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We present polarization profiles for 24 millisecond pulsars observed at 820 and 1500 MHz with the Green Bank Telescope by the NANOGrav pulsar timing array. We use Mueller matrix solutions calculated from observations of PSRs B1929+10 and J1022+1001 to calibrate the data. We discuss the polarization profiles, which can be used to constrain pulsar emission geometry, and also present the discovery of very low intensity average profile components ("microcomponents") in four pulsars. Using the rotation measures we measured for each pulsar, we calculate the Galactic magnetic field parallel to the line of sight for different lines of sight through the interstellar medium. We fit for linear and sinusoidal trends in time in the rotation measure, dispersion measure, and Galactic magnetic field. We detect rotation measure variations with a period of one year in some pulsars but overall find that the variations in these parameters are more consistent with a stochastic origin.

Summary Integrated array tomography combines fluorescence and electron imaging of ultrathin sections in one microscope, and enables accurate high‐resolution correlation of fluorescent proteins to cell organelles and membranes. Large numbers of serial sections can be imaged sequentially to produce aligned volumes from both imaging modalities, thus producing enormous amounts of data that must be handled and processed using novel techniques. Here, we present a scheme for automated detection of fluorescent cells within thin resin sections, which could then be used to drive automated electron image acquisition from target regions via ‘smart tracking’. The aim of this work is to aid in optimization of the data acquisition process through automation, freeing the operator to work on other tasks and speeding up the process, while reducing data rates by only acquiring images from regions of interest. This new method is shown to be robust against noise and able to deal with regions of low fluorescence.

In this article, we present PolNet, an open-source software tool for the study of blood flow and cell-level biological activity during vessel morphogenesis. We provide an image acquisition, segmentation, and analysis protocol to quantify endothelial cell polarity in entire in vivo vascular networks. In combination, we use computational fluid dynamics to characterize the hemodynamics of the vascular networks under study. The tool enables, to our knowledge for the first time, a network-level analysis of polarity and flow for individual endothelial cells. To date, PolNet has proven invaluable for the study of endothelial cell polarization and migration during vascular patterning, as demonstrated by two recent publications. Additionally, the tool can be easily extended to correlate blood flow with other experimental observations at the cellular/molecular level. We release the source code of our tool under the Lesser General Public License.

In this paper, we present PolNet, an open source software tool for the study of blood flow and cell-level biological activity during vessel morphogenesis. We provide an image acquisition, segmentation, and analysis protocol to quantify endothelial cell polarity in entire in vivo vascular networks. In combination, we use computational fluid dynamics to characterise the haemodynamics of the vascular networks under study. The tool enables, for the first time, network-level analysis of polarity and flow for individual endothelial cells. To date, PolNet has proven invaluable for the study of endothelial cell polarisation and migration during vascular patterning, as demonstrated by our recent papers (Franco 2015, Franco 2016a). Additionally, the tool can be easily extended to correlate blood flow with other experimental observations at the cellular/molecular level. We release the source code of our tool under the LGPL licence.

Platelet responses to activating agonists are influenced by common\ud population variants within or near G protein-coupled receptor (GPCR)\ud genes that affect receptor activity. However, the impact of rare GPCR\ud gene variants is unknown. We describe the rare single nucleotide variants\ud (SNVs) in the coding and splice regions of 18 GPCR genes in\ud 7,595 exomes from the 1,000-genomes and Exome Sequencing\ud Project databases and in 31 cases with inherited platelet function disorders\ud (IPFDs). In the population databases, the GPCR gene target\ud regions contained 740 SNVs (318 synonymous, 410 missense, 7 stop\ud gain and 6 splice region) of which 70 % had global minor allele frequency\ud (MAF) < 0.05 %. Functional annotation using six computational\ud algorithms, experimental evidence and structural data identified\ud 156/740 (21 %) SNVs as potentially damaging to GPCR function, most\ud commonly in regions encoding the transmembrane and C-terminal intracellular\ud receptor domains. In 31 index cases with IPFDs (Gi-pathway\ud defect n=15; secretion defect n=11; thromboxane pathway defect\ud n=3 and complex defect n=2) there were 256 SNVs in the target\ud regions of 15 stimulatory platelet GPCRs (34 unique; 12 with\ud MAF< 1 % and 22 with MAF≥ 1 %). These included rare variants predicting\ud R122H, P258T and V207A substitutions in the P2Y12 receptor\ud that were annotated as potentially damaging, but only partially explained\ud the platelet function defects in each case. Our data highlight\ud that potentially damaging variants in platelet GPCR genes have low\ud individual frequencies, but are collectively abundant in the population.\ud Potentially damaging variants are also present in pedigrees with IPFDs\ud and may contribute to complex laboratory phenotypes.

Endothelial cells respond to molecular and physical forces in development and vascular homeostasis. Deregulation of endothelial responses to flow-induced shear is believed to contribute to many aspects of cardiovascular diseases including atherosclerosis. However, how molecular signals and shear-mediated physical forces integrate to regulate vascular patterning is poorly understood. Here we show that endothelial non-canonical Wnt signalling regulates endothelial sensitivity to shear forces. Loss of Wnt5a/Wnt11 renders endothelial cells more sensitive to shear, resulting in axial polarization and migration against flow at lower shear levels. Integration of flow modelling and polarity analysis in entire vascular networks demonstrates that polarization against flow is achieved differentially in artery, vein, capillaries and the primitive sprouting front. Collectively our data suggest that non-canonical Wnt signalling stabilizes forming vascular networks by reducing endothelial shear sensitivity, thus keeping vessels open under low flow conditions that prevail in the primitive plexus.

The malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress.

Kinetic Monte Carlo simulations are used to examine the effect of high-energy, ‘hot’ delocalised charge transfer (HCT) states for donor:acceptor and mixed:aggregate blends, the latter relating to polymer:fullerene photovoltaic devices. Increased fullerene aggregation is shown to enhance charge generation and short-circuit device current – largely due to the increased production of HCT states at the aggregate interface. However, the instances where HCT states are predicted to give internal quantum efficiencies in the region of 50% do not correspond to HCT delocalisation or electron mobility measured in experiments. These data therefore suggest that HCT states are not the primary cause of high quantum efficiencies in some polymer:fullerene OPVs. Instead it is argued that HCT states are responsible for the fast charge generation seen in spectroscopy, but that regional variation in energy levels are the cause of long-term, efficient free-charge generation.

We compute upper limits on the nanohertz-frequency isotropic stochastic gravitational wave background (GWB) using the 9-year data release from the North American Nanohertz Observatory for Gravitational Waves (NANOGrav) collaboration. We set upper limits for a GWB from supermassive black hole binaries under power law, broken power law, and free spectral coefficient GW spectrum models. We place a 95\% upper limit on the strain amplitude (at a frequency of yr$^{-1}$) in the power law model of $A_{\rm gw} < 1.5\times 10^{-15}$. For a broken power law model, we place priors on the strain amplitude derived from simulations of Sesana (2013) and McWilliams et al. (2014). We find that the data favor a broken power law to a pure power law with odds ratios of 22 and 2.2 to one for the McWilliams and Sesana prior models, respectively. The McWilliams model is essentially ruled out by the data, and the Sesana model is in tension with the data under the assumption of a pure power law. Using the broken power-law analysis we construct posterior distributions on environmental factors that drive the binary to the GW-driven regime including the stellar mass density for stellar-scattering, mass accretion rate for circumbinary disk interaction, and orbital eccentricity for eccentric binaries, marking the first time that the shape of the GWB spectrum has been used to make astrophysical inferences. We then place the most stringent limits so far on the energy density of relic GWs, $��_\mathrm{gw}(f)\,h^2 < 4.2 \times 10^{-10}$, yielding a limit on the Hubble parameter during inflation of $H_*=1.6\times10^{-2}~m_{Pl}$, where $m_{Pl}$ is the Planck mass. Our limit on the cosmic string GWB, $��_\mathrm{gw}(f)\, h^2 < 2.2 \times 10^{-10}$, translates to a conservative limit of $G��, 21 pages, 12 figures. Please send any comments/questions to justin.ellis18@gmail.com

Asexual stage Plasmodium falciparum replicates\ud and undergoes a tightly regulated developmental\ud process in human erythrocytes. One mechanism\ud involved in the regulation of this process is posttranslational\ud modification (PTM) of parasite proteins.\ud Palmitoylation is a PTM in which cysteine residues\ud undergo a reversible lipid modification, which can\ud regulate target proteins in diverse ways. Using complementary\ud palmitoyl protein purification approaches\ud and quantitative mass spectrometry, we\ud examined protein palmitoylation in asexual-stage\ud P. falciparum parasites and identified over 400 palmitoylated\ud proteins, including those involved in cytoadherence,\ud drug resistance, signaling, development,\ud and invasion. Consistent with the prevalence of\ud palmitoylated proteins, palmitoylation is essential\ud for P. falciparum asexual development and influences\ud erythrocyte invasion by directly regulating\ud the stability of components of the actin-myosin invasion\ud motor. Furthermore, P. falciparum uses palmitoylation\ud in diverse ways, stably modifying some\ud proteins while dynamically palmitoylating others.\ud Palmitoylation therefore plays a central role in regulating\ud P. falciparum blood stage development.

Skeletal muscle consists of a nonlinear, anisotropic, fibrous contractile material. Besides, these properties are distributed non-uniformly across the muscle, which itself can have a complex geometry. Traditional models can not predict the actual local behaviour of the muscle, because uniformity and/or simple geometries are assumed. We present a model, which takes into account the active contractile properties using a Distributed Moment approximated Huxley model and the passive tissue with a three dimensional nonlinear anisotropic elastic model. The model is approximated numerically with the finite element method. The main features of the model are illustrated with simulations of an isometric contraction of a geometrically simple muscle for a plane stress and a plane strain situation.Large differences between both situations demonstrate the importance of this type of modelling.