Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia

Hydroxyurea treatment is recommended for children with sickle cell anemia (SCA) living in high-resource malaria-free regions, but its safety and efficacy in malaria-endemic sub-Saharan Africa, where the greatest sickle-cell burden exists, remain unknown. In vitro studies suggest hydroxyurea could increase malaria severity, and hydroxyurea-associated neutropenia could worsen infections. NOHARM (Novel use Of Hydroxyurea in an African Region with Malaria) was a randomized, double-blinded, placebo-controlled trial conducted in malaria-endemic Uganda, comparing hydroxyurea to placebo at 20 ± 2.5 mg/kg per day for 12 months. The primary outcome was incidence of clinical malaria. Secondary outcomes included SCA-related adverse events (AEs), clinical and laboratory effects, and hematological toxicities. Children received either hydroxyurea (N = 104) or placebo (N = 103). Malaria incidence did not differ between children on hydroxyurea (0.05 episodes per child per year; 95% confidence interval [0.02, 0.13]) vs placebo (0.07 episodes per child per year [0.03, 0.16]); the hydroxyurea/placebo malaria incidence rate ratio was 0.7 ([0.2, 2.7]; P = .61). Time to infection also did not differ significantly between treatment arms. A composite SCA-related clinical outcome (vaso-occlusive painful crisis, dactylitis, acute chest syndrome, splenic sequestration, or blood transfusion) was less frequent with hydroxyurea (45%) than placebo (69%; P = .001). Children receiving hydroxyurea had significantly increased hemoglobin concentration and fetal hemoglobin, with decreased leukocytes and reticulocytes. Serious AEs, sepsis episodes, and dose-limiting toxicities were similar between treatment arms. Three deaths occurred (2 hydroxyurea, 1 placebo, and none from malaria). Hydroxyurea treatment appears safe for children with SCA living in malaria-endemic sub-Saharan Africa, without increased severe malaria, infections, or AEs. Hydroxyurea provides SCA-related laboratory and clinical efficacy, but optimal dosing and monitoring regimens for Africa remain undefined. This trial was registered at www.clinicaltrials.gov as #NCT01976416

The Structure of Barium in the hcp Phase Under High Pressure

Recent experimental results on two hcp phases of barium under high pressure show interesting variation of the lattice parameters. They are here interpreted in terms of electronic structure calculation by using the LMTO method and generalized pseudopotential theory (GPT) with a NFE-TBB approach. In phase II the dramatic drop in c/a is an instability analogous to that in the group II metals but with the transfer of s to d electrons playing a crucial role in Ba. Meanwhile in phase V, the instability decrease a lot due to the core repulsion at very high pressure. PACS numbers: 62.50+p, 61.66Bi, 71.15.Ap, 71.15Hx, 71.15LaComment: 29 pages, 8 figure

Macrophages exposed continuously to lipopolysaccharide and other agonists that act via toll-like receptors exhibit a sustained and additive activation state

BACKGROUND: Macrophages sense microorganisms through activation of members of the Toll-like receptor family, which initiate signals linked to transcription of many inflammation associated genes. In this paper we examine whether the signal from Toll-like receptors [TLRs] is sustained for as long as the ligand is present, and whether responses to different TLR agonists are additive. RESULTS: RAW264 macrophage cells were doubly-transfected with reporter genes in which the IL-12p40, ELAM or IL-6 promoter controls firefly luciferase, and the human IL-1β promoter drives renilla luciferase. The resultant stable lines provide robust assays of macrophage activation by TLR stimuli including LPS [TLR4], lipopeptide [TLR2], and bacterial DNA [TLR9], with each promoter demonstrating its own intrinsic characteristics. With each of the promoters, luciferase activity was induced over an 8 hr period, and thereafter reached a new steady state. Elevated expression required the continued presence of agonist. Sustained responses to different classes of agonist were perfectly additive. This pattern was confirmed by measuring inducible cytokine production in the same cells. While homodimerization of TLR4 mediates responses to LPS, TLR2 appears to require heterodimerization with another receptor such as TLR6. Transient expression of constitutively active forms of TLR4 or TLR2 plus TLR6 stimulated IL-12 promoter activity. The effect of LPS, a TLR4 agonist, was additive with that of TLR2/6 but not TLR4, whilst that of lipopeptide, a TLR2 agonist, was additive with TLR4 but not TLR2/6. Actions of bacterial DNA were additive with either TLR4 or TLR2/6. CONCLUSIONS: These findings indicate that maximal activation by any one TLR pathway does not preclude further activation by another, suggesting that common downstream regulatory components are not limiting. Upon exposure to a TLR agonist, macrophages enter a state of sustained activation in which they continuously sense the presence of a microbial challenge

Corals in the hottest reefs in the world exhibit symbiont fidelity not flexibility

Reef-building corals are at risk of extinction from ocean warming. While some corals can enhance their thermal limits by associating with dinoflagellate photosymbionts of superior stress tolerance, the extent to which symbiont communities will reorganize under increased warming pressure remains unclear. Here we show that corals in the hottest reefs in the world in the Persian Gulf maintain associations with the same symbionts across 1.5 years despite extreme seasonal warming and acute heat stress (≥35°C). Persian Gulf corals predominantly associated with Cladocopium (clade C) and most also hosted Symbiodinium (clade A) and/or Durusdinium (clade D). This is in contrast to the neighbouring and milder Oman Sea, where corals associated with Durusdinium and only a minority hosted background levels of Cladocopium. During acute heat stress, the higher prevalence of Symbiodinium and Durusdinium in bleached versus nonbleached Persian Gulf corals indicates that genotypes of these background genera did not confer bleaching resistance. Within symbiont genera, the majority of ITS2 rDNA type profiles were unique to their respective coral species, confirming the existence of host-specific symbiont lineages. Notably, further differentiation among Persian Gulf sites demonstrates that symbiont populations are either isolated or specialized over tens to hundreds of kilometres. Thermal tolerance across coral species was associated with the prevalence of a single ITS2 intragenomic sequence variant (C3gulf), definitive of the Cladocopium thermophilum group. The abundance of C3gulf was highest in bleaching-resistant corals and at warmer sites, potentially indicating a specific symbiont genotype (or set of genotypes) that may play a role in thermal tolerance that warrants further investigation. Together, our findings indicate that co-evolution of host–Symbiodiniaceae partnerships favours fidelity rather than flexibility in extreme environments and under future warming

Non-imaging method: 3D scanning.

Three-dimensional body scanning is used to determine surface anthropometry characteristics such as body volume, segment lengths and girths. Three-dimensional scanning systems use laser, light or infrared technologies to acquire shape and software to allow manual or automatically extracted measures. Body posture during scanning is important to ensure accurate measures can be made from the images. The image vary depending on the configuration, resolution and accuracy of the scanner

Structure stability in the simple element sodium under pressure

The simple alkali metal Na, that crystallizes in a body-centred cubic structure at ambient pressure, exhibits a wealth of complex phases at extreme conditions as found by experimental studies. The analysis of the mechanism of stabilization of some of these phases, namely, the low-temperature Sm-type phase and the high-pressure cI16 and oP8 phases, shows that they satisfy the criteria for the Hume-Rothery mechanism. These phases appear to be stabilized due to a formation of numerous planes in a Brillouin-Jones zone in the vicinity of the Fermi sphere of Na, which leads to the reduction of the overall electronic energy. For the oP8 phase, this mechanism seems to be working if one assumes that Na becomes divalent metal at this density. The oP8 phase of Na is analysed in comparison with the MnP-type oP8 phases known in binary compounds, as well as in relation to the hP4 structure of the NiAs-type

Quantum control, quantum information processing, and quantum-limited metrology with trapped ions

We briefly discuss recent experiments on quantum information processing using trapped ions at NIST. A central theme of this work has been to increase our capabilities in terms of quantum computing protocols, but we have also applied the same concepts to improved metrology, particularly in the area of frequency standards and atomic clocks. Such work may eventually shed light on more fundamental issues, such as the quantum measurement problem.Comment: Proceedings of the International Conference on Laser Spectroscopy (ICOLS), 10 pages, 5 figure

Graded and Binary Responses in Stochastic Gene Expression

Recently, several theoretical and experimental studies have been undertaken to probe the effect of stochasticity on gene expression (GE). In experiments, the GE response to an inducing signal in a cell, measured by the amount of mRNAs/proteins synthesized, is found to be either graded or binary. The latter type of response gives rise to a bimodal distribution in protein levels in an ensemble of cells. One possible origin of binary response is cellular bistability achieved through positive feedback or autoregulation. In this paper, we study a simple, stochastic model of GE and show that the origin of binary response lies exclusively in stochasticity. The transitions between the active and inactive states of the gene are random in nature. Graded and binary responses occur in the model depending on the relative stability of the activated and deactivated gene states with respect to that of mRNAs/proteins.The theoretical results on binary response provide a good description of the ``all-or-none'' phenomenon observed in an eukaryotic system.Comment: to be published in Physical Biolog

The FANTOM web resource: from mammalian transcriptional landscape to its dynamic regulation

The genome-scale data collected by the FANTOM4 collaborative research project are presented as an integrated web resource

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions