The current standard model of cosmology successfully describes a variety of measurements, but the nature of its main ingredients, dark matter and dark energy, remains unknown. Euclid is a medium-class mission in the Cosmic Vision 2015-2025 programme of the European Space Agency (ESA) that will provide high-resolution optical imaging, as well as near-infrared imaging and spectroscopy, over about 14,000 deg^2 of extragalactic sky. In addition to accurate weak lensing and clustering measurements that probe structure formation over half of the age of the Universe, its primary probes for cosmology, these exquisite data will enable a wide range of science. This paper provides a high-level overview of the mission, summarising the survey characteristics, the various data-processing steps, and data products. We also highlight the main science objectives and expected performance.

The interaction between radio-jets and quasar host galaxies plays a paramount role in quasar/galaxy co-evolution. However, very little has been known so far about this interaction at very high-z. Here, we present new Atacama Large Millimeter/submillimeter Array (ALMA) observations in Band 7 and Band 3 of six radio-loud quasars' host galaxies at $z > 5$. We recover [CII] 158 $\mu$m line and underlying dust continuum emission at $>2\sigma$ for five sources, while we obtain upper limits for the CO(6-5) emission line and continuum for the remaining source. At the spatial resolution of our observations ($\sim$1.0"-1.4"), we do not recover perturbed/extended morphologies or kinematics, signatures of potential mergers. These galaxies already host large quantities of gas, with [CII]-based star formation rates of $30-400 M_{\odot} $yr$^{-1}$. Building their radio/sub-mm spectral energy distributions (SEDs), we find that in at least four cases the 1mm continuum intensity arises from a combination of synchrotron and dust emission, with an initial estimation of synchrotron contribution at 300 GHz of $\gtrsim$10%. We compare the properties of the sources inspected here with a large collection of radio-quiet sources from the literature, as well as a sample of radio-loud quasars from previous studies, at comparable redshift. We recover a potential mild decrease in $L_{\rm [CII]}$ for the radio-loud sources, which might be due to a suppression of the cool gas emission due to the radio-jets. We do not find any [CII]-emitting companion galaxy candidate around the five radio-loud quasars observed in Band 7: given the depth of our dataset, this result is still consistent with that observed around radio-quiet quasars. Further higher-spatial resolution observations, over a larger frequency range, of high-z radio-loud quasars hosts will allow for a better understanding of the physics of such sources.

This study aims at identifying luminous quasars at $z>5.7$ among X-ray-selected sources in the eROSITA Final Equatorial-Depth Survey (eFEDS) in order to place a lower limit on black hole accretion well into the epoch of re-ionisation. We confirm the low significance detection with eROSITA of a previously known, optically faint $z=6.56$ quasar from the Subaru High-z Exploration of Low-luminosity Quasars (SHELLQs) survey. We obtained a pointed follow-up observation of the source with the Chandra X-ray telescope in order to confirm the eROSITA detection. Using new near-infrared spectroscopy, we derived the physical properties of the super-massive black hole. Finally, we used this detection to infer a lower limit on the black hole accretion density rate at $z>6$. The Chandra observation confirms the eFEDS source as the most distant blind X-ray detection to date. The derived X-ray luminosity is high with respect to the rest-frame optical emission of the quasar. With a narrow MgII line, low derived black hole mass, and high Eddington ratio, as well as its steep photon index, the source shows properties that are similar to local narrow-line Seyfert 1 galaxies, which are thought to be powered by young super-massive black holes. In combination with a previous high-redshift quasar detection in the field, we show that quasars with $L_{2-10 \, \mathrm{keV}}>10^{45} \, \mathrm{erg \, s^{-1}}$ dominate accretion onto super-massive black holes at $z\sim 6$.

We present bolometric luminosities, black hole masses and Eddington ratios for 42 luminous quasars at z>6 using high signal-to-noise ratio VLT/X-Shooter spectra, acquired in the enlarged ESO Large Programme XQR-30. In particular, we derive bolometric luminosities from the rest-frame 3000 A, luminosities using a bolometric correction from the literature, and the black hole masses by modelling the spectral regions around the CIV 1549A and the MgII 2798A emission lines, with scaling relations calibrated in the local universe. We find that the black hole masses derived from both emission lines are in the same range, and the scatter of the measurements agrees with expectations from the scaling relations. The MgII-derived masses are between (0.8-12) x 10^9 Msun, and the derived Eddington ratios are within 0.13-1.73, with a mean (median) of 0.84 (0.72). By comparing the total sample of quasars at z>5.8, from this work and from the literature, to a bolometric luminosity distribution-matched sample at z 1.5, we find that quasars at high redshift host slightly less massive black holes which accrete slightly more rapidly than at lower-z, with a difference in the mean Eddington ratios of the two samples of 0.27, in agreement with recent literature work.

ABSTRACT The final phase of the reionization process can be probed by rest-frame UV absorption spectra of quasars at z ≳ 6, shedding light on the properties of the diffuse intergalactic medium within the first Gyr of the Universe. The ESO Large Programme ‘XQR-30: the ultimate XSHOOTER legacy survey of quasars at z ≃ 5.8–6.6’ dedicated ∼250 h of observations at the VLT to create a homogeneous and high-quality sample of spectra of 30 luminous quasars at z ∼ 6, covering the rest wavelength range from the Lyman limit to beyond the Mg ii emission. Twelve quasar spectra of similar quality from the XSHOOTER archive were added to form the enlarged XQR-30 sample, corresponding to a total of ∼350 h of on-source exposure time. The median effective resolving power of the 42 spectra is R ≃ 11 400 and 9800 in the VIS and NIR arm, respectively. The signal-to-noise ratio per 10 km s−1 pixel ranges from ∼11 to 114 at λ ≃ 1285 Å rest frame, with a median value of ∼29. We describe the observations, data reduction, and analysis of the spectra, together with some first results based on the E-XQR-30 sample. New photometry in the H and K bands are provided for the XQR-30 quasars, together with composite spectra whose characteristics reflect the large absolute magnitudes of the sample. The composite and the reduced spectra are released to the community through a public repository, and will enable a range of studies addressing outstanding questions regarding the first Gyr of the Universe.

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.

We present Multi Unit Spectroscopic Explorer (MUSE) observations of the gas-rich major merger BR1202−0725 at z ∼ 4.7, which constitutes one of the most overdense fields known in the early universe. We utilize these data in conjunction with existing Atacama Large Millimeter/submillimeter Array (ALMA) observations to compare and contrast the spatially resolved ionized- and cool-gas content of this system, which hosts a quasar (QSO), a submillimeter galaxy (SMG), the two known optical companion Lyα emitters (“LAE 1” and “LAE 2”), and an additional companion discovered in this work “LAE 3” just 5″ to the north of the QSO. We find that QSO BR1202−0725 exhibits a large Lyα halo, covering ≈55 pkpc on-sky at surface-brightness levels of SB ≥ 1 × 10−17 erg s−1 cm−2 arcsec−2. In contrast, the SMG, of similar far-infrared luminosity and star formation rate (SFR), does not exhibit such a Lyα halo. The QSO’s halo exhibits high velocity widths (∼1000 km s−1) but the gas motion is to some extent kinematically coupled with the previously observed [C ii] bridge between the QSO and the SMG. We note that the object known in the literature as LAE 2 shows no local peak of Lyα emission, rather, its profile is more consistent with being part of the QSO’s extended Lyα halo. The properties of LAE 3 are typical of high-redshift LAEs; we measure FLyα(LAE 3) = 0.24 ± 0.03 × 10−16 erg s−1 cm−2, corresponding to SFRLyα ≈ 5.0 ± 0.5 M⊙ yr−1. The velocity width is Δv(LAE 3) ≈ 400 km s−1, and the equivalent width is EW0( Å, consistent with star formation being the primary driver of Lyα emission. We also note a coherent absorption feature at ∼−400 km s−1 in spectra from at least three objects; the QSO, LAE 1, and LAE 2, which could imply the presence of an expanding neutral gas shell with an extent of at least 24 pkpc.

THE COMPLETE METALLICITY MEASUREMENTS AT z ≤ 0.41. Y. Niino1, K. Aoki2, T. Hashimoto1, T. Hattori2, S. Ishikawa3, N. Kashikawa1, G. Kosugi1, M. Onoue3, J. Toshikawa1, and K. Yabe4, 1National Astronomical Observatory of Japan, 2-21-1 Osawa, Mitaka, Tokyo 181-8588, Japan, 2Subaru Telescope, National Astronomical Observatory of Japan, 650 North A‘ohoku Place, Hilo, HI 96720, USA., 3Department of Astronomy, School of Science, SOKENDAI (The Graduate University for Advanced Studies), 2-21-1 Osawa, Mitaka, Tokyo 181-8588, Japan, 4Kavli Institute for the Physics and Mathematics of the Universe, The University of Tokyo, Kashiwanoha, Kashiwa 277-8583, Japan

S-1 (combination of tegafur, gimeracil, and oteracil) and irinotecan (CPT) have different mechanisms of action. Combined therapy of S-1 and CPT is an attractive option for anthracycline and taxane-refractory breast cancer. Patients with advanced HER2-negative breast cancer previously treated with anthracycline and taxane and with measurable lesions were eligible for the trial. Those with brain metastases and homozygous for UGT1A1*6 or *28 or compound heterozygous (*6/*28) were excluded. A 3 + 3 dose escalation design was used in phase I (Level 1: CPT 80 mg/m2 on days 1 and 8, and S-1 80 mg/m2 on days 1-14, every 3 weeks; Level 2: CPT 100 mg/m2 and S-1 80 mg/m2). The objectives were to determine the recommended dose (RD) for the phase II (primary for phase I) study, response rate (RR, primary for phase II), progression-free survival (PFS), and safety in relation to UGT1A1. Pharmacokinetics (PK) of CPT and circulating endothelial cells (CEC) as pharmacodynamics (PD) of S-1 were analysed. Thirty-seven patients (13 for phase I, 24 for phase II) were enrolled. One patient at level 1 developed grade (G) 3 non-haematological toxicity and another at level 2 developed G4 neutropenia; therefore, level 2 was used as the RD. Common adverse events and their rates in the UGT1A1 wt/wt and wt/*6 or *28 heterozygous groups were diarrhoea, 25% and 46%; vomiting, 17% and 9%; anorexia, 25% and 9%; and fatigue, 25% and 9% respectively. As shown in Table 1 and supported by PK data, PFS seemed better for the UGT1A1 wt/*6 or *28 group compared to that for the wt/wt group. There also seemed to be an association between clinical benefit and suppression of CD34+ CEC by S-1 (Wilcoxon p = 0.047).Tabled 1Efficacy results of Level 2 patients (n = 29, 6 for phase I and 23 for phase II)Wild/Wild (n = 15)Wild/*6 or *28 (n = 14)Response Rate1 (7%)3 (21%)-Clinical Benefit Rate4 (27%)5 (36%)-Median PFS (month)8.312.3HR = 0.47 (p = 0.0600)Median OS (month)17.423.1HR = 0.74 (p = 0.5607) Open table in a new tab A combination of CPT and S-1 is effective in patients having recurrent/metastatic breast cancer, and further study of the underlying pharmacogenomics/PK/PD is warranted.

Galacto-oligosaccharides (GOSs) are recognized as prebiotics beneficial to human health through their abilities to modulate gut microbiota. On the other hand, it has been reported that immediate allergic reactions are caused by a GOS product (Bc-GOS) produced by treating lactose with β-galactosidase derived from Bacillus circulans. The objective of this study was to create a safer GOS product that is less likely to cause GOS-induced allergy (GOS-AL). First, we identified two derivatives of tetrasaccharide sugar chains in Bc-GOS as the factors responsible for GOS-AL by histamine release test (HRT) using blood samples obtained from two GOS-AL patients. Through our search for non-allergic GOS, we developed a new GOS product, SK-GOS, which was produced by catalyzing lactose with β-galactosidase derived from Sporobolomyces singularis and Kluyveromyces lactis. We regard it as a hypoallergic and safe GOS product that does not cause GOS-AL.

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 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.

Guava leaf tea (GLT) contains guava leaf polyphenol (Gvpp), which regulates the absorption of dietary carbohydrate from the intestines. Borderline diabetics, who are at high risk of development of diabetes, take GLT to suppress a rapid increase of blood sugar level after meals. However, patients with diabetes in whom diabetic drugs or warfarin as a blood thinner are prescribed also take GLT with the expectation of glycemic control. Therefore, we studied whether GLT had potential for inhibition or induction of cytochrome P450 (CYP) and an influence on the action of warfarin. Extract of guava leaf (GvEx) consists of carbohydrate and polyphenols, which are Gvpp, quercetin, and ellagic acid. These polyphenols, but not GvEx, showed a certain level of inhibition of human‐cDNA‐expressed CYPs. In a comparison of GLT and grapefruit juice, GLT showed weaker inhibition of CYP activities and of midazolam 1′‐hydroxylation than grapefruit juice. Furthermore, neither liver weight nor CYP3A expression in the liver was changed in rats that received GvEx for 90 days compared with the control group. When rats were concomitantly treated with GLT and warfarin, the prolongation of clotting time of blood by warfarin was not influenced. These data suggest that GLT is unlikely to interact with drugs. Copyright © 2012 John Wiley & Sons, Ltd.

Irinotecan hydrochloride (CPT-11) is a useful drug for cancer chemotherapy but sometimes induces severe diarrhea clinically. CPT-11 is mainly activated to SN-38 by carboxylesterase (CES) and then detoxified to SN-38 glucuronide (SN-38G) by UDP-glucuronosyltransferase (UGT) in the liver. SN-38G is excreted via bile and de-conjugated to SN-38 by β-glucuronidase (β-GLU) in the intestinal content. In order to clarify the alleviative effect of antibiotics on CPT-11-induced diarrhea, we examined whether penicillin G and streptomycin (SM) alleviate CPT-11-induced delayed-onset diarrhea using three diarrheal models, i.e., Wistar rats with repeated dosing of CPT-11 (60 mg/kg/day i.v. for 4 consecutive days) and Wistar and Gunn rats with a single dosing of CPT-11 (200 and 20 mg/kg i.v., respectively). Gunn rats have an inherited deficiency of UGT1A and cannot conjugate SN-38 to SN-38G. Therefore, onset of CPT-11-induced diarrhea in Gunn rats is not affected by β-GLU activity. SM alleviated diarrhea in all three diarrheal models. The alleviation of diarrhea by SM in Gunn rats indicated that the effect of SM occurred by a mechanism other than the inhibition of β-GLU activity. SM decreased CPT-11 and/or SN-38 concentrations in intestinal tissues and alleviated epithelial damage from the ileum to colon. SM did not inhibit β-GLU activity in the cecal content. SM also inhibited the intestinal absorption of CPT-11 and decreased CES activity and increased UGT activity in the intestinal epithelium. These findings indicated that SM decreased the exposure of CPT-11 and SN-38 to the intestinal epithelium by inhibiting the absorption of CPT-11 from the intestinal lumen and the change of CES and UGT activities in the intestinal epithelium and alleviated delayed-onset diarrhea.

p-Cresol, an end product of aromatic amino acids, is produced from food proteins by intestinal bacteria, and is detectable in blood and feces. Especially, blood and fecal levels of p-cresol are high in chronic renal failure (CRF) patients. Although it has been suggested that p-cresol is toxic in the body, the effect of p-cresol on immune responses has not yet been clarified. In this study, we investigated the effect of p-cresol on IL-12 production of macrophages stimulated with Lactobacillus casei strain Shirota (LcS) in vitro. Pre-incubation with p-cresol inhibited IL-12 p40 production of LcS-stimulated J774.1 cells, a murine macrophage-like cell line, in a dose-dependent manner. IL-12 p40 and p70 production of LcS-stimulated murine peritoneal macrophages was also inhibited by p-cresol. The inhibitory effect was not dependent on the cytotoxicity of p-cresol. These results indicate that blood and fecal p-cresol may have adverse effects on the host defense system in CRF patients.

To evaluate the safety of two probiotic bacterial strains, Lactobacillus casei strain Shirota (LcS) and Bifidobacterium breve strain Yakult (BbY), these probiotics were orally administered to Lewis rats with experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We examined three experimental designs by combining different antigen types and probiotic administration periods: (1) EAE was induced with a homogenate of guinea pig spinal cord as the sensitizing antigen, and LcS was orally administered from one week before this sensitization until the end of the experiment; (2) EAE was induced using guinea pig originated myelin basic protein (MBP) as the sensitizing antigen, and LcS was orally administered from one week before this sensitization to the end of the experiment; (3) EAE was induced using guinea pig MBP as the sensitizing antigen, and the probiotic strains (LcS and BbY) were administered starting in infancy (two weeks old) and continued until the end of the experiment. In experiment 1, oral administration of LcS tended to suppress the development of neurological symptoms. Differences in neurological symptoms between the control group and the administration groups did not reach statistical significance in experiments 2 and 3. These results support the notion that neither LcS nor BbY exacerbates autoimmune disease.

We applied two methods of broth microdilution and Etest for measuring minimal inhibition concentration (MIC) of lactic acid bacteria and bifidobacteria for 15 antimicrobial agents to compare the feasibility, reproducibility, and equivalence of the two methods. Both methods were originally described by the European projects PROSAFE and ACE-ART. In 84% combinations of strains and antimicrobial agents MIC differences between the two methods were within one Log2 dilution. In the case of rifampicin the difference between the two methods was more than ten fold. We further determined MICs of 70 strains (14 strains of Lactobacillus delbrueckii ssp. bulgaricus, 16 strains of Lactococcus lactis, 30 strains of Streptococcus thermophilus, and 10 strains of Bifidobacterium longum) by the broth microdilution method. In most cases, MIC distributions were uni-modal and within 5 Log2 dilutions except for the MIC distribution of L. lactis to the aminoglycoside group which was broader. These data are a good basis for improving knowledge of antimicrobial susceptibility of lactic acid bacteria and bifidobacteria, and can be used to revise tentative epidemiological cut-off values.

A series of safety tests were undertaken on a novel galacto-oligosaccharide (GOS) produced from lactose by a two-step enzymatic process involving Sporobolomyces singularis and Kluyveromyces lactis. Bacterial reverse mutation and chromosomal aberration tests, with or without metabolic activation, were performed. These tests showed no mutagenesis in the Ames assay or in Escherichia coli WP2uvrA, and no chromosomal aberrations in cultured fibroblast cells from Chinese hamster lungs (CHL/IU). Micronuclei were not induced in the reticulocytes of mouse peripheral blood following oral administration of GOS. In a 90-day repeated oral dose toxicity study in rats, GOS was administered at 0, 500, 1000 and 2000 mg/kg to male and female Sprague-Dawley rats. There were no GOS-related changes in clinical signs, body weight, water intake, feed intake, urinalysis, ophthalmology, haematology, blood chemistry, organ weights, gross pathology or histopathology in any of the treatment groups compared to the control group. The no observed adverse effect level (NOAEL) of GOS was at least 2000 mg/kg/day in both males and females.

Bacterial ATP helps T H 17 cells The intestinal lamina propria, a layer of cells forming part of the mucous membrane, boasts a complicated mix of cell populations, including the selective presence of T H 17 or T helper 17 cells, the subset of T helpers that produces interleukin 17. A study in mice now shows that commensal bacteria activate a unique subset of intestinal dendritic cells to induce interleukin-6 production and TGF- beta activation, thereby promoting the local differentiation of T H 17 cells. It is the ATP that the bacteria produce that promotes this effect. This finding highlights the importance of commensal bacteria and ATP in immuno-logical diseases, and may help in determining the mechanisms by which aberrant T H 17 cell responses result in immune disorders including inflammatory bowel diseases.

p-Cresol is a metabolite of aromatic amino acid metabolism produced by intestinal microflora, and its formation is influenced by intestinal conditions. Fasting drastically changes intestinal conditions. However, the effect of fasting on p-cresol production is unclear. In this study, serum and cecal p-cresol levels were determined in non-fasted rats and in rats fasting for either 12 or 18 h. Serum p-cresol increased significantly with 12-h fasting (3.44 +/- 2.15 nmol/ml; P<0.05) and 18-h fasting (5.40 +/- 2.20; P<0.001) as compared to the level in the non-fasted rats (1.02 +/- 0.50). Cecal p-cresol levels of the 12-h fasted (272.6 +/- 313.2 nmol/cecum) and 18-h fasted rats (436.6 +/- 190.8; P<0.01) were higher than those in non-fasted rats (27.1 +/- 21.9). The total cecal protein in content did not change with 18-h fasting. However, the cecal protein concentration increased significantly with fasting (P<0.001), and correlated closely with total cecal p-cresol contents (P<0.001). These results indicate that fasting enhances p-cresol production in the rat cecum, resulting in accumulation of serum p-cresol. We presume that the increase in p-cresol produced by fasting is related to the enhancement of bacterial nitrogen metabolism via an increased concentration of endogenous protein in the cecum.