Fetal movements as a predictor of health

The key determinant to a fetus maintaining its health is through adequate perfusion and oxygen transfer mediated by the functioning placenta. When this equilibrium is distorted, a number of physiological changes including reduced fetal growth occur to favour survival. Technologies have been developed to monitor these changes with a view to prolong intrauterine maturity whilst reducing the risks of stillbirth. Many of these strategies involve complex interpretation, for example Doppler ultrasound for fetal blood flow and computerisedcomputerized analysis of fetal heart rate changes. However, even with these modalities of fetal assessment to determine the optimal timing of delivery, fetal movements remain integral to clinical decision making. In high risk cohorts with fetal growth restriction, the manifestation of a reduction in perceived movements may warrant an expedited delivery. Despite this, there remains has been little evolution in the development of technologies to objectively define evaluate normal fetal movement behavior for behavior, and where there has, there has been no linkage to clinical useapplication. In tThis review we is an attempt to understand synthesize currently available literature on the value of fetal movement analysis as a method of assessing fetal wellbeing, and show how interdisciplinary developments in this area may aid in improvements to clinical outcomes

HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α

Many patients with hematological neoplasms fail to mobilize sufficient numbers of hematopoietic stem cells (HSCs) in response to granulocyte colony-stimulating factor (G-CSF) precluding subsequent autologous HSC transplantation. Plerixafor, a specific antagonist of the chemokine receptor CXCR4, can rescue some but not all patients who failed to mobilize with G-CSF alone. These refractory poor mobilizers cannot currently benefit from autologous transplantation. To discover alternative targetable pathways to enhance HSC mobilization, we studied the role of hypoxia-inducible factor-1α (HIF-1α) and the effect of HIF-1α pharmacological stabilization on HSC mobilization in mice. We demonstrate in mice with HSC-specific conditional deletion of the Hif1a gene that the oxygen-labile transcription factor HIF-1α is essential for HSC mobilization in response to G-CSF and Plerixafor. Conversely, pharmacological stabilization of HIF-1α with the 4-prolyl hydroxylase inhibitor FG-4497 synergizes with G-CSF and Plerixafor increasing mobilization of reconstituting HSCs 20-fold compared with G-CSF plus Plerixafor, currently the most potent mobilizing combination used in the clinic

Prenatal growth map of the mouse knee joint by means of deformable registration technique.

Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63μm) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions computed from repeated images were found for both epiphyses (between 1.3μm and 1.4μm for the proximal tibia and between 0.7μm and 1.0μm for the femur, along all directions). The protocol was found to be reproducible with maximum Modified Housdorff Distance (MHD) differences equal to 1.9 μm and 1.5 μm for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps with MHD of 21.7 μm and 21.9 μm for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors

Identification of Mechanosensitive Genes during Embryonic Bone Formation

Although it is known that mechanical forces are needed for normal bone development, the current understanding of how biophysical stimuli are interpreted by and integrated with genetic regulatory mechanisms is limited. Mechanical forces are thought to be mediated in cells by “mechanosensitive” genes, but it is a challenge to demonstrate that the genetic regulation of the biological system is dependant on particular mechanical forces in vivo. We propose a new means of selecting candidate mechanosensitive genes by comparing in vivo gene expression patterns with patterns of biophysical stimuli, computed using finite element analysis. In this study, finite element analyses of the avian embryonic limb were performed using anatomically realistic rudiment and muscle morphologies, and patterns of biophysical stimuli were compared with the expression patterns of four candidate mechanosensitive genes integral to bone development. The expression patterns of two genes, Collagen X (ColX) and Indian hedgehog (Ihh), were shown to colocalise with biophysical stimuli induced by embryonic muscle contractions, identifying them as potentially being involved in the mechanoregulation of bone formation. An altered mechanical environment was induced in the embryonic chick, where a neuromuscular blocking agent was administered in ovo to modify skeletal muscle contractions. Finite element analyses predicted dramatic changes in levels and patterns of biophysical stimuli, and a number of immobilised specimens exhibited differences in ColX and Ihh expression. The results obtained indicate that computationally derived patterns of biophysical stimuli can be used to inform a directed search for genes that may play a mechanoregulatory role in particular in vivo events or processes. Furthermore, the experimental data demonstrate that ColX and Ihh are involved in mechanoregulatory pathways and may be key mediators in translating information from the mechanical environment to the molecular regulation of bone formation in the embryo

Mechanical Influences on Morphogenesis of the Knee Joint Revealed through Morphological, Molecular and Computational Analysis of Immobilised Embryos

Very little is known about the regulation of morphogenesis in synovial joints. Mechanical forces generated from muscle contractions are required for normal development of several aspects of normal skeletogenesis. Here we show that biophysical stimuli generated by muscle contractions impact multiple events during chick knee joint morphogenesis influencing differential growth of the skeletal rudiment epiphyses and patterning of the emerging tissues in the joint interzone. Immobilisation of chick embryos was achieved through treatment with the neuromuscular blocking agent Decamethonium Bromide. The effects on development of the knee joint were examined using a combination of computational modelling to predict alterations in biophysical stimuli, detailed morphometric analysis of 3D digital representations, cell proliferation assays and in situ hybridisation to examine the expression of a selected panel of genes known to regulate joint development. This work revealed the precise changes to shape, particularly in the distal femur, that occur in an altered mechanical environment, corresponding to predicted changes in the spatial and dynamic patterns of mechanical stimuli and region specific changes in cell proliferation rates. In addition, we show altered patterning of the emerging tissues of the joint interzone with the loss of clearly defined and organised cell territories revealed by loss of characteristic interzone gene expression and abnormal expression of cartilage markers. This work shows that local dynamic patterns of biophysical stimuli generated from muscle contractions in the embryo act as a source of positional information guiding patterning and morphogenesis of the developing knee joint

Validation of OMPS Suomi NPP and OMPS NOAA‐20 Formaldehyde Total Columns With NDACC FTIR Observations

We validate formaldehyde (HCHO) vertical column densities (VCDs) from Ozone Mapping and Profiler Suite Nadir Mapper (OMPS-NM) instruments onboard the Suomi National Polar-orbiting Partnership (Suomi NPP) satellite for 2012–2020 and National Oceanic and Atmospheric Administration-20 (NOAA-20) satellite for 2018–2020, hereafter referred to as OMPS-NPP and OMPS-N20, with ground-based Fourier-Transform Infrared (FTIR) observations of the Network for the Detection of Atmospheric Composition Change (NDACC). OMPS-NPP/N20 HCHO products reproduce seasonal variability at 24 FTIR sites. Monthly variability of OMPS-NPP/N20 has a very good agreement with FTIR, showing correlation coefficients of 0.83 and 0.88, respectively. OMPS-NPP (N20) biases averaged over all sites are −0.9 (4) ± 3 (6)%. However, at clean sites (with VCDs 4.0 × 10$^{15}$ molecules cm$^{−2}$, negative biases of −15% ± 4% appear for OMPS-NPP, but OMPS-N20 shows smaller bias of 0.5% ± 6% due to its smaller ground pixel footprints. Therefore, smaller satellite footprint sizes are important in distinguishing small-scale plumes. In addition, we discuss a bias correction and provide lower limit for the monthly uncertainty of OMPS-NPP/N20 HCHO products. The total uncertainty for OMPS-NPP (N20) at clean sites is 0.7 (0.8) × 10$^{15}$ molecules cm$^{−2}$, corresponding to a relative uncertainty of 32 (30)%. In the case of HCHO VCDs > 4.0 × 10$^{15}$ molecules cm$^{−2}$, however, the relative uncertainty in HCHO VCDs for OMPS-NPP (N20) decreases to 31 (18)%

Limb proportions show developmental plasticity in response to embryo movement

Animals have evolved limb proportions adapted to different environments, but it is not yet clear to what extent these proportions are directly influenced by the environment during prenatal development. The developing skeleton experiences mechanical loading resulting from embryo movement. We tested the hypothesis that environmentally-induced changes in prenatal movement influence embryonic limb growth to alter proportions. We show that incubation temperature influences motility and limb bone growth in West African Dwarf crocodiles, producing altered limb proportions which may, influence post-hatching performance. Pharmacological immobilisation of embryonic chickens revealed that altered motility, independent of temperature, may underpin this growth regulation. Use of the chick also allowed us to merge histological, immunochemical and cell proliferation labelling studies to evaluate changes in growth plate organisation, and unbiased array profiling to identify specific cellular and transcriptional targets of embryo movement. This disclosed that movement alters limb proportions and regulates chondrocyte proliferation in only specific growth plates. This selective targeting is related to intrinsic mTOR (mechanistic target of rapamycin) pathway activity in individual growth plates. Our findings provide new insights into how environmental factors can be integrated to influence cellular activity in growing bones and ultimately gross limb morphology, to generate phenotypic variation during prenatal development

First Report of Circulating MicroRNAs in Tumour Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder characterized by recurrent episodes of long-lasting fever and inflammation in different regions of the body, such as the musculo-skeletal system, skin, gastrointestinal tract, serosal membranes and eye. Our aims were to evaluate circulating microRNAs (miRNAs) levels in patients with TRAPS, in comparison to controls without inflammatory diseases, and to correlate their levels with parameters of disease activity and/or disease severity. Expression levels of circulating miRNAs were measured by Agilent microarrays in 29 serum samples from 15 TRAPS patients carrying mutations known to be associated with high disease penetrance and from 8 controls without inflammatory diseases. Differentially expressed and clinically relevant miRNAs were detected using GeneSpring GX software. We identified a 6 miRNAs signature able to discriminate TRAPS from controls. Moreover, 4 miRNAs were differentially expressed between patients treated with the interleukin (IL)-1 receptor antagonist, anakinra, and untreated patients. Of these, miR-92a-3p and miR-150-3p expression was found to be significantly reduced in untreated patients, while their expression levels were similar to controls in samples obtained during anakinra treatment. MiR-92b levels were inversely correlated with the number of fever attacks/year during the 1st year from the index attack of TRAPS, while miR-377-5p levels were positively correlated with serum amyloid A (SAA) circulating levels. Our data suggest that serum miRNA levels show a baseline pattern in TRAPS, and may serve as potential markers of response to therapeutic intervention

Tropospheric emissions: Monitoring of pollution (TEMPO)

TEMPO was selected in 2012 by NASA as the first Earth Venture Instrument, for launch between 2018 and 2021. It will measure atmospheric pollution for greater North America from space using ultraviolet and visible spectroscopy. TEMPO observes from Mexico City, Cuba, and the Bahamas to the Canadian oil sands, and from the Atlantic to the Pacific, hourly and at high spatial resolution (~2.1 km N/S×4.4 km E/W at 36.5°N, 100°W). TEMPO provides a tropospheric measurement suite that includes the key elements of tropospheric air pollution chemistry, as well as contributing to carbon cycle knowledge. Measurements are made hourly from geostationary (GEO) orbit, to capture the high variability present in the diurnal cycle of emissions and chemistry that are unobservable from current low-Earth orbit (LEO) satellites that measure once per day. The small product spatial footprint resolves pollution sources at sub-urban scale. Together, this temporal and spatial resolution improves emission inventories, monitors population exposure, and enables effective emission-control strategies. TEMPO takes advantage of a commercial GEO host spacecraft to provide a modest cost mission that measures the spectra required to retrieve ozone (O), nitrogen dioxide (NO), sulfur dioxide (SO), formaldehyde (HCO), glyoxal (CHO), bromine monoxide (BrO), IO (iodine monoxide), water vapor, aerosols, cloud parameters, ultraviolet radiation, and foliage properties. TEMPO thus measures the major elements, directly or by proxy, in the tropospheric O chemistry cycle. Multi-spectral observations provide sensitivity to O in the lowermost troposphere, substantially reducing uncertainty in air quality predictions. TEMPO quantifies and tracks the evolution of aerosol loading. It provides these near-real-time air quality products that will be made publicly available. TEMPO will launch at a prime time to be the North American component of the global geostationary constellation of pollution monitoring together with the European Sentinel-4 (S4) and Korean Geostationary Environment Monitoring Spectrometer (GEMS) instruments.Peer Reviewe