Suppression of black-hole growth by strong outflows at redshifts 5.8-6.6.

Bright quasars, powered by accretion onto billion-solar-mass black holes, already existed at the epoch of reionization, when the Universe was 0.5-1 billion years old1. How these black holes formed in such a short time is the subject of debate, particularly as they lie above the correlation between black-hole mass and galaxy dynamical mass2,3 in the local Universe. What slowed down black-hole growth, leading towards the symbiotic growth observed in the local Universe, and when this process started, has hitherto not been known, although black-hole feedback is a likely driver4. Here we report optical and near-infrared observations of a sample of quasars at redshifts 5.8 ≲ z ≲ 6.6. About half of the quasar spectra reveal broad, blueshifted absorption line troughs, tracing black-hole-driven winds with extreme outflow velocities, up to 17% of the speed of light. The fraction of quasars with such outflow winds at z ≳ 5.8 is ≈2.4 times higher than at z ≈ 2-4. We infer that outflows at z ≳ 5.8 inject large amounts of energy into the interstellar medium and suppress nuclear gas accretion, slowing down black-hole growth. The outflow phase may then mark the beginning of substantial black-hole feedback. The red optical colours of outflow quasars at z ≳ 5.8 indeed suggest that these systems are dusty and may be caught during an initial quenching phase of obscured accretion5.

Intestinal microflora are necessary for development of spontaneous adenocarcinoma of the large intestine in T-cell receptor beta chain and p53 double-knockout mice.

This study was conducted to confirm the hypothesis that intestinal microflora are required for the development of adenocarcinoma in the colon of the TCRbeta and p53 double-knockout (TCRbeta-/- p53-/-) mouse. Germ-free TCRbeta-/- p53-/- mice were produced. At 7 weeks of age, the animals were divided into two groups (n = 10/group), and one of these groups was conventionalized. Animals of both groups were subjected to histopathological examination for adenocarcinoma of the colon at 4 months of age. There was no development of adenocarcinoma of the colon among the germ-free mice, whereas in the conventionalized group, adenocarcinomas of the ileocecum and cecum were detected in 70% of animals. These results indicate the usefulness of the TCRbeta-/- p53-/- mouse as a colon cancer animal model that develops spontaneous adenocarcinoma of the colon early in life, and suggest that intestinal microflora play a major role in the development of adenocarcinoma of the colon in this animal model.

A new meiotic endonuclease from Coprinus meiocytes.

Two different types of Coprinus meiotic nuclease have been previously reported by the authors which are believed to be involved in meiotic chromosome recombination [1,2]. A third meiotic endonuclease was purified from the cap tissues of the basidiocarp of Coprinus cinereus. The enzyme is a 60 kDa molecule composed of a monopolypeptide as revealed by SDS-PAGE and FPLC-Sephacryl S-300 gel filtration. The enzyme belongs to a type of endonuclease which can preferentially digest single-stranded DNA and requires divalent cations as a co-factor, most commonly Mg2+ ions. In the presence of this co-factor, the enzyme converts the supercoiled plasmid DNA (form I) to both the relaxed form (form II) and the linear form (form III). Ca2+ ions can also function as a co-factor, though, in this case, not only is form I plasmid converted to form II, but a few ladder bands between form I and form II are also produced. The Ca2+ ion effect as a cofactor can be prevented with ATP. Immunohistochemical observation shows that the enzyme is distributed in the surface of the gills, which contain the meiotic tissues. These characteristics clearly differ from those of the meiotic nucleases reported previously.

Fatty acids selectively inhibit eukaryotic DNA polymerase activities in vitro.

The in vitro relationship between eukaryotic DNA polymerases and fatty acids was investigated. Some fatty acids strongly inhibited the activities of DNA polymerase alpha and/or beta in vitro. The kinetics of inhibition by linoleic acid showed that DNA polymerase alpha was non-competitively inhibited with respect to the DNA template and substrate (dTTP), while DNA polymerase beta was inhibited competitively with both DNA and substrate.

Specific species of intestinal bacteria influence the induction of aberrant crypt foci by 1,2-dimethylhydrazine in rats.

To shed light on the association of intestinal microflora with the development of colon cancer, we studied the modifying effects of intestinal microflora on the occurrence of 1,2-dimethylhydrazine (DMH)-induced colonic aberrant crypt foci (ACF) in germfree (GF), gnotobiotic (GB) and conventionalized (Cvd) rats. In the first part of this study, 10 week old germfree Fischer-344 rats were randomly assigned to three groups and two groups of rats were orally inoculated with mixtures of pure culture of Escherichia coli, Enterococcus faecium, and several strains of Bacteroides and Clostridium species (GB), or feces from conventional rats (Cvd). Inoculated rats were given two weekly i.p. injections of DMH (20 mg/kg body wt) at 13 and 14 weeks of age. Rats were sacrificed 11 or 34 weeks after the last DMH injection for ACF scoring. The total number of ACF, ACF with four or more crypts/focus, and mean number of aberrant crypts per focus (crypt multiplicity) in GB rats sacrificed at week 34 were 168% (P < 0.001), 442% (P < 0.001) and 138% (P < 0.001) of those in GF rats, respectively. On the other hand, the same values in Cvd rats were 42% (P < 0.001), 147% (P = 0.246) and 159% (P < 0.001) of those in GF rats, respectively. Similar results were observed in rats that were sacrificed at week 11. In the second part of this study, the effect of colonization of Bifidobacterium breve on the ACF profiles was examined in GB rats. The number of ACF with four or more crypts/focus and crypt multiplicity in GB plus B. breve rats at week 11 were significantly lower than those of GB rats (P < 0.01, and P < 0.05, respectively), although the former was not statistically significant at week 34. These findings suggest that some intestinal bacteria might behave as promoters and some as anti-promoters in colon carcinogenesis.

Intravenous cyclosporine and tacrolimus caused anaphylaxis but oral cyclosporine capsules were tolerated in an allogeneic bone marrow transplant recipient.

A Japanese female patient with angioimmunoblastic T cell lymphoma underwent allogeneic bone marrow transplantation (BMT) from her brother. Cyclosporine at a dose of 3 mg/kg was started by continuous infusion over 24 h on day -1 of BMT. Within a couple of minutes after the infusion was begun, she developed diffuse pruritic erythema on her whole body and tachycardia. The infusion was immediately stopped and corticosteroid was given, resulting in disappearance of the erythema gradually. She was then switched to intravenous tacrolimus. However, she suffered urticalial erythema again. Since polyoxyethylated castor oil, a solubilizer used in the injective formulation of both cyclosporine and tacrolimus, is considered to be responsible for the reaction, she was given oral capsules of cyclosporine (Sandimmun) in which polyoxyethylated castor oil was not contained. No further anaphylactic reaction was observed. The BM cells were successfully engrafted without causing severe GVHD. She was discharged on cyclosporine capsules without any further adverse effects. Anaphylaxis to intravenous cyclosporine and tacrolimus is a very rare but a serious complication. Our present case indicates that oral capsule of Sandimmun is a safe alternative to prevent GVHD in such a case of anaphylactic reaction against intravenous formulation.

Sex-dependent toxicity of a novel acyl-CoA:cholesterol acyltransferase inhibitor, YIC-C8-434, in relation to sex-specific forms of cytochrome P450 in rats.

YIC-C8-434 is a novel inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT). To clarify the toxicity of YIC-C8-434, the compound was given orally to Sprague-Dawley rats for 28 days at 0, 4, 20, 100, or 500 mg/kg/day. The toxicity of the drug differed significantly between male and female rats. In female rats treated at 500 mg/kg, many symptoms including moribund condition, suppression of weight gain and food consumption, abnormal blood chemistry, and decreases in organ weights (thymus, ovaries, and uterus) were observed. In male rats by contrast, no significant toxicity was observed at any dose. After a single administration of YIC-C8-434 at 500 mg/kg, female rats had a higher blood concentration of the compound than male rats. Little elimination of YIC-C8-434 was observed in female rats on analysis of drug-elimination kinetics. Furthermore, the metabolism of YIC-C8-434 was analyzed using rat hepatic microsomal preparations from both sexes. Consistent with the observations in vivo, hepatic microsomes from male rats better metabolized YIC-C8-434 than those from females. In addition, the metabolism of YIC-C8-434 by hepatic microsomes from male rats was blocked by SKF525A, a P450 inhibitor. Inhibition experiments using anti-rat CYP1A1, CYP1A2, CYP2B1, CYP2C11, CYP2E1, CYP3A2, and CYP4A1 antisera indicated that CYP3A2 played the predominant role in the metabolism of YIC-C8-434 in rats. Since there is less CYP3A2 in the liver of female than male rats, the involvement of CYP3A2 in YIC-C8-434 metabolism has implications for the sex-related metabolic activity and toxicity of YIC-C8-434.

Modified irinotecan hydrochloride (CPT-11) administration schedule improves induction of delayed-onset diarrhea in rats.

PURPOSE: Clinically, diarrhea is the major dose-limiting toxicity of irinotecan hydrochloride (CPT-11). Using a rat model, we attempted to decrease the incidence of delayed-onset diarrhea by modifying the administration schedule of CPT-11, and studied the pharmacokinetics in this model in relation to the incidence of diarrhea. METHODS: CPT-11 (total dose, 240 mg/kg) was administered intravenously (i.v.) to rats according to various schedules, and the incidence of delayed-onset diarrhea was monitored. RESULTS: Administration of CPT-11 at a dose of 60 mg/kg once daily for four consecutive days induced severe diarrhea, while at 30 mg/kg twice daily at an interval of 9 h (daily dose 60 mg/kg) for four consecutive days alleviated the diarrheal symptoms, and at 30 or 40 mg/kg once daily for eight or six consecutive days, respectively. diarrhea was hardly induced. With the first schedule, mucosal impairment of the cecal epithelium was observed, including wall thickening, edema, decrease in crypt number and size, and formation of pseudomembrane-like substance, whereas these changes were less severe with the second schedule and were hardly observed with the other two schedules. The areas under the plasma and cecal tissue concentration-time curves (AUCpla and AUCcec), the maximum plasma concentrations (Cmax) and the biliary excretions of CPT-11 and its metabolites, 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) in rats depended on the daily dose of CPT-11. Exceptionally, CPT-11 Cmax was significantly lower and SN-38 AUCcec was larger in the animals treated at 30 mg/kg twice daily than in those treated at 60 mg/kg once daily. CONCLUSION: These results suggested that the duration of exposure to both CPT-11 and SN-38 of the intestinal epithelium and CPT-11 plasma Cmax are closely related to the incidence and severity of CPT-11-induced delayed-onset diarrhea in rats.

A Reovirus Causes Hypovirulence of Rosellinia necatrix.

ABSTRACT White root rot, caused by Rosellinia necatrix, is a serious soilborne disease of fruit trees and other woody plants. R. necatrix isolate W370 contains 12 segments of double-stranded RNA (dsRNA) that is believed to represent a possible member of the family Reoviridae. W370 was weakly virulent and its hyphal-tip strains became dsRNA free and strongly virulent. The 12 segments of W370dsRNA were transmitted to hygromycin B-resistant strain RT37-1, derived from a dsRNA-free strain of W370 in all or none fashion through hyphal contact with W370. The W370dsRNA-transmitted strains were less virulent than their parent strain RT37-1 on apple seedlings, with mortality ranging between 0 to 16.7% in apple seedlings that were inoculated with the W370dsRNA-containing strains and 50 to 100% for seedlings inoculated with the dsRNA-free strains. Some W370dsRNA-containing strains killed greater than 16.7% of seedlings, but these were found to have lost the dsRNA in planta. These results indicate that W370dsRNA is a hypovirulence factor in R. necatrix. In addition, a strain lost one segment (S8) of W370dsRNA during subculture, and the S8-deficient mutant strain also exhibits hypovirulence in R. necatrix.

Ganglioneuroma: computed tomography and magnetic resonance features.

12 patients who had histological proven ganglioneuromas were investigated by computed tomography (CT) and magnetic resonance (MR) imaging. CT scans (n = 11), conventional spin-echo MR images (n = 10) and dynamic MR images (n = 5) were acquired. All lesions showed a well defined, oval shape. Five lesions (42%) showed calcification which was punctate in four and coarse in one on CT. CT attenuation was predominantly low in three of 10 (30%) and intermediate in the remaining seven (70%). In all lesions MR signals were mainly of low intensity on T1 weighted images (T1WI) and of high intensity on T2 weighted images (T2WI). Dynamic MR studies in five cases showed a lack of early enhancement but gradual increasing enhancement. One case had a ganglioneuroblastoma component which showed soft-tissue density and coarse calcifications on CT scans, MR images with intermediate intensity on T1WI and T2WI and early enhancement and little washout on dynamic MR images. In conclusion, ganglioneuroma typically shows punctate calcification and low attenuation on CT and marked hyperintensity on T2WI with gradual increasing enhancement on dynamic MR images. If a ganglioneuroma has atypical CT and MR features, coexistence of a malignant component should be considered.

Comedogenicity of squalene monohydroperoxide in the skin after topical application.

The comedogenicity of squalene peroxides was examined on the rabbit ear skin after topical application of squalene-monohydroperoxide (Sq-OOH), the initial product when squalene was irradiated with UV-A. Since comedogenic products from UV-irradiated squalene were extracted with methanol solution, we isolated Sq-OOH by reverse-phased HPLC with a methanol mobile phase solvent. The degree of comedogenic reaction induced by Sq-OOH was higher than that of well-known comedogenic cosmetic ingredients. Unlike two other mono-peroxides, tert-butyl hydroperoxide and cumene-mono-hydroperoxide, Sq-OOH induced comedo-formation in the rabbit ear skin. However, the comedogenicity of reduced Sq-OOH, squalene-hydroxide (Sq-OH) and squalene itself was lower than that of Sq-OOH. These results indicate that Sq-OOH is a potent comedogenic mono-hydroperoxide chemical to rabbit skin.

No toxicity caused by organ accumulation of CPT-11 on multiple injections under clinical regimens in rats.

We investigated the accumulation of CPT-11 and its metabolite (SN-38) in various organs and toxicities on multiple injections of CPT-11 under clinical regimens in SD rats. CPT-11 (16.7 mg/kg equivalent to 100 mg/m2) was administered intravenously by a single injection, or by multiple injections in 1 course (once a week for three consecutive weeks) or 3 courses (1 course repeated 3 times at intervals of 2 weeks). There was no tendency for CPT-11 and SN-38 to accumulate in any organs regardless of the number of injections. Treatment-related changes were not observed in the general condition, body weight, hematology, biochemistry, and organ weights. Histopathological changes induced by CPT-11 were not persistent and the rats made a rapid recovery after the administrations. From these results, it is suggested that there is no toxicity caused by accumulation of CPT-11 and its active metabolite, SN-38, in organs under clinical regimens in rats.

A mucinous histochemical study on malignancy of aberrant crypt foci (ACF) in rat colon.

The relationship between malignancy and number of crypts (crypt multiplicity) comprising aberrant crypt foci (ACF) was investigated, by studying changes in the mucous nature of ACF with 5 crypts or less, ACF with 6-13 crypts, adenomas and invasive adenocarcinomas induced by 1,2-dimethylhydrazine in distal colon of rats. A paradoxical Con A-staining was performed for goblet cell mucins. Of the sulfomucin-dominant ACF with 1-3 crypts, 82.6% had labile class III mucin, similar to the distal colon in the normal rats. However, in most of the goblet cell mucin produced by the ACF with 4-5 crypts with an indicated relation to colorectal carcinoma or the sialomucin (SiM) -dominant ACF with 1-3 crypts, mucin types other than class I were rarely present. The incidence of class I mucin decreased with the increase in crypt multiplicity of ACF or in the degree of histological malignancy, with the lowest incidence of 40% in adenocarcinomas. In contrast, the incidence of class II mucin increased markedly with the increase in crypt multiplicity of ACF or in the degree of histological malignancy, with the highest incidence in adenocarcinomas (95%). The ACF with 6-13 crypts had a mucous profile similar to that of adenomas. These results suggested that malignancy of ACF related to the crypt multiplicity. In the ACF with 1-3 crypts, SiM-dominant ACF had the potential to progress to malignant lesions.

A one-generation reproduction toxicity study in rats treated orally with a novel galacto-oligosaccharide.

Galacto-oligosaccharide (GOS) is a naturally occurring prebiotic that beneficially affects the host by selectively stimulating growth and/or activity of one or a limited number of colon bacteria to improve host health. A novel GOS was administered by gavage to male and female Sprague Dawley rats at 0, 500, 1000, and 2000 mg/kg/day for 10 weeks. In males, administration of GOS was initiated prior to mating and continued for 91 days. Females received GOS beginning 2 weeks prior to mating through day 20 of lactation. Parents were observed daily, and body weight (BW) and feed consumption were measured. Vaginal smears, mating behavior, and observation of delivery/lactation were evaluated in parents. Effects on the reproductive function of parents including gonad function, estrous cycle, mating performance, fertility, delivery and lactation, and effects on the growth and development of pups were examined. No deaths occurred, and no general toxicological effects or abnormal reproductive functions were observed in any dose group. Pups were observed at birth and the following measurements were undertaken: BW, external differentiations, sensory functions, and reflex reactions during lactation and just prior to necropsy. No external malformations or differences in the number of pups, in the sex ratio, or BW at birth occurred in any dose group. Growth and development of pups were normal. The No Observed Effect Level for reproductive function of male and female parent animals and for the growth and development of their offspring was at least 2000 mg/kg/day.

A 6-week oral gavage toxicity study of a novel galacto-oligosaccharide in juvenile rats.

A novel galacto-oligosaccharide (GOS) was administered by gavage to groups (10 males and 10 females) of Sprague-Dawley specific pathogen-free rats for 6 weeks from day 4 after birth at doses of 0, 500, 1000, or 2000 mg/kg/day. Each pup was subjected to a variety of observations to examine for development effects/changes after birth: general condition, clinical signs, functional examinations, grip strength and spontaneous movement, body weight and feed consumption, external differentiation, ophthalmological examination, urinalysis (including water consumption), hematology, blood chemistry, necropsy, organ weight, and histopathology. During the study period, no deaths occurred in any group and there were no observed effects from administration of GOS. Therefore, it was concluded that GOS had no effects on the development of animals 4 days after birth. Since, there were no abnormalities due to administration of GOS in the macroscopic examination, organ weight or histopathology of the reproductive organs or differentiation (incisor eruption and eyelid opening) of males or females, it was concluded that repeated oral administration of GOS at 2000 mg/kg/day for 6 weeks from day 4 after birth had : no effects on postnatal development. The no observed effect level of GOS by repeated oral administration for 6 weeks from day 4 after birth was 2000 mg/kg/day for both males and females under the conditions of this study.