Effective proton-neutron interaction near the drip line from unbound states in 25,26 F

Background: Odd-odd nuclei, around doubly closed shells, have been extensively used to study proton-neutron interactions. However, the evolution of these interactions as a function of the binding energy, ultimately when nuclei become unbound, is poorly known. The F26 nucleus, composed of a deeply bound π0d5/2 proton and an unbound ν0d3/2 neutron on top of an O24 core, is particularly adapted for this purpose. The coupling of this proton and neutron results in a Jπ=11+-41+ multiplet, whose energies must be determined to study the influence of the proximity of the continuum on the corresponding proton-neutron interaction. The Jπ=11+,21+,41+ bound states have been determined, and only a clear identification of the Jπ=31+ is missing. Purpose: We wish to complete the study of the Jπ=11+-41+ multiplet in F26, by studying the energy and width of the Jπ=31+ unbound state. The method was first validated by the study of unbound states in F25, for which resonances were already observed in a previous experiment. Method: Radioactive beams of Ne26 and Ne27, produced at about 440AMeV by the fragment separator at the GSI facility were used to populate unbound states in F25 and F26 via one-proton knockout reactions on a CH2 target, located at the object focal point of the R3B/LAND setup. The detection of emitted γ rays and neutrons, added to the reconstruction of the momentum vector of the A-1 nuclei, allowed the determination of the energy of three unbound states in F25 and two in F26. Results: Based on its width and decay properties, the first unbound state in F25, at the relative energy of 49(9) keV, is proposed to be a Jπ=1/2- arising from a p1/2 proton-hole state. In F26, the first resonance at 323(33) keV is proposed to be the Jπ=31+ member of the Jπ=11+-41+ multiplet. Energies of observed states in F25,26 have been compared to calculations using the independent-particle shell model, a phenomenological shell model, and the ab initio valence-space in-medium similarity renormalization group method. Conclusions: The deduced effective proton-neutron interaction is weakened by about 30-40% in comparison to the models, pointing to the need for implementing the role of the continuum in theoretical descriptions or to a wrong determination of the atomic mass of F26

Outcomes of patients hospitalized for acute decompensated heart failure: does nesiritide make a difference?

<p>Abstract</p> <p>Background</p> <p>Nesiritide is indicated in the treatment of acute decompensated heart failure. However, a recent meta-analysis reported that nesiritide may be associated with an increased risk of death. Our goal was to evaluate the impact of nesiritide treatment on four outcomes among adults hospitalized for congestive heart failure (CHF) during a three-year period.</p> <p>Methods</p> <p>CHF patients discharged between 1/1/2002 and 12/31/2004 from the Adventist Health System, a national, not-for-profit hospital system, were identified. 25,330 records were included in this retrospective study. Nesiritide odds ratios (OR) were adjusted for various factors including nine medications and/or an APR-DRG severity score.</p> <p>Results</p> <p>Initially, treatment with nesiritide was found to be associated with a 59% higher odds of hospital mortality (Unadjusted OR = 1.59, 95% confidence interval [CI]: 1.31–1.93). Adjusting for race, low economic status, APR-DRG severity of illness score, and the receipt of nine medications yielded a nonsignificant nesiritide OR of 1.07 for hospital death (95% CI: 0.85–1.35). Nesiritide was positively associated with the odds of prolonged length of stay (all adjusted ORs = 1.66) and elevated pharmacy cost (all adjusted ORs > 5).</p> <p>Conclusion</p> <p>In this observational study, nesiritide therapy was associated with increased length of stay and pharmacy cost, but not hospital mortality. Randomized trials are urgently needed to better define the efficacy, if any, of nesiritide in the treatment of decompensated heart failure.</p

Seasonality in pulmonary tuberculosis among migrant workers entering Kuwait

<p>Abstract</p> <p>Background</p> <p>There is paucity of data on seasonal variation in pulmonary tuberculosis (TB) in developing countries contrary to recognized seasonality in the TB notification in western societies. This study examined the seasonal pattern in TB diagnosis among migrant workers from developing countries entering Kuwait.</p> <p>Methods</p> <p>Monthly aggregates of TB diagnosis results for consecutive migrants tested between January I, 1997 and December 31, 2006 were analyzed. We assessed the amplitude (<it>α</it>) of the sinusoidal oscillation and the time at which maximum (<it>θ</it>°) TB cases were detected using Edwards' test. The adequacy of the hypothesized sinusoidal curve was assessed by <it>χ</it>²goodness-of-fit test.</p> <p>Results</p> <p>During the 10 year study period, the proportion (per 100,000) of pulmonary TB cases among the migrants was 198 (4608/2328582), (95% confidence interval: 192 – 204). The adjusted mean monthly number of pulmonary TB cases was 384. Based on the observed seasonal pattern in the data, the maximum number of TB cases was expected during the last week of April (<it>θ</it>° = 112°; <it>P </it>< 0.001). The amplitude (± se) (<it>α </it>= 0.204 ± 0.04) of simple harmonic curve showed 20.4% difference from the mean to maximum TB cases. The peak to low ratio of adjusted number of TB cases was 1.51 (95% CI: 1.39 – 1.65). The <it>χ</it>²goodness-of-test revealed that there was no significant (<it>P </it>> 0.1) departure of observed frequencies from the fitted simple harmonic curve. Seasonal component explained 55% of the total variation in the proportions of TB cases (100,000) among the migrants.</p> <p>Conclusion</p> <p>This regularity of peak seasonality in TB case detection may prove useful to institute measures that warrant a better attendance of migrants. Public health authorities may consider re-allocation of resources in the period of peak seasonality to minimize the risk of <it>Mycobacterium tuberculosis </it>infection to close contacts in this and comparable settings in the region having similar influx of immigrants from high TB burden countries. Epidemiological surveillance for the TB risk in the migrants in subsequent years and required chemotherapy of detected cases may contribute in global efforts to control this public health menace.</p

Phenotype Enhancement Screen of a Regulatory spx Mutant Unveils a Role for the ytpQ Gene in the Control of Iron Homeostasis

Spx is a global regulator of genes that are induced by disulfide stress in Bacillus subtilis. The regulon that it governs is comprised of over 120 genes based on microarray analysis, although it is not known how many of these are under direct Spx control. Most of the Spx-regulated genes (SRGs) are of unknown function, but many encode products that are conserved in low %GC Gram-positive bacteria. Using a gene-disruption library of B. subtilis genomic mutations, the SRGs were screened for phenotypes related to Spx-controlled activities, such as poor growth in minimal medium and sensitivity to methyglyoxal, but nearly all of the SRG mutations showed little if any phenotype. To uncover SRG function, the mutations were rescreened in an spx mutant background to determine which mutant SRG allele would enhance the spx mutant phenotype. One of the SRGs, ytpQ was the site of a mutation that, when combined with an spx null mutation, elevated the severity of the Spx mutant phenotype, as shown by reduced growth in a minimal medium and by hypersensitivity to methyglyoxal. The ytpQ mutant showed elevated oxidative protein damage when exposed to methylglyoxal, and reduced growth rate in liquid culture. Proteomic and transcriptomic data indicated that the ytpQ mutation caused the derepression of the Fur and PerR regulons of B. subtilis. Our study suggests that the ytpQ gene, encoding a conserved DUF1444 protein, functions directly or indirectly in iron homeostasis. The ytpQ mutant phenotype mimics that of a fur mutation, suggesting a condition of low cellular iron. In vitro transcription analysis indicated that Spx stimulates transcription from the ytpPQR operon within which the ytpQ gene resides. The work uncovers a link between Spx and control of iron homeostasis

Fluctuations in spo0A Transcription Control Rare Developmental Transitions in Bacillus subtilis

Phosphorylated Spo0A is a master regulator of stationary phase development in the model bacterium Bacillus subtilis, controlling the formation of spores, biofilms, and cells competent for transformation. We have monitored the rate of transcription of the spo0A gene during growth in sporulation medium using promoter fusions to firefly luciferase. This rate increases sharply during transient diauxie-like pauses in growth rate and then declines as growth resumes. In contrast, the rate of transcription of an rRNA gene decreases and increases in parallel with the growth rate, as expected for stable RNA synthesis. The growth pause-dependent bursts of spo0A transcription, which reflect the activity of the spo0A vegetative promoter, are largely independent of all known regulators of spo0A transcription. Evidence is offered in support of a “passive regulation” model in which RNA polymerase stops transcribing rRNA genes during growth pauses, thus becoming available for the transcription of spo0A. We show that the bursts are followed by the production of phosphorylated Spo0A, and we propose that they represent initial responses to stress that bring the average cell closer to the thresholds for transition to bimodally expressed developmental responses. Measurement of the numbers of cells expressing a competence marker before and after the bursts supports this hypothesis. In the absence of ppGpp, the increase in spo0A transcription that accompanies the entrance to stationary phase is delayed and sporulation is markedly diminished. In spite of this, our data contradicts the hypothesis that sporulation is initiated when a ppGpp-induced depression of the GTP pool relieves repression by CodY. We suggest that, while the programmed induction of sporulation that occurs in stationary phase is apparently provoked by increased flux through the phosphorelay, bet-hedging stochastic transitions to at least competence are induced by bursts in transcription

Imbalanced Lignin Biosynthesis Promotes the Sexual Reproduction of Homothallic Oomycete Pathogens

Lignin is incorporated into plant cell walls to maintain plant architecture and to ensure long-distance water transport. Lignin composition affects the industrial value of plant material for forage, wood and paper production, and biofuel technologies. Industrial demands have resulted in an increase in the use of genetic engineering to modify lignified plant cell wall composition. However, the interaction of the resulting plants with the environment must be analyzed carefully to ensure that there are no undesirable side effects of lignin modification. We show here that Arabidopsis thaliana mutants with impaired 5-hydroxyguaiacyl O-methyltransferase (known as caffeate O-methyltransferase; COMT) function were more susceptible to various bacterial and fungal pathogens. Unexpectedly, asexual sporulation of the downy mildew pathogen, Hyaloperonospora arabidopsidis, was impaired on these mutants. Enhanced resistance to downy mildew was not correlated with increased plant defense responses in comt1 mutants but coincided with a higher frequency of oomycete sexual reproduction within mutant tissues. Comt1 mutants but not wild-type Arabidopsis accumulated soluble 2-O-5-hydroxyferuloyl-l-malate. The compound weakened mycelium vigor and promoted sexual oomycete reproduction when applied to a homothallic oomycete in vitro. These findings suggested that the accumulation of 2-O-5-hydroxyferuloyl-l-malate accounted for the observed comt1 mutant phenotypes during the interaction with H. arabidopsidis. Taken together, our study shows that an artificial downregulation of COMT can drastically alter the interaction of a plant with the biotic environment

Transcription elongation factors represent in vivo cancer dependencies in glioblastoma

Glioblastoma is a universally lethal cancer with a median survival of approximately 15 months1. Despite substantial efforts to define druggable targets, there are no therapeutic options that meaningfully extend glioblastoma patient lifespan. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology2–4 for use in orthotopic patient-derived xenograft (PDX) models, creating a high-throughput negative selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators necessary for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, supporting targeting the transcription elongation machinery as a therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of ‘cancer dependencies’ not identified by previous in vitro approaches, which could supply untapped opportunities for therapeutic intervention