Globular cluster formation within the Aquarius simulation

The Aquarius project is a very high-resolution simulation capable of resolving the full mass range of potential globular cluster (GC) formation sites. With a particle mass mp= 1.4 × 104 M¿, Aquarius yields more than 100 million particles within the virial radius of the central halo which has a mass of 1.8 × 1012 M¿, similar to that of the Milky Way. With this particle mass, dark matter concentrations (haloes) that give rise to GCs via our formation criteria contain a minimum of ~2000 particles. Here, we use this simulation to test a model of metal-poor GC formation based on collapse physics. In our model, GCs form when the virial temperatures of haloes first exceed 104 K as this is when electronic transitions allow the gas to cool efficiently. We calculate the ionizing flux from the stars in these first clusters and stop the formation of new clusters when all the baryonic gas of the Galaxy is ionized. This is achieved by adopting reasonable values for the star formation efficiencies and escape fraction of ionizing photons which result in similar numbers and masses of clusters to those found in the Milky Way. The model is successful in that it predicts ages (peak age ~13.3 Gyr) and a spatial distribution of metal-poor GCs which are consistent with the observed populations in the Milky Way. The model also predicts that less than 5 per cent of GCs within a radius of 100 kpc have a surviving dark matter halo, but the more distant clusters are all found in dark matter concentrations. We then test a scenario of metal-rich cluster formation by examining mergers that trigger star formation within central gas discs. This results in younger (~7¿13.3 Gyr), more centrally located clusters (40 metal-rich GCs within 18 kpc from the centre of the host) which are consistent with the Galactic metal-rich population. We test an alternate model in which metal-rich GCs form in dwarf galaxies that become stripped as they merge with the main halo. This process is inconsistent with observed metal-rich globulars in the Milky Way because it predicts spatial distributions that are far too extended

Benzoate dioxygenase from<em> Ralstonia eutropha</em> B9 – unusual regiochemistry of dihydroxylation permits rapid access to novel chirons

Oxidation of benzoic acid by a microorganism expressing benzoate dioxygenase leads to the formation of an unusualipso,orthoarenecis-diol in sufficient quantities to be useful for synthesis.</p

RPPA-based proteomics recognizes distinct epigenetic signatures in chronic lymphocytic leukemia with clinical consequences

The chronic lymphocytic leukemia (CLL) armamentarium has evolved significantly, with novel therapies that inhibit Bruton Tyrosine Kinase, PI3K delta and/or the BCL2 protein improving outcomes. Still, the clinical course of CLL patients is highly variable and most previously recognized prognostic features lack the capacity to predict response to modern treatments indicating the need for new prognostic markers. In this study, we identified four epigenetically distinct proteomic signatures of a large cohort of CLL and related diseases derived samples (n = 871) using reverse phase protein array technology. These signatures are associated with clinical features including age, cytogenetic abnormalities [trisomy 12, del(13q) and del(17p)], immunoglobulin heavy-chain locus (IGHV) mutational load, ZAP-70 status, Binet and Rai staging as well as with the outcome measures of time to treatment and overall survival. Protein signature membership was identified as predictive marker for overall survival regardless of other clinical features. Among the analyzed epigenetic proteins, EZH2, HDAC6, and loss of H3K27me3 levels were the most independently associated with poor survival. These findings demonstrate that proteomic based epigenetic biomarkers can be used to better classify CLL patients and provide therapeutic guidance

PKQuest: capillary permeability limitation and plasma protein binding – application to human inulin, dicloxacillin and ceftriaxone pharmacokinetics

BACKGROUND: It is generally assumed that the tissue exchange of antibiotics is flow limited (complete equilibration between the capillary and the tissue water). This assumption may not be valid if there is a large amount of plasma protein binding because the effective capillary permeability depends on the product of the intrinsic capillary permeability (PS) and the fraction of solute that is free in the blood (fw(B)). PKQuest, a new generic physiologically based pharmacokinetic software routine (PBPK), provides a novel approach to modeling capillary permeability in which the only adjustable parameter is the PS of muscle. METHODS: All the results were obtained by applying PKQuest to previously published human pharmacokinetic data. RESULTS: The PKQuest analysis suggests that the highly protein bound antibiotics dicloxacillin and ceftriaxone have a significant capillary permeability limitation. The human muscle capillary PS of inulin, dicloxacillin and ceftriaxone was 0.6, 13 and 6 ml/min/100 gm, respectively. The ceftriaxone protein binding is non-linear, saturating at high plasma concentrations. The experimental ceftriaxone data over a wide range of intravenous inputs (0.15 to 3 gms) was well described by PKQuest. PKQuest is the first PBPK that includes both permeability limitation and non-linear binding. CONCLUSIONS: Because of their high degree of plasma protein binding, dicloxacillin and ceftriaxone appear to have a diffusion limited exchange rate between the blood and tissue and are not flow limited as had been previously assumed. PKQuest and all the examples are freely available at

Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization

‘New and important careers’: how women excelled at the BBC, 1923–1939

From its beginnings in 1923, the BBC employed a sizeable female workforce. The majority were in support roles as typists, secretaries and clerks but, during the 1920s and 1930s, a significant number held important posts. As a modern industry, the BBC took a largely progressive approach towards the ‘career women’ on its staff, many of whom were in jobs that were developed specifically for the new medium of broadcasting. Women worked as drama producers, advertising representatives and Children’s Hour Organisers. They were talent spotters, press officers and documentary makers. Three women attained Director status while others held significant administrative positions. This article considers in what ways it was the modernity and novelty of broadcasting, combined with changing employment possibilities and attitudes towards women evident after the First World War, that combined to create the conditions in which they could excel