Trophoblast lineage-specific differentiation and associated alterations in preeclampsia and fetal growth restriction.

The human placenta is a poorly-understood organ, but one that is critical for proper development and growth of the fetus in-utero. The epithelial cell type that contributes to primary placental functions is called "trophoblast," including two main subtypes, villous and extravillous trophoblast. Cytotrophoblast and syncytiotrophoblast comprise the villous compartment and contribute to gas and nutrient exchange, while extravillous trophoblast invade and remodel the uterine wall and vessels, in order to supply maternal blood to the growing fetus. Abnormal differentiation of trophoblast contributes to placental dysfunction and is associated with complications of pregnancy, including preeclampsia (PE) and fetal growth restriction (FGR). This review describes what is known about the cellular organization of the placenta during both normal development and in the setting of PE/FGR. It also explains known trophoblast lineage-specific markers and pathways regulating their differentiation, and how these are altered in the setting of PE/FGR, focusing on studies which have used human placental tissues. Finally, it also highlights remaining questions and needed resources to advance this field

Astronomical random numbers for quantum foundations experiments

Photons from distant astronomical sources can be used as a classical source of randomness to improve fundamental tests of quantum nonlocality, wave-particle duality, and local realism through Bell's inequality and delayed-choice quantum eraser tests inspired by Wheeler's cosmic-scale Mach-Zehnder interferometer gedankenexperiment. Such sources of random numbers may also be useful for information-theoretic applications such as key distribution for quantum cryptography. Building on the design of an "astronomical random-number generator" developed for the recent "cosmic Bell" experiment [Handsteiner et al., Phys. Rev. Lett. 118, 060401 (2017)], in this paper we report on the design and characterization of a device that, with 20-nanosecond latency, outputs a bit based on whether the wavelength of an incoming photon is greater than or less than 700 nm. Using the one-meter telescope at the Jet Propulsion Laboratory (JPL) Table Mountain Observatory, we generated random bits from astronomical photons in both color channels from 50 stars of varying color and magnitude, and from 12 quasars with redshifts up to $z = 3.9$. With stars, we achieved bit rates of $\sim 1 \times 10^6$ Hz / m$^2$, limited by saturation for our single-photon detectors, and with quasars of magnitudes between 12.9 and 16, we achieved rates between $\sim 10^2$ and $2 \times 10^3$ Hz /m$^2$. For bright quasars, the resulting bitstreams exhibit sufficiently low amounts of statistical predictability as quantified by the mutual information. In addition, a sufficiently high fraction of bits generated are of true astronomical origin in order to address both the locality and freedom-of-choice loopholes when used to set the measurement settings in a test of the Bell-CHSH inequality.Comment: 17 pages, 12 figures. References added and minor edits to match published versio

Resistance-gene-directed discovery of a natural-product herbicide with a new mode of action.

Bioactive natural products have evolved to inhibit specific cellular targets and have served as lead molecules for health and agricultural applications for the past century1-3. The post-genomics era has brought a renaissance in the discovery of natural products using synthetic-biology tools4-6. However, compared to traditional bioactivity-guided approaches, genome mining of natural products with specific and potent biological activities remains challenging4. Here we present the discovery and validation of a potent herbicide that targets a critical metabolic enzyme that is required for plant survival. Our approach is based on the co-clustering of a self-resistance gene in the natural-product biosynthesis gene cluster7-9, which provides insight into the potential biological activity of the encoded compound. We targeted dihydroxy-acid dehydratase in the branched-chain amino acid biosynthetic pathway in plants; the last step in this pathway is often targeted for herbicide development10. We show that the fungal sesquiterpenoid aspterric acid, which was discovered using the method described above, is a sub-micromolar inhibitor of dihydroxy-acid dehydratase that is effective as a herbicide in spray applications. The self-resistance gene astD was validated to be insensitive to aspterric acid and was deployed as a transgene in the establishment of plants that are resistant to aspterric acid. This herbicide-resistance gene combination complements the urgent ongoing efforts to overcome weed resistance11. Our discovery demonstrates the potential of using a resistance-gene-directed approach in the discovery of bioactive natural products

Assessing the accuracy of a large observational registry of neovascular age-related macular degeneration

PURPOSE To evaluate the accuracy of an observational database that tracks real-world treatment outcomes for neovascular age-related macular degeneration. METHODS We audited 245 randomly sampled eyes from 189 patients with 3,356 visits from 11 doctors in the Fight Retinal Blindness! DATABASE Sex, birth year, previous treatments received, treatment, and visual acuity were validated against the clinical notes. Error rates, the proportion of missed visits (the number of visits present in the patient record but not entered into Fight Retinal Blindness!), the level of agreement using Cohen's kappa (κ) and intraclass correlation coefficients, and positive and negative predictive values were calculated. A visual acuity error was defined as an absolute difference of ≥5 letters. RESULTS The overall error rate was 3.5% (95% confidence interval: 3.1-3.9). The error rate for visual acuity was 5.1% (95% confidence interval: 4.2-5.9) and <5% for the remaining fields. The level of agreement for each field ranged from good to excellent (κ or intraclass correlation ≥ 0.75). The positive predictive value and negative predictive value for visits were 99% and 89%, respectively. The proportion of missed visits was 10.2%. CONCLUSION Accuracy of the Fight Retinal Blindness! database was good (>95%). The rate of missed visits was high, possibly due to the high burden of retrospective data entry or patients switching practitioners during treatment

F22RS SGR 6 (Provost List - Dean\u27s List for LSU Online)

To Urge and Request LSU to create a “Provost’s List” to provide a college honor to LSU online students who complete 12 hours of coursework across two (2) consecutive terms in a traditional spring or fall semester with a 3.5 grade point averag

Delayed Wound Closure in Fibromodulin-Deficient Mice Is Associated with Increased TGF-β3 Signaling

Fibromodulin (FMOD), a small leucine-rich proteoglycan, mediates scarless fetal skin wound repair through, in part, transforming growth factor-Β (TGF-Β) modulation. Using an adult fmod-null (fmod -/-) mouse model, this study further elucidates the interplay between FMOD and TGF-Β expression during cutaneous repair and scar formation. Full-thickness skin wounds on fmod -/- and wild-type (WT) mice were closed primarily and analyzed. Histomorphometry revealed delayed dermal cell migration leading to delayed wound closure and significantly increased scar size in fmod -/- mice relative to WT, which was partially rescued by exogenous FMOD administration. In addition, fmod -/- wounds exhibited early elevation (within 24 hours post-wounding) of type I and type II TGF-Β receptors as well as unexpectedly high fibroblast expression of TGF-Β3, a molecule with reported antifibrotic and antimigratory effects. Consistent with elevated fibroblastic TGF-Β3, fmod -/- fibroblasts were significantly less motile than WT fibroblasts. fmod -/- fibroblasts were also more susceptible to migration inhibition by TGF-Β3, leading to profound delays in dermal cell migration. Increased scarring in fmod -/- mice indicates that TGF-Β3\u27s antimotility effects predominate over its antifibrotic effects when high TGF-Β3 levels disrupt early fibroblastic wound ingress. These studies demonstrate that FMOD presence is critical for proper temporospatial coordination of wound healing events and normal TGF-Β bioactivity. © 2011 The Society for Investigative Dermatology

Cosmic Bell Test: Measurement Settings from Milky Way Stars

Bell’s theorem states that some predictions of quantum mechanics cannot be reproduced by a local-realist theory. That conflict is expressed by Bell’s inequality, which is usually derived under the assumption that there are no statistical correlations between the choices of measurement settings and anything else that can causally affect the measurement outcomes. In previous experiments, this “freedom of choice” was addressed by ensuring that selection of measurement settings via conventional “quantum random number generators” was spacelike separated from the entangled particle creation. This, however, left open the possibility that an unknown cause affected both the setting choices and measurement outcomes as recently as mere microseconds before each experimental trial. Here we report on a new experimental test of Bell’s inequality that, for the first time, uses distant astronomical sources as “cosmic setting generators.” In our tests with polarization-entangled photons, measurement settings were chosen using real-time observations of Milky Way stars while simultaneously ensuring locality. Assuming fair sampling for all detected photons, and that each stellar photon’s color was set at emission, we observe statistically significant ≳7.31σ and ≳11.93σ violations of Bell’s inequality with estimated p values of ≲1.8×10[superscript -13] and ≲4.0×10[superscript -33], respectively, thereby pushing back by ∼600  years the most recent time by which any local-realist influences could have engineered the observed Bell violation.Austrian Academy of SciencesAustrian Science Fund (Projects SFB F40 (FOQUS) and CoQuS W1210-N16)Austria. Federal Ministry of Science, Research, and EconomyNational Science Foundation (U.S.) (INSPIRE Grant PHY-1541160 and SES-1056580)Massachusetts Institute of Technology. Undergraduate Research Opportunities Progra

A generic testing framework for agent-based simulation models

International audienceAgent-based modelling and simulation (ABMS) had an increasing attention during the last decade. However, the weak validation and verification of agent-based simulation models makes ABMS hard to trust. There is no comprehensive tool set for verification and validation of agent-based simulation models, which demonstrates that inaccuracies exist and/or reveals the existing errors in the model. Moreover, on the practical side, many ABMS frameworks are in use. In this sense, we designed and developed a generic testing framework for agent-based simulation models to conduct validation and verification of models. This paper presents our testing framework in detail and demonstrates its effectiveness by showing its applicability on a realistic agent-based simulation case study

Dynamic de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.</p