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.

Genetic characteristics of the HeLa cell.

The genotype of the patient Henrietta Lacks from whose cervical carcinoma the HeLa cell was derived was deduced from the phenotypes of her husband and children, and from studies of the HeLa cell. Hemizygous expression of glucose-6-phosphate dehydrogenase in HeLa, together with the deduced heterozygosity of Mrs. Lacks, is consistent with clonal origin of her neoplasm.

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.

Identification and characterization of a gene regulating enzymatic glycosylation which is induced by diabetes and hyperglycemia specifically in rat cardiac tissue.

Primary cardiac abnormalities have been frequently reported in patients with diabetes probably due to metabolic consequences of the disease. Approximately 2,000 mRNA species from the heart of streptozotocin-induced diabetic and control rats were compared by the mRNA differential display method, two of eight candidate clones thus isolated (DH1 and 13) were confirmed by Northern blot analysis. The expression of clone 13 was increased in the heart by 3.5-fold (P < 0.05) and decreased in the aorta by twofold (P < 0.05) in diabetes as compared to control. Sequence analysis showed that clone 13 is a rat mitochondrial gene. DH1 was predominantly expressed in the heart with an expression level 6.8-fold higher in the diabetic rats than in control (P < 0.001). Insulin treatment significantly (P < 0.001) normalized the expression of DH1 in the hearts of diabetic rats. DH1 expression was observed in cultured rat cardiomyocytes, but not in aortic smooth muscle cells or in cardiac derived fibroblasts. The expression in cardiomyocytes was regulated by insulin and glucose concentration of culture media. The full length cDNA of DH1 had a single open-reading frame with 85 and 92% amino acid identity to human and mouse UDP-GlcNAc:Gal beta 1-3GalNAc alpha R beta 1-6 N-acetylglucosaminyltransferase (core 2 GlcNAc-T), respectively, a key enzyme determining the structure of O-linked glycosylation. Transient transfection of DH1 cDNA into Cos7 cells conferred core 2 GlcNAc-T enzyme activity. In vivo, core 2 GlcNAc-T activity was increased by 82% (P < 0.05) in diabetic hearts vs controls, while the enzymes GlcNAc-TI and GlcNAc-TV responsible for N-linked glycosylation were unchanged. These results suggest that core 2 GlcNAc-T is specifically induced in the heart by diabetes or hyperglycemia. The induction of this enzyme may be responsible for the increase in the deposition of glycoconjugates and the abnormal functions found in the hearts of diabetic rats.

Glucose activation of liver glycogen synthase. Insulin-mediated restoration of glucose effect in diabetic rats is blocked by protein synthesis inhibitor.

The loss of glucose regulation of glycogen synthase in perfused livers from diabetic rats was associated with a substantial reduction in synthase phosphatase activity. Treatment of diabetic rats with insulin alone resulted in total restoration of the glucose effect and synthase phosphatase activity, while simultaneous treatment with cycloheximide severely reduced the hormonal effect. Although treatment of normal rats with cycloheximide had no effect on glucose activation of synthase, it did result in severe depletion of liver glycogen, increased liver glycogen phosphorylase activity, and elevation of liver adenosine 3',5'-monophosphate (cyclic AMP), but without elevation of liver protein kinase activity. Simultaneous treatment of alloxan-diabetic rats with insulin and cycloheximide resulted in reduction of total liver glycogen, increased phosphorylase activity, a reduction in the ability of insulin to lower hepatic cyclic AMP, and a further reduction of protein kinase activity. In summary, the effect of insulin treatment of diabetic rats to restore glucose regulation of hepatic glycogen synthase probably involves synthesis of new protein, and the data remain consistent with the hypothesis that the defect may be due to a diabetes-related deficiency in a specific synthase phosphatase and/or alteration of the synthase molecule itself.

Cyclic AMP-mediated activation of hepatic glycogenolysis by fructose.

Isolated livers from fed and fasted rats were perfused for 30 min with recirculating blood-buffer medium containing no added substrate and then switched to a flow-through perfusion using the same medium for an additional 5, 10 and 30 min. Continuous infusion of fructose for the final 5, 10 or 30 min resulted in activation of glycogen phosphorylase, an increase in the activity of protein kinase, elevated levels of tissue adenosine 3', 5'-monophosphate (cyclic AMP), and no consistent effect on glycogen synthase. Infusion of glucose under the same conditions resulted in activation of glycogen synthase, inactivation of glycogen phosphorylase, no change in protein kinase, and no consistent change in tissue cyclic AMP. These results demonstrate that while glucose promotes hepatic glycogen synthesis, fructose promotes activation of the enzymatic cascade responsible for glycogen breakdown.

Adenosine 3',5'-monophosphate-dependent protein kinase(s) in diploid and SV40 transformed human fibroblasts.

Cyclic AMP-dependent protein kinases (EC 2.7.1.37; ATP:protein phosphotransferase) in the human diploid fibroblast WI-38 and an SV40-transformant WI-38-VA13-2RA (VA13) have been compared on the basis of their concentrations in cells, isoenzyme composition and susceptibility to hormonal activation. In high population density cultures, total soluble cyclic AMP-dependent kinase activities measured with histone were essentially the same in WI-38 and VA13. Two soluble protein kinase forms separated by chromatography on DEAE-cellulose were present in both cell lines. The concentration of cyclic AMP required for half-maximal activation of both enzyme forms was 10-30 nM. Overall kinase stimulation was greater for the Peak I enzymes. Kinase activation induced in the presence of 0.5 M KCl was more rapid and complete for the Peak I enzymes. Under conditions which elevated the concentration of cyclic AMP in WI-38 and VA13 cells the activities of the soluble histone kinases were increased. Incubation of the cells with either of 5.7 micronM prostaglandin E1 or 1 micronM isopropylnorepinephrine induced complete activation of the cyclic AMP-dependent histone kinases within 5 min and maintained the effect for 20 min. When intracellular cyclic AMP levels were raised by prostaglandin E1, activation of glycogen phosphorylase (assayed-AMP) suggested that this enzyme cascade involving cyclic AMP-dependent protein kinase(s) was intact and responsive in both cell lines.

Phosphorylation of rat heart glycogen synthase: studies in cardiomyocytes and in vitro phosphorylations with cAMP-dependent kinase and protein phosphatase-1.

The phosphorylation of glycogen synthase has been studied in freshly isolated adult rat cardiomyocytes. Six peaks of 32P-labeled tryptic peptides are recovered via C-18 high performance liquid chromatography (HPLC) when synthase is immunoprecipitated from 32P-labeled cardiomyocytes and digested with trypsin. When epinephrine treated cells are used as a source of enzyme, the same HPLC profile is obtained with a dramatic enhancement of 32P recovered in two of the HPLC peaks. In vitro phosphorylation of rat heart synthase by cAMP-dependent protein kinase stimulates the conversion of synthase from the I to the D form and results in the recovery of the same tryptic peptides from the C-18 as is the case for synthase derived from cardiomyocytes. Treatment of cAMP-dependent kinase phosphorylated synthase with protein phosphatase-1 leads to a reactivation of the enzyme and a dephosphorylation of the same tryptic peptides that are selectively phosphorylated in epinephrine treated cardiomyocytes. These results are discussed in relation to hormonal control of glycogen metabolism in cardiac tissue.

Cyclic GMP accumulation in normal and diabetic primary culture adult rat ventricular cardiomyocytes: a minor role for nitric oxide in phosphorylase activation.

The potential role of nitric oxide in the diabetes-induced hypersensitive activation of glycogen phosphorylase by epinephrine was investigated in adult rat ventricular cardiomyocytes. Pretreatment of normal and diabetic-derived cells with 1 mM sodium nitroprusside significantly diminished the phosphorylase activation response by nearly 20% in both normal and diabetic myocytes but failed to alter the hypersensitivity of the diabetic cells. Nitroprusside increased cGMP levels in both normal and diabetic myocytes although the effect was more pronounced in the diabetic cells. Epinephrine did not alter cellular cGMP content and cGMP levels were consistently lower in diabetic myocytes when compared with normal myocytes. Preincubation of ventricular myocytes with the nitric oxide synthase inhibitor L-iminoethyl ornithine did not affect phosphorylase activation. These data indicate that nitric oxide plays a minor role in phosphorylase activation by epinephrine in rat cardiomyocytes and suggest that signal transduction via nitric oxide is not affected by the onset of diabetes.

Sequence homologies between type 1 and type 2A protein phosphatases.

The Mr = 33,000 catalytic fragment of rabbit skeletal muscle type 1 protein phosphatase was digested with trypsin after reduction and alkylation. The resulting peptides were isolated, subjected to automated Edman degradation, and their sequences compared to the deduced peptide sequence of the bovine type 2A protein phosphatase cDNA. Of 10 tryptic peptides from the type 1 phosphatase that were sequenced, nine showed a high degree of homology with the type 2A phosphatase. This provides the first direct sequence comparison suggesting that the type 1 and type 2 protein phosphatases, distinguished functionally by their substrate specificities and sensitivity to inhibitors, make up part of a family of closely related gene products with similar structures.

Isolation of partial cDNAs for rat liver and muscle glycogen phosphorylase isozymes.

cDNA clones for the rat liver and muscle glycogen phosphorylase isozymes have been isolated using isozyme-selective antibodies and libraries prepared in the expression vector, lambda gt11. A 1.2 kb cDNA coding for the carboxy-terminal domain of rat liver phosphorylase was found to have 82% homology with the amino acid sequence of rabbit muscle phosphorylase. Limited sequencing of rat muscle phosphorylase cDNA indicated a 95% homology with the rabbit muscle enzyme. The rat liver clone has eight additional amino acid residues at the COOH-terminus compared to the rat muscle clone. Furthermore, 17 of 26 (65%) residues between amino acids 815-840 differ between liver and muscle isozymes. The similarity in enzymatic properties and conservation of structure except at the COOH-terminus suggest that the liver and muscle phosphorylase isozymes do not exist in order to have significant differences in the regulation of glycogen breakdown in the two tissues. Rather, the phosphorylase isozymes probably evolved for tissue-specific transcriptional regulation of the genes in liver and muscle.

Adverse effects of fructose in perfused livers of diabetic rats.

Livers isolated from both fed normal and alloxan diabetic rats were perfused for 30 min using Krebs-Henseleit bicarbonate blood buffer medium followed by 10 min flow-through infusions with either 5 mM or 28 mM fructose concentrations. In livers of normal and diabetic rats, both 5 mM and 28 mM fructose concentrations produced an elevation in tissue cyclic AMP levels, activation of glycogen phosphorylase, increased protein kinase activity, decreased tissue ATP levels, large increases in tissue fructose-1-phosphate, and variable effects upon glycogen synthase. These results are consistent with previously reported cyclic AMP mediated activation of glycogen phosphorylase by fructose via protein kinase in normal rat liver. In addition, both 5 mM and 28 mM fructose infusion resulted in large decreases in normal and diabetic synthase phosphatase activity. Therefore, these results in both normal and diabetic livers are inconsistent with a direct beneficial effect of fructose in the isolated perfused rat liver.

A field evaluation of pro-benzimidazole, benzimidazole, and non-benzimidazole anthelmintics in horses.

The effectiveness of 1 pro-benzimidazole (pro-BZD) drug, 3 benzimidazole (BZD) drugs, and 3 non-benzimidazole (non-BZD) drugs in keeping fecal egg counts below 50 eggs per gram 2 and 4 weeks after treatment at 6-week intervals was compared in groups of brood mares and yearlings at 2 Standardbred farms. In a preliminary study (December 1978 to April 1979) as well as major study (April to November 1979), horses were kept in the same groups in the same areas. In the major study, treatments were arranged in a Latin square design. On farm 1, which had a history of repeated use of BZD drug since 1964, the non-BZD drugs, dichlorvos and pyrantel pamoate, rated 83%-100% in their ability to suppress egg counts below 50 eggs per gram. They were significantly better (P less than 0.05) than pro-BZD (febantel) or BZD (cambendazole, fenbendazole, mebendazole) drugs, which rated 13%-58%. Phenothiazine-piperazine-carbon disulfide rated 60%-77% on farm 1 and also was significantly better (P less than 0.05) than pro-BZD or BZD drugs. On farm 2, which had a history of limited use BZD drugs, there was no significant difference between the 3 classes of anthelmintics, which all rated between 67% and 100%. Results of larval culture showed small strongyles to be the major source of high egg counts. In all groups of horses, irrespective of the treatment, there was a marked increase in fecal egg counts by 6 weeks after treatment.

Fenbendazole for treatment of Paragonimus kellicotti infection in dogs.

The effect of fenbendazole therapy was studied in 9 dogs with pulmonary paragonimiasis induced by inoculation of metacercariae (25/dog) of Paragonimus kellicotti. At 42 to 47 days after 6 dogs were inoculated, they were given fenbendazole in 2 divided doses totaling 50 mg (4 dogs) or 100 mg (2 dogs)/kg of body weight each day for 10 to 14 days. Three dogs were not treated. The passage of Paragonimus eggs in the feces ceased after 3 days at the high dosage and after 3 to 8 days at the low dosage. All dogs were euthanatized and necropsied on day 14. Live flukes were not recovered from the lungs of any treated dog, but 15, 19, and 23 live flukes were recovered from the untreated dogs.