A massive core for a cluster of galaxies at a redshift of 4.3.

Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts 7 . However, recent detections of possible protoclusters hosting such starbursts8-11 do not support the kind of rapid cluster-core formation expected from simulations 12 : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star-formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today.

Author Correction: A massive core for a cluster of galaxies at a redshift of 4.3.

Change history: In this Letter, the Acknowledgements section should have included the following sentence: "The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.". This omission has been corrected online.

Galaxy growth in a massive halo in the first billion years of cosmic history.

According to the current understanding of cosmic structure formation, the precursors of the most massive structures in the Universe began to form shortly after the Big Bang, in regions corresponding to the largest fluctuations in the cosmic density field. Observing these structures during their period of active growth and assembly-the first few hundred million years of the Universe-is challenging because it requires surveys that are sensitive enough to detect the distant galaxies that act as signposts for these structures and wide enough to capture the rarest objects. As a result, very few such objects have been detected so far. Here we report observations of a far-infrared-luminous object at redshift 6.900 (less than 800 million years after the Big Bang) that was discovered in a wide-field survey. High-resolution imaging shows it to be a pair of extremely massive star-forming galaxies. The larger is forming stars at a rate of 2,900 solar masses per year, contains 270 billion solar masses of gas and 2.5 billion solar masses of dust, and is more massive than any other known object at a redshift of more than 6. Its rapid star formation is probably triggered by its companion galaxy at a projected separation of 8 kiloparsecs. This merging companion hosts 35 billion solar masses of stars and has a star-formation rate of 540 solar masses per year, but has an order of magnitude less gas and dust than its neighbour and physical conditions akin to those observed in lower-metallicity galaxies in the nearby Universe. These objects suggest the presence of a dark-matter halo with a mass of more than 100 billion solar masses, making it among the rarest dark-matter haloes that should exist in the Universe at this epoch.

South Pole Telescope optics.

The South Pole Telescope is a 10 m diameter, wide-field, offset Gregorian telescope with a 966-pixel, millimeter-wave, bolometer array receiver. The telescope has an unusual optical system with a cold stop around the secondary. The design emphasizes low scattering and low background loading. All the optical components except the primary are cold, and the entire beam from prime focus to the detectors is surrounded by cold absorber.

Fast molecular outflow from a dusty star-forming galaxy in the early Universe.

Galaxies grow inefficiently, with only a small percentage of the available gas converted into stars each free-fall time. Feedback processes, such as outflowing winds driven by radiation pressure, supernovae, or supermassive black hole accretion, can act to halt star formation if they heat or expel the gas supply. We report a molecular outflow launched from a dust-rich star-forming galaxy at redshift 5.3, 1 billion years after the Big Bang. The outflow reaches velocities up to 800 kilometers per second relative to the galaxy, is resolved into multiple clumps, and carries mass at a rate within a factor of 2 of the star formation rate. Our results show that molecular outflows can remove a large fraction of the gas available for star formation from galaxies at high redshift.

Comparative aflatoxin B1 mutagenesis of Salmonella typhimurium TA 100 in metabolic and photoactivation systems.

Salmonella typhimurium TA 100 was mutagenized with photoactivated aflatoxin B1 (AFB1) and AFB2. Levels of mutagenesis induced by AFB1 correlated with levels of in vitro covalent binding of [3H]AFB1 to calf thymus DNA. The same phenomenon was observed with AFB2. Photoactivated AFB1 induced lethality in the mutagenized cultures, and AFB2 failed to do so. Extraction of nucleic acids from cultures mutagenized by photoactivated or metabolically activated [3H]AFB1 revealed that: (a) in situ levels of [3H]AFB1 binding to DNA were proportional to induction of mutational and lethal events in both cases; (b) mammalian metabolism and photoactivation produced AFB1:DNA lesions possessing comparable lethality and mutagenicity; and (c) [3H]AFB1 binding levels to bacterial RNA did not correlate with mutagenesis and lethality.

DNA strand scission and apurinic sites induced by photoactivated aflatoxins.

Covalent binding of photoactivated aflatoxins to DNA in vitro under close-to-physiological conditions resulted in the formation of apurinic sites and in strand scission. Linearized pBR322 DNA was randomly fragmented, and supercoiled DNA was relaxed during the binding reaction. A primary amine facilitated fragmentation and relaxation. Quantitative measurements of relaxation revealed that the probability of a binding event to be converted into a DNA chain break was approximately 3-5% in the absence of a primary amine. The presence of the latter increased the probability approximately 2- to 3-fold. The results are compatible with the model that photoactivated aflatoxins bind to guanines on DNA; some of these guanine adducts are released, creating apurinic sites. The latter are converted into DNa chain breaks at physiological pH and temperature. Thus, apurinic sites and DNA chain breaks must be considered as quantitatively important (genotoxic) DNA damage induced by aflatoxins.

Structure-activity relationships in the mutagenicity and cytotoxicity of putative metabolites and related analogs of benzene derived from the valence tautomers benzene oxide and oxepin.

A series of putative metabolites and related analogs of benzene, derived from the valence tautomers benzene oxide and oxepin, was tested for mutagenicity (reversions to histidine prototrophy and forward mutations to resistance to 8-azaguanine) and for cytotoxicity by the Ames Salmonella mutagenicity test. Benzene was not mutagenic in either assay. The benzene oxide-oxepin system and benzene dihydrodiol induced point mutations but not frameshifts. 4,5-sym-Oxepin oxide, which is a putative metabolite of the oxepin valence tautomer; 3,6-diazo-cyclohexane-1,6-3,4-dioxide, a synthetic precursor of sym-oxepin oxide; and transoid-4,11-dioxatricyclo(5.1 0)undeca-1,6-diene, a stable bridge-head diene analog of sym-oxepin oxide, were toxic but not mutagenic in both assays. 4H-Pyran-4-carboxaldehyde, a stable acid catalyzed rearrangement product of sym-oxepin oxide, was not mutagenic and much less cytotoxic than sym-oxepin oxide. Stable analogs of the valence tautomer benzene oxide, namely syn-indan-3a,7a-oxide and syn-2-hydroxyindan-3a,7a-oxide, were mutagenic and induced point mutations. All compounds were cytotoxic to Salmonella. Firstly, the apparent decay times of these chemicals, especially that of sym-oxepin oxide, were surprisingly longer than expected, as judged by quantitative plate diffusion assays. Secondly, it is concluded that if benzene oxide is further metabolized in its oxepin tautomeric form, toxic but not mutagenic products are formed. Thirdly, the relatively weak mutagenicity of benzene oxide may be mainly due to its instability and corresponding low probability to reach intracellular polynucleotide targets, whereas stable analogs of benzene oxide are relatively more potent mutagens.

Promotion of glutathione-gamma-glutamyl transpeptidase-dependent lipid peroxidation by copper and ceruloplasmin: the requirement for iron and the effects of antioxidants and antioxidant enzymes.

Oxidative damage (lipid peroxidation, LPO) induced in a completely defined system containing glutathione (GSH), purified gamma-glutamyl transpeptidase (GGT), and EDTA- and ADP-chelated ferric iron was enhanced by catalytic amounts of cupric ions and by ceruloplasmin (CP). The enhancement depended on GSH concentration, GGT activity, the presence of iron, and the chelation of copper by o-phenanthroline. High concentrations of CP inhibited LPO. Cu- and CP-enhanced, GSH-GGT-driven LPO was inhibited by the chain-breaking radical scavengers butylated hydroxyanisol, alpha-tocopherol, and Trolox C (a synthetic analog of alpha-tocopherol) but not by the hydroxyl scavenger mannitol. Ascorbic acid increased LPO in the presence of Cu or CP. Cu-enhanced LPO was partially sensitive to superoxide dismutase but not to catalase or horseradish peroxidase. The results indicate that Cu and CP enhance thiol-driven LPO and promote thiol-dependent mutagenesis by a very similar, if not the same, mechanism and are in agreement with the idea that this enhancement is due to redox reactions of chelated Cu and Fe, rather than to the reactivity of Cu in the Fenton reaction.

Role of copper and ceruloplasmin in oxidative mutagenesis induced by the glutathione-gamma-glutamyl transpeptidase system and by other thiols.

Glutathione is activated to a mutagen by gamma-glutamyl transpeptidase. Other thiols, such as cysteine, penicillamine, cysteine ethylester, and cysteinylglycine, are direct mutagens in the Ames Salmonella mutagenicity test. Thiol mutagenesis is oxidative in nature and involves H2O2 and possibly hydroxyl radicals. Transition metals are crucial for thiol autoxidation. The role of copper and ceruloplasmin (CP) in thiol-dependent mutagenesis was studied in Salmonella typhimurium strain TA102. Cu and CP at low concentrations enhanced thiol-dependent mutagenesis in the presence, but not in the absence, of added Fe. The degree of enhancement depended on the type of thiol. At high Cu or CP concentrations, thiol mutagenesis was inhibited. Cu also decreased the mutagenicity of H2O2. Cu- and CP-enhanced mutagenesis were inhibited by radical scavengers, catalase, and peroxidase but not by superoxide dismutase. The effects of Cu and CP on thiol-dependent mutagenesis were similar to their effects on thiol-driven lipid peroxidation. The results indicate that the role of Cu and CP in the enhancement of thiol mutagenesis is the facilitation of the transfer of electrons from a thiol to iron, rather than in catalysis of the Fenton reaction.

Gamma-glutamyl transpeptidase-dependent mutagenicity and cytotoxicity of gamma-glutamyl derivatives: a model for biochemical targeting of chemotherapeutic agents.

Many carcinomas in humans are rich in gamma-glutamyl transpeptidase (GGT), a plasma membrane enzyme that reacts with extracellular substrates. Thus, biochemical targeting of chemotherapeutic agents may be achieved by converting anticancer drugs into their gamma-glutamyl derivatives. Chemical conversion of phenylhydrazine (PH) and biochemical modification of daunomycin (DM) into their gamma-glutamyl derivatives gamma-glutamyl phenylhydrazine (GGPH) and gamma-glutamyl DM (GGDM) resulted in the abolishment of their mutagenicity and cytotoxicity, as judged by decreased viability and increased mutant yields in cultures of several Salmonella Ames strains. Commercial gamma-glutamyl-p-nitroanilide (GGPNA) was not toxic or mutagenic. Mutagenicity and/or cytotoxicity of these gamma-glutamyl derivatives were restored upon reaction with GGT, with concomitant release of PH, and p-nitroaniline (PNA). The GGT-dependent release of DM from GGDM was demonstrated by thin layer chromatography (TLC), spectral analysis, and specific mutagenicity. Mutagenicity and/or cytotoxicity of gamma-glutamyl derivatives increased in the presence of glycylglycine, a GGT activator, and decreased in the presence of serine-borate, a GGT inhibitor. GGDM retained considerable DNA binding capacity. Its inability to kill and mutagenize was due to altered transport properties. The results are compatible with the notion that gamma-glutamylation is a feasible method for biochemical targeting of drugs containing a primary amino group to GGT-rich tumors.

Synergism between aflatoxins in covalent binding to DNA and in mutagenesis in the photoactivation system.

Aflatoxins (AFs) produce singlet oxygen upon their exposure to UV (365-nm) light. Singlet oxygen in turn activates them to mutagens and DNA-binding species. DNA binding and mutagenesis by AFs were enhanced in D2O as compared to reactions in H2O, and a singlet oxygen scavenger inhibited mutagenesis. DNA photobinding of 3H-AFB1 increased in the presence of unlabeled AFB2, and the addition of AFB2 enhanced mutagenesis by AFB1 in a synergistic manner. These results are compatible with the notion that singlet oxygen, formed by one aflatoxin molecule, can readily activate another aflatoxin molecule. This may bear an environmental implication in that the weakly carcinogenic AFB2, which is often produced in nature together with AFB1, may be important in enhancing the activation of AFB1 by sunlight.

Mutagenicity and cytotoxicity of the carcinogen-mutagen aflatoxin B1 in Streptococcus pneumoniae (Pneumococcus) and Salmonella typhimurium: dependence on DNA repair functions.

Strains R6, R6x and R6uvr-1 of Streptococcus pneumoniae (Pneumococcus) are sensitive to the cytotoxic effects of the mutagen/carcinogen aflatoxin B1 (AFB1). R6uvr-1 is more prone to the cytotoxic effects of AFB1 than the repair-proficient parental strain, R6. The same differential susceptibility of strains R6, R6x and R6uvr-1 was observed when UV light replaced metabolically activated AFB1. All pneumococcal strains were immutable by AFB1. AFB1 mutagenesis in Salmonella typhimurium strains was dependent on a functional RecA gene product. The enhancing effects of delta uvrB and plasmid pKM101 were found to be additive. Data presented are consistent with the following: (i) AFB1 toxic effects are due mainly to DNA binding of AFB1; (ii) AFB1 mutagenesis is dependent on error-prone DNA repair; (iii) Pneumococcus lacks an active error-prone (SOS) DNA-repair system.

Glutathione mutagenesis in Salmonella typhimurium TA100: dependence on a single enzyme, gamma-glutamyltranspeptidase.

Glutathione was mutagenic in Salmonella typhimurium strain TA100 in the presence of purified mammalian gamma-glutamyltranspeptidase. Glutathione disulfide, gamma-glutamyl glutamic acid, and S-methyl-glutathione were not mutagenic under the same conditions. Glutathione-mediated, gamma-glutamyltranspeptidase-dependent mutagenesis of TA100 cells was inhibited by serine-borate complex, a known gamma-glutamyltranspeptidase inhibitor, and potentiated by glycylglycine, a known gamma-glutamyltranspeptidase enhancer. It is concluded that this enzyme is necessary and sufficient to activate glutathione to a mutagen.

Autoxidation and mutagenicity of sodium bisulfite.

An inverse correlation exists between the autoxidation of bisulfite and its mutagenicity in Salmonella. Temperature, pH, and the addition of mannitol, ethanol, or Oxoid broth affect both autoxidation and mutagenicity. A decrease in autoxidation resulted in an increase in the half-life of the parent compound, bisulfite, and its availability for uptake by the cells, leading to increased mutagenesis. The autoxidation of bisulfite is known to produce both sulfur- and oxygen-centered free radicals. The lack of mutagenicity of ammonium persulfate and peroxymonosulfate, which generate the radicals SO4- and SO5-, respectively, argues against the involvement of these oxygen-centered radicals in bisulfite mutagenesis. Inhibition of mutagenesis by the radical spin-trapping agent, DMPO, is consistent with the hypothesis that the sulfur-centered radical, SO3-, plays an important role in bisulfite mutagenesis. The mechanism of bisulfite mutagenesis suggested in this study may have relevance to other known effects attributed to bisulfite, i.e., co-carcinogenesis and immune hypersensitivity.

Effect of pH on mutagenesis by thiols in Salmonella typhimurium TA102.

The mutagenicity of thiol (SH)-containing compounds was tested in Salmonella typhimurium TA102 in the liquid preincubation method. Cysteinyl-glycine (CG), cysteine ethyl ester (CEE), L- and D-penicillamine (PA), cysteine (Cys) and glutathione (GSH) were mutagenic to strain TA102 without metabolic activation. On a molar basis, CG was the most potent mutagen. The mutagenicity of the remaining compounds decreased in the order specified above. The mutagenic response of each thiol-containing compound was a function of the pKa of the thiol group and the pH of the preincubation mixture. This indicates that a thiolate anion, rather than a free thiol, is required for mutagenesis.

The effects of antioxidants and enzymes involved in glutathione metabolism on mutagenesis by glutathione and L-cysteine.

The effects of small molecular weight antioxidants and antioxidant enzymes on the mutagenicities of glutathione (GSH) and L-cysteine were studied in Salmonella typhimurium strain TA102. GSH and cysteine mutagenesis were inhibited by antioxidants and radical scavengers such as alpha-tocopherol, Trolox C, butylated hydroxyanisole (BHA), and retinyl acetate. Superoxide dismutase (SOD) had no effect, but catalase and horseradish peroxidase (HRP) inhibited mutagenesis. The heat-denatured enzymes had no effect on mutagenesis. Cysteine mutagenesis was enhanced by native and by heat-denatured rat-kidney post-mitochondrial supernatant, and by ferric ions. H2O2 and the H2O2-generating system of glucose-glucose oxidase (GOX) were mutagenic in TA102. Synergistic increases in mutagenesis were obtained in systems containing combinations of GSH or cysteine, with either H2O2 or the H2O2-generating system of glucose-GOX. GSH peroxidase (GPX) had no effect on mutagenesis of GSH or of H2O2, whereas the synergistic increase in mutagenesis by a combination of GSH and H2O2 was effectively inhibited by GPX. The results suggest strongly that, at least in biochemically-defined systems, GSH and cysteine mutagenesis are oxidative in nature, and involve reactive forms of oxygen and/or other radicals.

Frequency multiplexed superconducting quantum interference device readout of large bolometer arrays for cosmic microwave background measurements.

A technological milestone for experiments employing transition edge sensor bolometers operating at sub-Kelvin temperature is the deployment of detector arrays with 100s-1000s of bolometers. One key technology for such arrays is readout multiplexing: the ability to read out many sensors simultaneously on the same set of wires. This paper describes a frequency-domain multiplexed readout system which has been developed for and deployed on the APEX-SZ and South Pole Telescope millimeter wavelength receivers. In this system, the detector array is divided into modules of seven detectors, and each bolometer within the module is biased with a unique ∼MHz sinusoidal carrier such that the individual bolometer signals are well separated in frequency space. The currents from all bolometers in a module are summed together and pre-amplified with superconducting quantum interference devices operating at 4 K. Room temperature electronics demodulate the carriers to recover the bolometer signals, which are digitized separately and stored to disk. This readout system contributes little noise relative to the detectors themselves, is remarkably insensitive to unwanted microphonic excitations, and provides a technology pathway to multiplexing larger numbers of sensors.