A fast radio burst localized to a massive galaxy.

Intense, millisecond-duration bursts of radio waves (named fast radio bursts) have been detected from beyond the Milky Way1. Their dispersion measures-which are greater than would be expected if they had propagated only through the interstellar medium of the Milky Way-indicate extragalactic origins and imply contributions from the intergalactic medium and perhaps from other galaxies2. Although several theories exist regarding the sources of these fast radio bursts, their intensities, durations and temporal structures suggest coherent emission from highly magnetized plasma3,4. Two of these bursts have been observed to repeat5,6, and one repeater (FRB 121102) has been localized to the largest star-forming region of a dwarf galaxy at a cosmological redshift of 0.19 (refs. 7-9). However, the host galaxies and distances of the hitherto non-repeating fast radio bursts are yet to be identified. Unlike repeating sources, these events must be observed with an interferometer that has sufficient spatial resolution for arcsecond localization at the time of discovery. Here we report the localization of a fast radio burst (FRB 190523) to a few-arcsecond region containing a single massive galaxy at a redshift of 0.66. This galaxy is different from the host of FRB 121102, as it is a thousand times more massive, with a specific star-formation rate (the star-formation rate divided by the mass) a hundred times smaller.

Aflatoxin P-1: a new aflatoxin metabolite in monkeys.

A new phenolic derivative of aflatoxin B(1), appearing mainly in conjugated form, was identified as the principal urinary metabolite of aflatoxin B(1) in rhesus monkeys. Its identification in human urine might facilitate estimation of aflatoxin exposure in human populations.

Parathyroid hormone stimulation of renal phosphoinositide metabolism is a cyclic nucleotide-independent effect.

The effects of parathyroid hormone (PTH) and cyclic nucleotides on renal phosphoinositide metabolism were studied using cortical tubules isolated from dog kidneys. PTH stimulated the initial rates of 32Pi incorporation into phosphatidylinositol 4'5'-diphosphate, phosphatidylinositol 4'-monophosphate, phosphatidylinositol and phosphatidic acid. PTH also caused a 45-55% increase in the actual tissue levels of these phospholipids by 5 min of incubation. By 30 min of incubation, the levels of 32Pi incorporated were similar in PTH and control flasks, but the actual levels of the phosphoinositides remained elevated, indicating stimulation of their turnover. Additional evidence of increased turnover of phosphatidylinositol was obtained from tubules pre-incubated with myo-[2-3H]inositol. PTH stimulated a rapid short-lived decrement in [3H]phosphatidylinositol while total phosphatidylinositol levels increased, indicating increased turnover rates of phosphatidylinositol. In tubules pre-incubated with [14C]arachidonic acid, indicating utilization of diacylglycerol produced during turnover for resynthesis of phosphatidic acid and phosphoinositides. Cyclic nucleotides and phosphodiesterase inhibition failed to reproduce the effect of PTH on phosphoinositide metabolism. These studies indicate that PTH stimulates renal phosphoinositide metabolism through a mechanism independent of cAMP which results in a net synthesis of the phosphoinositides.

Teratogen metabolism: activation of thalidomide and thalidomide analogues to products that inhibit the attachment of cells to concanavalin A coated plastic surfaces.

Thalidomide metabolites inhibited the attachment of tumor cells to concanavalin A coated polyethylene surfaces. Thalidomide, itself, was non-inhibitory. Thalidomide activation to inhibitory products required hepatic microsomes, an NADPH-generating system, and molecular oxygen. Production of inhibitory metabolites was unaffected by either epoxide hydrolase or 1,2-epoxy-3,3,3-trichloropropane (TCPO), an inhibitor of epoxide hydrolase endogenous to hepatic S9 fraction. Therefore, the attachment inhibitor was probably not an arene oxide. Inhibition was not accompanied by cytotoxicity, as judged by trypan blue exclusion. Although uninduced hepatic microsomes from mice, rats and dogs had similar abilities to activate thalidomide, microsomes from Aroclor 1254 induced rats were relatively inactive in the system. Inhibitory metabolites were generated from the thalidomide analogues EM8 , EM12 , EM16 , EM87 , EM136 , EM255 , E350 , phthalimide, phthalimido-phthalimide, indan, 1- indanone and 1,3- indandione . Glutarimide , glutamic acid and phthalic acid did not activate to inhibitory products.

Transplantation of unrelated cord blood cells.

A 43-year-old woman with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia in acute phase received high-dose chemotherapy followed by transfusion of 12 randomly selected units of umbilical cord blood. HLA analysis showed cells of one donor from day +10 to day +43 post-transfusion. This unit was HLA class II identical with that of the patient.

Corneal elastosis. Appearance of band-like keratopathy and spheroidal degeneration.

Clinical and pathologic studies of six corneas from patients with band-like keratopathy and spheroid degeneration were performed. These included cases of noncalcific band keratopathy; in one case very early changes in Bowman membrane were demonstrated by light and electron microscopy. Two other corneas displayed more advanced degeneration that manifested clinically as irregular golden yellow plaques. One case of corneal spheroid degeneration was associated with lattice dystrophy of the cornea. The corneal deposits may be best characterized as a form of elastotic degeneration and were associated with intense autofluorescence.

Malignant fibrous histiocytoma of the orbit.

A 31-year-old woman had a mass in the posterior inferior orbit that progressively increased in size for almost two years. Histopathologic examination of an orbital biopsy specimen showed pleomorphic neoplastic cells arranged in a storiform pattern. The tumor cells were composed of hyperchromatic nuclei with prominent nucleoli and admixtures of fibroblasts. Electron microscopy demonstrated histiocyte-like cells with complex infoldings of plasma membrane, prominent mitochondria and golgi, and free ribosomes. Fibroblast-like cells displayed abundant rough endoplasmic reticulum and adjacent collagen fibrils. The diagnosis was malignant fibrous histiocytoma. An exenteration was performed and postoperative systemic chemotherapy with doxorubicin hydrochloride and methotrexate sodium sulfate was commenced. There was no evidence of recurrence two years later.

A new method for the generation and cyclization of iminyl radicals via the Hudson reaction.

[formula: see text] A mild new synthetic procedure has been developed for in situ generation and cyclization of iminyl radicals onto pendant alkenes, followed by functionalization of the resulting carbon radical by one of a variety of trapping reagents. The key process in the method involves production of the iminyl radical via treatment of an aldoxime or ketoxime with readily available 2,6-dimethylbenzenesulfinyl chloride at -50 degrees C to room temperature (Hudson reaction).

A new total synthesis of the marine tunicate alkaloid lepadiformine.

[reaction: see text]. A total synthesis of racemic lepadiformine has been achieved via a route that utilizes as key steps a novel stereocontrolled intramolecular spirocyclization of an allylsilane/N-acyliminium ion and the application of our radical-based methodology for production of N-acylimines from o-aminobenzamides.

Methodology for regioselective synthesis of substituted pyridines via intramolecular oximino malonate hetero Diels-Alder reactions.

[structure] Various substituted pyridines can be prepared regioselectively by a sequence involving an intramolecular thermal or high-pressure Diels-Alder cycloaddition of an oximino malonate dienophile tethered to a dienic carboxylic acid, followed by mild aromatization of the resulting cycloadduct with cesium carbonate in DMF at room temperature.

Juvenile glaucoma associated with goniodysgenesis.

Clinicopathologic studies, including electron microscopy, of trabeculectomy and peripheral iridectomy specimens from three patients with "juvenile" glaucoma revealed varying forms of maldevlopment of the chamber angle in all cases. A 20-year-old white woman (Case 1) had associated iridogoniodysgenesis with a pseudopolycoria-like iris pattern. In a 39-year-old white woman (Case 2), goniodysgenesis was associated with degenerated cell remnants in the angle "cleavage" area. A 15-year-old mentally retarded white boy (Case 3) displayed features of juvenile pigmentary glaucoma with associated goniodysgenesis and megalocornea.

Endothelial alterations in congenital corneal dystrophies.

We studied the clinical and ultrastructural findings in three different types of congenital endothelial dystrophies: hereditary posterior polymorphous dystrophy, congenital hereditary corneal dystrophy, and a nonhereditary congenital endothelial dystrophy. In the first patient, with hereditary posterior polymorphous dystrophy, a layer of epithelial-like cells was observed adjacent to endothelial cells on the posterior corneal surface. Descemet's membrane displayed a multilaminar pattern and consisted of an anterior, thin (3 mu), PAS-positive layer and a posterior, thicker (25 to 30 mu) zone of abnormal collagen. The second patient, with congenital hereditary endothelial dystrophy, showed a thickened multilaminar Descemet's membrane and scant endothelial cells. In the third patient with nonhereditary congenital endothelial dystrophy, the thickened Descemet's membrane was lined posteriorly by a retrocorneal fibrous membrane. A few degenerated endothelial cells were present. All three cases showed 100- to 110-nm banding posteriorly. In these three clinically distinct entities, electron microscopy was useful in demonstrating the unusual form of endothelial transformation to epithelial-like cells in one patient, in contrast to the more common fibroblast-like metaplasia of endothelial cells seen in the other two patients.

Evaluation of increased aqueous outflow after radial keratotomy in enucleated bovine eyes.

PURPOSE: We studied the efficacy of using radial keratotomy incisions as a surgical method of increasing outflow facility in enucleated bovine eyes. METHODS: Each freshly enucleated bovine eye (n = 23) was cannulated to a system measuring the rate of flow into the eyes. Preoperatively, corneal thickness measurements were determined for all treated eyes. Radial keratotomy was performed in 13 eyes and a control set of eyes (n = 10) had no surgical manipulation. The intraocular pressure was set at 16.9 mm Hg. A clear zone of 10 mm was used for each eye with the incision depth set at 100% of the pachymetric reading. One set of experimental eyes had incisions that remained in the clear cornea, and the other set had incisions that reached 2 mm beyond the limbus into sclera. Preoperative outflow measurements were performed on each eye. Postoperative measurements were made after 10 incisions and 20 incisions. All eyes were checked for perforation after surgery and discarded if a perforation was found. RESULTS: No eye included in the analysis was perforated. The preoperative (baseline) total flow rate was 27.90 +/- 3.72 mu 1/min at 16.9 mmHg. The flow rate increased by 23.5% (over baseline) with 20 radial keratotomy incisions. A paired t-test was used to statistically compare the outflow measurements before radial keratotomy and after the first and second set of radial incisions. The increases in flow were found to be statistically significant (P < .005) for both 10 and 20 radial incisions. CONCLUSION: Assuming the flow measurements (flow rate) in these experiments parallel outflow facility, radial keratotomy increases the outflow facility in enucleated bovine eyes.

Matched wideband low-noise amplifiers for radio astronomy.

Two packaged low noise amplifiers for the 0.3-4 GHz frequency range are described. The amplifiers can be operated at temperatures of 300-4 K and achieve noise temperatures in the 5 K range (<0.1 dB noise figure) at 15 K physical temperature. One amplifier utilizes commercially available, plastic-packaged SiGe transistors for first and second stages; the second amplifier is identical except it utilizes an experimental chip transistor as the first stage. Both amplifiers use resistive feedback to provide input reflection coefficient S11<-10 dB over a decade bandwidth with gain over 30 dB. The amplifiers can be used as rf amplifiers in very low noise radio astronomy systems or as i.f. amplifiers following superconducting mixers operating in the millimeter and submillimeter frequency range.

Teratogen metabolism: spontaneous decay products of thalidomide and thalidomide analogues are not bioactivated by liver microsomes.

Thalidomide and two analogues, EM87 and EM12, inhibited the attachment of tumor cells to concanavalin A-coated surfaces only if the drugs were first incubated with hepatic microsomes and cofactors. Most agents that inhibit attachment are demonstrated teratogens. Thalidomide undergoes spontaneous hydrolysis to at least 12 products in saline buffered to a pH of greater than 7. These hydrolysis products did not inhibit attachment nor could they be activated to inhibitory products with hepatic microsomes. Similarly EM12 and EM 87 hydrolysis products were neither inhibitory nor substrates for activation. If the three drugs were incubated in buffered saline, there was a progressive decline in their ability to act as substrates for activation to an inhibitory product. It was possible to remove microsomes from the incubation mixture following drug activation by centrifugation. This microsome-free mixture inhibited cell attachment. When mouse ovarian tumor (MOT) cells were added to the microsome-free mixture, attachment was inhibited. However, if the activated drugs were incubated in saline, there was a progressive decline in their ability to inhibit attachment. Decay rates differed for the three compounds. At a pH of 7.4, thalidomide, EM87, and EM12 required 3 h, 1h and 6h, respectively, to decay to control levels. These relative rates of decay are consistent with the relative teratogenicity of the three drugs.

Teratogen metabolism: thalidomide activation is mediated by cytochrome P-450.

A metabolite of thalidomide generated by hepatic microsomes inhibited the attachment of tumor cells to concanavalin A-coated polyethylene. Evidence that metabolite formation is mediated by microsomal cytochrome P-450 is presented. Microsomes incubated with thalidomide underwent a type I spectral shift. Metabolite formation was reduced or eliminated by carbon monoxide, SKF-525A, metyrapone, and N-octylamine. Superoxide dismutase treatment had no effect. Metabolite formation required microsomes and NADPH and was dependent on the length of 37 degrees C incubation. The metabolite could be isolated by successive hexane and chloroform extractions. It is likely the inhibitory thalidomide metabolite was generated by a minor cytochrome P-450 species. Whether this thalidomide metabolite is involved in the drug's teratogenic activity remains to be shown.

Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (-)-norsecurinine, and phyllanthine.

A new strategy for enantiospecific construction of the Securinega alkaloids has been developed and applied in total syntheses of (+)-14,15-dihydronorsecurinine (8), (-)-norsecurinine (6), and phyllanthine (2). The B-ring and C7 absolute stereochemistry of these biologically active alkaloids originated from trans-4-hydroxy-L-proline (10), which was converted to ketonitrile 13 via a high-yielding eight-step sequence. Treatment of this ketonitrile with SmI2 afforded the 6-azabicyclo[3.2.1]octane B/C-ring system 14, which is a key advanced intermediate for all three synthetic targets. Annulation of the A-ring of (-)-norsecurinine (6) with the required C2 configuration via an N-acyliminium ion alkylation was accomplished using radical-based amide oxidation methodology developed in these laboratories as a key step, providing tricycle 33. Annulation of the D-ring onto alpha-hydroxyketone 33 with the Bestmann ylide 45 at 12 kbar gave (+)-14,15-dihydronorsecurinine (8). In the securinine series, the D-ring was incorporated using an intramolecular Wadsworth-Horner-Emmons olefination of phenylselenylated alpha-hydroxyketone 47. The C14,15 unsaturation was installed late in the synthesis by an oxidative elimination of the selenoxide derived from tetracyclic butenolide 50 to give (-)-norsecurinine (6). The A-ring of phyllanthine (2) was formed from hydroxyketone 14 using a stereoselective Yb(OTf)3-promoted hetero Diels-Alder reaction of the derived imine 34 with Danishefsky's diene, affording adduct 35. Conjugate reduction and stereoselective equatorial ketone reduction of vinylogous amide 35 provided tricyclic intermediate 36, which could then be elaborated in a few steps to stable hydroxyenone 53 via alpha-selenophenylenone intermediate 52. The D-ring was then constructed, again using an intramolecular Wadsworth-Horner-Emmons olefination reaction to give phyllanthine (2).