A significant fraction of white dwarfs are observed to be polluted with metals despite high surface gravities and short settling times. The current theoretical model for this pollution is accretion ...of rocky bodies, which are delivered to the white dwarf through perturbations by orbiting planets. Using N-body simulations, we examine the possibility of a single planet as the source of pollution. We determine the stability of test particles on circular orbits in systems with a single planet located at 4 au for a range of masses and eccentricities, comparing the fractions that are ejected and accreted by the star. In particular, we compare the instabilities that develop before and after the star loses mass to form a white dwarf, a process which causes the semimajor axes of orbiting bodies to expand adiabatically. We determine that a planet must be eccentric (e > 0.02) to deliver significant (>0.5 per cent) amounts of material to the central body, and that the amount increases with the planetary eccentricity. This result is robust with respect to the initial eccentricities of the scattered particles in the case of planetary eccentricity above ∼0.4 and the case of randomly distributed particle longitude of pericentre. We also find that the efficiency of the pollution is enhanced as planetary mass is reduced. We demonstrate that a 0.03 MJup planet with substantial eccentricity (e > 0.4) can account for the observed levels of pollution for initial disc masses of the order of 1 M⊕. Such discs are well within the range estimated for initial planetesimals discs and well below that estimated for our own Solar system within the context of the Nice model. However, their long-term survival to the white dwarf stage is uncertain as estimates for the collisional evolution of planetesimal discs suggest they should be ground down below the required levels on Gyr time-scales. Thus, planetary scattering by eccentric, sub-Jovian planets can explain the observed levels of pollution in white dwarfs, but only if current estimates of the collisional erosion of planetesimal discs are in error.
Turgencin A, a potent antimicrobial peptide isolated from the Arctic sea squirt
, consists of 36 amino acid residues and three disulfide bridges, making it challenging to synthesize. The aim of the ...present study was to develop a truncated peptide with an antimicrobial drug lead potential based on turgencin A. The experiments consisted of: (1) sequence analysis and prediction of antimicrobial potential of truncated 10-mer sequences; (2) synthesis and antimicrobial screening of a lead peptide devoid of the cysteine residues; (3) optimization of in vitro antimicrobial activity of the lead peptide using an amino acid replacement strategy; and (4) screening the synthesized peptides for cytotoxic activities. In silico analysis of turgencin A using various prediction software indicated an internal, cationic 10-mer sequence to be putatively antimicrobial. The synthesized truncated lead peptide displayed weak antimicrobial activity. However, by following a systematic amino acid replacement strategy, a modified peptide was developed that retained the potency of the original peptide. The optimized peptide
displayed bactericidal activity, with minimal inhibitory concentrations of 7.8 µg/mL against
and 3.9 µg/mL against
, and no cytotoxic effects against mammalian cells. Preliminary experiments indicate the bacterial membranes as immediate and primary targets.
We investigate effects of quasiparticle poisoning in a Majorana island with strong tunnel coupling to normal-metal leads. In addition to the main Coulomb blockade diamonds, "shadow" diamonds appear, ...shifted by 1e in gate voltage, consistent with transport through an excited (poisoned) state of the island. Comparison to a simple model yields an estimate of parity lifetime for the strongly coupled island (∼1 μs) and sets a bound for a weakly coupled island (>10 μs). Fluctuations in the gate-voltage spacing of Coulomb peaks at high field, reflecting Majorana hybridization, are enhanced by the reduced lever arm at strong coupling. When converted from gate voltage to energy units, fluctuations are consistent with previous measurements.
Globular clusters trace the formation history of the spheroidal components of our Galaxy and other galaxies, which represent the bulk of star formation over the history of the Universe. The clusters ...exhibit a range of metallicities (abundances of elements heavier than helium), with metal-poor clusters dominating the stellar halo of the Galaxy, and higher-metallicity clusters found within the inner Galaxy, associated with the stellar bulge, or the thick disk. Age differences between these clusters can indicate the sequence in which the components of the Galaxy formed, and in particular which clusters were formed outside the Galaxy and were later engulfed along with their original host galaxies, and which were formed within it. Here we report an absolute age of 9.9 ± 0.7 billion years (at 95 per cent confidence) for the metal-rich globular cluster 47 Tucanae, determined by modelling the properties of the cluster's white-dwarf cooling sequence. This is about two billion years younger than has been inferred for the metal-poor cluster NGC 6397 from the same models, and provides quantitative evidence that metal-rich clusters like 47 Tucanae formed later than metal-poor halo clusters like NGC 6397.
The initial-final mass relation represents a mapping between the mass of a white dwarf remnant and the mass that the hydrogen-burning main-sequence star that created it once had. The empirical ...relation thus far has been constrained using a sample of image40 stars in young open clusters, ranging in initial mass from image2.75 to 7 image, and shows a general trend that connects higher mass main-sequence stars with higher mass white dwarfs. In this paper, we present CFHT CFH12K photometric and Keck LRIS multiobject spectroscopic observations of a sample of 22 white dwarfs in two older open clusters, NGC 7789 (image Gyr) and NGC 6819 (image Gyr). We measure masses for the highest signal-to-noise ratio spectra by fitting the Balmer lines to atmosphere models and place the first direct constraints on the low- mass end of the initial-final mass relation. Our results indicate that the observed general trend at higher masses continues down to low masses, with image main-sequence stars forming image white dwarfs. When added to our new data from the very old cluster NGC 6791, the relation is extended down to image (corresponding to image). This extension of the relation represents a fourfold increase in the total number of hydrogen-burning stars for which the integrated mass loss can now be calculated from empirical data, assuming a Salpeter initial mass function. The new leverage at the low-mass end is used to derive a purely empirical initial-final mass relation. The sample of white dwarfs in these clusters also shows several interesting systems that we discuss further: a DB (helium) white dwarf, a magnetic white dwarf, a DAB (mixed hydrogen/helium atmosphere or a double degenerate DA+DB) white dwarf(s), and two possible equal-mass da double degenerate binary systems.
Patients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies ...has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented.
Key eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10mg/kg every 2weeks until disease progression or intolerable toxicity for up to 24months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review.
Median patient age in this cohort (n=23) was 65years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% 95% confidence interval (CI) 5.0%–38.8%; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n=3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred.
Pembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.
NCT02054806
In July 2016, NASA’s
Juno
mission becomes the first spacecraft to enter polar orbit of Jupiter and venture deep into unexplored polar territories of the magnetosphere. Focusing on these polar ...regions, we review current understanding of the structure and dynamics of the magnetosphere and summarize the outstanding issues. The
Juno
mission profile involves (a) a several-week approach from the dawn side of Jupiter’s magnetosphere, with an orbit-insertion maneuver on July 6, 2016; (b) a 107-day capture orbit, also on the dawn flank; and (c) a series of thirty 11-day science orbits with the spacecraft flying over Jupiter’s poles and ducking under the radiation belts. We show how
Juno’s
view of the magnetosphere evolves over the year of science orbits. The
Juno
spacecraft carries a range of instruments that take particles and fields measurements, remote sensing observations of auroral emissions at UV, visible, IR and radio wavelengths, and detect microwave emission from Jupiter’s radiation belts. We summarize how these
Juno
measurements address issues of auroral processes, microphysical plasma physics, ionosphere-magnetosphere and satellite-magnetosphere coupling, sources and sinks of plasma, the radiation belts, and the dynamics of the outer magnetosphere. To reach Jupiter, the
Juno
spacecraft passed close to the Earth on October 9, 2013, gaining the necessary energy to get to Jupiter. The Earth flyby provided an opportunity to test
Juno
’s instrumentation as well as take scientific data in the terrestrial magnetosphere, in conjunction with ground-based and Earth-orbiting assets.
Upregulation of the proto-oncogene plasminogen activator inhibitor-1 (PAI-1) is a common hallmark of various solid tumours, but the mechanisms controlling its expression are not fully understood.
We ...investigate microRNAs (miRNAs) regulating PAI-1 in a panel of normal bladder urothelial biopsies, superficial Ta bladder tumours and invasive T1-T4 tumours using expression microarrays and qRT-PCR. The prognostic implications of PAI-1 deregulation are established by tissue microarray staining of non-muscle-invasive bladder tumours. MicroRNA repression of PAI-1 is assayed by ectopic miRNA expression, argonaute immunoprecipitation and luciferase assays.
We found that the miR-143/-145 cluster is downregulated in all stages of bladder cancer and inversely correlated with PAI-1 expression. Mature miR-143 and miR-145 are coordinately expressed, and both directly target the PAI-1 3'UTR, leading to reduced PAI-1 mRNA and protein levels. Furthermore, we show that PAI-1 and miR-145 levels may serve as useful prognostic markers for non-muscle-invasive bladder tumours for which accurate progressive outcome is currently difficult to predict.
This report provides the first evidence for direct miRNA regulation of PAI-1 in bladder cancer. We also demonstrate mRNA co-targeting by a cluster of non-family miRNAs, and suggest miR-145 and PAI-1 as clinically relevant biomarkers in bladder cancer.
Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an ...organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.
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