G4-Quartet·M+Borate Hydrogels

The ability to modulate the physical properties of a supramolecular hydrogel may be beneficial for biomaterial and biomedical applications. We find that guanosine (G 1), when combined with 0.5 equiv of potassium borate, forms a strong, self-supporting hydrogel with elastic moduli >10 kPa. The countercation in the borate salt (MB(OH)4) significantly alters the physical properties of the hydrogel. The gelator combination of G 1 and KB(OH)4 formed the strongest hydrogel, while the weakest system was obtained with LiB(OH)4, as judged by 1H NMR and rheology. Data from powder XRD, 1H double-quantum solid-state magic-angle spinning (MAS) NMR and small-angle neutron scattering (SANS) were consistent with a structural model that involves formation of borate dimers and G4·K+ quartets by G 1 and KB(OH)4. Stacking of these G4·M+ quartets into G4-nanowires gives a hydrogel. We found that the M+ cation helps stabilize the anionic guanosine-borate (GB) diesters, as well as the G4-quartets. Supplementing the standard gelator mixture of G 1 and 0.5 equiv of KB(OH)4 with additional KCl or KNO3 increased the strength of the hydrogel. We found that thioflavin T fluoresces in the presence of G4·M+ precursor structures. This fluorescence response for thioflavin T was the greatest for the K+ GB system, presumably due to the enhanced interaction of the dye with the more stable G4·K+ quartets. The fluorescence of thioflavin T increased as a function of gelator concentration with an increase that correlated with the system’s gel point, as measured by solution viscosit

Low dose influenza virus challenge in the ferret leads to increased virus shedding and greater sensitivity to oseltamivir

Ferrets are widely used to study human influenza virus infection. Their airway physiology and cell receptor distribution makes them ideal for the analysis of pathogenesis and virus transmission, and for testing the efficacy of anti-influenza interventions and vaccines. The 2009 pandemic influenza virus (H1N1pdm09) induces mild to moderate respiratory disease in infected ferrets, following inoculation with 106 plaque-forming units (pfu) of virus. We have demonstrated that reducing the challenge dose to 102 pfu delays the onset of clinical signs by 1 day, and results in a modest reduction in clinical signs, and a less rapid nasal cavity innate immune response. There was also a delay in virus production in the upper respiratory tract, this was up to 9-fold greater and virus shedding was prolonged. Progression of infection to the lower respiratory tract was not noticeably delayed by the reduction in virus challenge. A dose of 104 pfu gave an infection that was intermediate between those of the 106 pfu and 102 pfu doses. To address the hypothesis that using a more authentic low challenge dose would facilitate a more sensitive model for antiviral efficacy, we used the well-known neuraminidase inhibitor, oseltamivir. Oseltamivir-treated and untreated ferrets were challenged with high (106 pfu) and low (102 pfu) doses of influenza H1N1pdm09 virus. The low dose treated ferrets showed significant delays in innate immune response and virus shedding, delayed onset of pathological changes in the nasal cavity, and reduced pathological changes and viral RNA load in the lung, relative to untreated ferrets. Importantly, these observations were not seen in treated animals when the high dose challenge was used. In summary, low dose challenge gives a disease that more closely parallels the disease parameters of human influenza infection, and provides an improved pre-clinical model for the assessment of influenza therapeutics, and potentially, influenza vaccines

Fractional diffusion equation for an n-dimensional correlated Lévy walk.

Lévy walks define a fundamental concept in random walk theory that allows one to model diffusive spreading faster than Brownian motion. They have many applications across different disciplines. However, so far the derivation of a diffusion equation for an n-dimensional correlated Lévy walk remained elusive. Starting from a fractional Klein-Kramers equation here we use a moment method combined with a Cattaneo approximation to derive a fractional diffusion equation for superdiffusive short-range auto-correlated Lévy walks in the large time limit, and we solve it. Our derivation discloses different dynamical mechanisms leading to correlated Lévy walk diffusion in terms of quantities that can be measured experimentally

Multiple Translocation of the AVR-Pita Effector Gene among Chromosomes of the Rice Blast Fungus Magnaporthe oryzae and Related Species

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation

The role of changing geodynamics in the progressive contamination of Late Cretaceous to Late Miocene arc magmas in the southern Central Andes

The tectonic and geodynamic setting of the southern Central Andean convergent margin changed significantly between the Late Cretaceous and the Late Miocene, influencing magmatic activity and its geochemical composition. Here we investigate how these changes, which include changing slab-dip angle and convergence angles and rates, have influenced the contamination of the arc magmas with crustal material. Whole rock geochemical data for a suite of Late Cretaceous to Late Miocene arc rocks from the Pampean flat-slab segment (29–31 °S) of the southern Central Andes is presented alongside petrographic observations and high resolution age dating. In-situ U–Pb dating of magmatic zircon, combined with Ar–Ar dating of plagioclase, has led to an improved regional stratigraphy and provides an accurate temporal constraint for the geochemical data. A generally higher content of incompatible trace elements (e.g. Nb/Zr ratios from 0.019 to 0.083 and Nb/Yb from 1.5 to 16.4) is observed between the Late Cretaceous (~ 72 Ma), when the southern Central Andean margin is suggested to have been in extension, and the Miocene when the thickness of the continental crust increased and the angle of the subducting Nazca plate shallowed. Trace and rare earth element compositions obtained for the Late Cretaceous to Late Eocene arc magmatic rocks from the Principal Cordillera of Chile, combined with a lack of zircon inheritance, suggest limited assimilation of the overlying continental crust by arc magmas derived from the mantle wedge. A general increase in incompatible, fluid-mobile/immobile (e.g., Ba/Nb) and fluid-immobile/immobile (e.g., Nb/Zr) trace element ratios is attributed to the influence of the subducting slab on the melt source region and/or the influx of asthenospheric mantle. The Late Oligocene (~ 26 Ma) to Early Miocene (~ 17 Ma), and Late Miocene (~ 6 Ma) arc magmatic rocks present in the Frontal Cordillera show evidence for the bulk assimilation of the Permian–Triassic (P–T) basement, both on the basis of their trace and rare earth element compositions and the presence of P–T inherited zircon cores. Crustal reworking is also identified in the Argentinean Precordillera; Late Miocene (12–9 Ma) arc magmatic rocks display distinct trace element signatures (specifically low Th, U and REE concentrations) and contain inherited zircon cores with Proterozoic and P–T ages, suggesting the assimilation of both the P–T basement and a Grenville-aged basement. We conclude that changing geodynamics play an important role in determining the geochemical evolution of magmatic rocks at convergent margins and should be given due consideration when evaluating the petrogenesis of arc magmas.</p

Crustal recycling by subduction erosion in the central Mexican Volcanic Belt

Recycling of upper plate crust in subduction zones, or ‘subduction erosion’, is a major mechanism of crustal destruction at convergent margins. However, assessing the impact of eroded crust on arc magmas is difficult owing to the compositional similarity between the eroded crust, trench sediment and arc crustal basement that may all contribute to arc magma formation. Here we compare Sr–Nd–Pb–Hf and trace element data of crustal input material to Sr–Nd–Pb–Hf–He–O isotope chemistry of a well-characterized series of olivine-phyric, high-Mg# basalts to dacites in the central Mexican Volcanic Belt (MVB). Basaltic to andesitic magmas crystallize high-Ni olivines that have high mantle-like 3He/4He = 7–8 Ra and high crustal δ18Omelt = +6.3–8.5‰ implying their host magmas to be near-primary melts from a mantle infiltrated by slab-derived crustal components. Remarkably, their Hf–Nd isotope and Nd/Hf trace element systematics rule out the trench sediment as the recycled crust end member, and imply that the coastal and offshore granodiorites are the dominant recycled crust component. Sr–Nd–Pb–Hf isotope modeling shows that the granodiorites control the highly to moderately incompatible elements in the calc-alkaline arc magmas, together with lesser additions of Pb- and Sr-rich fluids from subducted mid-oceanic ridge basalt (MORB)-type altered oceanic crust (AOC). Nd–Hf mass balance suggests that the granodiorite exceeds the flux of the trench sediment by at least 9–10 times, corresponding to a flux of ⩾79–88 km3/km/Myr into the subduction zone. At an estimated thickness of 1500–1700 m, the granodiorite may buoyantly rise as bulk ‘slab diapirs’ into the mantle melt region and impose its trace element signature (e.g., Th/La, Nb/Ta) on the prevalent calc-alkaline arc magmas. Deep slab melting and local recycling of other slab components such as oceanic seamounts further diversify the MVB magmas by producing rare, strongly fractionated high-La magmas and a minor population of high-Nb magmas, respectively. Overall, the central MVB magmas inherit their striking geochemical diversity principally from the slab, thus emphasizing the importance of continental crust recycling in modern solid Earth relative to its new formation in modern subduction zones

Elongation, proliferation & migration differentiate endothelial cell phenotypes and determine capillary sprouting

<p>Abstract</p> <p>Background</p> <p>Angiogenesis, the growth of capillaries from preexisting blood vessels, has been extensively studied experimentally over the past thirty years. Molecular insights from these studies have lead to therapies for cancer, macular degeneration and ischemia. In parallel, mathematical models of angiogenesis have helped characterize a broader view of capillary network formation and have suggested new directions for experimental pursuit. We developed a computational model that bridges the gap between these two perspectives, and addresses a remaining question in angiogenic sprouting: how do the processes of endothelial cell elongation, migration and proliferation contribute to vessel formation?</p> <p>Results</p> <p>We present a multiscale systems model that closely simulates the mechanisms underlying sprouting at the onset of angiogenesis. Designed by agent-based programming, the model uses logical rules to guide the behavior of individual endothelial cells and segments of cells. The activation, proliferation, and movement of these cells lead to capillary growth in three dimensions. By this means, a novel capillary network emerges out of combinatorially complex interactions of single cells. Rules and parameter ranges are based on literature data on endothelial cell behavior in vitro. The model is designed generally, and will subsequently be applied to represent species-specific, tissue-specific in vitro and in vivo conditions.</p> <p>Initial results predict tip cell activation, stalk cell development and sprout formation as a function of local vascular endothelial growth factor concentrations and the Delta-like 4 Notch ligand, as it might occur in a three-dimensional in vitro setting. Results demonstrate the differential effects of ligand concentrations, cell movement and proliferation on sprouting and directional persistence.</p> <p>Conclusion</p> <p>This systems biology model offers a paradigm closely related to biological phenomena and highlights previously unexplored interactions of cell elongation, migration and proliferation as a function of ligand concentration, giving insight into key cellular mechanisms driving angiogenesis.</p

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

4MOST: Project overview and information for the First Call for Proposals

We introduce the 4-metre Multi-Object Spectroscopic Telescope (4MOST), a new high-multiplex, wide-field spectroscopic survey facility under development for the four-metre-class Visible and Infrared Survey Telescope for Astronomy (VISTA) at Paranal. Its key specifications are: a large field of view (FoV) of 4.2 square degrees and a high multiplex capability, with 1624 fibres feeding two low-resolution spectrographs ($R = \lambda/\Delta\lambda \sim 6500$), and 812 fibres transferring light to the high-resolution spectrograph ($R \sim 20\,000$). After a description of the instrument and its expected performance, a short overview is given of its operational scheme and planned 4MOST Consortium science; these aspects are covered in more detail in other articles in this edition of The Messenger. Finally, the processes, schedules, and policies concerning the selection of ESO Community Surveys are presented, commencing with a singular opportunity to submit Letters of Intent for Public Surveys during the first five years of 4MOST operations