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Single Ni 1- x Cu x TiO 3 (0.05 ≤ x ≤ 0.2) Ilmenite-type phases were successfully prepared through a solid-state reaction route using divalent metal nitrates as precursors and characterized. Their electrocatalytic performance for oxygen evolution reaction (OER) in alkaline media is presented. The Cu content was determined (0.05 ≤ x ≤ 0.2) by X-ray diffraction. A thorough powder neutron diffraction study was carried out to identify the subtle changes caused by copper substitution in the structure of NiTiO 3 . The evolution of the optical and magnetic properties with the Cu content was also investigated on the raw micrometer-sized particles. A reduction in particle size down to ≈15 nm was achieved by ball-milling the raw powder prepared by the solid-state reaction. The best catalytic activity for OER was obtained for nanometer-sized particles of Ni 0.8 Cu 0.2 TiO 3 drop-casted on the Cu plate. For this electrode, a current density of 10 mA cm -2 for oxygen production was generated at 345 and 470 mV applied overpotentials with 1 and 0.1 M NaOH solutions as electrolytes, respectively. The catalyst retained this OER activity at 10 mA cm -2 for long-term electrolysis with a faradic efficiency of 90% for O 2 production in a 0.1 M NaOH electrolyte.

We combine powder neutron diffraction, magnetometry and 57 Fe Mössbauer spectrometry to determine the nuclear and magnetic structures of a strongly interacting weberite-type inorganic-organic hybrid fluoride, Fe 2 F 5 (H taz). In this structure, Fe 2+ and Fe 3+ cations form magnetically frustrated hexagonal tungsten bronze layers of corner-sharing octahedra. Our powder neutron diffraction data reveal that, unlike its purely inorganic fluoride weberite counterparts which adopt a centrosymmetric Imma structure, the room-temperature nuclear structure of Fe 2 F 5 (H taz) is best described by a non-centrosymmetric Ima2 model with refined lattice parameters a = 9.1467(2) Å, b = 9.4641(2) Å and c = 7.4829(2) Å. Magnetic susceptibility and magnetization measurements reveal that strong antiferromagnetic exchange interactions prevail in Fe 2 F 5 (H taz) leading to a magnetic ordering transition at T N  = 93 K. Analysis of low-temperature powder neutron diffraction data indicates that below T N , the Fe 2+ sublattice is ferromagnetic, with a moment of 4.1(1) µ B per Fe 2+ at 2 K, but that an antiferromagnetic component of 0.6(3) µ B cants the main ferromagnetic component of Fe 3+ , which aligns antiferromagnetically to the Fe 2+ sublattice. The zero-field and in-field Mössbauer spectra give clear evidence of an excess of high-spin Fe 3+ species within the structure and a non-collinear magnetic structure. This article is part of the theme issue 'Mineralomimesis: natural and synthetic frameworks in science and technology'.

Here, we report a study of white-ochre powders with targeted composition MnWO 4 prepared via a coprecipitation method. Through X-ray total scattering combined with pair distribution function analysis and Rietveld refinement of X-ray diffraction data, we find that their crystal structure is similar to that of bulk-MnWO 4 , despite a mean crystallite size of 1.0-1.6 nm and a significant deviation of the average chemical composition from MnWO 4 . The chemical formula derived from elemental and thermogravimetric analyses is Mn 0.8 WO 3.6 (OH) 0.4 ·3H 2 O. X-ray absorption and magnetic susceptibility measurements show that Mn and W have the same oxidation states as in MnWO 4 . No magnetic ordering or spin glass or superparamagnetic behavior is observed above 2 K, unlike in the case of MnWO 4 nanocrystals having a mean size higher than 10 nm.

To understand how complex genetic networks perform and regulate diverse cellular processes, the function of each individual component must be defined. Comprehensive phenotypic studies of mutant alleles have been successful in model organisms in determining what processes depend on the normal function of a gene. These results are often ported to newly sequenced genomes by using sequence homology. However, sequence similarity does not always mean identical function or phenotype, suggesting that new methods are required to functionally annotate newly sequenced species. We have implemented comparative analysis by high-throughput experimental testing of gene dispensability in Saccharomyces uvarum , a sister species of Saccharomyces cerevisiae. We created haploid and heterozygous diploid Tn7 insertional mutagenesis libraries in S. uvarum to identify species-dependent essential genes, with the goal of detecting genes with divergent functions and/or different genetic interactions. Comprehensive gene dispensability comparisons with S. cerevisiae predicted diverged dispensability at 12% of conserved orthologs, and validation experiments confirmed 22 differentially essential genes. Despite their differences in essentiality, these genes were capable of cross-species complementation, demonstrating that trans- acting factors that are background-dependent contribute to differential gene essentiality. This study shows that direct experimental testing of gene disruption phenotypes across species can inform comparative genomic analyses and improve gene annotations. Our method can be widely applied in microorganisms to further our understanding of genome evolution., (© 2019 Sanchez et al.; Published by Cold Spring Harbor Laboratory Press.)

Aim/hypothesis: In utero exposure to maternal diabetes increases the risk of developing hypertension and cardiovascular disorders during adulthood. We have previously shown that this is associated with changes in vascular tone in favor of a vasoconstrictor profile, which is involved in the development of hypertension. This excessive constrictor tone has also a strong impact on vascular structure. Our objective was to study the impact of in utero exposure to maternal diabetes on vascular structure and remodeling induced by chronic changes in hemodynamic parameters. Methods and Results: We used an animal model of rats exposed in utero to maternal hyperglycemia (DMO), which developed hypertension at 6 months of age. At a pre-hypertensive stage (3 months of age), we observed deep structural modifications of the vascular wall without any hemodynamic perturbations. Indeed, in basal conditions, resistance arteries of DMO rats are smaller than those of control mother offspring (CMO) rats; in addition, large arteries like thoracic aorta of DMO rats have an increase of smooth muscle cell attachments to elastic lamellae. In an isolated perfused kidney, we also observed a leftward shift of the flow/pressure relationship, suggesting a rise in renal peripheral vascular resistance in DMO compared to CMO rats. In this context, we studied vascular remodeling in response to reduced blood flow by in vivo mesenteric arteries ligation. In DMO rats, inward remodeling induced by a chronic reduction in blood flow (1 or 3 weeks after ligation) did not occur by contrast to CMO rats in which arterial diameter decreased from 428 ± 17 μm to 331 ± 20 μm (at 125 mmHg, p = 0.001). In these animals, the transglutaminase 2 (TG2) pathway, essential for inward remodeling development in case of flow perturbations, was not activated in low-flow (LF) mesenteric arteries. Finally, in old hypertensive DMO rats (18 months of age), we were not able to detect a pressure-induced remodeling in thoracic aorta. Conclusions: Our results demonstrate for the first time that in utero exposure to maternal diabetes induces deep changes in the vascular structure. Indeed, the early narrowing of the microvasculature and the structural modifications of conductance arteries could be a pre-emptive adaptation to fetal programming of hypertension.

Continuous culture provides many benefits over the classical batch style of growing yeast cells. Steady-state cultures allow for precise control of growth rate and environment. Cultures can be propagated for weeks or months in these controlled environments, which is important for the study of experimental evolution. Despite these advantages, chemostats have not become a highly used system, in large part because of their historical impracticalities, including low throughput, large footprint, systematic complexity, commercial unavailability, high cost, and insufficient protocol availability. However, we have developed methods for building a relatively simple, low-cost, small footprint array of chemostats that can be run in multiples of 32. This "ministat array" can be applied to problems in yeast physiology and experimental evolution., (© 2017 Cold Spring Harbor Laboratory Press.)

Experimental evolution is one approach used to address a broad range of questions related to evolution and adaptation to strong selection pressures. Experimental evolution of diverse microbial and viral systems has routinely been used to study new traits and behaviors and also to dissect mechanisms of rapid evolution. This protocol describes the practical aspects of experimental evolution with yeast grown in chemostats, including the setup of the experiment and sampling methods as well as best laboratory and record-keeping practices., (© 2017 Cold Spring Harbor Laboratory Press.)

A series of triazole fluoride weberites (M 1-x 2+ M x 3+ )M 3+ F 5 (Htaz) 1-x (taz) x is obtained by hydrothermal synthesis. All phases are found to be isostructural to ZnAlF 5 (Htaz) by powder X-ray diffraction. Weberite structures are prone to induce the magnetic frustration of antiferromagnetic interactions originating from the cationic topology of HTB layers. The (nD) magnetic properties of (0D) Co-Ga, (1D) Zn-Fe, (3D) Fe-Ga, Mn-Fe, Co-Fe and Co-V couples are thus reported. Co 2+ or Fe 2+ magnetic anisotropy induces a negative magnetisation below T N and compensation temperatures for Mn-Fe and Co-Fe couples. All iron 3D magnetic phases exhibit high Néel temperatures, between 81 K and 102 K, and large |θ P /T N | ratios, signalling strong magnetic frustration. Their cation site occupancies and the deduced (de)protonation states of the amine are accurately determined by 57 Fe Mössbauer spectrometry. In addition, this spectroscopy evidences a subtle effect of the atmosphere that surrounds the samples: the magnetic ordering temperatures T N decrease significantly when the samples are cooled under vacuum with respect to samples that are cooled at ambient pressure. This novel phenomenon, which is highlighted for all studied (3D) triazole iron weberites, is reversible, and thus provides promising perspectives for understanding the underlying mechanism.

Background: High-dose chemotherapy plus autologous stem-cell transplantation has been the standard treatment for newly diagnosed multiple myeloma in adults up to 65 years of age. However, promising data on the use of combination therapy with lenalidomide, bortezomib, and dexamethasone (RVD) in this population have raised questions about the role and timing of transplantation., Methods: We randomly assigned 700 patients with multiple myeloma to receive induction therapy with three cycles of RVD and then consolidation therapy with either five additional cycles of RVD (350 patients) or high-dose melphalan plus stem-cell transplantation followed by two additional cycles of RVD (350 patients). Patients in both groups received maintenance therapy with lenalidomide for 1 year. The primary end point was progression-free survival., Results: Median progression-free survival was significantly longer in the group that underwent transplantation than in the group that received RVD alone (50 months vs. 36 months; adjusted hazard ratio for disease progression or death, 0.65; P<0.001). This benefit was observed across all patient subgroups, including those stratified according to International Staging System stage and cytogenetic risk. The percentage of patients with a complete response was higher in the transplantation group than in the RVD-alone group (59% vs. 48%, P=0.03), as was the percentage of patients in whom minimal residual disease was not detected (79% vs. 65%, P<0.001). Overall survival at 4 years did not differ significantly between the transplantation group and the RVD-alone group (81% and 82%, respectively). The rate of grade 3 or 4 neutropenia was significantly higher in the transplantation group than in the RVD-alone group (92% vs. 47%), as were the rates of grade 3 or 4 gastrointestinal disorders (28% vs. 7%) and infections (20% vs. 9%). No significant between-group differences were observed in the rates of treatment-related deaths, second primary cancers, thromboembolic events, and peripheral neuropathy., Conclusions: Among adults with multiple myeloma, RVD therapy plus transplantation was associated with significantly longer progression-free survival than RVD therapy alone, but overall survival did not differ significantly between the two approaches. (Supported by Celgene and others; IFM 2009 Study ClinicalTrials.gov number, NCT01191060 .).

High-throughput sequencing has enabled genetic screens that can rapidly identify mutations that occur during experimental evolution. The presence of a mutation in an evolved lineage does not, however, constitute proof that the mutation is adaptive, given the well-known and widespread phenomenon of genetic hitchhiking, in which a non-adaptive or even detrimental mutation can co-occur in a genome with a beneficial mutation and the combined genotype is carried to high frequency by selection. We approximated the spectrum of possible beneficial mutations in Saccharomyces cerevisiae using sets of single-gene deletions and amplifications of almost all the genes in the S. cerevisiae genome. We determined the fitness effects of each mutation in three different nutrient-limited conditions using pooled competitions followed by barcode sequencing. Although most of the mutations were neutral or deleterious, ~500 of them increased fitness. We then compared those results to the mutations that actually occurred during experimental evolution in the same three nutrient-limited conditions. On average, ~35% of the mutations that occurred during experimental evolution were predicted by the systematic screen to be beneficial. We found that the distribution of fitness effects depended on the selective conditions. In the phosphate-limited and glucose-limited conditions, a large number of beneficial mutations of nearly equivalent, small effects drove the fitness increases. In the sulfate-limited condition, one type of mutation, the amplification of the high-affinity sulfate transporter, dominated. In the absence of that mutation, evolution in the sulfate-limited condition involved mutations in other genes that were not observed previously-but were predicted by the systematic screen. Thus, gross functional screens have the potential to predict and identify adaptive mutations that occur during experimental evolution., Competing Interests: The authors have declared that no competing interests exist.

Temperature-dependent specific heat, magnetization and neutron diffraction data have been collected in zero magnetic field for polycrystalline samples of MnW1-x Mo x O4 (x  ⩽  0.2) solid solution whose end-member MnWO4 exhibits a magnetoelectric multiferroic phase (AF2 phase) between T 1  ≈  8 K and T 2  =  12.5 K. In MnW1-x Mo x O4, diamagnetic W(6+) are replaced with diamagnetic Mo(6+) cations and magnetic couplings among Mn(2+) (3d (5), S  =  5/2) ions are modified due the doping-induced tuning of the orbital hybridization between Mn 3d and O 2p states. It was observed that magnetic phase transition temperatures which are associated with the second-order AF3-to-paramagnetic (T N) and AF2-to-AF3 (T 2) transitions in pure MnWO4 slightly increase with the Mo content x. Magnetic specific heat data also indicate that the first-order AF1-to-AF2 phase transition at T 1 survives a weak doping x  ⩽  0.05. This latter phase transition becomes invisible above the base temperature 2 K for higher level of doping x  ⩾  0.10. Neutron powder diffraction datasets collected above 1.5 K for a sample of MnW0.8Mo0.2O4 were analyzed using the Rietveld method. The magnetic structure below  ≈  14 K is a helical incommensurate spin order with a temperature-independent propagation vector k  =  (-0.217(6), 0.5, 0.466(4)). This cycloidal magnetic structure is similar to the polar AF2 structure observed in MnWO4. The AF1 up-up-down-down collinear spin arrangement observed in MnWO4 is absent in our MnW0.8Mo0.2O4 sample.

In the yeast Saccharomyces cerevisiae, beneficial mutations selected during sulfate-limited growth are typically amplifications of the SUL1 gene, which encodes the high-affinity sulfate transporter, resulting in fitness increases of >35% . Cis-regulatory mutations have not been observed at this locus; however, it is not clear whether this absence is due to a low mutation rate such that these mutations do not arise, or they arise but have limited fitness effects relative to those of amplification. To address this question directly, we assayed the fitness effects of nearly all possible point mutations in a 493-base segment of the gene's promoter through mutagenesis and selection. While most mutations were either neutral or detrimental during sulfate-limited growth, eight mutations increased fitness >5% and as much as 9.4%. Combinations of these beneficial mutations increased fitness only up to 11%. Thus, in the case of SUL1, promoter mutations could not induce a fitness increase similar to that of gene amplification. Using these data, we identified functionally important regions of the SUL1 promoter and analyzed three sites that correspond to potential binding sites for the transcription factors Met32 and Cbf1 Mutations that create new Met32- or Cbf1-binding sites also increased fitness. Some mutations in the untranslated region of the SUL1 transcript decreased fitness, likely due to the formation of inhibitory upstream open reading frames. Our methodology-saturation mutagenesis, chemostat selection, and DNA sequencing to track variants-should be a broadly applicable approach., (Copyright © 2016 by the Genetics Society of America.)

Experimental evolution of microbes is a powerful tool to study adaptation to strong selection, the mechanism of evolution and the development of new traits. The development of high-throughput sequencing methods has given researchers a new ability to cheaply and easily identify mutations genome wide that are selected during the course of experimental evolution. Here we provide a protocol for conducting experimental evolution of yeast using chemostats, including fitness measurement and whole genome sequencing of evolved clones or populations collected during the experiment. Depending on the number of generations appropriate for the experiment, the number of samples tested and the sequencing platform, this protocol takes from 1 month to several months to be completed, with the possibility of processing several strains or mutants at once.

DNA replication errors are a major driver of evolution--from single nucleotide polymorphisms to large-scale copy number variations (CNVs). Here we test a specific replication-based model to explain the generation of interstitial, inverted triplications. While no genetic information is lost, the novel inversion junctions and increased copy number of the included sequences create the potential for adaptive phenotypes. The model--Origin-Dependent Inverted-Repeat Amplification (ODIRA)-proposes that a replication error at pre-existing short, interrupted, inverted repeats in genomic sequences generates an extrachromosomal, inverted dimeric, autonomously replicating intermediate; subsequent genomic integration of the dimer yields this class of CNV without loss of distal chromosomal sequences. We used a combination of in vitro and in vivo approaches to test the feasibility of the proposed replication error and its downstream consequences on chromosome structure in the yeast Saccharomyces cerevisiae. We show that the proposed replication error-the ligation of leading and lagging nascent strands to create "closed" forks-can occur in vitro at short, interrupted inverted repeats. The removal of molecules with two closed forks results in a hairpin-capped linear duplex that we show replicates in vivo to create an inverted, dimeric plasmid that subsequently integrates into the genome by homologous recombination, creating an inverted triplication. While other models have been proposed to explain inverted triplications and their derivatives, our model can also explain the generation of human, de novo, inverted amplicons that have a 2:1 mixture of sequences from both homologues of a single parent--a feature readily explained by a plasmid intermediate that arises from one homologue and integrates into the other homologue prior to meiosis. Our tests of key features of ODIRA lend support to this mechanism and suggest further avenues of enquiry to unravel the origins of interstitial, inverted CNVs pivotal in human health and evolution.

Polycrystalline samples of Mn1-xCuxWO4 (x ≤ 0.5) have been prepared by a solid-state synthesis as well as from a citrate synthesis at moderate temperature (850 °C). The goal is to study changes in the structural, magnetic, and dielectric properties of magnetoelectric type-II multiferroic MnWO4 caused by replacing Jahn-Teller-inactive Mn(2+) (d(5), S = 5/2) ions with Jahn-Teller-active Cu(2+) (d(9), S = 1/2) ions. Combination of techniques including scanning electron microscopy, powder X-ray and neutron diffraction, and Raman spectroscopy demonstrates that the polycrystalline samples with low copper content 0 ≤ x ≤ 0.25 are solid solution that forms in the monoclinic P2/c space group. Rietveld analyses indicate that Cu atoms substitutes for Mn atoms at the Mn crystallographic site of the MnWO4 structure and suggest random distributions of Jahn-Teller-distorted CuO6 octahedra in the solid solution. Magnetic susceptibility reveals that only 5% of Cu substitution suppresses the nonpolar collinear AF1 antiferromagnetic structure observed in pure MnWO4. Type-II multiferroicity survives a weak Cu substitution rate (x < 0.15). Multiferroic transition temperature and Néel temperature increase as the amount of Cu increases. New trends in some of the magnetic properties and in dielectric behaviors are observed for x = 0.20 and 0.25. Careful analysis of the magnetic susceptibility reveals that the incorporation of Cu into MnWO4 strengthens the overall antiferromagnetic interaction and reduces the magnetic frustration.

Aneuploidy is a hallmark of tumor cells, and yet the precise relationship between aneuploidy and a cell's proliferative ability, or cellular fitness, has remained elusive. In this study, we have combined a detailed analysis of aneuploid clones isolated from laboratory-evolved populations of Saccharomyces cerevisiae with a systematic, genome-wide screen for the fitness effects of telomeric amplifications to address the relationship between aneuploidy and cellular fitness. We found that aneuploid clones rise to high population frequencies in nutrient-limited evolution experiments and show increased fitness relative to wild type. Direct competition experiments confirmed that three out of four aneuploid events isolated from evolved populations were themselves sufficient to improve fitness. To expand the scope beyond this small number of exemplars, we created a genome-wide collection of >1,800 diploid yeast strains, each containing a different telomeric amplicon (Tamp), ranging in size from 0.4 to 1,000 kb. Using pooled competition experiments in nutrient-limited chemostats followed by high-throughput sequencing of strain-identifying barcodes, we determined the fitness effects of these >1,800 Tamps under three different conditions. Our data revealed that the fitness landscape explored by telomeric amplifications is much broader than that explored by single-gene amplifications. As also observed in the evolved clones, we found the fitness effects of most Tamps to be condition specific, with a minority showing common effects in all three conditions. By integrating our data with previous work that examined the fitness effects of single-gene amplifications genome-wide, we found that a small number of genes within each Tamp are centrally responsible for each Tamp's fitness effects. Our genome-wide Tamp screen confirmed that telomeric amplifications identified in laboratory-evolved populations generally increased fitness. Our results show that Tamps are mutations that produce large, typically condition-dependent changes in fitness that are important drivers of increased fitness in asexually evolving populations.

In the presence of "Ag2O" as a promoter, γ-MnO2 traps dihydrogen in its (2 × 1) and (1 × 1) tunnels. The course of this reaction was examined by analyzing the X-ray diffraction patterns of the HxMnO2/"Ag2O" system (0 ≤ x < 1) on the basis of pair distribution function and density functional theory (DFT) analyses. Hydrogen trapping occurs preferentially in the (2 × 1) tunnels of γ-MnO2, which is then followed by that in the (1 × 1) tunnels. Our DFT analysis shows that this process is thermodynamically favorable.

Population adaptation to strong selection can occur through the sequential or parallel accumulation of competing beneficial mutations. The dynamics, diversity, and rate of fixation of beneficial mutations within and between populations are still poorly understood. To study how the mutational landscape varies across populations during adaptation, we performed experimental evolution on seven parallel populations of Saccharomyces cerevisiae continuously cultured in limiting sulfate medium. By combining quantitative polymerase chain reaction, array comparative genomic hybridization, restriction digestion and contour-clamped homogeneous electric field gel electrophoresis, and whole-genome sequencing, we followed the trajectory of evolution to determine the identity and fate of beneficial mutations. During a period of 200 generations, the yeast populations displayed parallel evolutionary dynamics that were driven by the coexistence of independent beneficial mutations. Selective amplifications rapidly evolved under this selection pressure, in particular common inverted amplifications containing the sulfate transporter gene SUL1. Compared with single clones, detailed analysis of the populations uncovers a greater complexity whereby multiple subpopulations arise and compete despite a strong selection. The most common evolutionary adaptation to strong selection in these populations grown in sulfate limitation is determined by clonal interference, with adaptive variants both persisting and replacing one another.

During mitosis, kinetochores physically link chromosomes to the dynamic ends of spindle microtubules. This linkage depends on the Ndc80 complex, a conserved and essential microtubule-binding component of the kinetochore. As a member of the complex, the Ndc80 protein forms microtubule attachments through a calponin homology domain. Ndc80 is also required for recruiting other components to the kinetochore and responding to mitotic regulatory signals. While the calponin homology domain has been the focus of biochemical and structural characterization, the function of the remainder of Ndc80 is poorly understood. Here, we utilized a new approach that couples high-throughput sequencing to a saturating linker-scanning mutagenesis screen in Saccharomyces cerevisiae. We identified domains in previously uncharacterized regions of Ndc80 that are essential for its function in vivo. We show that a helical hairpin adjacent to the calponin homology domain influences microtubule binding by the complex. Furthermore, a mutation in this hairpin abolishes the ability of the Dam1 complex to strengthen microtubule attachments made by the Ndc80 complex. Finally, we defined a C-terminal segment of Ndc80 required for tetramerization of the Ndc80 complex in vivo. This unbiased mutagenesis approach can be generally applied to genes in S. cerevisiae to identify functional properties and domains.

In France, the cooperations between biological laboratories of the healthcare establishments increased after those realized in the private laboratories. The biologists are confronted with various hypotheses of organization. They are often complex because they may preserve the quality of the care and their continuity while realizing financial economies. These economies are mostly based on the global reduction in the staff and in the equipments by mutualising the biological tests with varying degrees. We describe the various elements to be taken into account (staff, activities, budget, quality, transport, materials) and propose many scenarios of cooperations, from a unique central shape to the transfer of very specialized tests, with their advantages and their inconveniences. The management of human aspects in these cooperations is determining to facilitate their success as well as a reliable preliminary inventory of fixtures.

Background: High-dose chemotherapy with autologous stem-cell transplantation is a standard treatment for young patients with multiple myeloma. Residual disease is almost always present after transplantation and is responsible for relapse. This phase 3, placebo-controlled trial investigated the efficacy of lenalidomide maintenance therapy after transplantation., Methods: We randomly assigned 614 patients younger than 65 years of age who had nonprogressive disease after first-line transplantation to maintenance treatment with either lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated) or placebo until relapse. The primary end point was progression-free survival., Results: Lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β(2)-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years. The rates of grade 3 or 4 peripheral neuropathy were similar in the two groups. The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group versus 1.2 per 100 patient-years in the placebo group (P=0.002). Median event-free survival (with events that included second primary cancers) was significantly improved with lenalidomide (40 months, vs. 23 months with placebo; P<0.001)., Conclusions: Lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival among patients with multiple myeloma. Four years after randomization, overall survival was similar in the two study groups. (Funded by the Programme Hospitalier de Recherche Clinique and others; ClinicalTrials.gov number, NCT00430365.).

Frustrated magnets with integer spin are predicted to have exotic physical properties including spin nematicity, yet few are known to exist. We report a new, frustrated S = 1 magnet, BaNi(3)(OH)(2)(VO(4))(2), which is the structural analogue of the mineral vesignieite. Magnetic frustration arises from a competition between ferromagnetic and antiferromagnetic ordering leading to a glassy transition at 19 K., (This journal is © The Royal Society of Chemistry 2012)

Salbutamol is a short-acting agonist of the β(2) adrenergic receptors sometimes misused or abused, which can result in various cardiovascular adverse effects. We report one case of fatal salbutamol misuse or abuse in a 36-year-old poorly controlled female asthmatic patient with a past medical history of alcoholism and a recent smoking cessation. She died shortly after hospital admission following acute dyspnea and sudden collapse at home. Toxicological analyses evidenced salbutamol overdose, and necropsy showed acute lung edema and marked dysplasia of the right ventricle and revealed the patient was pregnant. The involvement of an initial disorder of the ventricular rhythm leading to cardiac failure is suggested by the presence of several combined pro-arrhythmogenic factors, such as arrhythmogenic right ventricle dysplasia, hypoxemia related to bronchospasm and salbutamol overdose.

Severe but regressive toxic liver damage was observed in a 30-week pregnant woman due to acetaminophen poisoning. A cesarean section was performed 1 week later for suspected chorioamniotitis and the patient gave birth to an infant who only experienced complications of preterm birth. The lack of fetal liver damage following acute maternal paracetamol poisoning seems to be the rule, as shown by a review of the literature., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

High-quality, well-annotated genome sequences and standardized laboratory strains fuel experimental and evolutionary research. We present improved genome sequences of three species of Saccharomyces sensu stricto yeasts: S. bayanus var. uvarum (CBS 7001), S. kudriavzevii (IFO 1802(T) and ZP 591), and S. mikatae (IFO 1815(T)), and describe their comparison to the genomes of S. cerevisiae and S. paradoxus. The new sequences, derived by assembling millions of short DNA sequence reads together with previously published Sanger shotgun reads, have vastly greater long-range continuity and far fewer gaps than the previously available genome sequences. New gene predictions defined a set of 5261 protein-coding orthologs across the five most commonly studied Saccharomyces yeasts, enabling a re-examination of the tempo and mode of yeast gene evolution and improved inferences of species-specific gains and losses. To facilitate experimental investigations, we generated genetically marked, stable haploid strains for all three of these Saccharomyces species. These nearly complete genome sequences and the collection of genetically marked strains provide a valuable toolset for comparative studies of gene function, metabolism, and evolution, and render Saccharomyces sensu stricto the most experimentally tractable model genus. These resources are freely available and accessible through www.SaccharomycesSensuStricto.org.

Competing Interests: The authors have declared that no competing interests exist.

Suicide by ingestion of barium is exceptionally rare. Adverse health effects depend on the solubility of the barium compound. Severe hypokalemia, which generally occurs within 2 hours after ingestion, is the predominating feature of acute barium toxicity, subsequently leading to adverse effects on muscular activity and cardiac automaticity. We report one case of acute poisoning with barium nitrate, a soluble barium compound. A 75-year-old woman was hospitalized after suicidal ingestion of a burrow mole fumigant containing 12.375 g of barium nitrate. About 1 hour post-ingestion, she was only complaining of abdominal pain. The ECG recording demonstrated polymorphic ventricular premature complexes (VPCs). Laboratory data revealed profound hypokalemia (2.1 mmol/L). She made a complete and uneventful recovery after early and massive potassium supplementation combined with oral magnesium sulphate to prevent barium nitrate absorption.

This work shows that the combination of first-principles calculations and (51)V NMR experiments is a powerful tool to elucidate the location of surface hydroxyl groups and to precisely describe the hydrogen bond network in the complex decavanadate cluster Cs(4)[H(2)V(10)O(28)].4H(2)O, enhancing the strength of NMR crystallography. The detailed characterization of H-bond networks for these kinds of inorganic compounds is of primary importance and should benefit from the DFT-NMR predictions by considering explicitly the periodic boundary conditions. The determination of the Cs(4)[H(2)V(10)O(28)].4H(2)O structure by single-crystal X-ray diffraction was not sufficiently accurate to provide the location of protons. From available diffraction data, five different protonated model structures have been built and optimized using DFT-based methods. The possible interconversion of two decavanadate isomers through a proton exchange is evaluated by calculating the energy barrier and recording variable-temperature (1)H MAS NMR spectra. First-principles calculations of (51)V NMR parameters clearly indicate that these parameters are very sensitive to the local intermolecular hydrogen-bonding interactions. Considering the DFT error limits, the fairly good agreement between calculated and experimental NMR parameters arising from the statistical modeling of the data allows the unambiguous assignment of the five (51)V NMR signals and, thus, the location of OH surface ligands in the decavanadate cluster. In particular, first-principles calculations accurately reproduce the (51)V quadrupolar parameters. These results are fully consistent with (51)V 3QMAS NMR spectra recorded with and without (1)H decoupling. Finally, correlations are established between local octahedral VO(6) deformations and (51)V NMR parameters (C(q) and Deltadelta), which will be useful for the characterization of a wide range of chemical species containing vanadium(V).

Background: Experimental evolution of microbial populations provides a unique opportunity to study evolutionary adaptation in response to controlled selective pressures. However, until recently it has been difficult to identify the precise genetic changes underlying adaptation at a genome-wide scale. New DNA sequencing technologies now allow the genome of parental and evolved strains of microorganisms to be rapidly determined., Results: We sequenced >93.5% of the genome of a laboratory-evolved strain of the yeast Saccharomyces cerevisiae and its ancestor at >28x depth. Both single nucleotide polymorphisms and copy number amplifications were found, with specific gains over array-based methodologies previously used to analyze these genomes. Applying a segmentation algorithm to quantify structural changes, we determined the approximate genomic boundaries of a 5x gene amplification. These boundaries guided the recovery of breakpoint sequences, which provide insights into the nature of a complex genomic rearrangement., Conclusions: This study suggests that whole-genome sequencing can provide a rapid approach to uncover the genetic basis of evolutionary adaptations, with further applications in the study of laboratory selections and mutagenesis screens. In addition, we show how single-end, short read sequencing data can provide detailed information about structural rearrangements, and generate predictions about the genomic features and processes that underlie genome plasticity.

Our knowledge of yeast genomes remains largely dominated by the extensive studies on Saccharomyces cerevisiae and the consequences of its ancestral duplication, leaving the evolution of the entire class of hemiascomycetes only partly explored. We concentrate here on five species of Saccharomycetaceae, a large subdivision of hemiascomycetes, that we call "protoploid" because they diverged from the S. cerevisiae lineage prior to its genome duplication. We determined the complete genome sequences of three of these species: Kluyveromyces (Lachancea) thermotolerans and Saccharomyces (Lachancea) kluyveri (two members of the newly described Lachancea clade), and Zygosaccharomyces rouxii. We included in our comparisons the previously available sequences of Kluyveromyces lactis and Ashbya (Eremothecium) gossypii. Despite their broad evolutionary range and significant individual variations in each lineage, the five protoploid Saccharomycetaceae share a core repertoire of approximately 3300 protein families and a high degree of conserved synteny. Synteny blocks were used to define gene orthology and to infer ancestors. Far from representing minimal genomes without redundancy, the five protoploid yeasts contain numerous copies of paralogous genes, either dispersed or in tandem arrays, that, altogether, constitute a third of each genome. Ancient, conserved paralogs as well as novel, lineage-specific paralogs were identified.

The 11.3-Mb genome of the yeast Lachancea (Saccharomyces) kluyveri displays an intriguing compositional heterogeneity: a region of approximately 1 Mb, covering almost the whole left arm of chromosome C (C-left), has an average GC content of 52.9%, which is significantly higher than the 40.4% global GC content of the rest of the genome. This region contains the MAT locus, which remains normal in composition. The excess of GC base pairs affects both coding and noncoding sequences, and thus is not due to selective pressure acting on protein sequences. It leads to a strong codon usage bias and alters the amino acid composition of the 457 proteins encoded on C-left that do not show obvious bias for functional categories, or the presence of paralogs or orthologs of essential genes of Saccharomyces cerevisiae. They share significant synteny conservation with other species of the Saccharomycetaceae, and phylogenetic analysis indicates that C-left originates from a Lachancea species. In contrast, there is a complete absence of transposable elements in C-left, whereas 18 elements per megabase are distributed across the rest of the genome. Comparative hybridization of synchronized cells using high-density genome arrays reveals that C-left is replicated later during S phase than the rest of the genome. Two possible primary causes of this major compositional heterogeneity are discussed: an ancient hybridization of two related species with very distinct GC composition, or an intrinsic mechanism, possibly associated with the loss of the silent cassettes from C-left that progressively increased the GC content and generated the delayed replication of this chromosomal arm.

Acute poisonings involving chloroquine are common in sharp contrast to those involving proguanil, another antimalarial drug. A 39-year-old woman ingested a combination of 11.2 g chloroquine and 22.4 g proguanil (i.e., 112 tablets of the commercial product Savarine). She presented with cardiovascular disorders typically associated with chloroquine overdose, but unexpectedly bone marrow aplasia developed on day 3 post-ingestion that required granulocyte-colony stimulating factor administration, and recovered on days 10-14. Toxicological analysis evidenced both chloroquine and proguanil in the patient's serum and ruled out the involvement of any major myelotoxic drug. This is seemingly the first report of bone marrow aplasia following acute poisoning with chloroquine and proguanil. The antifolinic effect of proguanil is hypothesized to have potentiated the still debated myelotoxicity of chloroquine in this patient.

Objective: A new electronic injection device, the Easypod, has been developed to administer growth hormone (GH). This study assessed the use of this device in common practice., Materials and Methods: Results are from the French arm (one centre) of an international, open-label, uncontrolled study. Subjects were children already using, or about to start, GH therapy. Children used the Easypod device for 60 days. The main outcome measures were patients' or, if appropriate, their parents' qualitative overall impression of the device and the usefulness of its features after 15 days' use, as evaluated by questionnaire., Results: At day 15, all participants (20/20) described their overall impression of the Easypod device as "good" or "very good". All participants rated the display of the remaining drug in the cartridge, the preprogrammed dosing, the onscreen instructions and the automatic-needle attachment as "useful" or "very useful". The device's audible/visible signals and customisable injection depth and speed were each rated as "useful" or "very useful" by 19/20 participants and the skin sensor, customisable needle-insertion speed and dose-injection confirmation were each rated as such by 18/20 participants. Electronic display of the date and time of the last injection and the dose history were considered "useful" or "very useful" by 17/20 and 15/20 participants, respectively. At day 60, 17/17 respondents expressed a preference for continuing to use the device., Conclusion: These results show that the features of Easypod are considered useful in routine practice and the majority of participants expressed a desire to continue using the device.

The propensity of segmental duplications (SDs) to promote genomic instability is of increasing interest since their involvement in numerous human genomic diseases and cancers was revealed. However, the mechanism(s) responsible for their appearance remain mostly speculative. Here, we show that in budding yeast, replication accidents, which are most likely transformed into broken forks, play a causal role in the formation of SDs. The Pol32 subunit of the major replicative polymerase Poldelta is required for all SD formation, demonstrating that SDs result from untimely DNA synthesis rather than from unequal crossing-over. Although Pol32 is known to be required for classical (Rad52-dependant) break-induced replication, only half of the SDs can be attributed to this mechanism. The remaining SDs are generated through a Rad52-independent mechanism of template switching between microsatellites or microhomologous sequences. This new mechanism, named microhomology/microsatellite-induced replication (MMIR), differs from all known DNA double-strand break repair pathways, as MMIR-mediated duplications still occur in the combined absence of homologous recombination, microhomology-mediated, and nonhomologous end joining machineries. The interplay between these two replication-based pathways explains important features of higher eukaryotic genomes, such as the strong, but not strict, association between SDs and transposable elements, as well as the frequent formation of oncogenic fusion genes generating protein innovations at SD junctions., Competing Interests: The authors have declared that no competing interests exist.

The members of the CuMo1-xWxO4 series (0alpha transition can occur between 260 and 360 K, and the alpha-->gamma transition between 175 and 275 K as a function of x. The control of the alpha/gamma transition temperatures with x is related to the larger propensity of tungsten compared to molybdenum, to adopt a tetrahedral environment.

A neutron spin-echo investigation of the low temperature spin dynamics in two well-characterized kagomé bilayer compounds SrCr9xGa12-9xO19 (x=0.95, SCGO) and Ba2Sn2ZnCr7xGa10-7xO22 (x=0.97, BSZCGO) reveals two novel features. One is the slowing down of the relaxation rate without critical behavior at Tg, where a macroscopic spin-glass-like freezing occurs. The second is, in SCGO at 4 K (approximately Tg)

Objective: To estimate the frequency of the metabolic syndrome (MS) and of the insulin resistance syndrome (IRS) in overweight or obese French children and to determine the risk factors., Design, Patients and Methods: A total of 308 overweight and obese children [166 girls, 142 boys, aged 7-17 years; median body mass index (BMI) 4.7 standard deviation (SD) (Q1-Q3: 3.9-5.8) adjusted for age and sex] were included. The frequency of the MS was assessed with the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) criteria and the frequency of the IRS with World Health Organization (WHO) criteria., Results: The overall frequency of MS and IRS was 15.9% and 42.5%, respectively. The most common component, after abdominal obesity (95.8%) and IR (71.8%), was elevated systolic blood pressure (28.6%). The frequency of glucose tolerance disorders was low (3.6%). The frequency of MS was independently influenced by homeostatic model assessment (HOMA) (P = 0.06) and waist-to-hip ratio (P = 0.09), whereas the frequency of IRS was influenced by adiposity (degree of obesity: P = 0.02; waist-to-hip ratio: P = 0.05), puberty (P = 0.05) and mother's BMI (P = 0.01). Ethnicity had no effect on either MS or IRS., Conclusions: Metabolic complications and IR are frequent in overweight and obese children whereas the frequency of glucose tolerance disorders is very low. IRS is more prevalent than MS, indicating a major role of IR, which could precede the other metabolic complications in obese children. IRS is a relevant marker for the risk of type 2 diabetes (T2D) and cardiovascular complications in obese European children.

The requirement for safe and optimal administration of cytotoxic drugs led us to test a new product manufactured by Codan. The transfer set (CONNECT SET) and the administration set (CYTO-AD-SET) were assessed successively by pharmacist assistance within a centralized unit for cytotoxic drug preparation and by the nursing staff in an ambulatory unit. Transfer sets can be handled in the centralized units without using needles, but with an increased sterilization load and production cost. Assessment of the administration sets demonstrated time saving for the nursing staff. These materials require significant expenditures, careful training, and a change in treatment routine, but provide important time savings for the nursing staff and considerable improvement in the safety of handling cytotoxic drugs.

As valpromide is a prodrug of valproic acid (valproate), the clinical presentation of overdoses with either valpromide or valproate sodium is generally considered similar. Whereas plasma peak levels and signs of central nervous system depression occur within a few hours after the acute ingestion of regular-release forms of valproate sodium, delayed toxicity and time to peak levels following valpromide ingestion can be seen as shown by the three reported cases. They were initially considered as mild because patients presented with no or only moderate symptoms and serum valproate levels were below or at therapeutic levels on admission more than 3 hours post-ingestion in two of the three patients. Serum valproate levels were not monitored until marked deterioration more than 10 hours after ingestion. At the time of deterioration, serum valproate was at toxic level in the three reported cases. Therefore, large intake of valpromide should be closely monitored because no or moderate symptoms together with low plasma levels in the first few hours after ingestion do not exclude a subsequent severe intoxication. Despite the usual favourable outcome and the poor correlation between plasma levels and toxic symptoms, patients should not be discharged until plasma levels are documented to remain at low levels for at least 10 hours after the ingestion of valpromide and the patient asymptomatic.

The association between paracetamol overdose and prolonged prothrombin time due to hepatic failure is well recognized. However, little is known of the possibility that paracetamol overdose can prolong the prothrombin time without overt hepatic failure. The few data from the literature suggest this is either due to a reduction in the functional levels of the vitamin K-dependent clotting factors by elevated doses of paracetamol, or a consequence of the administration of the antidote N-acetylcystein. The three reported cases provide further evidence that paracetamol overdose can be associated with a prolongation in the prothrombin time without overt hepatic failure. Even though the prothrombin time provides useful prognosis information, decisions regarding the management of these patients should not solely be based on this endpoint to avoid misinterpretation of the accuracy and the severity of liver failure.

Non-myeloablative allogeneic stem cell transplantation has been reported to induce sustained complete remission even in advanced diseases (acute leukemia, lymphomas). The tolerance of this procedure allows treatment of poor candidates to conventional allogeneic transplantation with persisting or relapsing myeloma patients. Twelve patients previously treated with at least VAD regimen and autologous transplantation were included. All patients had a serum beta2 microglobuline >3 mg/l at diagnosis. The conditioning regimen consisted of fludarabine 25 mg/m/day x 5, antithymoglobulin 2.5 mg/kg/day x 5, busulphan 2 mg/kg/day x 2; the transplant was peripheral stem cells (except one) from an HLA-matched sibling and was followed by cyclosporin for 45 to 90 days. This treatment results in a well-tolerated procedure (no mucositis, duration of aplasia <7 days). A dramatic graft anti-myeloma effect is documented even in progressive disease (11/12 PR + CR, 4/12 CR). However, five patients underwent CMV disease, one died of CMV encephalitis (UPN 3) and delayed severe GVHD occurred in four patients. Our data suggest that a better survival could be achieved when patients are transplanted with a controlled disease. In high risk patients, we now propose a non-myeloablative transplantation in addition to the conventional and intensive chemotherapy as first-line of treatment.

Immunological control of acute leukemia may be achieved after allogeneic transplant. Despite promising preliminary results, the impact of immunotherapy with interleukin-2 (r-IL-2) on patients with acute leukemia (AL), in first complete remission (CR1) remains unclear. We conducted a prospective multicenter randomized trial to compare outcome in patients with AL in CR1, treated with autologous bone marrow transplantation (BMT) with or without postgraft r-IL-2. One hundred and thirty patients with AL in CR1 (myeloblastic (AML): N = 78; lymphoblastic (ALL): N = 52) were randomized at time of BMT to receive (N = 65) or not (N = 65) r-IL-2. r-IL-2 (RU 49637 from Roussel Uclaf) was started after hematological recovery, as a five cycle regimen (12 M IU/m2/day continuous infusion on day 1-5, 15-17, 29-31,43-45 and 57-59). The two groups were balanced for patient and transplant characteristics. Analysis was based on an intent to treat. Thirty-eight (59%) of the 65 patients randomized into the study group started r-IL-2 at a median of sixty-eight days (23-140) after transplant and received 77% (16-100) of the scheduled dosage. They received a median of 120 x 10(6) IU/m2 (25-156) over 10 (3-13) days during a total median period of 56 (3-78) days. With a median follow-up of 7 years (5.4-8.1 years), 79 patients relapsed (study group: 43 (66%); control group: 36 (55%): p = NS). Survival and leukemia-free survival estimates were 33% (23-45) versus 43% (22-52) and 29% (19-41) versus 36% (24-51) respectively for study and control groups (all p = NS). These results show that leukemic control after autologous BMT is not increased by r-IL-2 therapy. Further studies should investigate more appropriate r-IL-2 schedules and the possibilities offered by better antigen recognition and activated effector cells.

Introduction: Recently, a report has suggested the efficacy and safety of thalidomide in refractory multiple myeloma. In an attempt to assess the efficacy and tolerance of thalidomide in advanced multiple myeloma (on behalf of the Intergroupe Franchophone dy Myelome (IFM)), we report the preliminary experience of the IFM with this drug., Materials and Methods: Patients with advanced multiple myeloma (n=27) were treated with an oral dose of thalidomide (median 400 mg/day). At the start of treatment, all patients had active disease and 20 patients had received at least one autologous transplantation., Results: Median follow-up was 105 days from the first administration. The serum and/or urine levels of the M-component were reduced by at least 75% in four patients including one patient with a >90% reduction, by at least 50% in five patients and by at least 25% in three patients, giving a total response rate of 45% (12 out of 27 patients). Nine patients had stable disease and six patients had progressed disease. Short-term side-effects of thalidomide were generally moderate., Conclusion: This study confirms that thalidomide is an effective agent in patients with advanced myeloma.

To further define the frequency, clinical and biological features of familial multiple myeloma we performed a retrospective study of related patients who presented with multiple myeloma. Most cases of familial multiple myeloma were observed in siblings (10/15), in whom the mean age at diagnosis was similar to unrelated multiple myeloma. In successive generations the mean age at diagnosis was lower. Monoclonal component was identical (IgG kappa) in seven families. Familial history of monoclonal gammopathy of undetermined significance was observed in three families. Five other prospective studies of 1263 patients identified four affected families (3.2 per 1000 cases of multiple myeloma), and raise the question of a genetic background in multiple myeloma.