Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
Wilms tumor gene on the X chromosome (WTX) is a putative tumor suppressor gene in Wilms tumor, but its expression and functions in other tumors are unclear. Colorectal cancer (CRC) is the third ...leading cause of cancer-related deaths in women and the second leading cause in men in the United States. We demonstrated that WTX frequently lost in CRC which was highly correlated with cell proliferation, tumor invasion and metastasis. Mechanistically, WTX loss disrupts the interaction between RhoGDIα and CDC42 by losing of the binding with RhoGDIα and triggers the activation of CDC42 and its downstream cascades, which promotes CRC development and liver metastasis. The aberrant upregulation of miR-20a/miR-106a were identified as the reason of WTX loss in CRC both in vivo and in vitro. These study defined the mechanism how miR-20a/miR-106a-mediated WTX loss regulates CRC progression and metastasis, and provided a potential therapeutic target for preventing CRC progression.
Mussel-inspired poly(catecholamine) coatings from polydopamine (PDA) have been widely studied to design functional coatings for various materials. The chemical precursor of dopamine (DA), levodopa ...(l-DOPA, 3,4-dihydroxyphenyl-l-alanine), is known as the main element of mussel adhesive foot protein, but it is relatively hard to be constructed into a desirable coating on a given material surface under the same conditions as those for DA. Herein, we report a codeposition strategy to achieve the rapid fabrication of mussel-inspired coatings by l-DOPAwith polyethyleneimine (PEI) and to deeply understand the formation mechanism of those aggregates and coatings from l-DOPA/PEI. DFT calculations, fluorescence spectra, nuclear magnetic resonance analysis, and liquid chromatography–tandem mass spectrometry identification demonstrate that the formation of l-DOPA/PEI aggregates is effectively accelerated by PEI crosslinking with those intermediates of oxidized l-DOPA, including l-DOPAquinone and 5,6-dihydroxyindole-2-carboxylic acid as well as 5,6-dihydroxyindole, through Michael-addition and Schiff-base reactions. Therefore, we can facilely control the growth rate and the particle size of the l-DOPA/PEI aggregates in the deposition solution by adjusting the concentration of PEI. The coating formation rate of l-DOPA/PEI is four times faster than that of PDA and DA/PEI within 12 h. These l-DOPA/PEI coatings are demonstrated to display potential as structure colors, superhydrophilic surfaces, and antibacterial materials.
Sudden changes of the solar wind dynamic pressure have significant impacts on the dynamics of the magnetosphere‐ionosphere system. On 18 February 2011, a sudden decrease in solar wind dynamic ...pressure was observed by the Wind satellite, which drove the entire magnetosphere‐ionosphere system as recorded in many ground‐based and space‐based measurements. In the magnetosphere, Time History of Events and Macroscale Interactions during Substorms (THEMIS) spacecraft observed a counterclockwise plasma flow vortex propagating tailward. Near the magnetic footprints of the THEMIS spacecraft, the ground magnetometers observed magnetic field variations that corresponded to a counterclockwise vortex in the equivalent ionospheric currents, which in turn indicated the presence of upward field‐aligned currents. The all‐sky imager at RANK station near the THEMIS footprints also observed a simultaneous enhancement of the auroral brightness. Therefore, this comprehensive case study demonstrates a causal chain that links the solar wind dynamic pressure variations to magnetospheric, ionospheric, and auroral activities.
Plain Language Summary
In the near‐Earth space, the shape and dynamics of the magnetosphere and the ionosphere are strongly affected by solar wind variations. There have been numerous studies demonstrating the effects of magnetospheric compression caused by a sudden enhancement in the solar wind dynamic pressure. However, the opposite case with sudden decrease in the solar wind dynamic pressure has been rarely investigated. Here we perform a comprehensive, observational study to demonstrate the consequences of sudden decrease of solar wind dynamic pressure in the entire magnetosphere‐ionosphere system, which include the formation of magnetospheric flow vortices, generation of field‐aligned currents, perturbations of the geomagnetic field, and enhancement of auroral brightness near the magnetic footprints of the magnetospheric flow vortices. In other words, this case study provides a causal chain that shows the magnetospheric, ionospheric, and auroral responses to a sudden decrease of the solar wind dynamic pressure.
Key Points
Small‐scale auroral brightening is observed after a sudden decrease in solar wind dynamic pressure
Solar wind discontinuity produces a tailward‐moving magnetospheric flow vortex associated with field‐aligned currents
Clear relationship between upward field‐aligned currents, ionospheric currents, and auroral activities are presented
Numerous variations are known to occur in the chloroplast genomes of parasitic plants. We determined the complete chloroplast genome sequences of two hemiparasitic species, Taxillus chinensis and T. ...sutchuenensis, using Illumina and PacBio sequencing technologies. These species are the first members of the family Loranthaceae to be sequenced. The complete chloroplast genomes of T. chinensis and T. sutchuenensis comprise circular 121,363 and 122,562 bp-long molecules with quadripartite structures, respectively. Compared with the chloroplast genomes of Nicotiana tabacum and Osyris alba, all ndh genes as well as three ribosomal protein genes, seven tRNA genes, four ycf genes, and the infA gene of these two species have been lost. The results of the maximum likelihood and neighbor-joining phylogenetic trees strongly support the theory that Loranthaceae and Viscaceae are monophyletic clades. This research reveals the effect of a parasitic lifestyle on the chloroplast structure and genome content of T. chinensis and T. sutchuenensis, and enhances our understanding of the discrepancies in terms of assembly results between Illumina and PacBio.
Unveiling the signal transduction of phytohormone abscisic acid (ABA) and its regulatory mechanisms is critical for developing the strategies toward improving plant responses to stressful ...environments. ABA signaling is perceived and mediated by multiple PYR/PYL receptors, whose post-translational modifications, especially phosphorylation, remain largely unknown. In this study, we demonstrate that Arabidopsis EL1-like (AEL) protein, a casein kinase that regulates various physiological processes, phosphorylate PYR/PYLs to promote their ubiquitination and degradation, resulting in suppressed ABA responses. Arabidopsis ael triple mutants display hypersensitive responses to ABA treatment, which is consistent with the suppressed degradation of PYR/PYL proteins. PYR/PYLs are phosphorylated in vivo and mutation of the conserved AEL phosphorylation sites results in reduced phosphorylation, ubiquitination, and degradation of PYR/PYLs, and hence enhanced ABA responses. Taken together, these results demonstrate that AEL-mediated phosphorylation plays crucial roles in regulating the stability and function of PYR/PYLs, providing significant insights into the post-translational regulation of PYR/PYL receptors and ABA signaling.
We show that AELs are novel components of ABA signaling and that deficiency of AELs results in hypersensitive ABA responses. AELs interact with and phosphorylate ABA receptor PYR/PYLs, but ABA can suppress the interaction between AELs and PYR/PYLs. We further demonstrate that AEL-mediated phosphorylation plays crucial roles in regulating the stability and function of PYR/PYLs, providing significant insights into the post-translational regulation of PYR/PYL receptors and ABA signaling.
Abstract
We present the physical parameters (p, T, q, i, f) of 380 Kepler contact binary systems (hereafter called CBs). A statistical study on the CBs is carried out based on a Kepler photometric ...database. Our samples were selected from the Kepler Eclipsing Binary Catalogue of EW-type eclipsing binaries with periods around 0.2–1 d and amplitudes greater than $5\%$. The physical parameters were obtained by fitting the Kepler light curves with the Wilson–Devinney eclipsing binary modeling program. Our sample of CBs contains 160 A-type and 220 W-type CBs. The fill-out factor distribution indicated that CBs generally have shallow fill-out; the proportion of CBs with fill-out factors less than $30\%$ is around $70\%$, which may be related to the formation and evolution of the CBs. The period–temperature relationship of CBs is consistent with previous studies, which is the well-known period–color relationship. The distribution between mass ratio and fill-out factor can provide some information for studying the deep, low-mass ratio contact binaries and CBs which have a large mass ratio. The mass–radius diagram shows that there is a similar linear relationship between the primary and secondary stars while the primary stars are located almost on the ZAMS line; this could be related to the internal nuclear reaction within the primary and secondary stars.
Dipolarizing flux bundles transport magnetic flux to the inner and dayside magnetosphere, heat the plasma sheet, and provide a seed population to the radiation belt. The magnetic perturbation ahead ...of them, often referred to as a dipolarization front (DF), is asymmetric with a small Bz dip followed by a sharp Bz enhancement. The Bz dip is thought to be generated from dawnward currents carried by DF‐reflected ions; after reflection, these earthward moving ions gyrate clockwise and contribute to dawnward diamagnetic currents ahead of the front. Using observations of hundreds of DFs, we investigate this hypothesis. We find that the depth of the Bz dip as a function of the front azimuth depends on DF propagation speed and ambient plasma density. These statistical signatures support the hypothesis that the Bz dip is caused by ion reflection and suggest that secondary currents carried by these reflected ions can reshape the front significantly.
Key Points
Dawnward currents carried by DF‐reflected ions can generate precursor Bz dips
Predicted signatures of Bz dips are consistent with statistical results
Distortion of moving flux tubes is explained without invoking other mechanisms
•Behenic acid is a suitable bio-renewable resource to produce bio-fuel oil using catalytic cracking.•Little fraction of aromatic compounds presented in bio-fuel oil.•Carbon chain of fatty acid was ...cracked to form short carbon chain carboxyl firstly.•ESI FT-ICR MS experiment was an effective method to analyze bio-fuel oil heavy compounds.
In order to obtain diesel-like bio-fuel oil, behenic acid was selected to carry out fast pyrolysis. The decomposition temperature of behenic acid was in the range of 250–450°C at 20k/min according to TG experiment. The bio-fuel oil mainly contained alkane, alkene and fatty acid. Components of products were C13–C20 hydrocarbon. Little fraction of aromatic compounds was found in bio-fuel oil. According to ESI FT-ICR MS analysis results, the oxygen containing compounds in bio-fuel oil were mainly O2–O4 classes, with the O3 being the major class. According to GC–MS and ESI FT-ICR MS results, it was found that the carbon chain of behenic acid was cracked to form short carbon chain carboxyl firstly. And then decarboxylation reaction carried out. In other means carboxyl groups were more stable than carbon chain of fatty acid. The probable mechanism of O4 species was free radical reaction. The recommended pyrolysis path was also proposed. Diesel-like bio-fuel oil can be obtained using behenic acid catalytic cracking.
Seashells are natural body armors with superior mechanical strength and ultra-high toughness compared with their major constituent counterparts. What building blocks and architecture render seashells ...such mechanical prowess? In this study, micro/nanoscale structural and mechanical characterization of conch shells (Busycon carica) has been carried out. Here we show direct evidence that the previously claimed single-crystal third-order lamellae – the basic building blocks in conch shells are essentially assembled with aragonite nanoparticles of the size ranging from 20 to 45nm. The nanoparticle-constructed third-order lamellae are not brittle, but ductile. The three-order crossed-lamellar architecture interlocks cracks via crack deflection along the interfaces in a three-dimensional manner, thus confining the damage in a small region. The findings advance the understanding of the mystery of conch shell’s mechanical robustness, provide additional design guidelines for developing bioinspired nanomaterials, and lay a constitutive foundation for modeling the deformation behavior of seashells.
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