Physical Structure of Small Wolf-Rayet Ring Nebulae

We have selected the seven most well-defined WR ring nebulae in the LMC (Br 2, Br 10, Br 13, Br 40a, Br 48, Br 52, and Br 100) to study their physical nature and evolutionary stages. New CCD imaging and echelle observations have been obtained for five of these nebulae; previous photographic imaging and echelle observations are available for the remaining two nebulae. Using the nebular dynamics and abundances, we find that the Br 13 nebula is a circumstellar bubble, and that the Br 2 nebula may represent a circumstellar bubble merging with a fossil main-sequence interstellar bubble. The nebulae around Br 10, Br 52, and Br 100 all show influence of the ambient interstellar medium. Their regular expansion patterns suggest that they still contain significant amounts of circumstellar material. Their nebular abundances would be extremely interesting, as their central stars are WC5 and WN3-4 stars whose nebular abundances have not been derived previously. Intriguing and tantalizing implications are obtained from comparisons of the LMC WR ring nebulae with ring nebulae around Galactic WR stars, Galactic LBVs, LMC LBVs, and LMC BSGs; however, these implications may be limited by small-number statistics. A SNR candidate close to Br 2 is diagnosed by its large expansion velocity and nonthermal radio emission. There is no indication that Br 2's ring nebula interacts dynamically with this SNR candidate.Comment: 20 pages, Latex (aaspp4.sty), 2 figures, accepted by the Astronomical Journal (March 99 issue

Crowded field 3D spectroscopy of LBV candidates in M33

We present integral field spectroscopy of the LBV candidate stars B416 and v532 in the local group galaxy M33. B416 is surrounded by an elongated ring-like nebula, which has a projected radius of 20x30 pc. From the datacube we create ionization and radial velocity maps of the nebula. The excitation of the gas decreases towards the outer part of the ring, while the inner part of the nebula is filled with a more excited gas. In the EW direction the ring is seen to expand with a maximum projected velocity amplitude of about 40 km/s. The eastern part approaches the observer. We estimate the nebula dynamical lifetime 8*10E5 years. It could be a residual MS bubble, which indicates a main-sequence or pre-LBV status of the star. We classify B416 as an "iron star" or B[e]-supergiant. In v532 an elongated nebula has been marginally detected. The total projected size of the nebula along the main axis is 30 pc, and the total radial velocity gradient is 44+/-11 km/s. v532 exhibits both strong photometric and spectral variability. At the time of our observations it was in an intermediate brightness state with a rich nitrogen spectrum. We classify v532 as an LBV, showing LBV Ofpe/WN transitions. We stress the importance of integral field spectroscopy as the optimal technique for studying nebulae and the evolution of LBV-like stars in nearby galaxies.Comment: 12 pages, 10 Postscript figures, A&A accepte

Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe

Background: HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods: This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results: At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32-3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by ana

Standing genetic variation and the evolution of drug resistance in HIV

Drug resistance remains a major problem for the treatment of HIV. Resistance can occur due to mutations that were present before treatment starts or due to mutations that occur during treatment. The relative importance of these two sources is unknown. We study three different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment with a single dose of nevirapine and interruption of treatment. For each of these three cases good data are available from literature, which allows us to estimate the probability that resistance evolves from standing genetic variation. Depending on the treatment we find probabilities of the evolution of drug resistance due to standing genetic variation between 0 and 39%. For patients who start triple-drug combination therapy, we find that drug resistance evolves from standing genetic variation in approximately 6% of the patients. We use a population-dynamic and population-genetic model to understand the observations and to estimate important evolutionary parameters. We find that both, the effective population size of the virus before treatment, and the fitness of the resistant mutant during treatment, are key-parameters that determine the probability that resistance evolves from standing genetic variation. Importantly, clinical data indicate that both of these parameters can be manipulated by the kind of treatment that is used.Comment: 33 pages 6 figure

Intramolecular Cohesion of Coils Mediated by Phenylalanine–Glycine Motifs in the Natively Unfolded Domain of a Nucleoporin

The nuclear pore complex (NPC) provides the sole aqueous conduit for macromolecular exchange between the nucleus and the cytoplasm of cells. Its diffusion conduit contains a size-selective gate formed by a family of NPC proteins that feature large, natively unfolded domains with phenylalanine–glycine repeats (FG domains). These domains of nucleoporins play key roles in establishing the NPC permeability barrier, but little is known about their dynamic structure. Here we used molecular modeling and biophysical techniques to characterize the dynamic ensemble of structures of a representative FG domain from the yeast nucleoporin Nup116. The results showed that its FG motifs function as intramolecular cohesion elements that impart order to the FG domain and compact its ensemble of structures into native premolten globular configurations. At the NPC, the FG motifs of nucleoporins may exert this cohesive effect intermolecularly as well as intramolecularly to form a malleable yet cohesive quaternary structure composed of highly flexible polypeptide chains. Dynamic shifts in the equilibrium or competition between intra- and intermolecular FG motif interactions could facilitate the rapid and reversible structural transitions at the NPC conduit needed to accommodate passing karyopherin–cargo complexes of various shapes and sizes while simultaneously maintaining a size-selective gate against protein diffusion

Ice loss from the East Antarctic Ice Sheet during late Pleistocene interglacials

Understanding ice sheet behaviour in the geological past is essential for evaluating the role of the cryosphere in the climate system and for projecting rates and magnitudes of sea level rise in future warming scenarios1,2,3,4. Although both geological data5,6,7 and ice sheet models3,8 indicate that marine-based sectors of the East Antarctic Ice Sheet were unstable during Pliocene warm intervals, the ice sheet dynamics during late Pleistocene interglacial intervals are highly uncertain3,9,10. Here we provide evidence from marine sedimentological and geochemical records for ice margin retreat or thinning in the vicinity of the Wilkes Subglacial Basin of East Antarctica during warm late Pleistocene interglacial intervals. The most extreme changes in sediment provenance, recording changes in the locus of glacial erosion, occurred during marine isotope stages 5, 9, and 11, when Antarctic air temperatures11 were at least two degrees Celsius warmer than pre-industrial temperatures for 2,500 years or more. Hence, our study indicates a close link between extended Antarctic warmth and ice loss from the Wilkes Subglacial Basin, providing ice-proximal data to support a contribution to sea level from a reduced East Antarctic Ice Sheet during warm interglacial intervals. While the behaviour of other regions of the East Antarctic Ice Sheet remains to be assessed, it appears that modest future warming may be sufficient to cause ice loss from the Wilkes Subglacial Basin

Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer

Drugs that inhibit estrogen receptor-α (ER) activity have been highly successful in treating and reducing breast cancer progression in ER-positive disease. However, resistance to these therapies presents a major clinical problem. Recent genetic studies have shown that mutations in the ER gene are found in >20% of tumours that progress on endocrine therapies. Remarkably, the great majority of these mutations localize to just a few amino acids within or near the critical helix 12 region of the ER hormone binding domain, where they are likely to be single allele mutations. Understanding how these mutations impact on ER function is a prerequisite for identifying methods to treat breast cancer patients featuring such mutations. Towards this end, we used CRISPR-Cas9 genome editing to make a single allele knock-in of the most commonly mutated amino acid residue, tyrosine 537, in the estrogen-responsive MCF7 breast cancer cell line. Genomic analyses using RNA-seq and ER ChIP-seq demonstrated that the Y537S mutation promotes constitutive ER activity globally, resulting in estrogen-independent growth. MCF7-Y537S cells were resistant to the anti-estrogen tamoxifen and fulvestrant. Further, we show that the basal transcription factor TFIIH is constitutively recruited by ER-Y537S, resulting in ligand-independent phosphorylation of Serine 118 (Ser118) by the TFIIH kinase, cyclin-dependent kinase (CDK)7. The CDK7 inhibitor, THZ1 prevented Ser118 phosphorylation and inhibited growth of MCF7-Y537S cells. These studies confirm the functional importance of ER mutations in endocrine resistance, demonstrate the utility of knock-in mutational models for investigating alternative therapeutic approaches and highlight CDK7 inhibition as a potential therapy for endocrine-resistant breast cancer mediated by ER mutations

Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1

An accessible sialyllactose moiety on viral membrane gangliosides is shown to be essential for HIV-1 uptake into mature dendritic cells, thereby promoting viral transfer and infection of bystander CD4+ T lymphocytes