for blood lactate levels]. / Evaluation de deux méthodes de dosage de la concentration sanguine de lactate.

We evaluated two automated methods for measuring blood levels of lactates with Integra 800 (Roche Diagnostics) and ABL 725 (Radiometer). Our evaluation had shown a within run imprecision of 1% (Intégra 800) and 2% (ABL 725) and a between-assay imprecision of 2% (Intégra 800) and 5% (ABL 725). The two methodologies appeared very well associated. The selective electrode remains expensive but it is very interesting because it saves a blood sample.

Tunneling Splittings in Water Clusters from Path Integral Molecular Dynamics.

We present calculations of tunneling splittings in selected small water clusters, based on a recently developed path integral molecular dynamics (PIMD) method. The ground-rotational-state tunneling motions associated with the largest splittings in the water dimer, trimer, and hexamer are considered, and we show that the PIMD predictions are in very good agreement with benchmark quantum and experimental results. As the tunneling spectra are highly sensitive to both the details of the quantum dynamics and the potential energy surface, our calculations are a validation of the MB-Pol surface as well as the accuracy of PIMD. The favorable scaling of PIMD with system size paves the way for calculations of tunneling splittings in large, nonrigid molecular systems with motions that cannot be treated accurately by other methods, such as the semiclassical instanton.

Spontaneous emergence of sequence-dependent rosettelike folding of chromatin fiber.

In the crowded environment of the eukaryotic nucleus, the presence of intrinsic structural defects is shown to predispose chromatin fiber to spontaneously form rosettelike structures. These multilooped patterns self-organize through entropy-driven clustering of sequence-induced fiber defects by depletive forces prior to any external factors coming into play. They provide an attractive description of replication foci that are observed in interphase mammalian nuclei as stable chromatin domains of autonomous DNA replication and gene expression. Experimental perspectives for in vivo visualization of rosettelike organization of the chromatin fiber via the clustering of recently identified putative replication initiation zones are discussed.

[Is the bronchial atresia prenatal diagnosis possible?]. / Le diagnostic anténatal d'atrésie bronchique est-il possible ?

Bronchial atresia is a rare congenital malformation of the lung. The main-stem segmental or lobar bronchus fails to construct normally, which can lead to accumulation of mucus within the distal bronchi or lung hyperinflation of the obstructed lobe. The prenatal diagnosis is rare and difficult. We report two cases of fetuses who presented pathological examination of the lung on the ultrasonography, at 22 weeks of gestation, suspect of prenatal bronchial atresia diagnosis. We analysed this malformation through a literature review in order to discuss differential diagnosis to be evoked, as well as appropriate perinatal management.

[Doppler waveforms patterns of vascular anastomoses in monochorionic twin pregnancies. A report of three cases and review of the literature]. / Mise en évidence des anastomoses vasculaires par la vélocimétrie doppler dans les grossesses gémellaires monochoriales. Revue de la littérature à propos de trois cas.

Three cases of intermittent absent end-diastolic and reversed end-diastolic flow velocity (A/REDV) are reported in the proximal umbilical artery of the growth-retarded twin in monochorionic twin pregnancies. This typical doppler velocimetric pattern has been related to arterio-arterial anastomoses in two cases of intra-uterine growth retardation and in one case of twin-twin transfusion syndrome. According to the literature, superficial arterio-arterial anastomoses may be detected by doppler colour velocimetry in 75 to 85% of cases, while identification of arteriovenous connections is more difficult to be documented in vivo (50% of cases in experienced hands). The role of superficial vascular anastomoses, either arterio-arterial or venovenous, and that of deep arteriovenous communications is now well documented in the main complications of monochorionic pregnancies, particularly for twin-twin transfusion syndrome, intrauterine growth retardation, intrauterine fetal death and acardiac twins.

[Combining corticosteroid and aspirin for the prevention of recurrent villitis or intervillositis of unknown etiology]. / Association des corticoïdes à l'aspirine pour la prévention des récidives de villite ou d'intervillite chroniques d'étiologie indéterminée.

We report the cases of two patients who had a favorable outcome with aspirin and corticosteroid therapy during pregnancy for chronic villitis of unknown etiology complicated by labor asphyxia and further intrauterine fetal demise in one gravida 3 patient and for chronic intervillositis of unknown etiology diagnosed after three perinatal deaths in another patient (gravida 4). Chronic villitis of unknown etiology (CVUE) is detected in 7 to 33% of placentas, mainly after intrauterine growth retardation (IUGR), unexplained prematurity, preeclampsia, perinatal asphyxia and intrauterine fetal death (IUFD). The less frequent chronic intervillositis of unknown etiology (CIUE) (0.6 to 0.9/1.000) has been implicated in recurrent severe pregnancy complications, such as spontaneous abortions, IUGR and IUFD. Histopathology and immunohistology are in favor of an immune response against the foreign fetal allograft. The favorable results obtained with corticosteroids and aspirin remain to be confirmed by larger series.

[What signs should you look for ultrasound (2D/3D) to affirm the good location of tubal implants? About a retrospective study of 92 cases]. / Quels signes échographiques doit-on rechercher (2D/3D) pour affirmer la bonne localisation des implants tubaires ? À propos d'une étude rétrospective de 92 cas.

OBJECTIVE: The aim of this study is to propose an analysis of the route and the curvature of the Essure® system in 3D ultrasound to determine their correct location so as not to miss a tubal perforation. METHODS: This is a retrospective single center study during 2 years analyzing 92 3D ultrasound performed by a single sonographer. Implant placement was performed by different operators. One prescribed 3D ultrasound control in case of difficulties with the installation; other indications where systematics. RESULTS: The Essure®'s position is right in 79% of cases. Twenty-eight implants appear incorrectly positioned on ultrasound 3D positioning. Abnormalities found are those described by the classification proposed in the literature. In one case, the curvature of the implant, not taking into account this classification, allowed to evoke a tubal perforation. Among the 28 cases of non-visualized implants in place, 3 cases of wrong position of the implant were confirmed by additional examinations (laparoscopy or HSG). For 14 cases, the ASP or HSG disproved the wrong position of the implants. In other cases, we did not have other complementary examinations. CONCLUSION: Ultrasonography 3D seems to be the method of choice to control implants for simple implementation and good reproducibility. However, the interpretation of 3D ultrasound images is sometimes difficult. The study of the curvature of the implant should be systematically analyzed not to miss a tubal perforation.