Shell Evolution towards

The level structure of the neutron-rich ^{77}Cu nucleus is investigated through ß-delayed γ-ray spectroscopy at the Radioactive Isotope Beam Factory of the RIKEN Nishina Center. Ions of ^{77}Ni are produced by in-flight fission, separated and identified in the BigRIPS fragment separator, and implanted in the WAS3ABi silicon detector array, surrounded by Ge cluster detectors of the EURICA array. A large number of excited states in ^{77}Cu are identified for the first time by correlating γ rays with the ß decay of ^{77}Ni, and a level scheme is constructed by utilizing their coincidence relationships. The good agreement between large-scale Monte Carlo shell model calculations and experimental results allows for the evaluation of the single-particle structure near ^{78}Ni and suggests a single-particle nature for both the 5/2_{1}^{-} and 3/2_{1}^{-} states in ^{77}Cu, leading to doubly magic ^{78}Ni.

An Escalation for Bivariate Binary Endpoints Controlling the Risk of Overtoxicity (EBE-CRO): Managing Efficacy and Toxicity in Early Oncology Clinical Trials.

For about a decade, early clinical development in oncology is facing new challenges. This is due to two main reasons. The first one is linked to the developed molecular targeted agents (MTA) themselves for which the maximum tolerated dose (MTD) is no longer the only dose of interest. The second reason is related to the fact that costs and attrition rates are huge. When selecting a dose, evidence of early activity signal becomes required for future engagements. This implies the need to handle both toxicity and activity endpoints in the analysis and also in the dose escalation design of early-phase trials. We propose a model-based design taking into account both safety and activity for dose escalation. The proposed model involves a bivariate Gaussian latent variable depending on a monotonic toxicity curve and a quadratic activity curve. This model is fitted under the Bayesian framework that allows the incorporation of prior information. The predictive distributions of dose-response curves are used to lead the dose recommendation. Uncertainty in the dose-response relationship is taken into account to calculate the probability of being an over-toxic or a target dose. The proposed design is compared to two other widely used methods.

First Evidence of Shape Coexistence in the

The N=48 ^{80}Ge nucleus is studied by means of ß-delayed electron-conversion spectroscopy at ALTO. The radioactive ^{80}Ga beam is produced through the isotope separation on line photofission technique and collected on a movable tape for the measurement of γ and e^{-} emission following ß decay. An electric monopole E0 transition, which points to a 639(1) keV intruder 0_{2}^{+} state, is observed for the first time. This new state is lower than the 2_{1}^{+} level in ^{80}Ge, and provides evidence of shape coexistence close to one of the most neutron-rich doubly magic nuclei discovered so far, ^{78}Ni. This result is compared with theoretical estimates, helping to explain the role of monopole and quadrupole forces in the weakening of the N=50 gap at Z=32. The evolution of intruder 0_{2}^{+} states towards ^{78}Ni is discussed.

Two-dimensional segmentation for analyzing Hi-C data.

MOTIVATION: The spatial conformation of the chromosome has a deep influence on gene regulation and expression. Hi-C technology allows the evaluation of the spatial proximity between any pair of loci along the genome. It results in a data matrix where blocks corresponding to (self-)interacting regions appear. The delimitation of such blocks is critical to better understand the spatial organization of the chromatin. From a computational point of view, it results in a 2D segmentation problem. RESULTS: We focus on the detection of cis-interacting regions, which appear to be prominent in observed data. We define a block-wise segmentation model for the detection of such regions. We prove that the maximization of the likelihood with respect to the block boundaries can be rephrased in terms of a 1D segmentation problem, for which the standard dynamic programming applies. The performance of the proposed methods is assessed by a simulation study on both synthetic and resampled data. A comparative study on public data shows good concordance with biologically confirmed regions. AVAILABILITY AND IMPLEMENTATION: The HiCseg R package is available from the Comprehensive R Archive Network and from the Web page of the corresponding author.

Management of threatened preterm delivery in France: a national practice survey (the EVAPRIMA study).

OBJECTIVES: To describe the management of threatened preterm delivery (TPD) in France 3 years after publication of the French guidelines and to analyse the factors of variation of the practices observed. DESIGN: Population-based study. SETTING: Representative sample of French maternity units. The study included 107 hospitals, accounting for 20% of all French maternity units. POPULATION: Women hospitalised for TPD during May 2005. METHODS: Cross-sectional national practice survey. RESULTS: Of the 734 admissions for TPD, 12.1% involved premature rupture of membranes and 12.9% were in utero transfers. Women admitted for TPD accounted for roughly 6% of all annual deliveries, regardless of the unit's level of care, and 42.4% of these women delivered preterm: none delivered before 32 weeks in level 1 maternity units, 11.6% in level 2 and 88.4% in level 3. Transvaginal cervical ultrasound was performed for 54.5% of the women with intact membranes. Tocolysis was administered in 87.1% of women with intact membranes, with 45.6% of such women receiving this intervention for longer than 48 hours. First-line tocolytics used were calcium channel blockers (53.7%), beta-agonists (34.7%) or atosiban (8.8%), but their distribution differed substantially according to level of care. Maintenance tocolysis was administered to 385 women (59.8%) with intact membranes. Of the women admitted before 34 weeks, 21.1% did not receive corticosteroids. CONCLUSIONS: Practices for the management of TPD vary widely and appear to depend on the level of care. Some practices appear less than optimal, especially those related to duration of tocolysis, maintenance tocolysis, antenatal corticosteroid and use of cervical ultrasound.

Newborn follow-up after discharge from the maternity unit: Compliance with national guidelines.

BACKGROUND: In the context of shorter hospital stays in maternity units, in 2014 the French health authorities issued guidelines for newborn follow-up after discharge from maternity units. A medical visit is recommended between the 6th and 10th day of life, as are home visits from midwives. This study was designed to evaluate compliance with these guidelines. METHODS: The study was observational, prospective, multicenter, and was conducted in March and April 2015 in three maternity units in northern France that participate in the Baby Friendly Hospital Initiative (BFHI). Follow-up practices (medical visit between the 6th and 10th day, home visits from a midwife) and demographic, social, and medical data were recorded during the stay in the maternity unit, and through a phone interview 1 month later, in singleton term-born infants. RESULTS: The study population included 108 mother-infant pairs. The recommended medical visit was effectively performed by a physician between the 6th and 10th day of life for 20 newborns (19%) (95% CI: [11; 26]). During the 1st month, at least one home visit from a midwife was recorded for 96 mother-infant pairs (89%). The only factor positively correlated with a medical visit between the 6th and 10th day was the mother's choice, made early during the hospital stay and independently of the real length of stay, for early discharge from the maternity unit. CONCLUSION: Compliance with national guidelines was poor for the recommended medical visit between the 6th and 10th day of life. Information needs to be improved.

Polymorphism and evolution of vulval precursor cell lineages within two nematode genera, Caenorhabditis and Oscheius.

BACKGROUND: The cell lineage of nematodes is mostly invariant for a given species, but varies between species. One can thus wonder how a cell lineage varies during evolution. We have started a microevolutionary approach within two genera by observing lineage variations of vulval precursor cells in different natural nematode populations of the same and closely related species. RESULTS: In Caenorhabditis elegans, the P3.p cell lineage is variable within a genetically homogeneous population and polymorphic between wild strains. Irrespective of its division pattern, P3.p is competent to form vulval tissue in different C. elegans strains, whereas it is not competent in C. briggsae. In Oscheius sp. 1, P4.p and P8.p lineages are strongly polymorphic. Within each genus, these intraspecies polymorphisms in cell lineages are amplified between closely related species. In Oscheius sp. 1, the large polymorphisms in P4.p and P8.p lineages allowed us to undertake a genetic analysis of the variation between two pairs of strains. Multiple loci are involved in cell lineage differences, and variation at one locus appears to have a relatively strong effect. In addition to these large lineage variations in cells that do not normally contribute to the vulva, we find minor variations (errors) in vulval lineages, which represent the precision level of the vulval-patterning process and point to a selection pressure for maintenance of a large vulval equivalence group. CONCLUSIONS: Polymorphisms in vulval cell lineage are found within a given nematode species, and could be instrumental in explaining evolutionary variations between closely related species.

Prevalence of localized rearrangements vs. transpositions among events induced by Drosophila P element transposase on a P transgene.

We have studied P transposase-induced events on a P[w] transgene, P[wd1], harboring the whole white gene with a 3.44-kb direct duplication of its 5' regulatory sequences (containing the ZESTE-binding region, ZBR). We have recovered mutations leading to an increase or a decrease of zeste1 repression, generally as the consequence of modifications of number of ZBR in close physical proximity and/or jumps to other sites. We describe mutants displaying deletions of the original duplicated sequence or increases in the number of repeats from two to three or four. Internal deletions are more frequent than amplifications. Both require the integrity of P-element ends. We have also observed a high frequency of double P elements localized at the original P[wd1] insertion site. These double P elements are arranged in nonrandom configurations. We discuss the frequencies and the possible mechanisms leading to the various types of derivatives, in light of the current models for P excision and transposition. We propose that the P transposase induces mainly localized events. Some of these could result from frequent changes of template during gap-repair DNA synthesis, and/or from abortive transposition.

A two-step bioconversion process for vanillin production from ferulic acid combining Aspergillus niger and Pycnoporus cinnabarinus.

A two-step bioconversion process of ferulic acid to vanillin was elaborated combining two filamentous fungi, Aspergillus niger and Pycnoporus cinnabarinus. In the first step, A. niger transformed ferulic acid to vanillic acid and in the second step vanillic acid was reduced to vanillin by P. cinnabarinus. Ferulic acid metabolism by A. niger occurred essentially via the propenoic chain degradation to lead to vanillic acid, which was subsequently decarboxylated to methoxyhydroquinone. In 3-day-old cultures of P. cinnabarinus supplied with vanillic-acid-enriched culture medium from A. niger as precursor source, vanillin was successfully produced. In order to improve the yields of the process, sequential additions of precursors were performed. Vanillic acid production by A. niger from ferulic acid reached 920 mg1-1 with a molar yield of 88% and vanillin production by P. cinnabarinus from vanillic acid attained 237 mg1-1 with a molar yield of 22%. However, the vanillic acid oxidative system producing methoxyhydroquinone was predominant in P. cinnabarinus cultures, which explained the relatively low level in vanillin.

An European open multicentre trial with auranofin in rheumatoid arthritis.

In 8 European countries a multicentre trial was started in 672 patients with RA. The safety and efficacy of Auranofin (oral gold), was evaluated. There seems to be no difference in response to treatment between patients treated with Auranofin 3 mg twice daily or 6 mg once daily. From the fourth month of treatment there is a statistically difference in improvements for following parameters : activity index of Chalkins, articular index of Lansbury, ESR, pain, morning stiffness, grip strength, number of swollen joints and number of tender joints. These data suggest that Auranofin can be considered as a valuable disease modifying antirheumatic drug (DMARD) in RA and that early onset of therapy can be advised. In most cases the treatment is well tolerated.

Bicriterion cluster analysis.

Cluster analysis is concerned with the problem of partitioning a given set of entities into homogeneous and well-separated subsets called clusters. The concepts of homogeneity and of separation can be made precise when a measure of dissimilarity between the entities is given. Let us define the diameter of a partition of the given set of entities into clusters as the maximum dissimilarity between any pair of entities in the same cluster and the split of a partition as the minimum dissimilarity between entities in different clusters. The problems of determining a partition into a given number of clusters with minimum diameter (i.e., a partition of maximum homogeneity) or with maximum split (i.e., a partition of maximum separation) are first considered. It is shown that the latter problem can be solved by the classical single-link clustering algorithm, while the former can be solved by a graph-theoretic algorithm involving the optimal coloration of a sequence of partial graphs, described in more detail in a previous paper. A partition into a given number of clusters will be called efficient if and only if there exists no partition into at most the same number of clusters with smaller diameter and not smaller split or with larger split and not larger diameter. Two efficient partitions are called equivalent if and only if they have the same values for the split and for the diameter.

Multiple lignin peroxidases of Phanerochaete chrysosporium INA-12.

Nine proteins with lignin peroxidase activity were separated from cultures of Phanerochaete chrysosporium INA-12 in glycerol as carbon source and non-nitrogen limited. Four lignin peroxidase isozymes (4, 5, 8, 9) were purified and characterized. Although differences in kinetic parameters could be shown, antibody reaction showed homology between isozymes. However, thermal stability studied, peptide mapping results, and N-terminal sequence analyses established a higher degree of homology between isozymes 4/5 and 8/9 types. Protein characterization and kinetic data indicate that lignin peroxidase isozymes 4, 5, 8, and 9 differ from described isozymes in strain BKM. The higher specific activity of lignin peroxidase isozymes in cultures with glycerol than in nitrogen-starved cultures accounts for the higher lignin peroxidase activity obtained in these conditions.

SU(VAR)3-7, a Drosophila heterochromatin-associated protein and companion of HP1 in the genomic silencing of position-effect variegation.

An increase in the dose of the Su(var)3-7 locus of Drosophila melanogaster enhances the genomic silencing of position-effect variegation caused by centromeric heterochromatin. Here we show that the product of Su(var)3-7 is a nuclear protein which associates with pericentromeric heterochromatin at interphase, whether on diploid chromosomes from embryonic nuclei or on polytene chromosomes from larval salivary glands. The protein also associates with the partially heterochromatic chromosome 4. As these phenotypes and localizations resemble those described by others for the Su(var)2-5 locus and its heterochromatin-associated protein HP1, the presumed co-operation of the two proteins was tested further. The effect of the dose of Su(var)3-7 on silencing of a number of variegating rearrangements and insertions is strikingly similar to the effect of the dose of Su(var)2-5 reported by others. In addition, the two loci interact genetically, and the two proteins co-immunoprecipitate from nuclear extracts. The results suggest that SU(VAR)3-7 and HP1 co-operate in building the genomic silencing associated with heterochromatin.

P-element transposition in Drosophila melanogaster: influence of size and arrangement in pairs.

In Drosophila melanogaster, several factors have been suggested to influence the rates of P-element transposition and excision, including position effects, size and structure of the elements and differences in transposase source. We have investigated the effect of the size of the starting P-element on the rates of excision and transposition. Four transgenes localized at the same insertion site on the X chromosome and which differ by the number of copies of an internal repeated sequence, were studied. Transgenes with sizes ranging from 11 kb to 22 kb excise at similar rates, and size does not correlate with the differences in transposition rate between them. We also studied the behavior of double P-elements, located at the same site and arranged in various configurations: nested, contiguous or separated by a few base pairs, in the same or reverse orientation. These double P-elements display different mobilities depending on the arrangement of the two transgenes. Transposition and excision rates were also studied for an insertion bearing four transgenes in very close proximity. Our results suggest that several neighboring elements could excise together. We also propose a new model to explain the formation of all the double P-elements we describe.

Development and evolution of a variable left-right asymmetry in nematodes: the handedness of P11/P12 migration.

In Caenorhabditis elegans, two lateral blast cells called P11/12L and P11/12R are symmetric left-right homologs at hatching, migrate subsequently in opposite anteroposterior directions during the first larval stage, and adopt two different fates, thus breaking the symmetry between them. Our results show that, unlike most other cell fate decisions in C. elegans, the orientation of P11/12L/R migration is highly biased, but not fixed. The handedness of their migration is linked to whole body handedness and is randomized in lin-12/Notch mutants and by ablation of the Y cell. Migration handedness is independent of P11 and P12 fate determination, previously shown to require the LIN-44/Wnt and the LIN-3/EGF pathways (L. I. Jiang and P. W. Sternberg, 1998, Development 125, 2337-2347). We further show that several changes in P11/12L/R asymmetry have occurred during nematode evolution: loss of asymmetry or reversals in orientation of migration. Strikingly, for most species studied, handedness of migration is highly biased but not fixed. Thus, whereas the final cell fate pattern of P11/12 is invariant, the developmental route leading to it is subject both to developmental indeterminacy and to evolutionary variations.

Microevolutionary studies in nematodes: a beginning.

Comparisons between related species often allow the detailed genetic analysis of evolutionary processes. Here we advocate the use of the nematode Caenorhabditis elegans (and several other rhabditid species) as model systems for microevolutionary studies. Compared to Drosophila species, which have been a mainstay of such studies, C. elegans has a self-fertilizing mode of reproduction, a shorter life cycle and a convenient cell-level analysis of phenotypic variation. Data concerning its population genetics and ecology are still scarce, however. We review molecular, behavioral and developmental intraspecific polymorphisms for populations of C. elegans, Oscheius sp. 1 and Pristionchus pacificus. Focusing on vulval development, which has been well characterized in several species, we discuss relationships between patterns of variations: (1) for a given genotype (developmental variants), (2) after mutagenesis (mutability), (3) in different populations of the same species (polymorphisms) and (4) between closely related species. These studies have revealed that evolutionary variations between sister species affect those characters that show phenotypic developmental variants, that are mutable and that are polymorphic within species.

The genomic silencing of position-effect variegation in Drosophila melanogaster: interaction between the heterochromatin-associated proteins Su(var)3-7 and HP1.

Position-effect variegation results from mosaic silencing by chromosomal rearrangements juxtaposing euchromatin genes next to pericentric heterochromatin. An increase in the amounts of the heterochromatin-associated Su(var)3-7 and HP1 proteins augments silencing. Using the yeast two-hybrid protein interaction trap system, we have isolated HP1 using Su(var)3-7 as a bait. We have then delimited three binding sites on Su(var)3-7 for HP1. On HP1, the C-terminal moiety, including the chromo shadow domain, is required for interaction. In vivo, both proteins co-localise not only in heterochromatin, but also in a limited set of sites in euchromatin and at telomeres. When delocalised to the sites bound by the protein Polycomb in euchromatin, HP1 recruits Su(var)3-7. Finally, and in contrast with euchromatin genes, a decrease in the amounts of both proteins enhances variegation of the light gene, one of the few genetic loci mapped within pericentric heterochromatin. This body of data supports a direct link between Su(var)3-7 and HP1 in the genomic silencing of position-effect variegation.