Involvement of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) in arsenic biomethylation and its role in arsenic-induced toxicity.

BackgroundIn humans, inorganic arsenic (iAs) is metabolized to methylated arsenical species in a multistep process mainly mediated by arsenic (+3 oxidation state) methyltransferase (AS3MT). Among these metabolites is monomethylarsonous acid (MMAIII), the most toxic arsenic species. A recent study in As3mt-knockout mice suggests that unidentified methyltransferases could be involved in alternative iAs methylation pathways. We found that yeast deletion mutants lacking MTQ2 were highly resistant to iAs exposure. The human ortholog of the yeast MTQ2 is N-6 adenine-specific DNA methyltransferase 1 (N6AMT1), encoding a putative methyltransferase.ObjectiveWe investigated the potential role of N6AMT1 in arsenic-induced toxicity.MethodsWe measured and compared the cytotoxicity induced by arsenicals and their metabolic profiles using inductively coupled plasma-mass spectrometry in UROtsa human urothelial cells with enhanced N6AMT1 expression and UROtsa vector control cells treated with different concentrations of either iAsIII or MMAIII.ResultsN6AMT1 was able to convert MMAIII to the less toxic dimethylarsonic acid (DMA) when overexpressed in UROtsa cells. The enhanced expression of N6AMT1 in UROtsa cells decreased cytotoxicity of both iAsIII and MMAIII. Moreover, N6AMT1 is expressed in many human tissues at variable levels, although at levels lower than those of AS3MT, supporting a potential participation in arsenic metabolism in vivo.ConclusionsConsidering that MMAIII is the most toxic arsenical, our data suggest that N6AMT1 has a significant role in determining susceptibility to arsenic toxicity and carcinogenicity because of its specific activity in methylating MMAIII to DMA and other unknown mechanisms

Young Stars and Outflows in the globule IC1396W

We have observed the IC1396W globule in a narrow band filter centred on the 1-0 S(1) line of molecular hydrogen and in the J, H, K' broad-band filters. Three molecular hydrogen outflows could be identified by means of H2 emission. The projected axes of the flows are parallel to each other. By means of the NIR images and IRAS/ISOPHOT data we could identify the driving sources of all outflows, the possible Class0 source IRAS21246+5743 and two red objects (Class1/2). NIR photometry reveals an embedded cluster of young stars in the globule, coinciding with FIR emission. Other young stars in the field are more or less clustered in several small groups, an indication that star formation takes place at different positions at the same time in such small globules.Comment: 6 pages, 3 figures, 2 tables, accepted for publication in A&

Site directed biotinylation of filamentous phage structural proteins

Filamentous bacteriophages have been used in numerous applications for the display of antibodies and random peptide libraries. Here we describe the introduction of a 13 amino acid sequence LASIFEAQKIEWR (designated BT, which is biotinylated in vivo by E. coli) into the N termini of four of the five structural proteins of the filamentous bacteriophage fd (Proteins 3, 7, 8 and 9). The in vivo and in vitro biotinylation of the various phages were compared. The production of multifunctional phages and their application as affinity reagents are demonstrated

Phase behavior and material properties of hollow nanoparticles

Effective pair potentials for hollow nanoparticles like the ones made from carbon (fullerenes) or metal dichalcogenides (inorganic fullerenes) consist of a hard core repulsion and a deep, but short-ranged, van der Waals attraction. We investigate them for single- and multi-walled nanoparticles and show that in both cases, in the limit of large radii the interaction range scales inversely with the radius, $R$, while the well depth scales linearly with $R$. We predict the values of the radius $R$ and the wall thickness $h$ at which the gas-liquid coexistence disappears from the phase diagram. We also discuss unusual material properties of the solid, which include a large heat of sublimation and a small surface energy.Comment: Revtex, 13 pages with 8 Postscript files included, submitted to Phys. Rev.

Long-term Safety of Epoetin Alfa-epbx for the Treatment of Anemia in ESKD: Pooled Analyses of Randomized and Open-label Studies

Rationale & Objective Epoetin alfa-epbx is a biosimilar to the reference product, epoetin alfa. We compare the safety of epoetin alfa-epbx versus epoetin alfa based on a pooled analysis of findings from 2 randomized, double-blind, comparative clinical studies, and report new data for the long-term safety of epoetin alfa-epbx. Study Design Pooled analyses of previously conducted studies. Setting & Participants Hemodialysis patients with anemia. Interventions Data from patients who received 1 or more subcutaneous or intravenous doses of study drug were integrated across route of administration in combined randomized groups (epoetin alfa-epbx, n = 423; epoetin alfa, n = 426). Data from patients who received 1 or more doses of epoetin alfa-epbx in either open-label extension trial were integrated across route of administration in a combined long-term safety studies group (n = 576). Outcomes Adverse events (AEs), immunogenicity, and other outcomes were assessed. Results Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were similar between combined randomized epoetin alfa-epbx and epoetin alfa, which had mean treatment durations of 18.1 and 17.7 weeks, respectively. Incidences of treatment-emergent AEs, serious AEs, and discontinuation of study drug treatment because of treatment-emergent AEs were 86.5%, 39.4%, and 6.6%, respectively, for the combined long-term safety studies group, which had a mean treatment duration of 40.0 weeks. In total, 12 patients across the combined randomized groups (epoetin alfa-epbx, n = 5; epoetin alfa, n = 7) and 9 patients in the combined long-term safety studies group tested anti-recombinant human erythropoietin antibody positive in 1 or more visits during study conduct. No patient in any group developed neutralizing antibodies or pure red blood cell aplasia. Limitations Epoetin alfa comparator not included in the long-term safety studies, greater cumulative exposure to study drug for epoetin alfa-epbx, shorter follow-up in the randomized studies, and potential for selection bias among patients in the open-label long-term safety studies. Conclusions This analysis reinforces previous conclusions of similar safety profiles between epoetin alfa-epbx and epoetin alfa. Furthermore, epoetin alfa-epbx had no unexpected safety signals during long-term treatment

Critical adsorption on curved objects

A systematic fieldtheoretic description of critical adsorption on curved objects such as spherical or rodlike colloidal particles immersed in a fluid near criticality is presented. The temperature dependence of the corresponding order parameter profiles and of the excess adsorption are calculated explicitly. Critical adsorption on elongated rods is substantially more pronounced than on spherical particles. It turns out that, within the context of critical phenomena in confined geometries, critical adsorption on a microscopically thin `needle' represents a distinct universality class of its own. Under favorable conditions the results are relevant for the flocculation of colloidal particles.Comment: 52 pages, 10 figure

Influence of solvent granularity on the effective interaction between charged colloidal suspensions

We study the effect of solvent granularity on the effective force between two charged colloidal particles by computer simulations of the primitive model of strongly asymmetric electrolytes with an explicitly added hard sphere solvent. Apart from molecular oscillating forces for nearly touching colloids which arise from solvent and counterion layering, the counterions are attracted towards the colloidal surfaces by solvent depletion providing a simple statistical description of hydration. This, in turn, has an important influence on the effective forces for larger distances which are considerably reduced as compared to the prediction based on the primitive model. When these forces are repulsive, the long-distance behaviour can be described by an effective Yukawa pair potential with a solvent-renormalized charge. As a function of colloidal volume fraction and added salt concentration, this solvent-renormalized charge behaves qualitatively similar to that obtained via the Poisson-Boltzmann cell model but there are quantitative differences. For divalent counterions and nano-sized colloids, on the other hand, the hydration may lead to overscreened colloids with mutual attraction while the primitive model yields repulsive forces. All these new effects can be accounted for through a solvent-averaged primitive model (SPM) which is obtained from the full model by integrating out the solvent degrees of freedom. The SPM was used to access larger colloidal particles without simulating the solvent explicitly.Comment: 14 pages, 16 craphic

GRB 071003: Broadband Follow-up Observations of a Very Bright Gamma-Ray Burst in a Galactic Halo

The optical afterglow of long-duration GRB 071003 is among the brightest yet to be detected from any GRB, with R ~ 12 mag in KAIT observations starting 42 s after the GRB trigger, including filtered detections during prompt emission. However, our high S/N ratio afterglow spectrum displays only extremely weak absorption lines at what we argue is the host redshift of z = 1.60435 - in contrast to the three other, much stronger Mg II absorption systems observed at lower redshifts. Together with Keck adaptive optics observations which fail to reveal a host galaxy coincident with the burst position, our observations suggest a halo progenitor and offer a cautionary tale about the use of Mg II for GRB redshift determination. We present early through late-time observations spanning the electromagnetic spectrum, constrain the connection between the prompt emission and early variations in the light curve (we observe no correlation), and discuss possible origins for an unusual, marked rebrightening that occurs a few hours after the burst: likely either a late-time refreshed shock or a wide-angle secondary jet. Analysis of the late-time afterglow is most consistent with a wind environment, suggesting a massive star progenitor. Together with GRB 070125, this may indicate that a small but significant portion of star formation in the early universe occurred far outside what we consider a normal galactic disk.Comment: 24 pages, 14 figures, 12 tables. Accepted for publication by ApJ. Contains minor revisions and additional author

Shotgun Phage Display - Selection for Bacterial Receptins or other Exported Proteins

Shotgun phage display cloning involves construction of libraries from randomly fragmented bacterial chromosomal DNA, cloned genes, or eukaryotic cDNAs, into a phagemid vector. The library obtained consists of phages expressing polypeptides corresponding to all genes encoded by the organism, or overlapping peptides derived from the cloned gene. From such a library, polypeptides with affinity for another molecule can be isolated by affinity selection, panning. The technique can be used to identify bacterial receptins and identification of their minimal binding domain, and but also to identify epitopes recognised by antibodies. In addition, after modification of the phagemid vector, the technique has also been used to identify bacterial extracytoplasmic proteins

QUEST-DMC:Background Modelling and Resulting Heat Deposit for a Superfluid Helium-3 Bolometer

We report the results of radioactivity assays and heat leak calculations for a range of common cryogenic materials, considered for use in the QUEST-DMC superfluid 3He dark matter detector. The bolometer, instrumented with nanomechanical resonators, will be sensitive to energy deposits from dark matter interactions. Events from radioactive decays and cosmic rays constitute a significant background and must be precisely modelled, using a combination of material screening and Monte Carlo simulations. However, the results presented here are of wider interest for experiments and quantum devices sensitive to minute heat leaks and spurious events, thus we present heat leak per unit mass or surface area for every material studied. This can inform material choices for other experiments, especially if underground operation is considered – where the radiogenic backgrounds will dominate even at shallow depths