Induction of controlled hypoxic pregnancy in large mammalian species.

Progress in the study of pregnancy complicated by chronic hypoxia in large mammals has been held back by the inability to measure long-term significant reductions in fetal oxygenation at values similar to those measured in human pregnancy complicated by fetal growth restriction. Here, we introduce a technique for physiological research able to maintain chronically instrumented maternal and fetal sheep for prolonged periods of gestation under significant and controlled isolated chronic hypoxia beyond levels that can be achieved by habitable high altitude. This model of chronic hypoxia permits measurement of materno-fetal blood gases as the challenge is actually occurring. Chronic hypoxia of this magnitude and duration using this model recapitulates the significant asymmetric growth restriction, the pronounced cardiomyopathy, and the loss of endothelial function measured in offspring of high-risk pregnancy in humans, opening a new window of therapeutic research.This work was supported by The British Heart Foundation and The Royal Society. DG is Professor of Cardiovascular Physiology & Medicine at the Department of Physiology Development & Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Gonville & Caius College, a Lister Institute Fellow and a Royal Society Wolfson Research Merit Award Holder.This is the final version of the article. It was first available from the American Physiological Society via http://dx.doi.org/10.14814/phy2.1261

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Developmental Expression and Glucocorticoid Control of the Leptin Receptor in Fetal Ovine Lung.

The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are well-established, although the role of leptin in lung development before birth is unclear. This study examined mRNA and protein levels of the signalling long-form leptin receptor (Ob-Rb) in fetal ovine lungs towards term, and after experimental manipulation of glucocorticoid levels in utero by fetal cortisol infusion or maternal dexamethasone treatment. In fetal ovine lungs, Ob-Rb protein was localised to bronchiolar epithelium, bronchial cartilage, vascular endothelium, alveolar macrophages and type II pneumocytes. Pulmonary Ob-Rb mRNA abundance increased between 100 (0.69 fractional gestational age) and 144 days (0.99) of gestation, and by 2-4-fold in response to fetal cortisol infusion and maternal dexamethasone treatment. In contrast, pulmonary Ob-Rb protein levels decreased near term and were halved by glucocorticoid treatment, without any significant change in phosphorylated signal transducer and activator of transcription-3 (pSTAT3) at Ser727, total STAT3 or the pulmonary pSTAT3:STAT3 ratio. Leptin mRNA was undetectable in fetal ovine lungs at the gestational ages studied. These findings demonstrate differential control of pulmonary Ob-Rb transcript abundance and protein translation, and/or post-translational processing, by glucocorticoids in utero. Localisation of Ob-Rb in the fetal ovine lungs, including alveolar type II pneumocytes, suggests a role for leptin signalling in the control of lung growth and maturation before birth.This work was supported by the Biotechnology and Biological Sciences Research Council (grant numbers S18103 and BB/H01697X/1).This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013611

Phase-rectified signal averaging method to predict perinatal outcome in infants with very preterm fetal growth restriction- a secondary analysis of TRUFFLE-trial

BACKGROUND: Phase-rectified signal averaging, an innovative signal processing technique, can be used to investigate quasi-periodic oscillations in noisy, nonstationary signals that are obtained from fetal heart rate. Phase-rectified signal averaging is currently the best method to predict survival after myocardial infarction in adult cardiology. Application of this method to fetal medicine has established significantly better identification than with short-term variation by computerized cardiotocography of growth-restricted fetuses. OBJECTIVE: The aim of this study was to determine the longitudinal progression of phase-rectified signal averaging indices in severely growth-restricted human fetuses and the prognostic accuracy of the technique in relation to perinatal and neurologic outcome. STUDY DESIGN: Raw data from cardiotocography monitoring of 279 human fetuses were obtained from 8 centers that took part in the multicenter European “TRUFFLE” trial on optimal timing of delivery in fetal growth restriction. Average acceleration and deceleration capacities were calculated by phase-rectified signal averaging to establish progression from 5 days to 1 day before delivery and were compared with short-term variation progression. The receiver operating characteristic curves of average acceleration and deceleration capacities and short-term variation were calculated and compared between techniques for short- and intermediate-term outcome. RESULTS: Average acceleration and deceleration capacities and short-term variation showed a progressive decrease in their diagnostic indices of fetal health from the first examination 5 days before delivery to 1 day before delivery. However, this decrease was significant 3 days before delivery for average acceleration and deceleration capacities, but 2 days before delivery for short-term variation. Compared with analysis of changes in short-term variation, analysis of (delta) average acceleration and deceleration capacities better predicted values of Apgar scores <7 and antenatal death (area under the curve for prediction of antenatal death: delta average acceleration capacity, 0.62 [confidence interval, 0.19–1.0]; delta short-term variation, 0.54 [confidence interval, 0.13–0.97]; P=.006; area under the curve for prediction Apgar <7: average deceleration capacity <24 hours before delivery, 0.64 [confidence interval, 0.52–0.76]; short-term variation <24 hours before delivery, 0.53 [confidence interval, 0.40–0.65]; P=.015). Neither phase-rectified signal averaging indices nor short-term variation showed predictive power for developmental disability at 2 years of age (Bayley developmental quotient, <95 or <85). CONCLUSIONS: The phase-rectified signal averaging method seems to be at least as good as short-term variation to monitor progressive deterioration of severely growth-restricted fetuses. Our findings suggest that for short-term outcomes such as Apgar score, phase-rectified signal averaging indices could be an even better test than short-term variation. Overall, our findings confirm the possible value of prospective trials based on phase-rectified signal averaging indices of autonomic nervous system of severely growth-restricted fetuses

Nanocrystalline diamond-glass platform for the development of three-dimensional micro- and nanodevices

Low-cost and robust platforms are key for the development of next-generation 3D micro- and nanodevices. To fabricate such platforms, nanocrystalline diamond (NCD) is a highly appealing material due to its biocompatibility, robustness, and mechanical, electrical, electrochemical, and optical properties, while glass substrates with through vias are ideal interposers for 3D integration due to the excellent properties of glass. However, developing devices that comprise NCD films and through glass vias (TGVs) has rarely been attempted due to a lack of effective process strategies. In this work, a low-cost process - free of photolithography and transfer-printing - for fabricating arrays of TGVs that are sealed with suspended portions of an ultra-thin NCD film on one side is presented. These highly transparent structures may serve as a platform for the development of microwells for single-cell culture and analysis, 3D integrated devices such as microelectrodes, and quantum technologies. The process is demonstrated by fabricating TGVs that are sealed with an NCD film of thickness 175 nm and diameter 60 mu m. The technology described can be extended by replacing NCD with silicon nitride or silicon carbide, allowing for the development of complex heterogeneous structures on the small scale

Ferroelectric switching in epitaxial GeTe films

In this paper, using a resonance-enhanced piezoresponse force microscopy approach supported by density functional theory computer simulations, we have demonstrated the ferroelectric switching in epitaxial GeTe films. It has been shown that in films with thickness on the order of several nanometers reversible reorientation of polarization occurs due to swapping of the shorter and longer Ge-Te bonds in the interior of the material. It is also hinted that for ultra thin films consisting of just several atomic layers weakly bonded to the substrate, ferroelectric switching may proceed through exchange of Ge and Te planes within individual GeTe layers

Advancing preservation: a chemometric approach for monitoring the degradation of protective coatings for bronze statues

Bronze outdoor statues are often covered by a corrosion patina that forms due to environmental exposure, providing both aesthetic value and, partly, a surface passivation. However, this patina does not prevent from decay by external factors such as pollution, UV radiation, and humidity. To mitigate these decay processes, protective coatings are commonly used, but existing solutions often have drawbacks related to health, durability, and the need for frequent reapplication. The development of reliable, long-term conservation methods is essential. This work focuses on evaluating coatings formulated with Paraloid (R) B44, incorporating non-toxic corrosion inhibitors and light stabilizers. A total of twenty-one coatings were subjected to accelerated aging with artificial sunlight, and their decay was monitored using a multi-analytical approach involving Fourier Transform Infrared Spectroscopy (FT-IR) and UV-Vis spectroscopy, both with benchtop and portable spectrometers. The aim is to propose a method that combines spectroscopic data with chemometrics, specifically Principal Component Analysis (PCA), to objectively assess coating decay over time. The results demonstrate that PCA provides a simple yet powerful tool to distinguish between different formulations, track their aging, and rationalize decay processes. This approach not only facilitates the comparative analysis of coatings but also holds potential for field applications using portable instruments. By integrating spectroscopy with chemometrics, this method aligns with the principles of green analytical chemistry, offering a non-invasive, efficient means to monitor the effectiveness of protective coatings for cultural heritage preservation

Boundary curvature effect on the wrinkling of thin suspended films

A relation between the boundary curvature κ and the wrinkle wavelength λ of a thin suspended film under boundary confinement is demonstrated. Experiments were performed with nanocrystalline diamond films of approximate thickness 184nm grown on glass substrates. By removing portions of the substrates after growth, suspended films with circular boundaries of radius 30–811 μm were fabricated. Due to residual stresses, the portions of the film bonded to the substrate are of approximate compressive prestrain 11×10⁻⁴ and the suspended portions of the film are azimuthally wrinkled at their boundary. Measurements show that λ decreases monotonically with κ, and a simple model that is in line with this trend is proposed. The model can be applied to design devices with functional wrinkles and can be adapted to gain insight into other systems such as plant leaves. A method for measuring residual compressive strain in thin films, which complements standard strain characterization methods, is also described

Improvement in the sustainability and stability of acrylic protective coatings for outdoor bronze artworks

Outdoor bronze artworks are an entrenched part of our urban landscape. They are usually covered by a patina resulting from their exposition to the environment. This patina plays an important aesthetic role and may provide some passivation on the surface, nonetheless it does not prevent the degradation processes promoted by external factors such as pollution, light and humidity. One of the strategies to slow down these unwanted processes is the application of protective coatings. The products currently available have some limitations due to the loss of effectiveness over time and poor environmental sustainability. With the aim of proposing more performing alternatives, coatings based on Paraloid (R) B44 modified with corrosion inhibitors and light stabilizers were prepared and characterized. Two non-toxic corrosion inhibitors were studied, 5-mercapto-1-pheniltetrazole (MPT) and 5-ethyl-1,3,4-thiadiazol-2-amine (AEDTA), comparing them with the traditional benzotriazole (BTA). The approach used aimed to identify the blend providing the most stable coatings. The chemical and physical properties of the coatings, such as colour, solubility, glass transition and composition, were studied and monitored over time. All coatings have shown adequate visual properties; however, corrosion inhibitors degrade some other properties of the coatings and need to be used in conjunction with light stabilizers. The permanence of corrosion inhibitors in the coatings over time was also studied by investigating the role of the support. The establishment of specific interactions between inhibitors and the bronze surface lengthens their permanence in the coatings compared to what happens with inert supports. Especially for AEDTA, the inhibitor retention within the coating and at the coating-bronze interface is better than for BTA and MPT. The effect of each of the additives on the photooxidation stability of the coating was evaluated and the most promising inhibitor and stabilizer combination was identified

EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies), 2013 . Scientific O pinion on Dietary Reference Values for molybdenum

Following a request from the European Commission, the Panel on Dietetic Products, Nutrition and Allergies (NDA) derived Dietary Reference Values (DRVs) for molybdenum. Molybdenum is efficiently and rapidly absorbed at a wide range of intakes, and the body is able to maintain homeostasis through the regulation of excretion via the urine. Molybdenum deficiency in otherwise healthy humans has not been observed and there are no biomarkers of molybdenum status. Various metabolic balance studies have been performed to establish molybdenum requirements. However, only one balance study, which was performed with a constant diet and under controlled conditions in adult men, was considered to be of sufficient duration. In this small study, balance was reported to be near zero when molybdenum intakes were 22 µg/day. Biochemical changes or symptoms suggestive of molybdenum deficiency were not observed, and it is possible that humans may be able to achieve molybdenum balance at even lower intakes. Data on molybdenum intakes and health outcomes were unavailable for the setting of DRVs for molybdenum. As the evidence required to derive an Average Requirement and a Population Reference Intake was considered insufficient, an Adequate Intake (AI) is proposed. Observed molybdenum intakes from mixed diets in Europe were taken into consideration in setting this value. An AI of 65 µg/day is proposed for adults; a figure that is based on molybdenum intakes at the lower end of the wide range of observed intakes. It is suggested that the adult AI also applies to pregnant and lactating women. An AI is also proposed for infants from seven months and for children based on extrapolation from the adult AI using isometric scaling and the reference body weights of the respective age groups