A dusty compact object bridging galaxies and quasars at cosmic dawn.

Understanding how super-massive black holes form and grow in the early Universe has become a major challenge1,2 since it was discovered that luminous quasars existed only 700 million years after the Big Bang3,4. Simulations indicate an evolutionary sequence of dust-reddened quasars emerging from heavily dust-obscured starbursts that then transition to unobscured luminous quasars by expelling gas and dust5. Although the last phase has been identified out to a redshift of 7.6 (ref. 6), a transitioning quasar has not been found at similar redshifts owing to their faintness at optical and near-infrared wavelengths. Here we report observations of an ultraviolet compact object, GNz7q, associated with a dust-enshrouded starburst at a redshift of 7.1899 ± 0.0005. The host galaxy is more luminous in dust emission than any other known object at this epoch, forming 1,600 solar masses of stars per year within a central radius of 480 parsec. A red point source in the far-ultraviolet is identified in deep, high-resolution imaging and slitless spectroscopy. GNz7q is extremely faint in X-rays, which indicates the emergence of a uniquely ultraviolet compact star-forming region or a Compton-thick super-Eddington black-hole accretion disk at the dusty starburst core. In the latter case, the observed properties are consistent with predictions from cosmological simulations7 and suggest that GNz7q is an antecedent to unobscured luminous quasars at later epochs.

Effect of proton pump inhibitors on the development of hypomagnesemia induced by panitumumab.

Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.

Hepatocyte destruction with enhanced collagen synthesis: characteristic feature of chronic hepatitis C patients on haemodialysis.

Hepatitis C virus (HCV) infection is frequent among patients with end-stage renal disease on haemodialysis and is considered to be an independent risk factor for mortality in this setting. However, only a few of these patients are treated with anti-hepatitis virus treatment before the development of end-stage renal disease. Recent guidelines recommend identification of patients with good prognoses who are in need of interferon treatment, but we know little of patients who must be treated urgently. Ninety-eight patients on haemodialysis (48 anti-HCV-positive and 50 anti-HCV-negative patients) were enrolled in this study; HCV RNA was detected in 43 anti-HCV-positive patients. Univariate analysis and multivariate regression analysis were applied to identify variables independently associated with persistent HCV infection. Seven variables were proven to be associated with persistent HCV infection. Among them, type IV collagen 7S and N-terminal propeptide of type III procollagen (P-III-P) were defined as independent variables useful in distinguishing HCV RNA-positive patients from HCV RNA-negative patients with 0.91 sensitivity, 0.91 specificity, 0.89 positive predictive value and 0.93 negative predictive value. Our observations suggest that hepatocyte destruction with enhanced liver fibrosis is a characteristic clinical feature of persistent HCV infection. Type IV collagen 7S of ≥ 5 ng/mL and/or P-III-P of ≥ 5 U/mL would be useful markers to identify patients in need of interferon treatment, which supports the idea of the Kidney Disease: Improving Global Outcomes guidelines that a good prognosis in patients with HCV infection on haemodialysis should prompt consideration for IFN treatment when applicable.

Superconductivity induced by longitudinal ferromagnetic fluctuations in UCoGe.

From detailed angle-resolved NMR and Meissner measurements on a ferromagnetic (FM) superconductor UCoGe (T(Curie)∼2.5 K and T(SC)∼0.6 K), we show that superconductivity in UCoGe is tightly coupled with longitudinal FM spin fluctuations along the c axis. We found that magnetic fields along the c axis (H∥c) strongly suppress the FM fluctuations and that the superconductivity is observed in the limited magnetic-field region where the longitudinal FM spin fluctuations are active. These results, combined with model calculations, strongly suggest that the longitudinal FM spin fluctuations tuned by H∥c induce the unique spin-triplet superconductivity in UCoGe. This is the first clear example that FM fluctuations are intimately related with superconductivity.

Making sense of postoperative CT imaging following laparoscopic partial nephrectomy.

The increasing popularity of laparoscopic partial nephrectomy (LPN) necessitates radiologists to become familiar with the operative techniques as well as normal and abnormal postoperative findings. Due to the varying presentation of abnormal changes following LPN and their similarities with other disease entities, radiologists should be cognizant of common pitfalls to avoid inadvertent misdiagnosis. A few common pitfalls discussed in this paper are the identification of laparoscopic port placement issues, recognizing a myriad of post-surgical materials, differentiating haemostatic materials from postoperative abscess and infection, non-absorbable suture material mimicking rim calcifications, as well as hints for differentiating exuberant granulation tissue from tumour recurrence.

Nafamostat mesilate, a noncalcium compound, as an anticoagulant, induces calcium-dependent haemolysis when infused with packed erythrocytes.

BACKGROUND: Nafamostat mesilate (NM), a protease inhibitor, is available for acute pancreatitis and disseminated intravascular coagulopathy and is used as an anticoagulant for haemodialysis in Japan. Co-infusion of red cell concentrates (RCC) and intravenous drugs is usually contraindicated. Because of limited venous access, adherence to the guidelines may be compromised in some clinical settings. Therefore, we investigated the influence of co-infusion of RCC and various anticoagulants on haemolysis in vitro. METHODS: We investigated the effect of co-incubation of RCC and various anticoagulant drugs [NM, gabexate mesilate (GM), heparin] in packed erythrocytes. We evaluated haemolysis using lactate dehydrogenase and free haemoglobin. In addition, we also evaluated the influence of co-incubation on phosphatidylserine (PS) expression on the erythrocyte membrane. RESULTS: GM and NM induced haemolysis in a dose-dependent manner, which was inhibited by removal of citrate and pretreatment with the calcium chelator, ethylenediaminetetraacetic acid. In a dynamic experiment using an infusion pump, NM not only induced haemolysis during co-infusion with RCC but also elevated PS expression dependent on extracellular calcium. CONCLUSION: NM and GM induce haemolysis in packed erythrocytes in the presence of citrate that is dependent on extracellular calcium.

Spermatogenic function in cats.

There are limited data on feline sperm production. We exhausted epididymal spermatozoa (i.e. the number of ejaculated spermatozoa <5 × 10(6)) by frequent semen collections using the artificial vagina method in five tomcats and determined the number of spermatozoa stored in the epididymis. We investigated the time (days) required for the number of epididymal spermatozoa to return to the pre-exhaustion level and determined the number of spermatozoa produced per day. After spermatozoa were exhausted by frequent semen collection, 6 or more days were required to return to the pre-exhaustion level. Based on the duration of resting (days) and total number of spermatozoa, the mean number of spermatozoa produced per day was 30 × 10(6).

The antisense homology box: a new motif within proteins that encodes biologically active peptides.

Amphiphilic peptides approximately fifteen amino acids in length and their corresponding antisense peptides exist within protein molecules. These regions (termed antisense homology boxes) are separated by approximately fifty amino acids. Because many sense-antisense peptide pairs have been reported to recognize and bind to each other, antisense homology boxes may be involved in folding, chaperoning and oligomer formation of proteins. The antisense homology box-derived peptide CALSVDRYRAVASW, a fragment of human endothelin A receptor, proved to be a specific inhibitor of endothelin peptide (ET-1) in a smooth muscle relaxation assay. The peptide was able to block endotoxin-induced shock in rats as well. Our finding of endothelin receptor inhibitor among antisense homology box-derived peptides indicates that searching proteins for this new motif may be useful in finding biologically active peptides.

Hopelessness and Depression Predict Sarcopenia in Advanced CKD and Dialysis: A Multicenter Cohort Study.

BACKGROUND/OBJECTIVES: Depression and hopelessness are frequently experienced in chronic kidney disease (CKD) and are generally associated with lessened physical activity. The aim of this study was to quantify the associations between sarcopenia as determined by SARC-F with both depression and hopelessness. DESIGN AND SETTING: This multicenter cohort study involving cross-sectional and longitudinal analyses was conducted in a university hospital and four general hospitals, each with a nephrology center, in Japan. PARTICIPANTS: Participants consisted of 314 CKD patients (mean age 67.6), some of whom were receiving dialysis (228, 73%). MEASUREMENTS: The main exposures were depression, measured using the Center for Epidemiologic Studies Depression (CES-D) questionnaire, and hopelessness, measured using a recently developed 18-item health-related hope scale (HR-Hope). The outcomes were sarcopenia at baseline and one year after, measured using the SARC-F questionnaire. Logistic regression models were applied. RESULTS: The cross-sectional and longitudinal analyses included 314 and 180 patients, respectively. Eighty-nine (28.3%) patients experienced sarcopenia at baseline, and 44 (24.4%) had sarcopenia at the one-year follow-up. More hopelessness (per 10-point lower, adjusted odds ratio [AOR]: 1.33, 95% confidence interval [95% CI] 1.12-1.58), depression (AOR: 1.87, 95% CI 1.003-3.49), age (per 10-year higher, AOR: 1.70, 95% CI 1.29-2.25), being female (AOR: 2.67, 95% CI 1.43-4.98), and undergoing hemodialysis (AOR, 2.92; 95% CI, 1.41-6.05) were associated with a higher likelihood of having baseline sarcopenia. More hopelessness (per 10-point lower, AOR: 1.69, 95% CI 1.14-2.51) and depression (AOR: 4.64, 95% CI: 1.33-16.2) were associated with a higher likelihood of having sarcopenia after one year. CONCLUSIONS: Among patients with different stages of CKD, both hopelessness and depression predicted sarcopenia. Provision of antidepressant therapies or goal-oriented educational programs to alleviate depression or hopelessness can be useful options to prevent sarcopenia.

Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice.

AIMS/HYPOTHESIS: Metformin, the major target of which is liver, is commonly used to treat type 2 diabetes. Although metformin activates AMP-activated protein kinase (AMPK) in hepatocytes, the mechanism of activation is still not well known. To investigate AMPK activation by metformin in liver, we examined the role of reactive nitrogen species (RNS) in suppression of hepatic gluconeogenesis. METHODS: To determine RNS, we performed fluorescence examination and immunocytochemical staining in mouse hepatocytes. Since metformin is a mild mitochondrial complex I inhibitor, we compared its effects on suppression of gluconeogenesis, AMPK activation and generation of the RNS peroxynitrite (ONOO(-)) with those of rotenone, a representative complex I inhibitor. To determine whether endogenous nitric oxide production is required for ONOO(-) generation and metformin action, we used mice lacking endothelial nitric oxide synthase (eNOS). RESULTS: Metformin and rotenone significantly decreased gluconeogenesis and increased phosphorylation of AMPK in wild-type mouse hepatocytes. However, unlike rotenone, metformin did not increase the AMP/ATP ratio. It did, however, increase ONOO(-) generation, whereas rotenone did not. Exposure of eNOS-deficient hepatocytes to metformin did not suppress gluconeogenesis, activate AMPK or increase ONOO(-) generation. Furthermore, metformin lowered fasting blood glucose levels in wild-type diabetic mice, but not in eNOS-deficient diabetic mice. CONCLUSIONS/INTERPRETATION: Activation of AMPK by metformin is dependent on ONOO(-). For metformin action in liver, intra-hepatocellular eNOS is required.

Idiotype-specific T lymphocytes. II. capability of generation of idiotype-specific T lymphocytes is determined by corresponding VH gene.

MOPC-104E (M104E) idiotype-specific and major histocompatibility complex-restricted T lymphocyte activities were investigated in BALB/c (Igh-1a) and its Igh-1-congenic strains of mice, such as C.AL-20 (Igh-1d), BAB-14 (Igh-1b), and CB-20 (Igh-1b). Idiotype-specific T lymphocytes could be induced in BALB/c and BAB-14 by immunization of viable M104E tumor cells followed by surgical removal and in vitro restimulation with the homologous tumor cells. On the other hand, C.AL-20 and CB-20 mice did not show the idiotype-recognizing capacity even though they could mount comparable cytotoxic T lymphocyte activities against M104E to BALB/c and BAB-14. The results strongly suggest that the inducibility of M104E cross-reactive idiotypy closely paralleled the producibility of corresponding idiotype-specific T lymphocytes. Genetically defined VH gene products might act as internal images that construct idiotype network systems.

Commitment of common T/Natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay.

We have established a new clonal assay system that can evenly support the development of T and natural killer (NK) cells. With this system, we show that all T cell progenitors in the earliest CD44(+)CD25(-)FcgammaRII/III(-) fetal thymus (FT) cell population retain NK potential, and that the NK lineage-committed progenitors (p-NK) also exist in this population. T cell lineage-committed progenitors (p-T), which are unable to generate NK cells, first appear at the CD44(+)CD25(-) FcgammaRII/III(+) stage in day 12 FT. The proportion of p-T markedly increases during the transition from the CD44(+)CD25(-) stage to the CD44(+)CD25(+) stage in day 14 FT. On the other hand, p-NK preferentially increase in number at the CD44(+)CD25(-) stage between days 12 and 14 of gestation. The production of p-NK continues up to the CD44(+)CD25(+) stage, but ceases before the rearrangement of T cell receptor beta chain genes. It was further shown that the CD44(+)CD25(-) CD122(+) population of day 14 FT exclusively contains p-NK. These results indicate that the earliest T cell progenitor migrating into the FT is T/NK bipotent, and strongly suggest that the bipotent progenitor continuously produces p-NK and p-T until the CD44(+)CD25(+) stage.

Involvement of transcription factors TCF-1 and GATA-3 in the initiation of the earliest step of T cell development in the thymus.

Flow cytometric and immunocytochemical analyses of murine fetal thymus (FT) cells with antibodies to various surface markers and transcription factors reveal that the synthesis of TCF-1 and GATA-3 protein begins simultaneously in a fraction of the most immature population of FT cells, which have the phenotype of CD4-CD8-CD44+CD25-. No TCF-1-producing cells is found in the fetal liver (FL). In CD44+CD25- FT cells, the production of TCF-1 is immediately followed by intracellular expression of CD3 epsilon. It is also found that the T cell development from FL, but not FT, progenitors in the FT organ culture system is severely inhibited by the addition of antisense oligonucleotides for either TCF-1 or GATA-3. These results strongly suggest that TCF-1 and GATA-3 play essential roles in the initiation of the earliest steps of T cell development in the thymus.

Daily chewing gum exercise for stabilizing the vertical occlusion.

We investigated the effects of a chewing gum exercise program on occlusal conditions and evaluated compliance of subjects. Thirty-five healthy adult volunteers (26 males and nine females) were asked to chew gum for 10-15 min before or after three meals daily for four weeks. Occlusal conditions were recorded as occlusal parameters, such as occlusal contact area, occlusal contact force, and pressure using dental prescale films. These parameters were evaluated by an Occluzer before the exercise period commenced, after four weeks of exercise, and then one month after the end of the exercise period. These parameters were statistically compared using one-way ANOVA. We found that: (i) after four weeks of exercise, anterior and posterior occlusal contact areas and forces were significantly (P < 0.05) increased and the increments were significantly (P < 0.05) higher in the anterior occlusal contact area and force than in the posterior occlusal contact area and force, (ii) the anteroposterior ratio of occlusal contact area and force increased, but not markedly, (iii) increased parameters had significantly (P < 0.05) decreased within one month after the end of the four-week exercise period, (iv) most participants did not complain for discomfort or stress during the exercise. The chewing gum exercise program could increase occlusal contact area and force and also move the anteroposterior occlusal balance forward. Patient compliance with the exercise is likely high enough to keep them exercising.

Reproductive interference in live-bearing fish: the male guppy is a potential biological agent for eradicating invasive mosquitofish.

The eradication of invasive exotic species is desirable but often infeasible. Here, we show that male guppies are a potential biological agent for eradicating invasive mosquitofish through the mechanism of reproductive interference, which is defined as any sexual behavior erratically directed at a different species that damages female and/or male fitness. Together with decades of data on species distribution, our field surveys suggest that mosquitofish initially became established on Okinawa Island before being replaced by the more recently introduced guppies. More importantly, our laboratory experiments suggest that reproductive interference was one of the mechanisms underlying this species exclusion, and that in this case, the negative effects were asymmetric, i.e., they only impacted mosquitofish. Reproductive interference may offer a safer and more convenient method of biological control than the traditional sterile male release method because radiation is not necessary.

Changes in hepatic key enzymes of dairy calves in early weaning production systems.

The objective of the present study was to describe plasma hormonal and metabolite profile and mRNA expression levels and activities of the enzymes pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK), and acetyl-coenzyme A (CoA) carboxylase in the liver of male Holstein calves before (1 and 3 wk of age) and after (8, 13, and 19 wk of age) weaning at 6 wk of age. The mean plasma concentration of acetate and beta-hydroxybutyrate increased, and that of plasma lactate and nonesterified fatty acids decreased with week, particularly after weaning. Plasma glucose concentration was lowest at 8 wk of age. The mean plasma concentration of insulin and glucagon did not change with time, and that of cortisol was greatest at 1 wk of age. In the liver, enzyme activity of PC was greatest at 1 wk of age and decreased with time. There was a significant relationship between the activity and the mRNA level for PC. Activity of PEPCK also decreased with week. Acetyl-CoA carboxylase activity tended to decrease with week, and activity at 13 wk of age was lower than that at other times. Expression of PC mRNA, but not that of PEPCK and acetyl-CoA carboxylase alpha, decreased with week. We conclude that the hepatic gluconeogenic enzymes and acetyl-CoA carboxylase activities tend to decrease with age, reflecting changes in plasma metabolites in early weaning production systems.

Thrombin induces striatal neurotoxicity depending on mitogen-activated protein kinase pathways in vivo.

Intracerebral hemorrhage represents stroke characterized by formation and expansion of hematoma within brain parenchyma. Blood-derived factors released from hematoma are considered to be involved in poor prognosis of this disorder. We previously reported that thrombin, a blood-derived serine protease, induced cytotoxicity in the cerebral cortex and the striatum in organotypic slice cultures, which depended on mitogen-activated protein kinase (MAPK) pathways. Here we investigated the mechanisms of thrombin cytotoxicity in the striatum in vivo. Thrombin microinjected into the striatum of adult rats induced neuronal death and microglial activation around the injection site. Neuronal loss without any sign of nuclear fragmentation was observed as early as 4 h after thrombin injection, which was followed by gradual neuronal death exhibiting nuclear fragmentation. Thrombin-induced damage assessed at 72 h after injection was partially but significantly reduced by concomitant administration of inhibitors of MAPK pathways. Activation of extracellular signal-regulated kinase (ERK) and p38 MAPK in response to thrombin was verified by Western blot analysis. Moreover, phosphorylated ERK and p38 MAPK were localized prominently in reactive microglia, and inhibition of microglial activation by minocycline attenuated thrombin-induced damage, suggesting that reactive microglia were responsible for thrombin-induced neuronal death. Thus, MAPK pathways and microglial activation may serve as therapeutic targets of pathogenic conditions associated with hemorrhagic stroke.

Synergistic effects of injection of bone marrow cells into both portal vein and bone marrow on tolerance induction in transplantation of allogeneic pancreatic islets.

We have established a new method for allogeneic pancreatic islet (PI) transplantation: relatively low doses of irradiation followed by simultaneous transplantation of PIs and bone marrow cells (BMCs) via the portal vein (PV). In the present study, we have compared this method with intra-bone marrow (IBM)-bone marrow transplantation (BMT), and with a combination of both methods. Streptozotocin (STZ)-induced diabetic-recipient rats, Fischer 344 (F344, RT1A(l), RT1B(l)), were irradiated 1 day before transplantation. PIs of Brown Norway rats (BN, RT1A(n), RT1B(n)) were transplanted into the liver of the diabetic F344 rats via the PV. BMCs from BN rats were injected into the recipients' bone marrow (IBM), PV or intravenously (IV) or by a simultaneous combination of PV plus IBM (PV+IBM). We compared graft survival among the groups of '9 Gy+IBM'(10/10 accepted), '9 Gy+PV'(7/10 accepted), '9 Gy+IV'(0/7 accepted), '9 Gy+PV+IBM'(8/8 accepted), '8.5 Gy+IBM'(4/9 accepted), '8.5 Gy+PV'(0/7 accepted), '8.5 Gy+IV'(0/7 accepted), '8.5 Gy+PV+IBM'(9/12 accepted), '8 Gy+IBM'(2/10 accepted) and '8 Gy+PV+IBM'(2/8 accepted). As we reported previously, PV-BMT is more effective in inducing the acceptance of allogeneic PIs than IV-BMT. However, IBM-BMT requires less pretreatment than PV-BMT. (PV+IBM)-BMT was found to be the most effective in inducing the acceptance of allogeneic PIs. These results suggest that allogeneic PI-transplantation in conjunction with (PV+IBM)-BMT could become a viable strategy.

Metabolism of 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil in mice.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.